Tag Archives: UCLA’s Jonsson Comprehensive Cancer Center

Experimental Drug NVP-BEZ235 Slows Ovarian Cancer Growth in Mice; Solid Tumor Clinical Trials Ongoing

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A study conducted recently at UCLA’s Jonsson Comprehensive Cancer Center found that experimental drug NVP-BEZ235, which blocks two points of a crucial cancer cell signaling pathway, inhibits the growth of ovarian cancer cells and significantly increases survival in an ovarian cancer mouse model.

A study conducted recently at  UCLA’s Jonsson Comprehensive Cancer Center (JCCC) found that an experimental drug, which blocks two points of a crucial cancer cell signaling pathway, inhibits the growth of ovarian cancer cells and significantly increases survival in an ovarian cancer mouse model.

Oliver Dorigo, M.D., Ph.D., Assistant Professor, Department of Gynecologic Oncology, Division Gynecologic Oncology, UCLA Jonnson Comprehensive Cancer Center; Member, JCCC Cancer Molecular Imaging Program Area

The Novartis Oncology drug, called NVP-BEZ235, also inhibits growth of ovarian cancer cells that have become resistant to the conventional treatment with platinum chemotherapy and helps to resensitize the cancer cells to the therapy. In addition, it enhances the effect of platinum chemotherapy on ovarian cancer cells that are still responding to the therapy, said the study’s senior author, Dr. Oliver Dorigo, an assistant professor of obstetrics and gynecology and a JCCC researcher.

“Platinum-based chemotherapy drugs are effective in treating ovarian cancers as long as the cancer cells remain sensitive to platinum,” Dorigo said. “But once the tumor becomes resistant, treating the cancer becomes very challenging. This is a significant clinical problem, since the majority of ovarian cancer patients develop resistance at some point during treatment. Breaking chemotherapy resistance is a difficult challenge, but crucial if we want to improve long-term survival for our patients.”

The study, performed on cells lines and mouse models, appears in the April 15 issue of the journal Clinical Cancer Research.

Over the last several years, Dorigo has been working in his laboratory to develop new therapies for ovarian cancer. About 22,000 American women are diagnosed each year with ovarian cancer, and more than 14,000 deaths are attributed to the disease annually. Dorigo has focused his research efforts on a pathway called PI3Kinase/Akt/mTOR, which, once activated, promotes ovarian cancer growth. The activated pathway also makes the cancer more aggressive and more likely to spread to other organs, Dorigo said, so targeting it offers great promise for more effective therapies for the disease.

In this two-year study, Dorigo and postdoctoral fellow Chintda Santiskulvong found that inhibiting two checkpoints of the pathway — PI3Kinase and mTOR — with NVP-BEZ235 decreased cancer growth, both in cell culture dishes and in mice with ovarian cancer. It also significantly increased survival in the mice, he said. More importantly, NVP-BEZ235 slowed growth of the ovarian cancer cells that had become resistant to platinum and helped to break that resistance.

“We were very encouraged to find that NPV-BEZ235 could resensitize the ovarian cancer cells to standard platinum treatment,” Dorigo said. “In addition, we found this drug to be more effective in inhibiting ovarian cancer cell growth than other drugs that target only one checkpoint, mTOR, in this pathway. We believe that NVP-BEZ235 has superior efficacy because of the dual effect on PI3Kinase and mTOR.”

The experimental drug is being tested as a single agent at the Jonsson Cancer Center in human clinical trials against other solid tumors. Researchers involved with those studies have said early results are encouraging.

John Glaspy, M.D., M.P.H., Co-Chief, Department of Medicine, Hematology/Oncology, UCLA Jonnson Comprehensive Cancer Center; JCCC Director, JCCC Clinical Research Unit; Member, Stand Up To Cancer Mangement Committee

“This is clearly a promising agent with activity in humans,” said Dr. John Glaspy, a professor of hematology–oncology and a Jonsson Cancer Center scientist involved with the studies. “We are still assessing its tolerability in patients.”

Dorigo said he hopes to initiate a clinical trial for women with ovarian cancer that tests the combination of NVP-BEZ235 with platinum chemotherapy, as he believes that the combination might be more effective than each drug alone.

The study was funded by the Ovarian Cancer Research Foundation/Liz Tilberis Scholarship, the Gynecologic Cancer Foundation/Florence and Marshall Schwid Ovarian Cancer Award, a STOP Cancer Career Development Award and the National Institutes of Health’s Women’s Reproductive Health Research Program.

About the UCLA Jonnson Comprehensive Cancer Center

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson Center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2010, the center was named among the top 10 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 10 of the last 11 years.

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Peptide Being Tested for Atherosclerosis Inhibits Ovarian Cancer Growth; Clinical Trial Planned

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A drug in testing to treat atherosclerosis significantly inhibited growth of ovarian cancer in both human cell lines and mouse models, marking the first such report of a peptide being used to fight malignancies, according to a study by researchers at UCLA’s Jonsson Comprehensive Cancer Center.

