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8 TAU Big ideas That Are Helping to Fight Cancer

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Ground-breaking research sheds lights on disease and treatments

Cancer is the world’s leading cause of death. It is notoriously hard to combat because it refers to 150 different conditions.

Multidisciplinary teams from across the TAU campus are working feverishly to understand the disease—its mechanisms and causes—as well as to develop treatments to slow and bar its inception and spread. The University’s Cancer Biology Research Center, for example, is the largest cancer center in Israel, with more than 600 researchers and 17 affiliated hospitals. These teams also work with international researchers at the world’s top institutions.

This World Cancer Day, here are eight of TAU’s top efforts to fight cancer:

1. Zapping Tumors: Alpha DaRT radiation treatment, created by TAU Profs. Itzhak Kelson and Yona Keisari (emeriti), from the Sackler Faculty of Exact Sciences and the Wise Faculty of Life Sciences respectively, shows 100% shrinkage rate in tumors. Developed by Alpha Tau Medical via Ramot, TAU’s business engagement center, it’s the first technology to provide highly localized and effective therapy of solid cancerous growths using alpha radiation.

2. Bye-bye Biopsies: Environmental engineer Prof. Alexander Golberg, of the Porter School of Environment and Earth Sciences, and his team developed a safer and more efficient method of tumor profiling, an alternative to biopsies. It is called electroporation, the application of high voltage pulsed electric fields to tissues. In addition to avoiding the potential damage caused by excision in biopsies, this new method can garner more precise and relevant information to facilitate diagnostics and treatment decisions.

3. Vaccine for Melanoma: TAU scientists, under the direction of Prof. Ronit Satchi-Fainaro​ of the Sackler School of Medicine, have applied nanotechnology to prevent melanoma, the most aggressive and fatal type of skin cancer.​​ “The war against cancer in general, and melanoma in particular, has advanced over the years…and now we have shown for the first time that it is possible to produce an effective nano-vaccine against melanoma,” says Prof. Satchi-Fainaro.

Prof. Ronit Satchi-Fainaro

4. Battling Leukemia: A new genetically encoded sensor isolates hidden leukemic cells, which may be more responsive to therapy. The sensor, invented by Dr. Michael Milyavsky of TAU’s Sackler School of Medicine and his team, could serve as a prototype for precision oncology which will help fight the deadly blood disease, for which the survival rate is “dismal.”

5. Breast Cancer Therapy: A ground-breaking study by TAU’s Prof. Neta Erez of the Sackler School of Medicine and her team pointed to a new way to increase chances of survival for breast cancer patients. The researchers discovered a mechanism by which breast cancer tumors “recruit” bone marrow cells to grow stronger; targeting these cells with new therapies could be an effective way of treating the disease.

6. Repurposing Drugs: An Israeli research team discovered that a safe, inexpensive and easily administered drug regimen can reduce cancer recurrences. Research led by Prof. Shamgar Ben-Eliyahu of TAU’s Gordon Faculty of Social Sciences and Sagol School of Neuroscience concluded that a drug regimen administered prior to and after surgery significantly reduces the risk of post-surgical cancer recurrence. The medications, a combination of a beta blocker (which relieves stress and high blood pressure) and an anti-inflammatory, may also improve the long-term survival rates of patients.

7. Blocking Skin Cancer Metastasis: TAU research revealed how melanoma spreads and found ways to stop the process before the metastatic stage.​ Prof. Carmit Levy and her team at the Wise Faculty of Life Sciences discovered how the disease, the most aggressive and lethal type of skin cancer, spreads to distant organs. Moreover, they found chemical substances that can stop the process and are therefore promising drug candidates.

Prof. Carmit Levy

8. HealthTECH World Cancer Day 2020: In addition to these landmark discoveries, TAU serves as a hub for cancer research. Today, ahead of World Cancer Day, the University is hosting a national conference on the latest developments in cancer research and treatment in the fields of biotechnology, nanotechnology and medicine. The conference will take place simultaneously with similar initiatives in France, Spain, Ireland and Portugal.

