Breakthrough rice bran nanoparticles show promise as affordable and targeted anticancer agent

Plant-derived nanoparticles have demonstrated significant anticancer effects. Researchers recently developed rice bran-derived nanoparticles (rbNPs) that efficiently suppressed cell proliferation and induced programmed cell death of only cancer cells. Furthermore, rbNPs successfully suppressed the growth of tumors in mice having aggressive adenocarcinoma in their peritoneal cavity, without any adverse effects. Given their low production costs and high efficacy, rbNPs hold great promise for developing affordable and safe anticancer agents.

Several types of conventional cancer therapies, such as radiotherapy or chemotherapy, destroy healthy cells along with cancer cells. In advanced stages of cancer, tissue loss from treatments can be substantial and even fatal. Cutting-edge cancer therapies that employ nanoparticles can specifically target cancer cells, sparing healthy tissue. Recent studies have demonstrated that plant-derived nanoparticles (pdNPs) that have therapeutic effects can be an effective alternative to traditional cancer treatments. However, no pdNPs have been approved as anticancer therapeutic agents till date.

Rice bran is a byproduct generated during rice refining process that has limited utility and low commercial value. However, it contains several compounds with anticancer properties, such as γ-oryzanol and γ-tocotrienol. To explore these therapeutic properties of rice bran, a team of researchers led by Professor Makiya Nishikawa from Tokyo University of Science (TUS) in Japan developed nanoparticles from rice bran and tested their effectiveness in mice models. Their study, published in Volume 22 of Journal of Nanobiotechnology on 16 March 2024, was co-authored by Dr. Daisuke Sasaki, Ms. Hinako Suzuki, Associate Professor Kosuke Kusamori, and Assistant Professor Shoko Itakura from TUS.

"In recent years, an increasing number of new drug modalities are being developed. At the same time, development costs associated with novel therapies have increased dramatically, contributing to the burden of medical expenses. To address this issue, we used rice bran, an industrial waste with anticancer properties, to develop nanoparticles," explains Prof. Nishikawa.

The study evaluated the anticancer effects of rice bran-derived nanoparticles (rbNPs), which were obtained by processing and purifying a suspension of Koshihikari rice bran in water. When a cancer cell line named colon26 was treated with rbNPs, cell division was arrested and programmed cell death was induced, indicating strong anticancer effects of the nanoparticles. The observed anticancer activity of rbNPs can be attributed to γ-tocotrienol and γ-oryzanol, that are easily taken up by cancer cells resulting in cell cycle arrest and programmed cell death. Additionally, rbNPs reduced the expression of proteins, such as β-catenin (a protein associated with Wnt signaling pathway involved in cell proliferation) and cyclin D1, which are known to promote cancer recurrence and metastases. Moreover, the rbNPs reduced the expression of β-catenin only in colon26 cells without affecting the non-cancerous cells.

"A key concern in the context of pdNPs is their low pharmacological activity compared to pharmaceutical drugs. However, rbNPs exhibited higher anticancer activity than DOXIL®, a liposomal pharmaceutical formulation of doxorubicin. Additionally, doxorubicin is cytotoxic to both cancer cells and non-cancerous cells, whereas rbNPs are specifically cytotoxic to cancer cells, suggesting that rbNPs are safer than doxorubicin," highlights Prof.Nishikawa.

To confirm the anticancer properties of rbNPs in the living body, the researchers injected rbNPs into mice having aggressive adenocarcinoma in their peritoneal cavity (enclosed by the diaphragm, abdominal muscles, and pelvis and houses organs like intestines, liver, and kidneys). They observed significant suppression of tumor growth with no adverse effects on the mice. Additionally, the rbNPs significantly inhibited metastatic growth of murine melanoma B16-BL6 cells in a lung metastasis mouse model.

Rice bran has several attributes that make it an excellent source of therapeutic pdNPs. Firstly, it is economic as compared to many other sources of pdNPs. Nearly 40% of the rice bran is discarded in Japan, providing a readily available source of raw material. Secondly, the preparation efficiency of rbNPs is higher than that of previously reported pdNPs. Besides being practical and safe as an anticancer therapeutic, the physicochemical properties of rbNPs are very stable. However, a few parameters, such as establishment of separation technologies at the pharmaceutical level, assessing production process control parameters, and evaluation of efficacy and safety in human cancer cell lines and xenograft animal models, must be investigated prior to clinical trials in humans.

In conclusion, rice bran, an agricultural waste product, is a source of therapeutic pdNPs that are affordable, effective, and safe, and has the potential to revolutionize cancer treatment in the future.

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Researchers turn back the clock on cancer cells to offer new treatment paradigm

St. Jude Children's Research Hospital scientists reversed an aggressive cancer, reverting malignant cells towards a more normal state. Rhabdoid tumors are an aggressive cancer which is missing a key tumor suppressor protein. Findings showed that with the missing tumor suppressor, deleting or degrading the quality control protein DCAF5 reversed the cancer cell state. These results suggest a new approach to curing cancer -- returning cancerous cells to an earlier, more normal state rather than killing cancer cells with toxic therapies -- may be possible. The results were published today in Nature.

"Rather than making a toxic event that kills rhabdoid cancer, we were able to reverse the cancer state by returning the cells toward normal," said senior author Charles W.M. Roberts, MD, PhD, Executive Vice President and St. Jude Comprehensive Cancer Center director. "This approach would be ideal, especially if this paradigm could also be applied to other cancers."

"We found a dependency which actually reverses the cancer state," said first author Sandi Radko-Juettner, PhD, a former St. Jude Graduate School of Biomedical Sciences student, now a Research Program Manager for the Hematological Malignancies Program at St. Jude. "Standard cancer therapies work by causing toxicities that also damage healthy cells in the body. Here, it appears that we're instead fixing the problem caused by the loss of a tumor suppressor in this rhabdoid cancer."

Drugging the un-targetable

In many cancers, there is no easily druggable target. Often, these cancers are caused by a missing tumor suppressor protein, so there is nothing to target directly as the protein is missing. Loss of tumor suppressors is much more common than a protein gaining the ability to drive cancer. Consequently, finding a way to intervene therapeutically in these tumors is a high priority. The researchers were looking for a way to treat an aggressive set of cancers caused by the loss of the tumor suppressor protein SMARCB1 when they found a new approach to treatment.

The St. Jude group found a little-studied protein, DCAF5, was essential to rhabdoid tumors missing SMARCB1. Initially, they identified DCAF5 as a target, using the Dependency Map (DepMap) portal, a database of cancer cell lines and the genes critical for their growth. DCAF5 was a top dependency in rhabdoid tumors. After the initial finding, the scientists genetically deleted or chemically degraded DCAF5. The cancer cells reverted to a non-cancerous state, persisting even in a long-term mouse model.

"We saw a spectacular response," Roberts said. "The tumors melted away."

Removing quality control to reverse cancer

Normally, SMARCB1 is an essential component of a larger chromatin-regulating complex of proteins called the SWI/SNF complex. Unexpectedly, the study found that in the absence of SMARCB1, DCAF5 recognizes SWI/SNF as abnormal and destroys the complex. When DCAF5 degrades them, the researchers showed that SWI/SNF re-forms and maintains its ability to open chromatin and regulate gene expression. While the SWI/SNF activity level in the absence of SMARCB1 was to a lesser extent than usual, it was nonetheless sufficient to reverse the cancer state fully.

"DCAF5 is doing a quality control check to ensure that these chromatin machines are built well," Roberts said. "Think of a factory assembling a machine. You need quality checks to examine and find faults and to pull it off the line if it doesn't meet standards. DCAF5 is doing such quality assessments for the assembly of SWI/SNF complexes, telling the cell to get rid of complexes if SMARCB1 is absent."

"The mutation of SMARCB1 shuts off gene programs that prevent cancer. By targeting DCAF5, we're turning those gene programs back on," Radko-Juettner said. "We're reversing the cancer state because the cell is becoming more 'normal' when these complexes aren't targeted for destruction by DCAF5."

Future therapeutic opportunities to reverse cancer

"From a therapeutic perspective, our results are fascinating," Radko-Juettner said. "DCAF5 is part of a larger family of DCAF proteins that have been shown to be drug targetable. We showed that when DCAF5 is absent, mice had no discernable health effects, so we could potentially target DCAF5. This can kill the cancer cells but shouldn't affect healthy cells. Targeting DCAF5 thus has the potential to avoid the off-target toxicity of radiation or chemotherapy, making it a promising therapeutic avenue to pursue."

Beyond DCAF5, the findings could have implications for other cancers driven by the loss of a tumor suppressor.

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Scientists uncover a startling -- and exploitable -- coordination of gene expression in tumors

A Ludwig Cancer Research study has identified a pair of genes whose expression by a type of immune cell within tumors is predictive of outcomes for cancer patients and is linked to a vast network of gene expression programs, engaged by multiple cell types in the tumor microenvironment, that control human cancers.

Researchers led by Ludwig Lausanne's Mikaël Pittet report in the current issue of Science that patients with higher expression of the gene CXCL9 in their tumor-associated macrophages had far better clinical outcomes than those with higher expression of a gene named SPP1 by the immune cells. Macrophages expressing the former gene, they show, are invariably poised to attack cancer cells, while those expressing SPP1 are in a state supportive of tumor growth. Most intriguing, however, is the discovery that when the ratio of CXCL9 to SPP1 is high in the tumor microenvironment (TME), gene expression programs in other TME cells indicate a similarly anti-tumor slant; a low CS ratio, on the other hand, invariably accompanies pro-tumor gene expression signatures across the TME.

