TAG: "Drugs"

New combination drug controls tumor growth, metastasis in mice


Combination shows greater potency against several diseases.

Bruce Hammond, UC Davis

Researchers at UC Davis, University of Massachusetts and Harvard Medical School have created a combination drug that controls both tumor growth and metastasis. By combining a COX-2 inhibitor, similar to Celebrex, and an epoxide hydrolase (sEH) inhibitor, the drug controls angiogenesis (blood vessel formation), limiting a tumor’s ability to grow and spread. The study appears today (July 14) in the journal Proceedings of the National Academy of Sciences.

“We’ve been studying the effects of COX and sEH inhibitors, both by themselves and in combination, for several years,” said senior author and UC Davis Distinguished Professor Bruce Hammock. “We were surprised to find that the dual inhibitor was more active than higher doses of each compound, either individually or together. By combining the two molecules into one we got much greater potency against several diseases and completely unique effects in terms of blocking tumor growth and metastasis.”

Both COX and sEH enzymes control lipid signaling, which has long been associated with inflammation, cell migration, proliferation, hypertension and other processes. COX inhibitors block production of inflammatory and pain-inducing lipids, while sEH inhibitors preserve anti-hypertensive, anti-inflammatory and analgesic compounds. Separate COX and sEH inhibitors were previously found to work together in reducing inflammation and neuropathic pain.

After testing individual COX-2 and sEH inhibitors, the team synthesized the drug (PTUTB), the first combined COX-2/sEH inhibitor. They then tested the dual inhibitor against human lung and breast tumors, both in vitro and in mice. They found that PTUTB blocked angiogenesis, inhibiting the proliferation of endothelial cells, which are critical to blood vessel formation. This in turn limited tumor growth and metastasis, reducing lung and breast tumor growth by 70 to 83 percent.

In breast and lung cancers, the dual inhibitor blocked angiogenesis, which blocked the growth of solid tumors,” said Hammock. “This represents a new mechanism to control blood vessel and tumor growth.”

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New compound treats both blindness and diabetes in animal studies


UCSF-led study offers fresh insights into role of cellular stress in degenerative illnesses.

In a new study led by UC San Francisco scientists, a chemical compound designed to precisely target part of a crucial cellular quality-control network provided significant protection, in rats and mice, against degenerative forms of blindness and diabetes.

In addition to opening a promising drug-development path for the wide range of diseases caused by cell loss, the new research offers a new view of the workings of the unfolded protein response (UPR), a cellular “life-or-death” signaling network: When cells are under stress, the UPR works to ensure that they produce properly configured proteins, but those cells not up to this task are quickly prompted by the UPR to self-destruct.

A component of the UPR known as the IRE1 pathway has generally been thought to handle the protective aspects of this response, promoting cell survival by providing cells with the biological resources they need to cope with stress, while a complementary pathway, called PERK, has been associated with cell death.

But in the new research, published in today’s (July 10) edition of Cell, when researchers used KIRA6, a small-molecule kinase inhibitor they designed to inhibit the actions of IRE1α — the molecular sensor that triggers the IRE1 pathway — they blocked cell death and preserved function in experimental models of two human diseases.

In two rat models of retinitis pigmentosa, a disease in which light-sensing cells in the eye progressively die off, causing blindness, KIRA6 preserved both the number of these cells and visual function. And in mice from a strain known as Akita, which carry a genetic mutation that causes diabetes in early life as stressed insulin-producing beta cells of the pancreas degenerate, KIRA6 protected beta cells from cell death, leading to a twofold increase in insulin production and improving blood glucose control.

“This is a huge advance in our field,” said co-senior author Scott A. Oakes, M.D., associate professor of pathology at UCSF. “On the surface these would seem to be two very different diseases, but IRE1-induced cell death is at the root of both of them.”

