Addition of Dasatinib (Sprycel) to Standard Chemo Cocktail May Enhance Effect in Certain Ovarian Cancers

“The addition of a chemotherapeutic drug for leukemia to a standard regimen of two other chemotherapy drugs appears to enhance the response of certain ovarian cancers to treatment, according to a pre-clinical study led by researchers in the Duke Comprehensive Cancer Center.  ‘We know that a pathway called SRC is involved in cell proliferation in certain types of cancers, including some ovarian cancers,’ said Deanna Teoh, MD, a fellow in gynecologic oncology at Duke and lead investigator on this study.  ‘By examining gene expression data, we determined that the combination of the leukemia drug dasatinib (Sprycel) made carboplatin and paclitaxel more effective in cell lines with higher levels of SRC expression and SRC pathway deregulation.’ …”

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Angeles Secord, MD, Gynecologic Oncologist, Duke University Medical Center & Senior Investigator on this study. Deanna Teoh, MD, Gynecologic Oncologist at Duke was the lead investigator.

“The addition of a chemotherapeutic drug for leukemia to a standard regimen of two other chemotherapy drugs appears to enhance the response of certain ovarian cancers to treatment, according to a pre-clinical study led by researchers in the Duke Comprehensive Cancer Center.

‘We know that a pathway called SRC is involved in cell proliferation in certain types of cancers, including some ovarian cancers,’ said Deanna Teoh, MD, a fellow in gynecologic oncology at Duke and lead investigator on this study.

‘By examining gene expression data, we determined that the combination of the leukemia drug dasatinib (Sprycel®) made carboplatin and paclitaxel more effective in cell lines with higher levels of SRC expression and SRC pathway deregulation.’

That synergistic effect, in which drugs used in combination strengthen each other’s efficacy, was absent when low SRC expression and low SRC pathway deregulation were present, Teoh said.

‘These findings indicate that we may be able to direct the use of a targeted therapy like dasatinib based on gene expression pathways in select ovarian cancers,’ she said.

The results of the study are being presented on a poster at the 100th annual American Association for Cancer Research meeting in Denver on April 19, 2009. The study was funded by the Prudent Fund and the National Institutes of Health.

‘Our ultimate goal is to offer personalized therapy for women with ovarian cancer,’ said Angeles Secord, MD, a gynecologic oncologist at Duke and senior investigator on this study.

‘Hopefully in the future we will apply targeted therapies to individual patients and their cancers in order to augment response to treatment while minimizing toxic side effects.’

For this study, researchers examined four ovarian cancer cell lines, known as IGROV1, SKOV3, OVCAR3 and A2780. Three of the cell lines demonstrated high activation of SRC and one demonstrated lower SRC expression.

All were treated in lab dishes with various combinations of the chemotherapeutic agents dasatinib, carboplatin and paclitaxel.

‘We found that the addition of dasatinib to standard therapy in the three cell lines with significant SRC pathway deregulation – IGROV1, OVCAR3 and A2780 – enhanced the response of the cancer cells to therapy,’ Teoh said.

‘Conversely, in SKOV3, which has minimal SRC protein expression and pathway deregulation, we saw the least amount of anti-cancer activity when we added dasatinib.’

It’s possible that by blocking the SRC activity with the dasatinib, we are enhancing the effect of the other chemotherapeutic agents, Teoh said.

The results of this study support the further investigation of targeted biologic therapy using a SRC inhibitor in some ovarian cancers, she said. Currently a phase I trial of a combination of dasatinib, paclitaxel and carboplatin is available for women with advanced or recurrent ovarian, tubal and peritoneal cancers.

Dasatinib is a chemotherapeutic that is currently FDA-approved for use in leukemia. It is manufactured by Bristol-Myers Squibb and is sold under the brand name Sprycel. Bristol-Myers Squibb provided the dasatinib used in this study.

Other researchers involved in this study include Tina Ayeni, Jennifer Rubatt, Regina Whitaker, Holly Dressman and Andrew Berchuck.”