"We were very surprised to find that just this one parameter -- the ratio of two genes primarily expressed by macrophages -- could tell us so much else about the tumor," said Pittet. "This is true for multiple types of solid tumors. It means that, despite their enormous complexity, the microenvironments of tumors are governed by a clear set of rules. We have described one of them in this study."

With further validation in prospective clinical studies, Pittet noted, the CS ratio could be an easily measured molecular marker of likely patient prognosis and a useful tool for the management of therapy. Beyond that, the networks of linked gene expression signatures across cell types identified by the study expose several potential molecular targets for the development of drugs that might tip the TME into a state more susceptible to treatments like immunotherapy.

Noncancerous cells of the TME play a critical role in the growth and viability of tumors. These include fibroblasts, which churn out the molecular filler of tissues, endothelial cells that build blood vessels, epithelial cells that line body cavities and a menagerie of immune cell species that variously help or hinder tumor growth. The possibility of targeting these cells to treat cancers is tantalizing because, unlike malignant cells, they do not mutate rapidly and are thus unlikely to evolve resistance to therapies.

Pittet and his colleagues were interested in how much the TME varies between tumors. To find out, they conducted an unbiased analysis of 52 primary and metastatic tumors from 51 patients with head and neck cancers, examining how global gene expression captured in individual cells but statistically analyzed across tumors as a whole corresponded to patient outcomes.

This approach identified CXCL9 and SPP1 -- whose expression is mutually exclusive in individual macrophages -- as being tightly linked to prognosis, and this turned out to be true for other solid cancers as well. The expression of the two genes, Pittet and colleagues show, is also more categorically associated with the anti-tumor or pro-tumor "polarity" of macrophages than currently used markers.

Notably, the ratio of CXCL9 and SPP1 expression (termed CShi or CSlow) was broadly consistent with the state of other types of TME cells in head and neck tumors and with several phenomena associated with pro- and anti-tumor effects. CShi tumors, for example, tended to be infiltrated with B and T lymphocytes and dendritic cells, which all drive anti-tumor immunity. Further, other cell types in these tumors engaged signaling molecules and pathways that fuel inflammation or otherwise instigate immune responses.

CSlow tumors, meanwhile, bore gene expression signatures associated with cancer growth and progression, such as adaptations to oxygen starvation, the formation of new blood vessels and the induction of cellular transformations that propel cancer metastasis.

"Just by looking at the ratio of these two genes in macrophages, you can deduce the molecular activity of tumor cells, endothelial cells, fibroblasts -- you name it," said Pittet. "This startling coherence means that tumors are not a chaotic place, that all these cell states within the TME are coordinated. This information has the potential to be very useful for the development of precision medicine strategies for cancer therapy."

Pittet and his colleagues will next examine whether the gene expression networks identified in their study can be used to prospectively predict patient outcomes or gauge likely responses to various therapies. They will also be looking in more detail at other coordinated axes of gene expression in the TME, how they interact with the CS ratio and how each influences the other.

"The big question is, what are the best ways to interfere therapeutically with this network, with the goal being benefit to the patient?" said Pittet.

Read more at Science Daily

Novel ultrasound uses microbubbles to open blood-brain barrier to treat glioblastoma in humans

A major impediment to treating the deadly brain cancer glioblastoma has been that the most potent chemotherapy can't permeate the blood-brain barrier to reach the aggressive brain tumor.

But now Northwestern Medicine scientists report results of the first in-human clinical trial in which they used a novel, skull-implantable ultrasound device to open the blood-brain barrier and repeatedly permeate large, critical regions of the human brain to deliver chemotherapy that was injected intravenously.

The four-minute procedure to open the blood-brain barrier is performed with the patient awake, and patients go home after a few hours. The results show the treatment is safe and well tolerated, with some patients getting up to six cycles of treatment.

This is the first study to successfully quantify the effect of ultrasound-based blood-brain barrier opening on the concentrations of chemotherapy in the human brain. Opening the blood-brain barrier led to an approximately four- to six-fold increase in drug concentrations in the human brain, the results showed.

Scientists observed this increase with two different powerful chemotherapy drugs, paclitaxel and carboplatin. The drugs are not used to treat these patients because they do not cross blood-brain barrier in normal circumstances.

In addition, this is the first study to describe how quickly the blood-brain barrier closes after sonication. Most of the blood-brain barrier restoration happens in the first 30 to 60 minutes after sonication, the scientists discovered. The findings will allow optimization of the sequence of drug delivery and ultrasound activation to maximize the drug penetration into the human brain, the authors said.

"This is potentially a huge advance for glioblastoma patients," said lead investigator Dr. Adam Sonabend, an associate professor of neurological surgery at Northwestern University Feinberg School of Medicine and a Northwestern Medicine neurosurgeon.

Temozolomide, the current chemotherapy used for glioblastoma, does cross the blood-brain barrier, but is a weak drug, Sonabend said.

The paper will be published May 2 in The Lancet Oncology.

The blood-brain barrier is a microscopic structure that shields the brain from the vast majority of circulating drugs. As a result, the repertoire of drugs that can be used to treat brain diseases is very limited. Patients with brain cancer cannot be treated with most drugs that are otherwise effective for cancer elsewhere in the body, as these do not cross the blood-brain barrier. Effective repurposing of drugs to treat brain pathology and cancer require their delivery to the brain.

In the past, studies that injected paclitaxel directly into the brain of patients with these tumors observed promising signs of efficacy, but the direct injection was associated with toxicity such as brain irritation and meningitis, Sonabend said.

Blood-brain barrier recloses after an hour

The scientists discovered that the use of ultrasound and microbubble-based opening of the blood-brain barrier is transient, and most of the blood-brain barrier integrity is restored within one hour after this procedure in humans.

"There is a critical time window after sonification when the brain is permeable to drugs circulating in the bloodstream," Sonabend said.

Previous human studies showed that the blood-brain barrier is completely restored 24 hours after brain sonication, and based on some animal studies, the field assumed that the blood-brain barrier is open for the first six hours or so. The Northwestern study shows that this time window might be shorter.

In another first, the study reports that using a novel skull-implantable grid of nine ultrasound emitters designed by French biotech company Carthera opens the blood-brain barrier in a volume of brain that is nine times larger than the initial device (a small single-ultrasound emitter implant). This is important because to be effective, this approach requires coverage of a large region of the brain adjacent to the cavity that remains in the brain after removal of glioblastoma tumors.

Clinical trial for patients with recurrent glioblastoma

The findings of the study are the basis for an ongoing phase 2 clinical trial the scientists are conducting for patients with recurrent glioblastoma. The objective of the trial -- in which participants receive a combination of paclitaxel and carboplatin delivered to their brain with the ultrasound technique -- is to investigate whether this treatment prolongs survival of these patients. A combination of these two drugs is used in other cancers, which is the basis for combining them in the phase 2 trial.

In the phase 1 clinical trial reported in this paper, patients underwent surgery for resection of their tumors and implantation of the ultrasound device. They started treatment within a few weeks after the implantation.

Scientists escalated the dose of paclitaxel delivered every three weeks with the accompanying ultrasound-based blood-brain barrier opening. In subsets of patients, studies were performed during surgery to investigate the effect of this ultrasound device on drug concentrations. The blood-brain barrier was visualized and mapped in the operating room using a fluorescent die called fluorescein and by MRI obtained after ultrasound therapy.

"While we have focused on brain cancer (for which there are approximately 30,000 gliomas in the U.S.), this opens the door to investigate novel drug-based treatments for millions of patients who suffer from various brain diseases," Sonabend said.

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Scientists make breakthrough for 'next generation' cancer treatment

Scientists at the University of East Anglia are a step closer to creating a new generation of light-activated cancer treatments.

The futuristic sounding treatment would work by switching on LED lights embedded close to a tumour, which would then activate biotherapeutic drugs.

These new treatments would be highly targeted and more effective than current state-of-the-art cancer immunotherapies.

New research published today reveals the science behind this innovative idea.

It shows how the UEA team have engineered antibody fragments -- which not only 'fuse' with their target but are also light activated.

It means that in future, immunotherapy treatments could be engineered to attack tumours more precisely than ever before.

The principal scientist for this study, Dr Amit Sachdeva, from UEA's School of Chemistry, said: "Current cancer treatments like chemotherapy kill cancer cells, but they can also damage healthy cells in your body such as blood and skin cells.

"This means that they can cause side effects including hair loss, feeling tired and sick, and they also put patients at increased risk of picking up infections.

"There has therefore been a very big drive to create new treatments that are more targeted and don't have these unwanted side-effects.

"Several antibodies and antibody fragments have already been developed to treat cancer. These antibodies are much more selective than the cytotoxic drugs used in chemotherapy, but they can still cause severe side effects, as antibody targets are also present on healthy cells."

Now, the UEA team has engineered one of the first antibody fragments that binds to, and forms a covalent bond with, its target -- upon irradiation with UV light of a specific wavelength.

Dr Sachdeva said: "A covalent bond is a bit like melting two pieces of plastic and fusing them together. It means that drug molecules could for example be permanently fixed to a tumour.

"We hope that our work will lead to the development of a new class of highly targeted light-responsive biotherapeutics. This would mean that antibodies could be activated at the site of a tumour and covalently stick to their target upon light activation.

"In other words, you could activate antibodies to attack tumour cells by shining light - either directly on to the skin, in the case of skin cancer, or using small LED lights that could be implanted at the site of a tumour inside the body.

"This would allow cancer treatment to be more efficient and targeted because it means that only molecules in the vicinity of the tumour would be activated, and it wouldn't affect other cells.

"This would potentially reduce side effects for patients, and also improve antibody residence time in the body."

"It would work for cancers like skin cancer, or where there is a solid tumour - but not for blood cancers like leukaemia.