The results are the culmination of “a gigantic project,” first to establish that the IRE1 pathway could drive degenerative disease, and then to design and test compounds to head off the damage, said UCSF’s Feroz Papa, M.D., Ph.D., associate professor of medicine and co-senior author, and a member of the California Institute for Quantitative Biosciences. “It took four years, over a hundred separate experiments in various contexts — not counting replications — and involved 24 researchers working in seven labs across four cities.”

KIRA6 is the latest in a series of compounds (the acronym stands for “Kinase-Inhibiting RNase Attenuators”) that were originally designed and synthesized in the labs of study co-authors Dustin J. Maly, Ph.D., associate professor of chemistry at The University of Washington, Seattle, and Bradley J. Backes, Ph.D., associate professor of medicine at UCSF.

“While KIRA6 showed efficacy in animals,” said Papa, “it is important to stress that more optimization through medicinal chemistry efforts is needed to develop this class of compounds to the stage where they could be tested for efficacy in humans through clinical trials.”

Oakes and Papa said that support from the Cleveland, Ohio-based Harrington Discovery Institute was crucial to sustaining this complex collaboration. Both scientists were 2013 winners of Scholar-Innovator Awards from the institute, which is part of The Harrington Project for Development and Discovery a $250 million national model to accelerate the development of medical breakthroughs by physician-scientists into medicines that benefit patients. Other critical support for the work came from the National Institutes of Health, the Juvenile Diabetes Research Foundation, the Burroughs Wellcome Fund, the American Cancer Society and the Howard Hughes Medical Institute.

Other UCSF researchers on the project included Douglas B. Gould, Ph.D., associate professor of ophthalmology; Michael German, M.D., professor of medicine; postdoctoral fellows Rajarshi Ghosh, Ph.D., and Likun Wang, Ph.D., and graduate student Eric S. Wang, all co-first authors; postdoctoral fellows Aeid Igbaria, Ph.D., Shuhei Morita, M.D., Ph.D., Kris Prado, M.D., Maike Thamsen, Ph.D., Hector Macias, Ph.D., and Marcel V. Alavi, Ph.D.; former research associate Deborah Caswell; graduate student Kurt F. Weiberth; and research associate Micah J. Gliedt. The team was also joined by other colleagues from The University of Washington, Seattle; The Miller School of Medicine at The University of Miami, Florida; and the Albert Einstein College of Medicine, in Bronx, New York.

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Innovative research tool pinpoints potential MS therapies


Study sifts through 1,000 FDA-approved compounds; one is quickly moved into clinical trial.

Jonah Chan, UC San Francisco

Using a novel screening platform to rapidly evaluate the cellular effects of 1,000 chemical compounds, a team led by UC San Francisco scientists has identified eight drugs that may stimulate nervous system repair in multiple sclerosis (MS).

All eight compounds have previously been approved by the U.S. Food and Drug Administration (FDA) for the treatment of other conditions. One of the most promising agents is an antihistamine, though the scientists caution that MS patients should not use the drug until clinical trials have established whether it can safely and effectively treat MS, and if it does, what the proper dosages and treatment regimens would be. Because of the drug’s emergence as a clear front-runner in the new study, a Phase 2 clinical trial to evaluate its effectiveness in MS is already under way at UCSF.

“A major unmet need in the development of therapeutics for repair in MS has been the ability to screen compounds in a high-throughput manner,” said Jonah Chan, Ph.D., the Debbie and Andy Rachleff Distinguished Professor of Neurology at UCSF and senior author of the new study. “Through a great deal of serendipity, combined with the hard work of outstanding students and colleagues, we have been able to address this need, and I am happy that we are already testing one compound in the clinic.”

The new research was published online July 6 in Nature Medicine.

The decision to focus on compounds already approved by the FDA was driven by study co-author Stephen L. Hauser, M.D., the Robert A. Fishman Professor and chair of the Department of Neurology at UCSF. As founder and director of UCSF’s interdisciplinary MS Research Group, Hauser has championed efforts to translate insights from basic neuroscience research into new therapies as quickly as possible. The new study is an exemplar of that strategy: only 14 months have elapsed since the team performed the first drug screen, and the phase two trial is already at its halfway point.