TAU study finds widespread misinterpretation of gene expression data

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Bias can be now be removed from data to filter out false results, researchers say

Reproducibility of research data is a major challenge in experimental biology. As data generated by genomic-scale techniques increases in complexity, this concern is becoming more and more worrisome. RNA-seq, one of the most widely used methods in modern molecular biology, allows in a single test the simultaneous measurement of the expression level of all genes in a given sample. New research by a Tel Aviv University group identifies a frequent technical bias in data generated by RNA-seq technology, which often leads to false results. The study was conducted by Dr. Shir Mandelbaum, Dr. Zohar Manber, Dr. Orna Elroy-Stein and Dr. Ran Elkon at TAU’s Sackler Faculty of Medicine and George S. Wise Faculty of Life Sciences and was published on November 12 in PLOS Biology. “Recent years have witnessed a growing alarm about false results in biological research, sometimes referred to as the reproducibility crisis,” Dr. Elkon, lead author of the study, says. “This study emphasizes the importance of proper statistical handling of data to lessen the number of misleading findings.”

Removing bias from science

A main goal of RNA-seq experiments is to characterize biological processes that are activated or repressed in response to different conditions. The researchers analyzed dozens of publicly available RNA-seq datasets to profile the cellular responses to numerous stresses. During the research, the scientists noticed that sets of particularly short or long genes repeatedly showed changes in the expression level measured by the apparent number of RNA transcripts from a given gene. Puzzled by this recurring pattern, the team wondered whether it reflected some universal biological response common to different triggers or whether it stemmed from some experimental condition. To tackle this question, they compared replicated samples from the same biological condition. Differences in gene expression between replicates can reflect technical effects that are not related to the experiment’s biological factor of interest. Unexpectedly, the same pattern of particularly short or long genes showing changes in expression level was observed in these comparisons between replicates. This pattern is the result of a technical bias that seemed to be coupled with gene length, the researchers say. Importantly, the TAU researchers were able to show how the length bias they detected in many RNA-seq datasets led to the false identification of specific biological functions as cellular responses to the conditions tested. “Such misinterpretation of the data could lead to completely misleading conclusions,” Dr. Elkon concludes. “In practical terms, the study also shows how this bias can be removed from the data, thus filtering out false results while preserving the biologically relevant ones.”

Fibroblasts involved in healing spur tumor growth in cancer

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Vital to healing wounds, fibroblasts have a “misguided” response to cancer cells, according to TAU researchers

The connective tissue cells known as fibroblasts are vitally important for our recovery from injury. Sensing tissue damage, they gravitate to the site of a wound, instigating an inflammatory response that mends damaged tissue. A new Tel Aviv University study published in Nature Communications finds that fibroblasts also play a devastating role in the development of breast cancer. In cancer tumors, fibroblasts are triggered to respond to tissue damaged by tumors and create inflammation. This inflammation facilitates tumor growth as well as metastases in the lungs. “We have shown, for the first time, that in breast cancer these fibroblasts activate a ‘misguided’ wound healing response, responding to the tissue damage caused by the cancerous growth,” explains Prof. Neta Erez of TAU’s Sackler Faculty of Medicine, who led the research for the study. “Inhibiting these inflammatory signaling pathways may be beneficial in preventing metastatic relapse of breast cancer.” The study was conducted by former TAU student Yoray Sharon and TAU MD-PhD student Nour Ershaid in Prof. Erez’s lab at TAU’s Department of Pathology.