"Development of these antibody fragments would not have been possible without pioneering work from several other research groups across the globe who developed and optimised methods for site-specific incorporation of non-natural amino acids into proteins expressed in live cells.

"We employed some of these methods to site-specifically install unique light-sensitive amino acids into antibody fragments."

If the researchers are successful in the next stages of their work, they hope to see the 'next generation' light-activated immunotherapies being used to treat cancer patients within five to 10 years.

Read more at Science Daily

Patient's own immune cells effective as living medicine for melanoma

A patient's own immune cells, multiplied into an army of billions of immune cells in a lab, can be used as a living medicine against metastatic melanoma, an aggressive form of skin cancer, as the TIL trial has shown. The TIL trial is the world's first comparative phase 3 trial looking into the effect of T cell therapy in melanoma, and solid tumors in general. Now that the results have come in , the Dutch National Health Care Institute will assess whether TIL therapy () could become a standard treatment, meaning that it will be covered by basic health insurance. The results are published in The New Engeland Journal of Medicine (NEJM) on December 8. The trial was headed by the Netherlands Cancer Institute in collaboration with the National Center for Cancer Immune Therapy in Copenhagen.

Powerful immunotherapy for metastatic melanoma

Medical oncologist John Haanen from the Netherlands Cancer Institute, who is leading the TIL trial, is very happy with the results: "Remember: these are patients with metastatic melanoma. Ten years ago, melanoma was so deadly that I would be seeing an entirely new patient population every year. Now I've been seeing some patients for ten years. This is largely due to the discovery of immunotherapy, which has revolutionized treatment for melanomas. But we still find that about half of people diagnosed with metastatic melanoma lose their lives within five years, so we're still not where we want to be -- not by a long shot. The TIL trial has shown that cell therapy using the patient's own immune cells is an extremely powerful immunotherapy for metastatic melanoma, and that this therapy still offers a high chance of improvement, even if other immunotherapies fail.'

World's first phase 3 study T cell therapy for melanoma

A melanoma is an aggressive form of skin cancer with a high rate of occurrence Ten years ago, a diagnosis with metastatic melanoma would almost certainly lead to death within the same year. In early clinical trials, cell therapy using the patient's own T cells as a "living drug" showed promising results. However, a comparative phase 3 trial would be necessary to include TIL therapy in the arsenal of regular treatments, and no such trial had ever been conducted. Medical oncologist John Haanen from the Netherlands Cancer Institute decided to take on this task by initiating an international trial in 2014: the TIL trial, which compared TIL therapy to standard immunotherapy with the checkpoint inhibitor ipilimumab. The results of the TIL trial will now be presented at the annual conference of the European Society for Medical Oncology.

Metastases smaller in half of the patient group

In almost half (49%) of the patients with metastatic melanoma who received TIL therapy, the metastases had shrunk. In 20% of patients, the metastases had even disappeared completely. This also proved to be the case in patients who had already received another treatment prior to their trial participation. These percentages were significantly higher than those among the patient group receiving standard immunotherapy (ipilimumab). In the latter group, metastases had shrunk in 21% of patients, while 7% saw a disappearance of the condition.

Progression-free survival after six months is 53%

The progression-free survival, which refers to the percentage of patients who do not experience disease progression after a specified time period, was 53% after six months for patients receiving TIL therapy, and 21% in the control group. At a median follow-up time of 33 months for all patients, the median progression-free survival of patients who had received TIL therapy was significantly better (7 months) than that of patients treated with ipilimumab (3 months).

Quality of life: return to professional life

While assessing a treatment's efficacy, more clinical trials nowadays also consider the patients' quality of life. Patients treated with TIL scored better in this area than those treated with ipilimumab. This applied to their general physical and emotional functioning as well as symptoms like fatigue, pain, or insomnia. "We also looked at whether they could resume their careers and noticed that people were going back to work," says physician-scientist Maartje Rohaan, who coordinated the trial. "That's wonderful to see." The differences in quality of life between the TIL patients and the control group were still visible after 60 weeks. As an added bonus, TIL therapy is much more cost-effective than immunotherapy with ipilimumab.

Read more about the TIL therapy

Compared to checkpoint inhibitors

The trial compared TIL therapy to a different type of immunotherapy using checkpoint inhibitor ipilimumab, which is a drug that reactivates the body's T cells that have been thwarted by the tumor so they can continue to kill the tumor cells. In 2014, when the TIL trial started, this was the only registered immunotherapy for patients with metastatic melanomas. Research leader Haanen: "We have to remember that this form of immunotherapy has also experienced a lot of development in recent years, with more and more research looking to find more effective treatments for metastatic melanoma, even for patients who have already received treatment without the desired effects. The results of the TIL trial are a good addition to this. We have shown that treatment using the patient's own T cells that have been multiplied outside the body, can be very effective in patients with metastatic melanoma, even if previous systemic treatment failed." read more about the different types of immunotherapy

Not an easy treatment

The TIL therapy itself, a one-time treatment, is not easy on the patient. All TIL patients experienced side effects to some degree, as did 96% of patients treated with ipilimumab. The side effects of the TIL therapy are usually not caused by the T cells themselves, but rather by the chemotherapy pre-treatment, which is required to make room for the billions of T cells, and by the rapidly successive post-treatments with growth factor interleukin-2, which ensures rapid growth of the T cells. This can lead to high fevers and chills. Haanen: "In the future we would like to find a way to avoid the use of high dose interleukin-2 by developing a more precise form of the treatment by using a growth factor that causes fewer side effects."

What do these results mean for patients with metastatic melanomas?

Now that the phase III trial has concluded with positive results, the researchers want the treatment to be covered by basic health insurance, making it accessible to patients in the Netherlands. The Dutch National Health Care Institute (Zorginstituut Nederland) is currently assessing whether TIL therapy meets the requirements (in terms of science and clinical practice as well as cost-effectiveness) so it can be included as a standard treatment in the basic health insurance package.

Patients in the Netherlands can participate in the TIL trial until the end of 2022, through a referral by their practicing physician. Treatment as part of this trial will be covered by basic health insurance. Now that the TIL therapy is proven to be effective, patients will no longer be randomized, meaning that all patients automatically receive TIL therapy if they meet certain criteria.

EMA

One thing that makes T cell therapy unique, is that this 'living medicine', the patient's own T cells, is produced at the Netherlands Cancer Institute itself, and not, as is often seen, at a pharmaceutical company. This is also known as 'academic pharma'. T cell therapies must be produced under extremely strict, hygienic conditions. To facilitate this, the Netherlands Cancer Institute has set up a special Biotherapeutics Unit. In order to be able to produce TIL for the European market following the results of the trial, the EMA, European Medicines Agency, must first give its approval. The way in which production is to take place outside the Netherlands will also be examined.

Read more at Science Daily

Gel-like, radioactive tumor implant obliterates pancreatic cancer in mice

Biomedical engineers at Duke University have demonstrated the most effective treatment for pancreatic cancer ever recorded in mouse models. While most mouse trials consider simply halting growth a success, the new treatment completely eliminated tumors in 80% of mice across several model types, including those considered the most difficult to treat.

The approach combines traditional chemotherapy drugs with a new method for irradiating the tumor. Rather than delivering radiation from an external beam that travels through healthy tissue, the treatment implants radioactive iodine-131 directly into the tumor within a gel-like depot that protects healthy tissue and is absorbed by the body after the radiation fades away.

The results appear online October 19 in the journal Nature Biomedical Engineering.

"We did a deep dive through over 1100 treatments across preclinical models and never found results where the tumors shrank away and disappeared like ours did," said Jeff Schaal, who conducted the research during his PhD in the laboratory of Ashutosh Chilkoti, the Alan L. Kaganov Distinguished Professor of Biomedical Engineering at Duke. "When the rest of the literature is saying that what we're seeing doesn't happen, that's when we knew we had something extremely interesting."

Despite accounting for only 3.2% of all cancer cases, pancreatic cancer is the third leading cause of cancer-related death. It is a very difficult to treat because its tumors tend to develop aggressive genetic mutations that make it resistant to many drugs, and it is typically diagnosed very late, when it has already spread to other sites in the body.

The current leading treatment combines chemotherapy, which keeps cells in a stage of reproduction vulnerable to radiation for longer periods of time, with a beam of radiation targeted at the tumor. This approach, however, is ineffective unless a certain threshold of radiation reaches the tumor. And despite recent advances in shaping and targeting radiation beams, that threshold is very difficult to reach without risking severe side effects.

Another method researchers have tried involves implanting a radioactive sample encased in titanium directly within the tumor. But because titanium blocks all radiation other than gamma rays, which travel far outside the tumor, it can only remain within the body for a short period of time before damage to surrounding tissue begins to defeat the purpose.

"There's just no good way to treat pancreatic cancer right now," said Schaal, who is now director of research at Cereius, Inc., a Durham, North Carolina biotechnology startup working to commercialize a targeted radionuclide therapy through a different technology scheme.

To skirt these issues, Schaal decided to try a similar implantation method using a substance made of elastin-like polypeptides (ELPs), which are synthetic chains of amino acids bonded together to form a gel-like substance with tailored properties. Because ELPs are a focus of the Chilkoti lab, he was able to work with colleagues to design a delivery system well suited for the task.

The ELPs exist in a liquid state at room temperature but form a stable gel-like substance within the warmer human body. When injected into a tumor along with a radioactive element, the ELPs form a small depot encasing radioactive atoms. In this case, the researchers decided to use iodine-131, a radioactive isotope of iodine, because doctors have used it widely in medical treatments for decades and its biological effects are well understood.