Co-author Ari Green, M.D., Debbie and Andy Rachleff Distinguished Professor of Neurology, is principal investigator on the phase two trial at UCSF, which is known as the ReBUILD trial. According to Green, the trial was expedited by the FDA’s granting of a New Drug Application exemption, which allows clinical researchers to study drugs in conditions for which they were not originally approved. The trial is still enrolling MS patients and is expected to be completed by the end of 2014.

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Key elements discovered for biofilm spreading


UC Merced findings could help in developing treatments for fungal biofilm infections.

Clarissa Nobile, UC Merced

A biology professor at the University of California, Merced, discovered mechanisms that allow a potentially fatal biofilm to spread and resist drugs.

The research was published last month in mBio, an open-access online journal by the American Society for Microbiology.

Professor Clarissa J. Nobile, who studies microbial communities, said the findings could help in developing treatments for fungal biofilm infections, specifically those formed by Candida albicans.

“There are no known biofilm-specific drugs on the market today for any microorganism,” Nobile said. The fungus is naturally found in the human gut and can cause yeast infections and oral thrush. Infections can also be caused by implanted medical devices, which provide surfaces for biofilms to form. The infections can be life-threatening.

Nobile pinpointed four core proteins — all members of a histone deacetylase complex — that control how the biofilm forms, and learned what happens when they’re changed.

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Sickle cell drug passes early phase trial


Clinical trial at UC Davis finds encouraging results.

Ted Wun, UC Davis

A potentially groundbreaking investigational drug designed to treat the painful vaso-occlusive crises that are the hallmark of sickle cell disease has been found to be safe following a clinical trial at UC Davis.

Vaso-occlusive crises, during which red blood cells slump together and impede blood flow, cause agonizing pain for people with sickle cell disease. The phase one clinical trial found the drug, called GMI 1070, safe, maintaining adequate blood concentrations, a key milestone for therapeutic benefit.

Published online today (July 2) in the journal Public Library of Science ONE (PLoS ONE), the study did not focus on the drug’s efficacy. However, there was evidence that it did improve blood flow and reduced the markers of cell activation, said Ted Wun, associate dean for research at the UC Davis School of Medicine.

“These are encouraging results,” said Wun. “Vaso-occlusive crises cause around 70,000-80,000 hospitalizations each year, and there are currently no specific treatments.”

Sickle cell disease is a chronic condition that affects approximately 100,000 people in the United State, mostly African Americans, and many more around the world. The disease can affect any organ, particularly kidneys, lungs and spleen. Patients experience many severe complications, including stroke, infections, pulmonary arterial hypertension and heart failure.

The disease is caused by abnormal hemoglobin, which change the shape of red blood cells into the tell-tale sickle shape. These misshapen red blood cells are both stiffer and stickier. Cell-adhesion proteins called selectins, which normally mediate interactions between cells, contribute to this abnormal stickiness. As a result, cells clump together and reduce blood flow, precipitating a vaso-occlusive crisis. The resultant severe pain is generally centered in the hips, back, and proximal long bones. However, abdominal and chest pain is also common.

“White blood cells bind to inflamed blood vessel walls and sickle red cells stick to white cells, but interestingly the initiating event is the white cells,” said Wun. “If we could interrupt that white cell interaction, we could stop the cycle that leads to vaso-occlusions.”

GMI 1070 is designed to do just that. By mimicking sugars attached to selectin proteins, which mediate the proteins’ stickiness, the drug inhibits three different selectins (L-, E- and P-selectin), increasing blood flow in animal models. However, the first round of human clinical trials was primarily focused on the drug’s safety and pharmacokinetics. In other words, the researchers wanted to know if there were any severe side effects and whether the drug maintained adequate concentrations in the blood.