When tumors “hijack” repair functions

According to the study, the inflammatory response of fibroblasts not only supports local tumor growth in the breast, but it also creates a hospitable niche for metastatic growth in the lungs. “The fibroblasts are ‘activated’ and, because of this activation, they recruit immune cells and affect blood vessels,” adds Prof. Erez. “In other words, breast tumors ‘hijack’ the physiologic response to tissue damage to facilitate their growth, and create a niche in a distant organ, the lungs, by ‘remote control.'” Research for the study was performed using transgenic and transplantable mouse models of breast cancer, and validated in human samples of breast cancer and in human expression data. The researchers isolated fibroblasts in transgenic mice from different stages of breast carcinogenesis and profiled the expression of all their genes. They were then able to identify that the inflammation pathway is unregulated in cancer-associated fibroblasts, as compared with fibroblasts isolated from normal mammary glands. Finally, they performed functional experiments to understand the role of this pathway in breast cancer. “Our findings encourage the design of preclinical and clinical studies to examine the benefits of targeting the inflammation pathway in breast cancer, which may be effective in blocking metastatic relapse,” concludes Prof. Erez. “We are now studying the microenvironment of metastasis in an effort to identify targets for preventive intervention that may inhibit metastatic relapse.”

Eating in sync with biological clock could replace diabetes treatment

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An early-morning, carb-filled meal improves glycemic control among type 2 diabetics, TAU researchers say

Type 2 diabetics inject themselves with insulin, a hormone that regulates the movement of sugar into liver, muscle and fat cells, up to four times a day. But insulin injections are linked to weight gain and the loss of control of blood sugar levels. This triggers a vicious cycle of higher insulin doses, continuous weight gain, a higher incidence of cardiovascular disease and other complications. A new Tel Aviv University study finds that a starch-rich breakfast consumed early in the morning coupled with a small dinner could replace insulin injections and other diabetes medications for many diabetics. “The traditional diabetic diet specifies six small meals spread throughout the day. But our research proposes shifting the starch-rich calories to the early hours of the day. This produces a glucose balance and improved glycemic control among type 2 diabetics,” explains Prof. Daniela Jakubowicz of TAU’s Sackler Faculty of Medicine and Wolfson Medical Center’s Diabetes Unit. “We believe that through this regimen it will be possible for diabetics to significantly reduce or even stop the injections of insulin, and most of antidiabetic medications, to achieve excellent control of glucose levels.”

A hearty breakfast and a light dinner

According to the new research, our metabolism and biological clock are optimized for eating in the morning and for fasting during the evening and night, when we are supposed to be asleep. “But the usual diet recommended for type 2 diabetes consists of several small meals evenly distributed throughout the day — for example, three meals and three snacks daily, including a snack before going to sleep to prevent a drop in sugar levels during the night,” Prof. Jakubowicz says. “But the ‘6M-diet,’ as this is called, has not been effective for sugar control, so diabetics require additional medication and insulin. And insulin injections lead to weight gain, which further increases blood sugar levels,” Prof. Jakubowicz adds. The researchers studied 29 type 2 diabetes participants and compared a new “3M-diet,” more in alignment with our biological clock, with a control group on the traditional 6M-diet. The experimental 3M-diet comprises a meal of bread, fruits and sweets in the early hours of the morning; a substantial lunch; and a small dinner specifically lacking starches, sweets and fruits. The group on the traditional 6M-diet did not lose weight and did not experience any improvement of sugar levels, requiring an increase in medication and insulin doses. But the group on the 3M-diet not only lost weight but also experienced substantially improved sugar levels.

Making insulin injections unnecessary

“Their need for diabetic medication, especially for insulin doses, dipped substantially. Some were even able to stop using insulin altogether,” adds Prof. Jakubowicz. “In addition, the 3M-diet improved the expression of biological clock genes. This suggests that the 3M-diet is not only more effective in controlling diabetes. It may also prevent many other complications such as cardiovascular disease, aging and cancer, which are all regulated by the biological clock genes.” The upregulation of the biological clock gene expression in the 3M-diet might be the mechanism behind its success, as it enhances insulin secretion and improves sugar delivery into the muscles, creating a balanced daytime and nocturnal glucose metabolism. The researchers are now investigating the role certain proteins play in breakfast foods consumed by diabetics.
 