The ELP depot encases the iodine-131 and prevents it from leaking out into the body. The iodine-131 emits beta radiation, which penetrates the biogel and deposits almost all its energy into the tumor without reaching the surrounding tissue. Over time, the ELP depot degrades into its constituent amino acids and is absorbed by the body -- but not before the iodine-131 has decayed into a harmless form of xenon.

"The beta radiation also improves the stability of the ELP biogel," Schaal said. "That helps the depot last longer and only break down after the radiation is spent."

In the new paper, Schaal and his collaborators in the Chilkoti laboratory tested the new treatment in concert with paclitaxel, a commonly used chemotherapy drug, to treat various mouse models of pancreatic cancer. They chose pancreatic cancer because of its infamy for being difficult to treat, hoping to show that their radioactive tumor implant creates synergistic effects with chemotherapy that relatively short-lived radiation beam therapy does not.

The researchers tested their approach on mice with cancers just under their skin created by several different mutations known to occur in pancreatic cancer. They also tested it on mice that had tumors within the pancreas, which is much more difficult to treat.

Overall, the tests saw a 100% response rate across all models, with the tumors being completely eliminated in three-quarters of the models about 80% of the time. The tests also revealed no immediately obvious side effects beyond what is caused by chemotherapy alone.

"We think the constant radiation allows the drugs to interact with its effects more strongly than external beam therapy allows," Schaal said. "That makes us think that this approach might actually work better than external beam therapy for many other cancers, too."

The approach, however, is still in its early preclinical stages and will not be available for human use anytime soon. The researchers say their next step is large animal trials, where they will need to show that the technique can be accurately done with the existing clinical tools and endoscopy techniques that doctors are already trained on. If successful, they look toward a Phase 1 clinical trial in humans.

"My lab has been working on developing new cancer treatments for close to 20 years, and this work is perhaps the most exciting we have done in terms of its potential impact, as late-stage pancreatic cancer is impossible to treat and is invariably fatal," Chilkoti said. "Pancreatic cancer patients deserve better treatment options than are currently available, and I am deeply committed to taking this all the way into the clinic."

Read more at Science Daily

New model helps identify mutations that drive cancer

Cancer cells can have thousands of mutations in their DNA. However, only a handful of those actually drive the progression of cancer; the rest are just along for the ride.

Distinguishing these harmful driver mutations from the neutral passengers could help researchers identify better drug targets. To boost those efforts, an MIT-led team has built a new computer model that can rapidly scan the entire genome of cancer cells and identify mutations that occur more frequently than expected, suggesting that they are driving tumor growth. This type of prediction has been challenging because some genomic regions have an extremely high frequency of passenger mutations, drowning out the signal of actual drivers

"We created a probabilistic, deep-learning method that allowed us to get a really accurate model of the number of passenger mutations that should exist anywhere in the genome," says Maxwell Sherman, an MIT graduate student. "Then we can look all across the genome for regions where you have an unexpected accumulation of mutations, which suggests that those are driver mutations."

In their new study, the researchers found additional mutations across the genome that appear to contribute to tumor growth in 5 to 10 percent of cancer patients. The findings could help doctors to identify drugs that would have greater chance of successfully treating those patients, the researchers say. Currently, at least 30 percent of cancer patients have no detectable driver mutation that can be used to guide treatment.

Sherman, MIT graduate student Adam Yaari, and former MIT research assistant Oliver Priebe are the lead authors of the study, which appears today in Nature Biotechnology. Bonnie Berger, the Simons Professor of Mathematics at MIT and head of the Computation and Biology group at the Computer Science and Artificial Intelligence Laboratory (CSAIL), is a senior author of the study, along with Po-Ru Loh, an assistant professor at Harvard Medical School and associate member of the Broad Institute of MIT and Harvard. Felix Dietlein, an associate professor at Harvard Medical School and Boston Children's Hospital, is also an author of the paper.

A new tool

Since the human genome was sequenced two decades ago, researchers have been scouring the genome to try to find mutations that contribute to cancer by causing cells to grow uncontrollably or evade the immune system. This has successfully yielded targets such as epidermal growth factor receptor (EGFR), which is commonly mutated in lung tumors, and BRAF, a common driver of melanoma. Both of these mutations can now be targeted by specific drugs.

While those targets have proven useful, protein-coding genes make up only about 2 percent of the genome. The other 98 percent also contains mutations that can occur in cancer cells, but it has been much more difficult to figure out if any of those mutations contribute to cancer development.

"There has really been a lack of computational tools that allow us to search for these driver mutations outside of protein-coding regions," Berger says. "That's what we were trying to do here: design a computational method to let us look at not only the 2 percent of the genome that codes for proteins, but 100 percent of it."

To do that, the researchers trained a type of computational model known as a deep neural network to search cancer genomes for mutations that occur more frequently than expected. As a first step, they trained the model on genomic data from 37 different types of cancer, which allowed the model to determine the background mutation rates for each of those types.

"The really nice thing about our model is that you train it once for a given cancer type, and it learns the mutation rate everywhere across the genome simultaneously for that particular type of cancer," Sherman says. "Then you can query the mutations that you see in a patient cohort against the number of mutations you should expect to see."

The data used to train the models came from the Roadmap Epigenomics Project and an international collection of data called the Pan-Cancer Analysis of Whole Genomes (PCAWG). The model's analysis of this data gave the researchers a map of the expected passenger mutation rate across the genome, such that the expected rate in any set of regions (down to the single base pair) can be compared to the observed mutation count anywhere across the genome.

Changing the landscape

Using this model, the MIT team was able to add to the known landscape of mutations that can drive cancer. Currently, when cancer patients' tumors are screened for cancer-causing mutations, a known driver will turn up about two-thirds of the time. The new results of the MIT study offer possible driver mutations for an additional 5 to 10 percent of the pool of patients.

One type of noncoding mutation the researchers focused on is called "cryptic splice mutations." Most genes consist of sequences of exons, which encode protein-building instructions, and introns, which are spacer elements that usually get trimmed out of messenger RNA before it is translated into protein. Cryptic splice mutations are found in introns, where they can confuse the cellular machinery that splices them out. This results in introns being included when they shouldn't be.

Using their model, the researchers found that many cryptic splice mutations appear to disrupt tumor suppressor genes. When these mutations are present, the tumor suppressors are spliced incorrectly and stop working, and the cell loses one of its defenses against cancer. The number of cryptic splice sites that the researchers found in this study accounts for about 5 percent of the driver mutations found in tumor suppressor genes.

Targeting these mutations could offer a new way to potentially treat those patients, the researchers say. One possible approach that is still in development uses short strands of RNA called antisense oligonucleotides (ASOs) to patch over a mutated piece of DNA with the correct sequence.

"If you could make the mutation disappear in a way, then you solve the problem. Those tumor suppressor genes could keep operating and perhaps combat the cancer," Yaari says. "The ASO technology is actively being developed, and this could be a very good application for it."

Another region where the researchers found a high concentration of noncoding driver mutations is in the untranslated regions of some tumor suppressor genes. The tumor suppressor gene TP53, which is defective in many types of cancer, was already known to accumulate many deletions in these sequences, known as 5' untranslated regions. The MIT team found the same pattern in a tumor suppressor called ELF3.

The researchers also used their model to investigate whether common mutations that were already known might also be driving different types of cancers. As one example, the researchers found that BRAF, previously linked to melanoma, also contributes to cancer progression in smaller percentages of other types of cancers, including pancreatic, liver, and gastroesophageal.

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Tumors partially destroyed with sound don't come back

Noninvasive sound technology developed at the University of Michigan breaks down liver tumors in rats, kills cancer cells and spurs the immune system to prevent further spread -- an advance that could lead to improved cancer outcomes in humans.

By destroying only 50% to 75% of liver tumor volume, the rats' immune systems were able to clear away the rest, with no evidence of recurrence or metastases in more than 80% animals.

"Even if we don't target the entire tumor, we can still cause the tumor to regress and also reduce the risk of future metastasis," said Zhen Xu, professor of biomedical engineering at U-M and corresponding author of the study in Cancers.

Results also showed the treatment stimulated the rats' immune responses, possibly contributing to the eventual regression of the untargeted portion of the tumor and preventing further spread of the cancer.

The treatment, called histotripsy, noninvasively focuses ultrasound waves to mechanically destroy target tissue with millimeter precision. The relatively new technique is currently being used in a human liver cancer trial in the United States and Europe.

In many clinical situations, the entirety of a cancerous tumor cannot be targeted directly in treatments for reasons that include the mass' size, location or stage. To investigate the effects of partially destroying tumors with sound, this latest study targeted only a portion of each mass, leaving behind a viable intact tumor. It also allowed the team, including researchers at Michigan Medicine and the Ann Arbor VA Hospital, to show the approach's effectiveness under less than optimal conditions.

"Histotripsy is a promising option that can overcome the limitations of currently available ablation modalities and provide safe and effective noninvasive liver tumor ablation," said Tejaswi Worlikar, a doctoral student in biomedical engineering. "We hope that our learnings from this study will motivate future preclinical and clinical histotripsy investigations toward the ultimate goal of clinical adoption of histotripsy treatment for liver cancer patients."

Liver cancer ranks among the top 10 causes of cancer related deaths worldwide and in the U.S. Even with multiple treatment options, the prognosis remains poor with five-year survival rates less than 18% in the U.S. The high prevalence of tumor recurrence and metastasis after initial treatment highlights the clinical need for improving outcomes of liver cancer.

Where a typical ultrasound uses sound waves to produce images of the body's interior, U-M engineers have pioneered the use of those waves for treatment. And their technique works without the harmful side effects of current approaches such as radiation and chemotherapy.