The trial included 15 sickle cell patients, five of whom were enrolled at UC Davis’s National Institutes of Health-supported Clinical and Translational Science Center. Overall, the drug was well tolerated, with only 16 complications, primarily headaches. With one exception, all complications were grade 1 or 2, the least severe. No participants discontinued the drug.

In the pharmacokinetic tests, patients were given a loading dose followed by smaller maintenance doses, which successfully maintained GMI 1070 blood concentrations.

Though secondary to safety and pharmacokinetics, the trial also showed marked decreases in P- and E-selectins, as well as other markers associated with coagulation and inflammation. The study also found small increases in blood flow.

In addition to these findings, a randomized double-blind phase two trial for GMI 1070 has also been completed. Preliminary results have been positive, and the study has been submitted for publication. A phase three trial currently is being planned.

“Vaso-occlusive crises generate intense pain and suffering,” said Wun. “If the phase three study confirms that GMI 1070 is effective, it would be a huge advance for the sickle cell community.”

GMI 1070 (trade name Rivipansel) is produced by GlycoMimetics Inc., a biotechnology company based in Gaithersburg, Maryland.The company sponsored the trial.

Other investigators included Anthony Cheung at UC Davis, Lori Styles and Frans Kuypers at Children’s Hospital and Research Institute Oakland, Laura DeCastro, Marilyn J. Telen at Duke University, William Kramer at, Kramer Consulting LLC, Seungshin Rhee at Rho Inc., and Henry Flanner, John L. Magnani and Helen Thackray at GlycoMimetics Inc.

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Specialty pharmacy program helps patients adhere to oral chemotherapy


UC Davis cancer center plans to expand the program this fall.

Patients enrolled in the program can make an appointment with a pharmacist or a nurse practitioner any time they have a question about their drug regimen.

A UC Davis program designed to better manage cancer patients taking oral chemotherapy drugs has demonstrated that one-on-one counseling, education and monitoring can improve adherence to potentially life-saving cancer treatments.

The rise in oral chemotherapy development and use has heightened the need for coordinated cancer care. Oncology pharmacists and physicians worked together at UC Davis Comprehensive Cancer Center to create the Medication Adherence Pilot Program to ensure that patients stick to their regimens to safely maximize the drugs’ effectiveness and minimize or manage side effects.

Oral chemotherapy prescriptions are on the rise because many newer drugs, which target individual genes involved in tumor growth, are being developed in oral formulations, said Ted Wun, a medical oncologist and chief of the Division of Hematology and Oncology.

In addition, oral chemotherapy agents are created to allow for more continuous exposure of the drug in the patient over time, which can be more effective and may be less toxic. When oral treatment is prescribed exclusively, patients require fewer office visits and may get a greater sense of control over their treatment, Wun said.

Unlike traditional chemotherapy, which takes place in special infusion centers with nursing care, patients taking oral chemotherapy drugs may experience potentially life-threatening side effects without the information or immediate support they need. Or, patients may stop taking the medication or not follow the directions correctly, which can affect treatment efficacy, produce misleading treatment results and cause higher mortality.

“Patients are monitored when they’re here, but when they go home, it’s harder to monitor,” said Josephine Lai, the cancer center’s pharmacy supervisor, who has been assessing oral chemotherapy adherence rates since 2012. “Unlike other chronic care medications, oral chemo drugs can be more complicated. For example, one agent, Xeloda (capecitabine), is taken every 12 hours within 30 minutes of a meal for two weeks followed by a one-week break, before a new cycle begins. Sometimes we see people who didn’t realize they had a break in between their cycles.”

To improve patient care, Lai and colleagues in the UC Davis Departments of Pharmacy and Internal Medicine, and the Division of Hematology and Oncology launched the Cancer Center Medication Adherence Pilot Program in September 2013.