A drug in testing to treat atherosclerosis significantly inhibited growth of ovarian cancer in both human cell lines and mouse models, marking the first such report of a peptide being used to fight malignancies, according to a study by researchers at UCLA’s Jonsson Comprehensive Cancer Center.

The study follows a previous discovery by the same group showing that a protein called apolipoprotein A-I (apoA-I) may be used as a biomarker to diagnose early stage ovarian cancer in patients, when it typically is asymptomatic and much easier to treat. These earlier findings could be vital to improving early detection, as more than 85 percent of ovarian cancer cases present in the advanced stages, when the cancer has already spread and patients are more likely to have a recurrence after treatment, said Dr. Robin Farias-Eisner, chief of gynecologic oncology and co-senior author of the study with Dr. Srinu Reddy, a professor of medicine.

Robin Farias-Eisner, M.D., Ph.D., Chief of Gynecologic Oncology, UCLA Jonsson Comprehensive Cancer Center

“The vast majority of ovarian cancer patients are diagnosed with advanced disease and the vast majority of those, after surgery and chemotherapy, will eventually become resistant to standard therapy,” Farias-Eisner said. “That’s the reason these patients die. Now, with this peptide as a potential therapy, and if successful in clinical trials, we may have a novel effective therapy for recurrent, chemotherapy-resistant ovarian cancer, without compromising the quality of life during treatment.”

The study was published Nov. 1, 2010 in the early online edition of the peer-reviewed journal Proceedings of the National Academy of Sciences.

In their previous work, Farias-Eisner, Reddy and their research teams identified three novel biomarkers that they used to diagnose early stage ovarian cancer. In September 2009, the U.S. Food and Drug Administration cleared the first laboratory test that can indicate the likelihood of ovarian cancer, OVA1™ Test, which includes the three biomarkers identified and validated by Farias-Eisner, Reddy and their research teams.

They observed that one of the markers, apoA-I, was decreased in patients with early stage disease. They wondered why the protein was decreased and set out to uncover the answer. They speculated that the protein might be protective, and may be preventing disease progression.

The protein, apoA-I, is the major component of HDL [high-density lipoprotein], the good cholesterol, and plays an important role in reverse cholesterol transport by extracting cholesterol and lipids from cells and transferring it to the liver for extraction. The protein also has anti-inflammatory and antioxidant properties. Because lipid transport, inflammation and oxidative stress are associated with the development and progression of cancer, Farias-Eisner and Reddy hypothesized that the reduced levels of apoA-I in ovarian cancer patients may be causal in disease progression.

Mice that were engineered to have many copies of human apoA-I gene showed very little cancer development when induced with ovarian cancer, while the mice without the extra copies of apoA-I showed much more disease. The mice with extra copies of the apoA-I gene also lived 30 to 50 percent longer than those who didn’t receive it.

Farias-Eisner and Reddy wanted to treat the mice that had more cancer with the protein apoA-I, but it was too large to conveniently administer, having 243 amino acids. The researchers then turned to apoA-I mimetic peptides—only 18 amino acids in length—that are being tested for cardiovascular diseases. That project had been ongoing for a number of years at UCLA, said Reddy, who is also a part of the cardiovascular research team led by Dr. Alan M. Fogelman, executive chair of the Department of Medicine.

Srinivasa T. Reddy, Ph.D., M.Sc., Professor, Division of Cardiology, Depart. of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles

“The smaller peptides mimic the larger apoA-I protein and provided us with agents we could give to the mouse to see if it was effective in fighting ovarian cancer,” said Reddy. “One of the peptides was being tested as an experimental therapy for atherosclerosis, so we already have some information on how it’s being tolerated in humans, which would be vital information to have if we progressed to human studies in ovarian cancer.”

The peptide, thus far, has caused little to no side effects in atherosclerosis patients, Reddy said, a hopeful sign that it might be well tolerated in ovarian cancer patients.

The mice that were given the peptide by injection had about 60 percent less cancer than the mice that did not receive the peptide, Farias-Eisner said. The peptide also was given in drinking water or in mouse food and proved to be as effective when administered that way.

“It was an exciting result,” Farias-Eisner said. “It looked like we had something that could be ingested or injected that might be very effective against ovarian cancer progression.”

Farias-Eisner said the peptide avidly binds oxidized lipids, one of which is known to stimulate cancer cells to survive and multiply. In the mouse studies, the mice that received peptide had significantly lower levels of this cancer promoting lipid.

An early phase clinical trial is being planned testing the peptide in patients with aggressive ovarian cancers that are resistant to chemotherapy, a group of patients whose median survival is just 40 months. Farias-Eisner hopes the study will be started and completed within two years.

The study was funded by the Womens Endowment, the Carl and Roberta Deutsch Family Foundation, the Joan English Fund for Women’s Cancer Research, the National Institutes of Health and the West Los Angeles Veterans Affairs Medical Center.

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2010, the Jonsson Cancer Center was named among the top 10 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 10 of the last 11 years. For more information on the Jonsson Cancer Center, visit our website at http://www.cancer.ucla.edu.

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