"Our transducer, designed and built at U-M, delivers high amplitude microsecond-length ultrasound pulses -- acoustic cavitation -- to focus on the tumor specifically to break it up," Xu said. "Traditional ultrasound devices use lower amplitude pulses for imaging."

The microsecond long pulses from UM's transducer generate microbubbles within the targeted tissues -- bubbles that rapidly expand and collapse. These violent but extremely localized mechanical stresses kill cancer cells and break up the tumor's structure.

Since 2001, Xu's laboratory at U-M has pioneered the use of histotripsy in the fight against cancer, leading to the clinical trial #HOPE4LIVER sponsored by HistoSonics, a U-M spinoff company. More recently, the group's research has produced promising results on histotripsy treatment of brain therapy and immunotherapy.

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How moles change into melanoma

Moles and melanomas are both skin tumors that come from the same cell called melanocytes. The difference is that moles are usually harmless, while melanomas are cancerous and often deadly without treatment. In a study published today in eLife Magazine, Robert Judson-Torres, PhD, Huntsman Cancer Institute (HCI) researcher and University of Utah (U of U) assistant professor of dermatology and oncological sciences, explains how common moles and melanomas form and why moles can change into melanoma.

Melanocytes are cells that give color to the skin to protect it from the sun's rays. Specific changes to the DNA sequence of melanocytes, called BRAF gene mutations, are found in over 75% of moles. The same change is also found in 50% of melanomas and is common in cancers like colon and lung. It was thought that when melanocytes only have the BRAFV600E mutation the cell stops dividing, resulting in a mole. When melanocytes have other mutations with BRAFV600E, they divide uncontrollably, turning into melanoma. This model is called "oncogene-induced senescence."

"A number of studies have challenged this model in recent years," says Judson-Torres. "These studies have provided excellent data to suggest that the oncogene-induced senescence model does not explain mole formation but what they have all lacked is an alternative explanation -- which has remained elusive."

With help from collaborators across HCI and the University of California San Francisco, the study team took moles and melanomas donated by patients and used transcriptomic profiling and digital holographic cytometry. Transcriptomic profiling lets researchers determine molecular differences between moles and melanomas. Digital holographic cytometry helps researchers track changes in human cells.

"We discovered a new molecular mechanism that explains how moles form, how melanomas form, and why moles sometimes become melanomas," says Judson-Torres.

The study shows melanocytes that turn into melanoma do not need to have additional mutations but are actually affected by environmental signaling, when cells receive signals from the environment in the skin around them that give them direction. Melanocytes express genes in different environments, telling them to either divide uncontrollably or stop dividing altogether.

"Origins of melanoma being dependent on environmental signals gives a new outlook in prevention and treatment," says Judson-Torres. "It also plays a role in trying to combat melanoma by preventing and targeting genetic mutations. We might also be able to combat melanoma by changing the environment."

These findings create a foundation for researching potential melanoma biomarkers, allowing doctors to detect cancerous changes in the blood at earlier stages. The researchers are also interested in using these data to better understand potential topical agents to reduce the risk of melanoma, delay development, or stop recurrence, and to detect melanoma early.

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Scientists find a new way to reverse immune suppression in tumors

Malignant tumors can enhance their ability to survive and spread by suppressing antitumor immune cells in their vicinity, but a study led by researchers at Weill Cornell Medicine and NewYork-Presbyterian has uncovered a new way to counter this immunosuppressive effect.

In the study, published Sept. 20 in Nature Cancer, the researchers identified a set of anti-immunosuppressive factors that can be secreted by cells called club cells that line airways in the lungs. They showed in a mouse model of lung cancer that these club cell factors inhibit highly potent immunosuppressive cells called myeloid-derived suppressor cells (MDSCs), which tumors often recruit to help them evade antitumor immune responses.

The inhibition of the MDSCs led to an increase in the number of antitumor T cells at the tumor site, and greatly improved the effectiveness of FDA approved PD1 immunotherapy.

"These club cell-secreted factors are able to nullify immune suppressor cells that otherwise help tumors escape an effective antitumor response," said co-senior author Dr. Vivek Mittal, director of research at the Neuberger Berman Lung Cancer Center and the Ford-Isom Research Professor of Cardiothoracic Surgery at Weill Cornell Medicine. "We're excited by the possibility of developing these club cell factors into a cancer treatment."

The research is part of a broad scientific effort in recent decades to find ways to harness the immune system against cancers. That effort has yielded treatments such as "immune checkpoint inhibitors" (ICIs) which partly undo tumors' immunosuppressive effects. In recent years, oncologists also have observed that ionizing radiation, long a standard treatment for many cancers, can further undo this immune suppression and thereby enhance the effectiveness of ICI treatments.

In the new study, Dr. Mittal and co-senior authors Dr. Nasser Altorki, chief of the Division of Thoracic Surgery at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center, and Dr. Dingcheng Gao, associate professor of cell and developmental biology at Weill Cornell Medicine, teamed up to determine how radiation has this immune-enhancing effect.

Using a mouse model of non-small-cell lung carcinoma, the most common form of lung cancer, they first established that this effect peaked at a moderate dose of radiation, and caused the quadrupling, to 40 percent, of the proportion of ICI-treated mice who survived tumor-free to the end of the two-month observation period.

The researchers then found that radiation has this effect by activating and stimulating the proliferation of lung-resident club cells, which are known to help protect and repair sensitive airway linings, in part by reducing inflammation.

"It's possible that we see a peak stimulation of these cells at a particular radiation dose because a lower dose doesn't stress the cells enough, whereas a higher dose kills them," said Dr. Altorki, who is also director of the Neuberger Berman Lung Cancer Research Center, the David B. Skinner, M.D. Professor of Thoracic Surgery and leader of the Experimental Therapeutics Program of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

The activated club cells secrete various molecules, and the researchers found that they could replace the radiation with a "club cocktail" of eight of these molecules and get essentially the same ICI-enhancing result.

They also determined that this immune-restoring effect of the club cell molecules stems from their inhibition of MDSCs -- which have long been seen as an obstacle to the improved efficacy of cancer immunotherapies.

To confirm the relevance of these laboratory findings to human cancers, the researchers looked at blood serum sampled from lung cancer patients in a clinical trial of radiotherapy plus ICI, conducted recently by Dr. Altorki and colleagues at Weill Cornell Medicine. They observed that levels of a key club cocktail molecule, CC10, were significantly elevated in most (5 of 8) of the patients who improved following the treatment, but in none (0 of 9) of the patients who failed to improve -- hinting that CC10 can help patients improve.

The researchers now are working to determine which of the molecules in their club cocktail are most important for inhibiting MDSCs and enhancing cancer treatments. They also plan to investigate whether these club cell molecules can inhibit MDSCs in other tumor contexts.

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Study illuminates origins of lung cancer in never smokers

A genomic analysis of lung cancer in people with no history of smoking has found that a majority of these tumors arise from the accumulation of mutations caused by natural processes in the body. This study was conducted by an international team led by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), and describes for the first time three molecular subtypes of lung cancer in people who have never smoked.

These insights will help unlock the mystery of how lung cancer arises in people who have no history of smoking and may guide the development of more precise clinical treatments. The findings were published September 6, 2021, in Nature Genetics.

"What we're seeing is that there are different subtypes of lung cancer in never smokers that have distinct molecular characteristics and evolutionary processes," said epidemiologist Maria Teresa Landi, M.D., Ph.D., of the Integrative Tumor Epidemiology Branch in NCI's Division of Cancer Epidemiology and Genetics, who led the study, which was done in collaboration with researchers at the National Institute of Environmental Health Sciences, another part of NIH, and other institutions. "In the future we may be able to have different treatments based on these subtypes."

Lung cancer is the leading cause of cancer-related deaths worldwide. Every year, more than 2 million people around the world are diagnosed with the disease. Most people who develop lung cancer have a history of tobacco smoking, but 10% to 20% of people who develop lung cancer have never smoked. Lung cancer in never smokers occurs more frequently in women and at an earlier age than lung cancer in smokers.

Environmental risk factors, such as exposure to secondhand tobacco smoke, radon, air pollution, and asbestos, or having had previous lung diseases, may explain some lung cancers among never smokers, but scientists still don't know what causes the majority of these cancers.

In this large epidemiologic study, the researchers used whole-genome sequencing to characterize the genomic changes in tumor tissue and matched normal tissue from 232 never smokers, predominantly of European descent, who had been diagnosed with non-small cell lung cancer. The tumors included 189 adenocarcinomas (the most common type of lung cancer), 36 carcinoids, and seven other tumors of various types. The patients had not yet undergone treatment for their cancer.

The researchers combed the tumor genomes for mutational signatures, which are patterns of mutations associated with specific mutational processes, such as damage from natural activities in the body (for example, faulty DNA repair or oxidative stress) or from exposure to carcinogens. Mutational signatures act like a tumor's archive of activities that led up to the accumulation of mutations, providing clues into what caused the cancer to develop. A catalogue of known mutational signatures now exists, although some signatures have no known cause. In this study, the researchers discovered that a majority of the tumor genomes of never smokers bore mutational signatures associated with damage from endogenous processes, that is, natural processes that happen inside the body.

As expected, because the study was limited to never smokers, the researchers did not find any mutational signatures that have previously been associated with direct exposure to tobacco smoking. Nor did they find those signatures among the 62 patients who had been exposed to secondhand tobacco smoke. However, Dr. Landi cautioned that the sample size was small and the level of exposure highly variable.

"We need a larger sample size with detailed information on exposure to really study the impact of secondhand tobacco smoking on the development of lung cancer in never smokers," Dr. Landi said.