Patients enrolled in the program can make an appointment with a pharmacist or a nurse practitioner anytime they have a question about their drug regimen. Pharmacists also check in regularly each month to monitor patients’ progress, notify oncologists of any issues and offer practical tips, such as how to maintain a medication calendar or handle a missed dose.

Early indications suggest the program is working. In one assessment of 44 patients enrolled in the pilot program, 92 percent adhered to their drug regimens. Today, 80 patients at UC Davis Comprehensive Cancer Center are enrolled in the program. Beginning this fall, the cancer center will employ a full-time pharmacist dedicated to the program, offering the services to all UC Davis cancer patients.

“This is a great example of interdisciplinary collaboration among pharmacists, physicians, nurse practitioners and nurses,” said Lai. “And for our patients, who already face enough challenges, we hope it makes their cancer care a little easier.”

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Autism-like symptoms reversed in mice


Old drug used for sleeping sickness may point to new treatment in humans.

Transmission electron micrograph of cell mitochondrion. (Image by Thomas Deerinck, UC San Diego)

In a further test of a novel theory that suggests autism is the consequence of abnormal cell communication, researchers at the UC San Diego School of Medicine report that an almost century-old drug approved for treating sleeping sickness also restores normal cellular signaling in a mouse model of autism, reversing symptoms of the neurological disorder in animals that were the human biological age equivalent of 30 years old.

The findings, published in today’s (June 17) online issue of Translational Psychiatry, follow up on similar research published last year by senior author Robert K. Naviaux, M.D., Ph.D., professor of medicine, pediatrics and pathology, and colleagues.

Naviaux said the findings fit neatly with the idea that autism is caused by a multitude of interconnected factors: “Twenty percent of the known factors associated with autism are genetic, but most are not. It’s wrong to think of genes and the environment as separate and independent factors. Genes and environmental factors interact.  The net result of this interaction is metabolism.”

Naviaux, who is co-director of the Mitochondrial and Metabolic Disease Center at UC San Diego, said one of the universal symptoms of autism is metabolic disturbances. “Cells have a halo of metabolites (small molecules involved in metabolism, the set of chemical processes that maintain life) and nucleotides surrounding them. These create a sort of chemical glow that broadcasts the state of health of the cell.”

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Groundbreaking lung cancer trial launched


UC Davis expert David Gandara a key architect of national effort.

David Gandara, UC Davis

UC Davis Comprehensive Cancer Center patients will soon be part of an unprecedented clinical trial designed to improve access to promising therapies and speed development of effective treatments for an advanced form of lung cancer, the leading cancer killer of both men and women.

The approach, known as Lung-MAP (Lung Cancer Master Protocol), or S1400, is the product a unique public-private collaboration among the National Cancer Institute (NCI), SWOG Cancer Research, Friends of Cancer Research, the Foundation for the National Institutes of Health (FNIH) and five pharmaceutical companies. It is the first of several planned large, genomically driven trials that will be conducted by the NCI’s newly formed National Clinical Trials Network.

Lung-MAP’s strategy uses cutting-edge genomic profiling to match patients with late-stage squamous cell carcinoma to investigational treatments that target the molecular drivers of their individual tumors.

David Gandara, an internationally renowned oncologist and lung cancer expert and director of the UC Davis Thoracic Oncology Program, is a lead architect of the effort and serves as one of three leaders of the national trial.

“This is an entirely new way of looking at the development of cancer drugs,” said Gandara. “This is no longer business as usual. This approach changes the paradigm.”

Frustrated with the slow pace of lung cancer clinical trials of experimental therapies and their high failure rate, he talked to NCI officials more than 10 years ago about a more innovative approach.

“If you think about both the monetary investment and also the patient resources, hundreds of millions of dollars and clinical trials enrolling many tens of thousands of patients are wasted because we have an ineffective way of developing new anti-cancer drugs,” he said.