TAU partners with Columbia University for Dual Degree Program

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For the first time, an Israeli university has a joint undergraduate program with an Ivy League university offering world-class education on two continents

Tel Aviv University, Israel’s largest and most comprehensive higher education institution, today announced that it will launch the Dual Degree Program with Columbia University – a first-of-its-kind partnership at TAU that will provide undergraduate students from around the world with an opportunity to pursue an exceptional liberal arts education and earn two degrees. Transcending traditional study abroad opportunities, the program will enable students to simultaneously earn two bachelor’s degrees—one from each institution—upon completion of the four-year program. The multidisciplinary educational experience will offer students the best of both universities while empowering them to succeed in an increasingly complex and fast-changing world. “This is the first time that an Israeli university is collaborating with an elite American institution to offer a dual undergraduate program of this kind,” said Professor Raanan Rein, Vice President of Tel Aviv University.

Best of both worlds

The program will begin with students spending their first two years at Tel Aviv University, studying within one of six academic tracks in the International  Program in the Liberal Arts at Lester and Sally Entin Faculty of Humanities. For the final two years, they will study at Columbia University, fulfilling its core curriculum and completing their majors. Dedicated Dual Degree Program advisors from both TAU and Columbia will be assigned to students as soon as they enroll, providing guidance and support on academics and student life. “I am especially excited about our partnership with Tel Aviv University, which is consistently ranked among the best academic institutions worldwide,” said Professor Lisa Rosen-Metsch, Dean, Columbia University School of General Studies. “By giving students the opportunity to study full time at a top-tier university in the Middle East before bringing them to study in the Ivy League, they will not only benefit from being immersed in a wide range of cultures and experiences, but will also make an immense contribution to the Columbia undergraduate classroom.” TAU’s B.A. in Liberal Arts provides a broad education in the humanities while allowing students to specialize in their areas of interest by choosing from six academic tracks, including Digital Culture and Communication, Jewish and Israel Studies, Middle Eastern Studies, Psychology, Philosophy, and Literature. The Dual Degree Program will welcome its inaugural class in the fall of 2020.

New Treatment Triggers Self-Destruction of Pancreatic Cancer Cells

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Research conducted on human pancreatic tumours transplanted in mice reveals promising results, TAU researchers say Pancreatic cancer is resistant to all current treatments. Patients have extremely poor chances of surviving for five years after being diagnosed. A new Tel Aviv University study finds that a small molecule has the ability to induce the self-destruction of pancreatic cancer cells. The research was conducted with xenografts — transplantations of human pancreatic cancer into immunocompromised mice. The treatment reduced the number of cancer cells by 90% in the developed tumors a month after being administered. The research holds great potential for the development of a new effective therapy to treat this aggressive cancer in humans. The study was led by Prof. Malca Cohen-Armon and her team at TAU’s Sackler Faculty of Medicine, in collaboration with Dr. Talia Golan’s team at the Cancer Research Center at Sheba Medical Center. It was published in the journal Oncotarget on October 22. “In research published in 2017, we discovered a mechanism that causes the self-destruction of human cancer cells during their duplication (mitosis) without affecting normal cells,” explains Prof. Cohen-Armon. “We have now harnessed this information to efficiently eradicate human pancreatic cancer cells in xenografts. The current results were obtained using a small molecule that evokes this self-destruction mechanism in a variety of human cancer cells. “The mice were treated with a molecule called PJ34, which is permeable in the cell membrane but affects human cancer cells exclusively. This molecule causes an anomaly during the duplication of human cancer cells, provoking their rapid cell death. Thus, cell multiplication itself resulted in cell death in the treated cancer cells.” A month after being injected with PJ34 daily for 14 days, the pancreatic cancer cells in the tumors of the treated mice experienced a relative drop of 90%. In one mouse, the tumor completely disappeared. “It is important to note that no adverse effects were observed, and there were no changes in the weight gain of the mice, nor in their behavior,” says Prof. Cohen-Armon. This mechanism acts efficiently in other types of cancer resistant to current therapies. The molecule PJ34 is being tested in pre-clinical trials according to FDA regulations before clinical trials begin.  