The genomic analyses also revealed three novel subtypes of lung cancer in never smokers, to which the researchers assigned musical names based on the level of "noise" (that is, the number of genomic changes) in the tumors. The predominant "piano" subtype had the fewest mutations; it appeared to be associated with the activation of progenitor cells, which are involved in the creation of new cells. This subtype of tumor grows extremely slowly, over many years, and is difficult to treat because it can have many different driver mutations. The "mezzo-forte" subtype had specific chromosomal changes as well as mutations in the growth factor receptor gene EGFR, which is commonly altered in lung cancer, and exhibited faster tumor growth. The "forte" subtype exhibited whole-genome doubling, a genomic change that is often seen in lung cancers in smokers. This subtype of tumor also grows quickly.

"We're starting to distinguish subtypes that could potentially have different approaches for prevention and treatment," said Dr. Landi. For example, the slow-growing piano subtype could give clinicians a window of opportunity to detect these tumors earlier when they are less difficult to treat. In contrast, the mezzo-forte and forte subtypes have only a few major driver mutations, suggesting that these tumors could be identified by a single biopsy and could benefit from targeted treatments, she said.

A future direction of this research will be to study people of different ethnic backgrounds and geographic locations, and whose exposure history to lung cancer risk factors is well described.

"We're at the beginning of understanding how these tumors evolve," Dr. Landi said. "This analysis shows that there is heterogeneity, or diversity, in lung cancers in never smokers."

Stephen J. Chanock, M.D., director of NCI's Division of Cancer Epidemiology and Genetics, noted, "We expect this detective-style investigation of genomic tumor characteristics to unlock new avenues of discovery for multiple cancer types."

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An omega-3 that's poison for tumors

So-called "good fatty acids" are essential for human health and much sought after by those who try to eat healthily. Among the Omega-3 fatty acids, DHA or docosahexaenoic acid is crucial to brain function, vision and the regulation of inflammatory phenomena.

In addition to these virtues, DHA is also associated with a reduction in the incidence of cancer. How it works is the subject of a major discovery by a multidisciplinary team of University of Louvain (UCLouvain) researchers, who have just elucidated the biochemical mechanism that allows DHA and other related fatty acids to slow the development of tumours. This is a major advance that has recently been published in the journal Cell Metabolism.

Key to the discovery: interdisciplinarity

In 2016, Olivier Feron's UCLouvain team, which specialises in oncology, discovered that cells in an acidic microenvironment (acidosis) within tumours replace glucose with lipids as an energy source in order to multiply. In collaboration with UCLouvain's Cyril Corbet, Prof. Feron demonstrated in 2020 that these same cells are the most aggressive and acquire the ability to leave the original tumour to generate metastases. Meanwhile, Yvan Larondelle, a professor in the UCLouvain Faculty of Bioengineering, whose team is developing improved dietary lipid sources, proposed to Prof. Feron that they combine their skills in a research project, led by PhD candidate Emeline Dierge, to evaluate the behaviour of tumour cells in the presence of different fatty acids.

Thanks to the support of the Fondation Louvain, the Belgian Cancer Foundation and the Télévie telethon, the team quickly identified that these acidotic tumour cells responded in diametrically opposite ways depending on the fatty acid they were absorbing. Within a few weeks, the results were both impressive and surprising. "We soon found that certain fatty acids stimulated the tumour cells while others killed them," the researchers explained. DHA literally poisons them.

A fatal overload

The poison acts on tumour cells via a phenomenon called ferroptosis, a type of cell death linked to the peroxidation of certain fatty acids. The greater the amount of unsaturated fatty acids in the cell, the greater the risk of their oxidation. Normally, in the acidic compartment within tumours, cells store these fatty acids in lipid droplets, a kind of bundle in which fatty acids are protected from oxidation. But in the presence of a large amount of DHA, the tumour cell is overwhelmed and cannot store the DHA, which oxidises and leads to cell death. By using a lipid metabolism inhibitor that prevents the formation of lipid droplets, researchers were able to observe that this phenomenon is further amplified, which confirms the identified mechanism and opens the door to combined treatment possibilities.

For their study, UCLouvain researchers used a 3D tumour cell culture system, called spheroids. In the presence of DHA, spheroids first grow and then implode. The team also administered a DHA-enriched diet to mice with tumours. The result: tumour development was significantly slowed compared to that in mice on a conventional diet.

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New research optimizes body's own immune system to fight cancer

A groundbreaking study led by engineering and medical researchers at the University of Minnesota Twin Cities shows how engineered immune cells used in new cancer therapies can overcome physical barriers to allow a patient's own immune system to fight tumors. The research could improve cancer therapies in the future for millions of people worldwide.

The research is published in Nature Communications, a peer-reviewed, open access, scientific journal published by Nature Research.

Instead of using chemicals or radiation, immunotherapy is a type of cancer treatment that helps the patient's immune system fight cancer. T cells are a type of white blood cell that are of key importance to the immune system. Cytotoxic T cells are like soldiers who search out and destroy the targeted invader cells.

While there has been success in using immunotherapy for some types of cancer in the blood or blood-producing organs, a T cell's job is much more difficult in solid tumors.

"The tumor is sort of like an obstacle course, and the T cell has to run the gauntlet to reach the cancer cells," said Paolo Provenzano, the senior author of the study and a biomedical engineering associate professor in the University of Minnesota College of Science and Engineering. "These T cells get into tumors, but they just can't move around well, and they can't go where they need to go before they run out of gas and are exhausted."

In this first-of-its-kind study, the researchers are working to engineer the T cells and develop engineering design criteria to mechanically optimize the cells or make them more "fit" to overcome the barriers. If these immune cells can recognize and get to the cancer cells, then they can destroy the tumor.

In a fibrous mass of a tumor, the stiffness of the tumor causes immune cells to slow down about two-fold -- almost like they are running in quicksand.

"This study is our first publication where we have identified some structural and signaling elements where we can tune these T cells to make them more effective cancer fighters," said Provenzano, a researcher in the University of Minnesota Masonic Cancer Center. "Every 'obstacle course' within a tumor is slightly different, but there are some similarities. After engineering these immune cells, we found that they moved through the tumor almost twice as fast no matter what obstacles were in their way."

To engineer cytotoxic T cells, the authors used advanced gene editing technologies (also called genome editing) to change the DNA of the T cells so they are better able to overcome the tumor's barriers. The ultimate goal is to slow down the cancer cells and speed up the engineered immune cells. The researchers are working to create cells that are good at overcoming different kinds of barriers. When these cells are mixed together, the goal is for groups of immune cells to overcome all the different types of barriers to reach the cancer cells.

Provenzano said the next steps are to continue studying the mechanical properties of the cells to better understand how the immune cells and cancer cells interact. The researchers are currently studying engineered immune cells in rodents and in the future are planning clinical trials in humans.

While initial research has been focused on pancreatic cancer, Provenzano said the techniques they are developing could be used on many types of cancers.

"Using a cell engineering approach to fight cancer is a relatively new field," Provenzano said. "It allows for a very personalized approach with applications for a wide array of cancers. We feel we are expanding a new line of research to look at how our own bodies can fight cancer. This could have a big impact in the future."

In addition to Provenzano, the study's authors included current and former University of Minnesota Department of Biomedical Engineering researchers Erdem D. Tabdanov (co-author), Nelson J. Rodríguez-Merced (co-author), Vikram V. Puram, Mackenzie K. Callaway, and Ethan A. Ensminger; University of Minnesota Masonic Cancer Center and Medical School Department of Pediatrics researchers Emily J. Pomeroy, Kenta Yamamoto, Walker S. Lahr, Beau R. Webber, Branden S. Moriarity; National Institute of Biomedical Imaging and Bioengineering researcher Alexander X. Cartagena-Rivera; and National Heart, Lung, and Blood Institute researcher Alexander S. Zhovmer, who is now at the Center for Biologic Evaluation and Research.

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Bacteria may aid anti-cancer immune response

 Cancer immunotherapy may get a boost from an unexpected direction: bacteria residing within tumor cells. In a new study published in Nature, researchers at the Weizmann Institute of Science and their collaborators have discovered that the immune system "sees" these bacteria and shown they can be harnessed to provoke an immune reaction against the tumor. The study may also help clarify the connection between immunotherapy and the gut microbiome, explaining the findings of previous research that the microbiome affects the success of immunotherapy.

Immunotherapy treatments of the past decade or so have dramatically improved recovery rates from certain cancers, particularly malignant melanoma; but in melanoma, they still work in only about 40% of the cases. Prof. Yardena Samuels of Weizmann's Molecular Cell Biology Department studies molecular "signposts" -- protein fragments, or peptides, on the cell surface -- that mark cancer cells as foreign and may therefore serve as potential added targets for immunotherapy. In the new study, she and colleagues extended their search for new cancer signposts to those bacteria known to colonize tumors.

Using methods developed by departmental colleague Dr. Ravid Straussman, who was one of the first to reveal the nature of the bacterial "guests" in cancer cells, Samuels and her team, led by Dr. Shelly Kalaora and Adi Nagler (joint co-first authors), analyzed tissue samples from 17 metastatic melanoma tumors derived from nine patients. They obtained bacterial genomic profiles of these tumors and then applied an approach known as HLA-peptidomics to identify tumor peptides that can be recognized by the immune system.

The research was conducted in collaboration with Dr. Jennifer A. Wargo of the University of Texas MD Anderson Cancer Center, Houston, Texas; Prof Scott N. Peterson of Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California; Prof Eytan Ruppin of the National Cancer Institute, USA; Prof Arie Admon of the Technion -- Israel Institute of Technology and other scientists.