Lung-MAP aims to establish a model of clinical testing that more efficiently meets the needs of patients, clinical investigators and drug developers. Instead of having to undergo multiple diagnostic tests to determine eligibility for many different studies, enrollees are tested just once according to a “master protocol” and assigned to one of five different trial arms, each testing a different drug from a different developer. The approach is cost-effective for researchers because it gives them easier access to relevant enrollees based on their genomic profiles, and ensures patients better access to promising drugs.

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Researchers report double dose of promising lung cancer findings


New drugs shown to increase survival time, fewer toxic side effects than standard treatments.

Researchers with UCLA’s Jonsson Comprehensive Cancer Center report that two new experimental drugs have shown great promise in the treatment of patients with non–small-cell lung cancer, which accounts for about 85 percent of all lung cancers. Lung cancer is the leading cause of cancer death in the United States.

The drugs — ramucirumab and CO-1868 — were shown in separate clinical trials to increase survival times with fewer toxic side effects than standard treatments. The findings were presented this week at the American Society of Clinical Oncology annual meeting in Chicago.

Ramucirumab: A new second-line defense

The standard therapy for patients with non–small-cell lung cancer after initial therapy, or when their disease worsens, is chemotherapy with a single drug. Overall, survival time among these patients is generally about 6 to 9 months. Less than 10 percent of patients respond to therapy, and even then, responses are usually of short duration.

Dr. Edward Garon, an assistant professor of hematology–oncology and member of the Jonsson Cancer Center, conducted an extensive multiyear Phase 3 clinical trial testing the investigational drug ramucirumab in a population of 1,253 patients with non–small-cell lung cancer whose cancer had progressed during or after first-line chemotherapy treatment.

Ramucirumab, which is being developed by Eli Lilly and Co., is an antibody that targets VEGFR-2, an extracellular protein that is important in the formation of the blood vessels that support cancer cells. Patients were given ramucirumab in combination with docetexal, a clinically approved chemotherapy drug considered the cornerstone of second-line treatment in advanced non–small-cell lung cancer.

Response to ramucirumab — that is, individuals whose tumors shrank — was 23 percent at the time the study was analyzed. The drug is the first new therapy for previously treated non–small-cell lung cancer pateints to improve overall survival, with findings showing a progression-free survival rate of 4.5 months and median overall survival of 10.5 months.

“We are excited to have a drug that lengthens survival time in lung cancer patients, who often have few options,” Garon said. “Although adverse effects were experienced by patients, most commonly neutropenia, fatigue and hypertension, toxicities were largely manageable with appropriate dose reductions and supportive care, and without substantial reduction in planned dose intensity.”

The research appears in the June edition of The Lancet.

Combating the T790M mutation with CO-1686

A major advance in understanding lung cancer has been the identification of specific mutations that drive the disease and which are presumed to be the initial genetic event that triggers cells to become cancerous. The Jonsson Cancer Center was one of a group of leading institutions that participated in the Lung Cancer Mutation Consortium, showed that personalized therapies could be directed at a large percentage of non–small-cell lung patients. (The cosortium’s findings were published last month in the Journal of the American Medical Association.)

One example of targetable mutations in lung cancer involved the identification of the EGFR (epidermal growth factor recepator) mutation. The discovery has resulted in a new class of targeted therapeutic agents called EGFR tyrosine kinase inhibitors. And while these inhibitors have delivered promising results, the duration of benefit to patients still remains relatively short, with progressive disease generally occurring about a year after the beginning of treatment. Tyrosine kinase inhibitor treatment is also complicated by side effects such as diarrhea and skin rash.

Recent studies have shown that when a patient develops resistance to EGFR inhibitors, more than half the time it is due to the emergence of a new “gatekeeper” mutation, called T790M. Currently, there are no targeted therapies approved for the treatment of this mutation.

CO-1686 is an oral investigational drug discovered being developed by Clovis Oncology to selectively target both the initial EGFR mutations and the T790M resistance mutation.