New Pulsed Electric Field Technology Could Allow for Less Invasive Tumor Molecular Profiling

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Electroporation bears less of the negative consequences of biopsies, say TAU, IDC, Technion researcher Current cancer treatment courses often begin with tissue biopsies. Biopsies, however, which involve the physical resection of a small tissue sample, can lead to localized tissue injury, bleeding, inflammation, and stress, as well as increased risk of metastasis. New technology developed by a team of researchers from Tel Aviv University (TAU), Herzliya Interdisciplinary (IDC), and Technion–Israel Institute of Technology may soon offer an alternative means of profiling tissues. The research finds that electroporation — the application of high voltage pulsed electric fields to tissues — enables minimally invasive extraction of RNA and proteins that reveal tissue-specific differential expression critical to molecular profiling. “Our new method can enhance the information surgeons obtain from biopsy, for example,” explains Prof. Alexander Golberg of TAU’s Porter School of Environment and Earth Sciences, a lead author of the study. “By harvesting molecules from suspicious areas, this method enables improved diagnostics of the site and produces information pertinent to treatment decisions, including molecular biomarkers.” Research for the study was conducted by TAU graduate student Julia Sheviryov, Dr. Oz Solomon of IDC, Leon Anavy of the Technion, and Prof Zohar Yakhini from IDC and the Technion. The research was published in Scientific Reports on October 31. By extracting tissue-specific molecules using a combination of high-voltage and short pulses applied to specific sites, the technology enables profiling RNA, proteins, or metabolites in tissue and tissue environments. This can improve the accuracy of tumor diagnostics, including the potential response to different therapies. For the research, the scientists used electroporation to extract proteins and RNA from several normal human tissues, including liver tissues, and from a liver cancer model in mice. They then used advanced bioinformatics tools to demonstrate that tissue types can be distinguished by identifying specific molecules in the extracted samples. “Further in vivo development of extraction methods based on electroporation can drive novel approaches to the molecular profiling of tumors and tumor environments, and thereby to related diagnosis practices,” Prof. Golberg concludes. “Now we have a new method with which to sample tissue in vivo. We can sample molecules without extracting cells and without the risky excision of tissue parts.” The researchers now plan to develop a device for local extraction, thus enabling tumor heterogeneity mapping and the in vivo probing of tumor environment molecular composition.

TAU researchers develop new treatment for rare genetic disorder

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Adolescents and young adults with familial adenomatous polyposis bear a high risk of developing cancer

Researchers from Tel Aviv University and Tel Aviv Sourasky Medical Center (Ichilov Hospital) have developed an innovative drug treatment for familial adenomatous polyposis (FAP), a rare, inherited condition that affects adolescents and young adults and often leads to colorectal cancer. The novel drug, based on antibiotics, inhibits the development of intestinal polyps that, left untreated, become cancerous. In a preliminary clinical trial, the condition of seven out of eight patients who completed the full treatment improved dramatically. The research was jointly led by Prof. Rina Rosin-Arbesfeld of the Department of Microbiology and Clinical Immunology at TAU’s Sackler School of Medicine and Prof. Revital Kariv of the Sackler School and the Department of Gastroenterology at Tel Aviv Sourasky Medical Center. FAP, which is characterized by multiple polyps along the gastrointestinal tract, especially in the large bowel, is caused by a mutation in the adenomatous polyposis coli (APC) gene. These mutations are also crucial for colorectal cancer development.

Why does FAP lead to colon cancer?

