BRAF Archives - Sanford Burnham Prebys

Tag: BRAF

Institute News

Solar power gone awry

AuthorZe’ev Ronai, PhD
Date

July 29, 2019

towel on beach - sun exposure - melenoma

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Are you enjoying the summer? Out grilling, swimming and hiking? Beware: those sunny days may come with a cost. 

When the sun’s rays touch your skin, they don’t stop there. Ultraviolet (UV) light enters your cells, and photons—tiny particles of light—landing on the proteins and DNA in your cells. With just the right amount of activation energy, proteins change their shape and function, and your DNA becomes damaged, or as we say—mutated. Under normal circumstances, cells use special proteins to repair mutated DNA, but when the repair proteins are damaged, DNA mutations become permanent.

Certain DNA segments called genes are more vulnerable to mutations than others. The BRAF gene, which normally makes a protein that controls cell growth, is mutated in more than 50% of melanomas—the most dangerous type of skin cancer. Melanoma appears when BRAF mutations crop up with other mutations in the same skin cell. For patients with these tumors, drugs that target BRAF and related proteins are often successful at slowing or stopping melanoma growth—but only for a while.

Unfortunately, patients who initially respond to such targeted therapy often relapse. Some patients relapse because their tumors generate a new mutation, making it resistant to the drug.  Overall, it may be only a small fraction of cells within the original tumor that develop resistance. So although 99.5% of the cancer cells in a tumor may have a mutated BRAF gene, the other 0.5% can harbor different mutations that either evolved during therapy or were present in the first place, but didn’t drive the initial tumor. For these patients, the bulk of BRAF mutant cancer cells are killed with targeted therapy, but another melanoma can evolve from the remaining 0.5%. This is why combination therapy, where drugs aim for multiple targets, are important.

But targeting every single mutation in a tumor may not be feasible. There will always be a fraction of cells with a different mutation that evolves, making patients vulnerable to a relapse. This is where attacking the tumor from another angle comes into play.  

Checkpoint immunotherapies—which have revolutionized the treatment of melanoma—attack tumors independent of their mutational makeup. They work by loosening the brakes of the immune system—brakes that normally prevent immune cells from attacking our own self. Tumors are very good at hiding from the immune system, but with the brakes released, tumors become exposed and are successfully attacked by the immune system, irrespective of their mutational makeup. 

But not everyone responds to immunotherapy—and we don’t yet know why. Is it the tumor? Is it the patient’s immune system? There is even evidence that the gut microbiome plays a role. Once we understand why some patients respond and or stop responding to immunotherapy, we can improve selection of patients for therapy, the effectiveness of these treatments and the possible combinations that work best. 

So where is skin cancer therapy headed? A combination of checkpoint immunotherapy with targeted therapies, as well as some new tricks we are learning, such as coaching tumor cells to be better recognized by the immune system, are moving the needle.

In my lab at Sanford Burnham Prebys we are dissecting the cell signals that drive cancer. Our studies are guided by data derived from patients’ tumors, coupled with advanced bioinformatics. We seek to understand how physiological processes are modified as cancer develops and how they can be exploited for cancer therapy. For example, we recently demonstrated a connection between the composition of the gut microbiome and the response to immunotherapy, establishing new paradigms, but raising important new questions. Can we better predict who will respond to immunotherapy? Can we enhance the response to immunotherapy by manipulating the gut microbiome? Can we make tumors that don’t initially respond start responding to immunotherapy? The bar is always raised, as one discovery opens so many new avenues to explore and advance our understanding, aspects that members of my lab are working hard on to answer.  

Yes—we are making progress. But preventing the initial sun exposure by using protective gear and sunscreens is needed now as much as ever.

Ze’ev Ronai, PhD, professor in Sanford Burnham Prebys’ Tumor Initiation and Maintenance Program, is a world-renowned cancer research expert and recipient of the Lifetime Achievement Award from the Society of Melanoma Research. The award recognizes his major and impactful contributions to melanoma research over the course of his career.