The HLA peptidomics analysis revealed nearly 300 peptides from 41 different bacteria on the surface of the melanoma cells. The crucial new finding was that the peptides were displayed on the cancer cell surfaces by HLA protein complexes -- complexes that are present on the membranes of all cells in our body and play a role in regulating the immune response. One of the HLA's jobs is to sound an alarm about anything that's foreign by "presenting" foreign peptides to the immune system so that immune T cells can "see" them. "Using HLA peptidomics, we were able to reveal the HLA-presented peptides of the tumor in an unbiased manner," Kalaora says. "This method has already enabled us in the past to identify tumor antigens that have shown promising results in clinical trials."

It's unclear why cancer cells should perform a seemingly suicidal act of this sort: presenting bacterial peptides to the immune system, which can respond by destroying these cells. But whatever the reason, the fact that malignant cells do display these peptides in such a manner reveals an entirely new type of interaction between the immune system and the tumor.

This revelation supplies a potential explanation for how the gut microbiome affects immunotherapy. Some of the bacteria the team identified were known gut microbes. The presentation of the bacterial peptides on the surface of tumor cells is likely to play a role in the immune response, and future studies may establish which bacterial peptides enhance that immune response, enabling physicians to predict the success of immunotherapy and to tailor a personalized treatment accordingly.

Moreover, the fact that bacterial peptides on tumor cells are visible to the immune system can be exploited for enhancing immunotherapy. "Many of these peptides were shared by different metastases from the same patient or by tumors from different patients, which suggests that they have a therapeutic potential and a potent ability to produce immune activation," Nagler says.

In a series of continuing experiments, Samuels and colleagues incubated T cells from melanoma patients in a laboratory dish together with bacterial peptides derived from tumor cells of the same patient. The result: T cells were activated specifically toward the bacterial peptides.

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Obesity impairs immune cell function, accelerates tumor growth

 

Cancer definition

Obesity has been linked to increased risk for over a dozen different types of cancer, as well as worse prognosis and survival. Over the years, scientists have identified obesity-related processes that drive tumor growth, such as metabolic changes and chronic inflammation, but a detailed understanding of the interplay between obesity and cancer has remained elusive.

Now, in a study in mice, Harvard Medical School researchers have uncovered a new piece of this puzzle, with surprising implications for cancer immunotherapy: Obesity allows cancer cells to outcompete tumor-killing immune cells in a battle for fuel.

Reporting in Cell on Dec. 9, the research team shows that a high-fat diet reduces the numbers and antitumor activity of CD8+ T cells, a critical type of immune cell, inside tumors. This occurs because cancer cells reprogram their metabolism in response to increased fat availability to better gobble up energy-rich fat molecules, depriving T cells of fuel and accelerating tumor growth.

"Putting the same tumor in obese and nonobese settings reveals that cancer cells rewire their metabolism in response to a high fat diet," said Marcia Haigis, professor of cell biology in the Blavatnik Institute at HMS and co-senior author of the study. "This finding suggests that a therapy that would potentially work in one setting might not be as effective in another, which needs to be better understood given the obesity epidemic in our society."

The team found that blocking this fat-related metabolic reprogramming significantly reduced tumor volume in mice on high-fat diets. Because CD8+ T cells are the main weapon used by immunotherapies that activate the immune system against cancer, the study results suggest new strategies for improving such therapies.

"Cancer immunotherapies are making an enormous impact on patients' lives, but they do not benefit everyone," said co-senior author Arlene Sharpe, the HMS George Fabyan Professor of Comparative Pathology and chair of the Department of Immunology in the Blavatnik Institute.

"We now know there is a metabolic tug-of-war between T cells and tumor cells that changes with obesity," Sharpe said. "Our study provides a roadmap to explore this interplay, which can help us to start thinking about cancer immunotherapies and combination therapies in new ways."

Haigis, Sharpe and colleagues investigated the effects of obesity on mouse models of different types of cancer, including colorectal, breast, melanoma and lung. Led by study co-first authors Alison Ringel and Jefte Drijvers, the team gave mice normal or high-fat diets, the latter leading to increased body weight and other obesity-related changes. They then looked at different cell types and molecules inside and around tumors, together called the tumor microenvironment.

Fatty paradox

The researchers found that tumors grew much more rapidly in animals on high-fat diets compared to those on normal diets. But this occurred only in cancer types that are immunogenic, which can contain high numbers of immune cells; are more easily recognized by the immune system; and are more likely to provoke an immune response.

Experiments revealed that diet-related differences in tumor growth depended specifically on the activity of CD8+ T cells, immune cells that can target and kill cancer cells. Diet did not affect tumor growth rate if CD8+ T cells were eliminated experimentally in mice.

Strikingly, high-fat diets reduced the presence of CD8+ T cells in the tumor microenvironment, but not elsewhere in the body. Those remaining in the tumor were less robust -- they divided more slowly and had markers of decreased activity. But when these cells were isolated and grown in a lab, they had normal activity, suggesting something in the tumor impaired these cells' function.

The team also encountered an apparent paradox. In obese animals, the tumor microenvironment was depleted of key free fatty acids, a major cellular fuel source, even though the rest of the body was enriched in fats, as expected in obesity.

These clues pushed the researchers to craft a comprehensive atlas of the metabolic profiles of different cell types in tumors under normal and high-fat diet conditions.

The analyses revealed that cancer cells adapted in response to changes in fat availability. Under a high-fat diet, cancer cells were able to reprogram their metabolism to increase fat uptake and utilization, while CD8+ T cells did not. This ultimately depleted the tumor microenvironment of certain fatty acids, leaving T cells starved for this essential fuel.

"The paradoxical depletion of fatty acids was one of the most surprising findings of this study. It really blew us away and it was the launch pad for our analyses," said Ringel, a postdoctoral fellow in the Haigis lab. "That obesity and whole-body metabolism can change how different cells in tumors utilize fuel was an exciting discovery, and our metabolic atlas now allows us to dissect and better understand these processes."

Hot and cold

Through several different approaches, including single-cell gene expression analyses, large-scale protein surveys and high-resolution imaging, the team identified numerous diet-related changes to metabolic pathways of both cancer and immune cells in the tumor microenvironment.

Of particular interest was PHD3, a protein that in normal cells has been shown to act as a brake on excessive fat metabolism. Cancer cells in an obese environment had significantly lower expression of PHD3 compared to in a normal environment. When the researchers forced tumor cells to overexpress PHD, they found that this diminished a tumor's ability to take up fat in obese mice. It also restored the availability of key free fatty acids in the tumor microenvironment.

Increased PHD3 expression largely reversed the negative effects of a high-fat diet on immune cell function in tumors. Tumors with high PHD3 grew slower in obese mice compared to tumors with low PHD3. This was a direct result of increased CD8+ T cell activity. In obese mice lacking CD8+ T cells, tumor growth was unaffected by differences in PHD3 expression.

The team also analyzed human tumor databases and found that low PHD3 expression was associated with immunologically "cold" tumors, defined by fewer numbers of immune cells. This association suggested that tumor fat metabolism plays a role in human disease, and that obesity reduces antitumor immunity in multiple cancer types, the authors said.

"CD8+ T cells are the central focus of many promising precision cancer therapies, including vaccines and cell therapies such as CAR-T," Sharpe said. "These approaches need T cells to have sufficient energy to kill cancer cells, but at the same time we don't want tumors to have fuel to grow. We now have amazingly comprehensive data for studying this dynamic and determining mechanisms that prevent T cells from functioning as they should."

More broadly, the results serve as a foundation for efforts to better understand how obesity affects cancer and the impact of patient metabolism on therapeutic outcomes, the authors said. While it's too early to tell if PHD3 is the best therapeutic target, the findings open the door for new strategies to combat cancer through its metabolic vulnerabilities, they said.

"We're interested in identifying pathways that we could use as potential targets to prevent cancer growth and to increase immune antitumor function," Haigis said. "Our study provides a high-resolution metabolic atlas to mine for insights into obesity, tumor immunity and the crosstalk and competition between immune and tumor cells. There are likely many other cell types involved and many more pathways to be explored."

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'Monster tumors' could offer new glimpse at human development

 Finding just the right model to study human development -- from the early embryonic stage onward -- has been a challenge for scientists over the last decade. Now, bioengineers at the University of California San Diego have homed in on an unusual candidate: teratomas.

Teratomas -- which mean "monstrous tumors" in Greek -- are tumors made up of different tissues such as bone, brain, hair and muscle. They form when a mass of stem cells differentiates uncontrollably, forming all types of tissues found in the body. Teratomas are generally considered an undesired byproduct of stem cell research, but UC San Diego researchers found an opportunity to study them as a model for human development.

Researchers report their work in a paper published Nov. 4 in Cell.

"We've been fascinated with the teratoma for quite a while," said Prashant Mali, a professor of bioengineering at the UC San Diego Jacobs School of Engineering. "Not only is the teratoma an intriguing tumor to look at in terms of the diversity of cell types, but it also has regions of organized tissue-like structures. This prompted us to explore its utility in both cell science and cell engineering contexts."

"There's no other model like it. In just one tumor, you can study all of these different lineages, all of these different organs, at the same time," said Daniella McDonald, an M.D/Ph.D. candidate in Mali's lab and co-first author of the study. "Plus, it's a vascularized model, it has a three-dimensional structure and it's human-specific tissue, making it the ideal model for recreating the context in which human development happens."

The team used teratomas grown from human stem cells injected under the skin of immunodeficient mice. They analyzed the teratomas with a technique called single-cell RNA sequencing, which profiles the gene expression of individual teratoma cells. The researchers were able to map 20 cell types, or "human lineages" (brain, gut, muscle, skin, etc.) that were consistently present in all the teratomas they analyzed.