Source: Addition of Dasatinib to Standard Chemo Cocktail May Enhance Effect in Certain Ovarian Cancer, by Duke Medicine News and Communications, News, Health Library, DukeHealth.org, April 13, 2009.

Secondary Sources:

Ovarian Cancers Detected Early May Be Less Aggressive

“The biology of ovarian cancers discovered at an early stage may render them slower growing and less likely to spread than more aggressive cancers, which typically are discovered in an advanced stage, according to a study led by investigators in the Duke Comprehensive Cancer Center.  This finding has implications for the question of whether screening for ovarian cancer could save lives. …”

“The biology of ovarian cancers discovered at an early stage may render them slower growing and less likely to spread than more aggressive cancers, which typically are discovered in an advanced stage, according to a study led by investigators in the Duke Comprehensive Cancer Center.  This finding has implications for the question of whether screening for ovarian cancer could save lives.

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Dr. Andrew Berchuck is Director of the Duke Division of Gynecologic Oncology, Duke Comprehensive Cancer Center, Durham, North Carolina

‘Our study showed that the ovarian cancers currently detected at an early stage have gene expression profiles that correlate with favorable outcome, rather than being representative of the entire spectrum of disease aggressiveness,’ said Andrew Berchuck, MD, a gynecologic oncologist at Duke and lead investigator on this study.  ‘This highlights the potential challenges of developing a screening test for this disease, because earlier detection of aggressive cases is essential if screening is to reduce ovarian cancer deaths.’

The results of this study and the implications for screening as an approach to decreasing mortality parallel the challenges seen in lung cancer and prostate cancer.  In those cancers, while screening approaches based on radiological imaging and/or blood markers detect cancers, it remains unclear whether cancer-related deaths are prevented because screening preferentially detects more benign cancers that are much less likely to be fatal, Berchuck said.

‘While these results could be seen as discouraging, it must be remembered that this information is an important piece of the ovarian cancer puzzle, and data like these that increase our understanding of the disease hopefully will eventually lead to breakthroughs in prevention, early detection and treatment of this deadly disease,’ Berchuck said.  Although there is currently no approved ovarian cancer screening test for the general population, the CA125 blood test and transvaginal ultrasound imaging currently are being evaluated in clinical trials.

The researchers looked at gene expression patterns in 166 ovarian cancer tissue samples taken from patients who were treated at Duke, H. Lee Moffitt Cancer Center, and Memorial Sloan-Kettering Cancer Center and from the Gynecologic Oncology Group Tumor Bank.  For this study, researchers examined samples of advanced ovarian cancers from patients who had experienced long-term survival — over seven years — and patients who had done extremely poorly, and died within three years of diagnosis.  The researchers used microarrays — a method for examining thousands of snippets of DNA — with about 22,000 probe sets to examine patterns of gene expression among the samples, and identified genes that were most predictive of survival.

‘We found that certain patterns predicted long-term survival and others predicted a poorer prognosis in advanced stage cases,’ Berchuck said. ‘Cancers that were detected at an early stage almost always shared gene expression characteristics with advanced stage cases that were long-term survivors, suggesting a shared favorable biology.’

The researchers published their results in the March 24, 2009, issue of the journal Clinical Cancer Research. The study was funded by the Gail Parkins Ovarian Cancer Research Fund and the National Institutes of Health.

Other researchers involved in this study include Edwin Iversen, Jingqin Luo, Jennifer Clarke, Hisani Horne, Angeles Secord, Jason Barnett, Susan Murphy, Holly Dressman, Jeffrey Marks of Duke; Douglas Levine and Jeff Boyd of Memorial Sloan-Kettering Cancer Center in New York City, NY; Miguel Alonso of the Universidad Autonoma de Madrid; and Johnathan Lancaster of H. Lee Moffitt Cancer Center and Research Institute.”

Primary SourceSpotlight:  Ovarian Cancers Detected Early May Be Less Aggressive, News Article, Duke Comprehensive Cancer Center, March 23, 2009.