Institute News

Scientists identify promising new melanoma drug

Authorsgammon
Date

November 25, 2015

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A new drug discovered by scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) may show promise for treating skin cancers that are resistant or unresponsive to today’s leading therapies.

In the United States, 5 million people are treated annually for skin cancer, and 9,000 people die from the deadliest form—melanoma—according to the US Department of Health and Human Services.

The new compound, named SBI-756, targets a specific molecular machine known as the translation initiation complex. These structures are in every cell and play the critical role of translating mRNA into proteins. In cancer cells the complex is impaired, producing extra protein and providing a growth advantage to tumors. SBI-756 causes the translation complex to dissociate, and was shown to inhibit melanoma cell growth in the study, published today in Cancer Research.

“The unique target of SBI-756 makes it especially promising for use in combination therapy,” said Ze’ev Ronai, senior author and scientific director of SBP’s La Jolla campus. “A major issue limiting the effectiveness of current melanoma therapies is that tumors become resistant to treatment. Combining drugs that come at a melanoma from different angles may help overcome the problem of drug resistance.”

About 50% of melanomas are caused by mutations in a specific gene called BRAF. Patients with these tumors are commonly prescribed vemurafenib, a BRAF inhibitor that shrinks tumors. However, many patients experience a relapse within weeks, months, or even years because tumors evolve and become resistant to the drug. A similar phenomenon is seen in mice, where treatment of BRAF melanomas results in an initial response, but 3-4 weeks later the tumors return.

The team found that if SBI-756 is co-administered with vemurafenib, the tumors disappeared and most importantly, they did not reoccur. Even in mice with advanced/late stage BRAF driven cancer, the reappearance of . These data suggests that SBI-756 provides a significant advantage in overcoming tumor resistance.

“The ability of this compound to delay or eliminate the formation of resistant melanomas is very exciting,” said Ronai.

In other forms of melanoma, caused by mutations in the genes NRAS and NF1—which are known as unresponsive to BRAF drugs—administering SBI-756 alone significantly the scientists found. The team is now testing whether combining SBI-756 with existing drugs used for treating these types of melanomas can make the tumors disappear.

Drugs that target the translation initiation complex have been intensely pursued in the past few years, not just for melanoma, but for a wide array of cancers. SBI-756 is considered a first-in-class drug because it is the first successful attempt to target a specific part of the complex called eIF4G1.

In fact, SBI-756 is the culmination of seven years of work in Ronai’s group—testing and tweaking the drug’s features to help it bind to the target more readily and to make it easier to formulate. The resulting compound is a significant improvement over the initial version.

“It appears that the dose we need to administer is very low. Even in the experiments where the drug was administered to mice with tumors over a significant period of time, we have not found any toxicity,” Ronai said.

“The finding of SBI-756 is also exciting for the possible treatment of diseases other than cancer, such as neurodegenerative diseases, where the activity of the translation initiation complex is reported to be higher,” said professor Nahum Sonenberg of McGill University, a world renowned leader in the field of protein translation.

“We hope that we’re going to come up with the next generation of the compound that can go into clinical trials—first in melanoma but likely in other tumors,” Ronai said.

The study was performed in collaboration with the Conrad Prebys Center for Chemical Genomics at SBP, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University (Canada), the National Cancer Institute, MD Anderson Cancer Center, and Yale University.

Institute News

Melanoma’s addiction to glutamine is the basis for cancer growth

Authorsgammon
Date

February 17, 2015

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Researchers at Sanford-Burnham have discovered that without a source of glutamine—one of the 20 amino acids used to build proteins—melanoma cells will stop proliferating and die. Their craving for glutamine stems from their ability to “abuse” this essential nutrient by using it as an additional source of carbon and energy. The findings present a rational basis for a treatment strategy that limits the supply of glutamine to tumors, potentially through nutritional interventions or inhibitors of glutamine uptake. The results of the study appear online in Oncotarget today. Continue reading “Melanoma’s addiction to glutamine is the basis for cancer growth”