The researchers then used the gene editing technology CRISPR-Cas9 to screen and knock out 24 genes known to regulate development. They found multiple genes that play roles in the development of multiple lineages.

"What's remarkable about this study is that we could use the teratoma to discover things in a much faster way. We can study all of these genes on all of these human lineages in a single experiment," said co-first author Yan Wu, who worked on this project as a Ph.D. student in the labs of Mali and UC San Diego bioengineering professor Kun Zhang. "With other models, like organoids, that separately model one lineage at a time, we would have had to run many different experiments to come up with the same results as we did here."

"Teratomas are a very unique type of human tissue. When examined through the lens of single-cell sequencing, we can see that they contain most major representative cell types in the human body. With that understanding, we suddenly have an extremely powerful platform to understand, manipulate and engineer human cells and tissues in a far more sophisticated way than what was previously possible," Zhang said.

The researchers also showed that they can "molecularly sculpt" the teratoma to be enriched in one lineage -- in this case, neural tissue. They accomplished this feat using a microRNA gene circuit, which acts like a molecular chisel by carving away unwanted tissues -- these are selectively killed off using a suicide gene -- and leaving behind the lineage of interest. The researchers say this has applications in tissue engineering.

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Breakthrough blood test developed for brain tumors

 Genetic mutations that promote the growth of the most common type of adult brain tumors can be accurately detected and monitored in blood samples using an enhanced form of liquid biopsy developed by researchers at Massachusetts General Hospital (MGH).

Comparing blood samples from patients with gliomas with tumor biopsy tissues from the same patients, Leonora Balaj, PhD, Bob S. Carter, MD, and other MGH investigators in the Department of Neurosurgery found that a novel digital droplet polymerase chain reaction (ddPCR) blood test they pioneered could accurately detect and monitor over time two mutations of the gene TERT. The mutations, labeled C228T and C250T, are known to promote cancer growth and are present in more than 60 percent of all gliomas, and in 80 percent of all high-grade gliomas, the most aggressive and life-threatening type.

Their discovery, which has the potential to substantially improve the diagnosis and monitoring of gliomas, is reported in the journal Clinical Cancer Research.

Gliomas are tumors of glia, central and peripheral nervous system cells that support and protect neurons, the cells that transmit electrical impulses.

Liquid biopsy is a method for detecting cancer by looking for fragments of tumor DNA that circulate in blood. The technique has been shown to be sensitive at detecting the presence of some forms of cancer, but brain tumors have until now posed a formidable barrier.

"Liquid biopsy is particularly challenging in brain tumors because mutant DNA is shed into the bloodstream at much lower level than any other types of tumors," Balaj says.

"By 'supercharging' our ddPCR assay with novel technical improvements, we showed for the first time that the most prevalent mutation in malignant gliomas can be detected in blood, opening a new landscape for detection and monitoring of the tumors," she says.

The researchers first tested the performance of the ddPCR assay in tumor tissue and found that the results were in perfect agreement with the results from an independently performed clinical laboratory assessment of TERT mutations in the tumor specimens.

They then looked at samples of blood plasma matched to patient tumors and found that the ddPCR assay could detect TERT mutations both in samples from MGH as well as from similarly matched plasma and tumor samples from collaborators at other institutions.

The ddPCR assay has an overall sensitivity (ability to detect the presence of a glioma) of 62.5 percent, which is a tenfold improvement over any prior assay for TERT mutations in the blood for brain tumors, compared to the standard of tissue-based detection of TERT mutations.

The test is easy to use, quick, and low cost, and could be performed in most laboratories, Balaj says. Importantly, the test can also be used to follow the course of disease. "We envision the future integration of tests like this one into the clinical care of our patients with brain tumors," says Carter, chief of Neurosurgery and co-director of the MGH Brain Tumor Center. "For example, if a patient has a suspected mass on MRI scanning, we can take a blood sample before the surgery and assess the presence of the tumor signature in the blood, and then use this signature as a baseline to monitor as the patient later receives treatment, both to gauge response to the treatment and gain early insight into any potential recurrence."

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Study sheds light on how cancer spreads in blood

A new study sheds light on proteins in particles called extracellular vesicles, which are released by tumor cells into the bloodstream and promote the spread of cancer. The findings suggest how a blood test involving these vesicles might be used to diagnose cancer in the future, avoiding the need for invasive surgical biopsies.

The research is a large-scale analysis of what are known as palmitoylated proteins inside extracellular vesicles, according to Dolores Di Vizio, MD, PhD, professor of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine at Cedars-Sinai. Di Vizio is co-corresponding author of the study, published online June 10 in the Journal of Extracellular Vesicles.

Extracellular vesicles have gained significant attention in the last decade because they contain proteins and other biologically important molecules whose information can be transferred from cell to cell. They are known to help cancer metastasize to distant sites in the body, but exactly how this happens is not clear.

To learn more about this process, the research team looked into a process called palmitoylation, in which enzymes transfer lipid molecules onto proteins. Palmitoylation can affect where proteins are located within cells, their activities and their contribution to cancer progression.

The investigators examined two types of extracellular vesicles, small and large, in samples of human prostate cancer cells. Using centrifuges, they separated the extracellular vesicles from the other cell materials and analyzed the levels of palmitoylation and the types of proteins present.

The team found extracellular vesicles derived from the cancer cells contained palmitoylated proteins that are associated with the spread of cancer. Further, when the team chemically suppressed the palmitoylation process, the level of some of these proteins went down in the extracellular vesicles.

"Our results suggest that protein palmitoylation may be involved in the selective packaging of proteins to different extracellular vesicle populations in the body," Di Vizio said. "This finding raises the possibility that by examining these proteins in extracellular vesicles in the bloodstream, we may be able to detect and characterize cancer in a patient in the future without performing a surgical biopsy."

Di Vizio said the next step in the research is to conduct a study in collaboration with her Cedars-Sinai colleagues and industry partners that will use advanced technologies, including mass spectrometry and flow cytometry, with the goal of identifying clinically significant prostate cancer at diagnosis.

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Study reveals first evidence inherited genetics can drive cancer's spread

Sometimes cancer stays put, but often it metastasizes, spreading to new locations in the body. It has long been suspected that genetic mutations arising inside tumor cells drive this potentially devastating turn of events.

Now researchers have shown for the first time that our own pre-existing genetics can promote metastasis.

A new study, published May 25 in Nature Medicine, suggests that differences in a single gene, carried within someone's genome from birth, can alter progression of melanoma, a type of skin cancer. The researchers suspect these inherited variations may have the same effect on other types of cancer as well.

"Patients often ask 'Why am I so unlucky? Why did my cancer spread?' As doctors, we never had an answer," says lead investigator Sohail Tavazoie, Leon Hess Professor and senior attending physician. "This research provides an explanation."

The discovery may transform how scientists think about cancer metastasis, and lead to a better understanding patients' risks in order to inform treatment decisions, Tavazoie says.

The mystery of metastasis

Metastasis occurs when cancer cells escape the original tissue to establish new tumors elsewhere, a phenomenon that leads to the majority of cancer deaths. Scientists have suspected that cancer cells, which initially emerge due to mutations inside normal cells, gain their travelling ability following further mutations. But after decades of searching, they have yet to find such a genetic change that could be proven to encourage metastasis.

Previous research in Tavazoie's lab had identified a gene called APOE, present in the DNA of all of the body's cells before any cancer arises, that can impact the spread of melanoma. The gene produces a protein that appears to interfere with a number of processes used by cancer cells to metastasize, such as forming blood vessels, growing deeper into healthy tissue, and withstanding assault from tumor-fighting immune cells.

Humans, however, carry one of three different versions of ApoE: ApoE2, ApoE3, and ApoE4. Benjamin Ostendorf, a physician scientist in the lab, hypothesized that these variants could explain why melanoma progresses differently in different people.

In experiments with mice possessing one of each of the versions of the gene, he and colleagues found tumors in those with ApoE4 grew the smallest and spread the least.

A closer look revealed that ApoE4 is the most effective version of ApoE in terms of enhancing the immune response to tumor cells. Compared to animals with other variants, the mice carrying ApoE4 showed a greater abundance of tumor-fighting T cells recruited into the melanoma tumor, as well as reduced blood vessels.

"We think that a major impact of the variations in ApoE arises from differences in how they modulate the immune system's attack," Ostendorf says.

Toward better treatment

Genetic data from more than 300 human melanoma patients echoed the mouse experiments: On average, people with ApoE4 survived the longest, while those with ApoE2 lived the shortest. This connection to outcomes suggests that doctors could look at patients' genetics to assess the risk of their cancer progressing.

It could also influence the course of treatment. Melanoma patients are sometimes given therapy that encourages their own immune systems to better fight the cancer. The team's analysis of information from such patients, as well as experiments with mice, showed that those with ApoE4 respond best to immune-boosting therapies.

Likewise, the researchers showed that an experimental compound that increases production of ApoE, RGX-104, was effective at helping mice with ApoE4 fight off tumors. RGX-104 is currently in clinical trials. (Tavazoie is a scientific cofounder of Rgenix, the company that developed RGX-104.)

Further research is needed to determine how to optimize treatments for patients with other ApoE variants, Tavazoie says. ApoE2, for instance, was associated with an increased risk of metastasis. The researchers evidence so far suggests that ApoE3's metastasis-suppressing ability falls between that of the other two. "We need to find those patients whose genetics put them at risk for poor survival and determine what therapies work best for them," Tavazoie says.

The implications may extend beyond cancer. Other studies have shown that variations in ApoE contribute to Alzheimer's disease: ApoE4 aggravates risk of this neurodegenerative disorder, in contrast to its suppression of cancer progression.

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