Dr. Jonathan Goldman, an assistant professor of hematology–oncology and member of the Jonsson Cancer Center, was one of the leaders of a study of 88 patients with advanced non–small-cell lung cancer who had previously been treated with an EGFR inhibitor and had developed resistantance. In a Phase 1 trial, CO-1686 was administered continuously to the patients in 21-day cycles.

Response to the drug was seen in 58 percent of the patients. The benefit has been durable, with more than 75 percent of patients still on the drug at the time the study was analyzed. Treatment-related side effects, including elevated blood sugar levels, were for the most part mild and manageable.

“The results we’ve seen with CO-1686 are very promising,” Goldman said. “Many of these responses are very dramatic, and the result is that patients can feel better and live longer, often with fewer side effects than chemotherapy.”

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UCLA scientists take brakes off immune system to fight deadly cancers


Experimental drug shows promising results in patients with skin and lung cancers.

Antoni Ribas, UCLA

Researchers at UCLA’s Jonsson Comprehensive Cancer Center are reporting promising treatment milestones for patients with deadly skin and lung cancers who are being treated with an experimental drug called MK-3475.

The drug is an antibody that targets a protein known as PD-1, which is expressed by immune cells. In the body, PD-1 acts as an immune checkpoint, tamping down the activity of T cells, which would otherwise attack cancer cells. MK-3475 takes the brakes off, allowing T cells to identify and attack cancer cells.

In May 2013, MK-3475 received a “breakthrough therapy” designation under the U.S. Food and Drug Administration’s accelerated approval program for the treatment of melanoma that has metastasized or is not removable through surgery.

In clinical trials at UCLA, doctors are seeing major treatment successes with MK-3475 in two types of cancer with historically low survival rates: metastatic melanoma, a malignant skin cancer that spreads aggressively to vital organs such as the brain, lungs and liver, and lung cancer, which causes the highest number of cancer deaths in the U.S. annually.

The findings were presented this week at the American Society of Clinical Oncology conference in Chicago.

Metastatic melanoma

Dr. Antoni Ribas, a professor of hematology–oncology and member of the Jonsson Cancer Center, led one of the largest Phase 1 studies in cancer, with 411 patients who had metastatic melanoma, which has an average five-year survival rate of less than 5 percent. The one-year overall survival rate was 69 percent for all patient subgroups.

Response to MK-3475 — that is, individuals whose tumors shrank — was continuing in 88 percent of patients at the time the study was analyzed, generally at 12-month follow-up. Tumors responded in patients on various dose regimens and in various subgroups, including those whose cancers had worsened on the drug ipilimumab; there are currently no treatment options with proven activity for these patients.

“We are seeing unprecedented durable responses with this drug,” Ribas said. “MK-3475 is working in patients who had not been treated, as well as those who had been given ipilimumab and other therapies. These are early data, but response rates of this magnitude in such a large sample, with only 4 percent of patients discontinuing because of drug-related side effects, indicate the importance of moving forward quickly with this drug.”

Overall, 34 percent of patients had responses to MK-3475, including 40 percent who had not been treated with ipilimumab and 28 percent whose cancer worsened despite ipilimumab treatment. Treatment-related side effects were generally mild and reversible; 8 percent of patients had serious side effects.

Non–small-sell lung cancer

Dr. Edward Garon, an assistant professor of hematology–oncology and member of the Jonsson Cancer Center, led a cohort of 217 patients with metastatic non–small-cell lung cancer whose disease worsened during or after at least one prior therapy. This MK-3475 research was the largest report of lung cancer patients being treated with this approach of inhibiting PD-1.

The standard therapy for patients in this situation is chemotherapy with a single drug. After one prior therapy, overall survival is generally about six to nine months. Less than 10 percent of patients respond to therapy, and even then, the responses are usually of short duration. Outcomes are typically worse in patients who have received two or more therapies, as was often the case in this study.