“To prevent the development of colorectal cancer, FAP patients are closely monitored via frequent colonoscopies to locate and remove their polyps,” Prof. Rosin-Arbesfeld says. “However, some patients must have their colons removed at a very young age, which dramatically affects their quality of life.” In its normal state, APC promotes the production of a protein that inhibits cancer development. But mutations to the APC gene produce an inactive protein that is unable to prevent the development of the polyps. In some FAP patients, the mutations in the APC gene are what are called “nonsense mutations.” “Each sequence of three nucleotides in the DNA is a code that tells the cell to produce a certain amino acid, which are the building blocks of the proteins produced in the body’s cells,” Prof. Rosin-Arbesfeld explains. “At the end of the protein coding sequence, there is usually a ‘stop codon’ to stop the protein production. But in FAP patients with a nonsense mutation, the APC’s stop codon appears prematurely, so the protein production stops prematurely, creating an inactive protein.”

Preventing surgical intervention

Previous experiments on cell cultures and mouse models in Prof. Rosin-Arbesfeld’s laboratory revealed that certain types of antibiotics caused cells to “ignore” the mutation stop codon and a normal protein resulted. These trials yielded promising results that led to the clinical trial at Tel Aviv Sourasky Medical Center. “Since the relevant antibiotics were already approved for human use, we decided to move directly from the laboratory to the clinic and to examine the treatment of FAP patients,” says Prof. Rosin-Arbesfeld. In the clinical study carried out by Prof. Kariv and Dr. Shlomi Cohen, director of the Pediatric Gastroenterology Unit at Dana-Dwek Children’s Hospital, 10 FAP patients received the novel antibiotic therapy. Eight of them completed the treatment, which lasted four months. Colonoscopies performed during and after the treatment showed that in seven patients the polyps significantly decreased in number. Moreover, the positive effects of the treatment were evident a year after it began. “Our goal as therapists, in addition to preventing cancer, is to improve the quality of life of our patients and their families and to enable them to live as full and normal lives as possible,” Prof. Kariv concludes. “The new therapeutic approach we are developing may allow patients to delay surgical intervention or even prevent it entirely.” The researchers recently won Tel Aviv University’s SPARK grant, which supports the development of applied research.

A better way to kill tumor cells

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Engineered cells may be harnessed in new immunotherapy for cancer patients, Tel Aviv University researchers say

There is now a multitude of therapies to treat cancer, from chemotherapy and radiation to immunotherapy and small molecule inhibitors. Chemotherapy is still the most widely used cancer treatment, but chemotherapy attacks all the rapidly dividing cells that it locates within the body, whether they’re ultimately harmful or beneficial. A new Tel Aviv University study led by Dr. Yaron Carmi of TAU’s Sackler Faculty of Medicine finds that a form of immunotherapy used to treat the blood cancer leukemia may be effective in treating other kinds of cancer as well. A form of leukemic immunotherapy known as chimeric antigen receptors (CAR) T-cell therapy may also be effective in killing solid tumor cells coated in specific antibodies, the researchers say. The study was published in the Journal of Clinical Investigation on August 26.

Using the body’s own immune system

“Chemotherapy damages all fast-growing cells, including hair follicles and cells that line the gastrointestinal tract, and this attack on healthy cells causes serious side effects, which include hair loss, nausea, mood changes, pain, anaemia, nerve and muscle problems, and kidney issues,” explains Dr. Carmi. “Immunotherapy, on the other hand, is a type of biological therapy that uses the body’s own immune system to seek out and destroy cancer cells. Engineered T cells have been proven very successful in treating blood cancer but attempts to use them to fight solid cancers have been disappointing. “Our engineered cells have now shown efficacy in attacking solid tumors as well,” Dr. Carmi says. CAR T-cell therapy is a form of immunotherapy that uses altered T cells to fight cancer. T cells are a type of lymphocyte, or white blood cell, that plays a central role in the immune response. T cells are collected from the patient and modified in the lab to produce structures called CARs on their surface. These receptors allow the T cells to attach to a specific antigen on the tumor cells and kill them.