Among lung cancer patients whose tumors expressed PD-L1, a target of PD-1 — who accounted for a majority of the study participants — 23 percent had a response to the MK-3475 therapy, and the responses were often durable.

“We are very excited about the preliminary results we are seeing with MK-3475 in these advanced lung cancer patients,” Garon said. “It is a very well tolerated drug, so the benefits are enhanced by the fact that it generally has very little negative effect on patient quality of life. We are conducting additional trials with MK-3475, and based on our work, we hope the drug will soon be available to patients throughout the world.”

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Melanoma of the eye caused by two gene mutations


Therapeutic target identified for treatment.

Researchers at the UC San Diego School of Medicine have identified a therapeutic target for treating the most common form of eye cancer in adults. They have also, in experiments with mice, been able to slow eye tumor growth with an existing FDA-approved drug.

The findings are published online in today’s (May 29) issue of the journal Cancer Cell.

“The beauty of our study is its simplicity,” said Kun-Liang Guan, Ph.D., professor of pharmacology at UC San Diego Moores Cancer Center and co-author of the study. “The genetics of this cancer are very simple and our results have clear implications for therapeutic treatments for the disease.”

The researchers looked specifically at uveal melanoma. Uveal collectively refers to parts of the eye, notably the iris, that contain pigment cells. As with melanoma skin cancer, uveal melanoma is a malignancy of these melanin-producing cells.

Approximately 2,000 people in the United States are diagnosed with uveal melanoma each year. If the cancer is restricted to just the eye, the standard treatment is radiation and surgical removal of the eye. But uveal melanoma often spreads to the liver, and determining the metastatic status of the disease can be difficult. In cases of uveal melanoma metastasis, patients typically succumb within two to eight months after diagnosis.

Scientists have long suspected a genetic association with uveal melanoma because one of two gene mutations is present in approximately 70 percent of all tumors. Until this study, however, they had not identified a mechanism that could explain why and how these mutations actually caused tumors.

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Pain killers may improve health of diabetics and the obese


Blocking pain receptor may improve lifespan, metabolic health.

Chili peppers

Blocking a pain receptor in mice not only extends their lifespan, it also gives them a more youthful metabolism, including an improved insulin response that allows them to deal better with high blood sugar.

“We think that blocking this pain receptor and pathway could be very, very useful not only for relieving pain, but for improving lifespan and metabolic health, and in particular for treating diabetes and obesity in humans,” said Andrew Dillin, a professor of molecular and cell biology at the University of California, Berkeley, and senior author of a new paper describing these results. “As humans age they report a higher incidence of pain, suggesting that pain might drive the aging process.”

The “hot” compound in chili peppers, capsaicin, is already known to activate this pain receptor, called TRPV1 (transient receptor potential cation channel subfamily V member 1). In fact, TRPV1 is often called the capsaicin receptor. Constant activation of the receptor on a nerve cell results in death of the neuron, mimicking loss of TRPV1, which could explain why diets rich in capsaicin have been linked to a lower incidence of diabetes and metabolic problems in humans.

More relevant therapeutically, however, is an anti-migraine drug already on the market that inhibits a protein called CGRP that is triggered by TRPV1, producing an effect similar to that caused by blocking TRPV1. Dillin showed that giving this drug to older mice restored their metabolic health to that of younger mice.

“Our findings suggest that pharmacological manipulation of TRPV1 and CGRP may improve metabolic health and longevity,” said Dillin, who is a Howard Hughes Medical Institute investigator and the Thomas and Stacey Siebel Distinguished Chair in Stem Cell Research. “Alternatively, chronic ingestion of compounds that affect TRPV1 might help prevent metabolic decline with age and lead to increased longevity in humans.”

Dillin and his colleagues at UC Berkeley and The Salk Institute for Biological Studies in La Jolla will publish their results in the May 22 issue of the journal Cell.

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