Fewer side effects, more precision

Side effects from immunotherapy may include severe inflammation, caused by an overactive immune system working to fight tumor cells. “Patients who utilize CAR T-cell therapy experience significantly fewer side effects than with chemotherapy,” adds Dr. Carmi. “And while chemotherapy is only effective while the drug is in the body, immunotherapy provides long-lasting protection against cancer. “Our lab discovered a distinct subset of helper T cells, also known as CD4+ T cells, that express the high-affinity receptor for IgG – an antibody – and efficiently kill tumor cells coated with these antibodies,” explains Dr. Carmi. “This method uses CAR T-cell therapy and combines it with antibody specificity. Based on this discovery we were able to engineer novel T cells with enhanced tumor-killing activity and higher specificity, compared with other T cell-based therapies for cancer. “Our engineered cells have the potential to overcome barriers usually faced by CAR T-cell therapy and have shown efficacy in solid tumors. This finding has the capability to change the way cancer is treated, demonstrating that the immune system can be utilized to identify and fight all types of cancer.”

Protein Mapping Pinpoints Why Most Metastatic Melanoma Patients Do Not Respond to Immunotherapy

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Lipid metabolism found to affect cancer cells’ visibility to the immune system, say TAU, Sheba Medical Center researchers

Tel Aviv University and Sheba Medical Center researchers say they have discovered why more than half of patients with metastatic melanoma do not respond to immunotherapy cancer treatments.

Wielding proteomics, an innovative “protein mapping” approach, a team of researchers led by Prof. Tami Geiger, Prof. Gal Markel, and Dr. Michal Harel of TAU’s Sackler School of Medicine and Sheba’s Ella Lemelbaum Institute for Immuno-Oncology have answered the burning question: Why do immunotherapy treatments greatly help some patients with melanoma but not affect 60 percent of metastatic melanoma patients?

The researchers, whose findings were published on September 5 in Cell, compared the responses of 116 melanoma patients to immunotherapy — one group in which immunotherapy was successful and a second in which immunotherapy was not successful. Harnessing proteomics, a powerful protein mapping technology, they discovered differences in the metabolism, or energy production process, of the cancer cells of the two groups.

“In recent years, a variety of cancer immunotherapy therapies have been used, therapies that strengthen the anti-cancer activity of the immune system,” explains Prof. Markel, a senior oncologist and scientific director of the Ella Lemelbaum Institute. “These treatments have been shown to be highly effective for some patients and have revolutionized oncology. However, many patients do not respond to immunotherapy, and it is critical to understand why.

“Can we predict who will respond? Can we alter treatment in order to increase responses? In our research, we focused on metastatic melanoma, a devastating disease that until recently had no efficient treatments. It was clear to us that pre-treatment samples from responders and non-responders would be key.”

To better understand treatment resistance mechanisms, the scientists examined tumors taken from 116 patients using proteomics.

“In the proteomic lab, we use an instrument called a mass-spectrometer, which enables global mapping of thousands of proteins,” explains Prof. Geiger, head of TAU’s Proteomics Lab. “We then followed up with extensive computational analysis to identify the proteins that differentiated between the response groups.”

The proteomic comparison identified major differences between responders and non-responders to immunotherapy. “In the responders, we found higher levels of proteins associated with lipid metabolism, which led to better recognition by the immune system,” says Prof. Geiger.

In collaboration with the Salk Institute in San Diego and Yale School of Medicine, researchers then examined their findings in melanoma tissue cultures and a mouse model of metastatic melanoma.

Using genetic engineering, they were able to silence the mechanism responsible for fatty acid metabolism.

“We found that upon silencing this metabolic pathway, the cancer cells manage to ‘hide’ from T-cells that are supposed to detect and destroy them,” says Prof. Geiger. “As a result, cancer in these mice developed at a faster rate compared to the control group.

“In our study, we identified a significant difference between melanoma patients who live for years thanks to immunotherapy, and patients who are not at all affected by the treatment.”

“These findings can also be relevant to many other malignancies,” adds Prof. Markel. “Now, in subsequent studies, we are looking for ways to improve the response to immunotherapy and expand the circle of patients who benefit from it. In addition, we are looking for a method that will allow clinicians to anticipate which patients will respond to treatments.”

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