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UCLA Researchers Significantly Inhibit Growth of Ovarian Cancer Cell Lines With FDA-Approved Leukemia Drug Dasatinib (Sprycel®)

Posted by Paul Cacciatore on November 11, 2009

The drug dasatinib (Sprycel®), approved for use by the U.S. Food and Drug Administration in patients with specific types of leukemia, significantly inhibited the growth and invasiveness of ovarian cancer cells and also promoted their death, say UCLA researchers in the November 10th issue of the British Journal of Cancer. The drug, when paired with a chemotherapy regimen, was even more effective in fighting ovarian cancer cell lines in which signaling of the Src family kinases — associated with approximately one-third of ovarian cancers– is activated. Clinical trials that involve the testing of dasatinib against ovarian cancer and solid tumors are currently ongoing.

Researchers affiliated with the University of California, Los Angeles (UCLA), Mayo Clinic and Harvard Medical School announced that they have established a biological rationale to support the clinical study of the U.S. Food & Drug Administration (FDA)-approved leukemia drug dasatinib (U.S. brand name: Sprycel®), either alone or in combination with chemotherapy, in patients with ovarian cancer. The study appears in the November 10th edition of the British Journal of Cancer.

Background

Dasatinib is an FDA-approved drug for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (ALL). Dasatinib is a small-molecule inhibitor that targets several tyrosine kinases, including the Src kinase family, Ephrin type-A receptor 2 ( EphA2) , and the focal adhesion kinase (FAK).

Src is the prototypic member of a family of nine non-receptor tyrosine kinases (Src, Lyn, Fyn, Lck, Hck, Fgr, Blk, Yrk, and Yes). The Src family kinase (SFK) proteins regulate four main cellular fuctions that ultimately control the behavior of transformed cancer cells:  cell proliferation, adhesion, invasion, and motility.

Eph receptors and ephrins are integral players in cancer formation and progression, and are associated with advanced ovarian cancer and poor clinical outcome.

FAK is a non-receptor tyrosine kinase involved in the regulation of cell adhesion, survival, and migration.  Preclinical studies indicate that FAK plays a signficant role in ovarian cancer cell migration and invasion.

Dasatinib Study Methodology & Findings

slamon1

One of the dasatinib study authors is Dennis J. Slamon, M.D. Ph.D. Dr. Slamon is the Director of Clinical/Translational Research & Director of the Revlon/UCLA Women's Cancer Research Program, at the UCLA Jonsson Comprehensive Cancer Center. He is also the co-discoverer of Herceptin®, a targeted therapy that revolutionized the treatment of HER-2 positive breast cancer.

The researchers carried out the study by testing the effects of dasatinib on human ovarian cancer cells in vitro, using a panel of 34 established human ovarian cancer cell lines.  The 34 cell lines selected were representative of the major epithelial ovarian cancer subtypes:

On this basis, the researchers examined the effects of dasatinib on ovarian tumor cell proliferation, invasion, apoptosis, and cell-cycle arrest.  To more fully understand the activity of dasatinib, the researchers also studied the efficacy of chemotherapeutic drugs (i.e., carboplatin and paclitaxel) in combination with dasatinib against ovarian cancer cells that were previously determined to be dasatinib-sensitive.

The overarching goals of the study were (i) to provide a rationale to test dasatinib as a single agent or in combination with chemotherapy in patients with ovarian cancer, and (ii) to identify molecular markers that may help define subsets of ovarian cancer patients most likely to benefit from treatment with dasatinib.

Significant findings reported in the dasatinib study are summarized below.

  • Concentration-dependent, anti-proliferative effects of dasatinib were seen in all ovarian cancer cell lines tested.
  • Dasatinib significantly inhibited tumor cell invasion, and induced tumor cell death, but was less effective in causing tumor cell-cycle arrest.
  • At a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for dasatinib plus carboplatin or paclitaxel.
  • 24 out of 34 (71%) representative ovarian cancer cell lines were highly sensitive (i.e.,  ≥ 60% growth inhibition) to dasatinib.
  • 6 cells lines were moderately sensitive (i.e., 40% – 59% growth inhibition) to dasatinib.
  • 4 cell lines were resistant (i.e., < 40% growth inhibition) to dasatinib.
  • When comparing dasatinib sensitivity between cell lines based solely upon histological subtype (i.e., serous papillary, clear cell, endometrioid, mucinous, and undifferentiated ovarian cancer cell lines), no single histological subtype was more sensitive than another.
  • Ovarian cancer cell lines with high expression of Yes, Lyn, Eph2A, caveolin-1 and 2, moesin, annexin-1 and 2 and uPA (urokinase-type Plasminogen Activator), as well as those with low expression of IGFBP2 (insulin-like growth factor binding protein 2), were particularly sensitive to dasatinib.
  • Ovarian cancer cell lines with high expression of HER-2 (Human Epidermal growth factor Receptor 2), VEGF (Vascular endothelial growth factor) and STAT3 (Signal Transducer and Activator of Transcription 3) were correlated with in vitro resistance to dasatinib.

Based upon the findings above, the researchers concluded that there is a clear biological rationale to support the clinical study of dasatinib, as a single agent or in combination with chemotherapy, in patients with ovarian cancer.

Konecny

Gottfried E. Konecny, M.D., UCLA Assistant Professor of Hematology/Oncology, UCLA Jonsson Comprehensive Cancer Center Researcher & First Author of the Dasatinib Study

Ovarian cancer, which will strike 21,600 women this year and kill 15,500, causes more deaths than any other cancer of the female reproductive system. Few effective therapies for ovarian cancer exist, so it would be advantageous for patients if a new drug could be found that fights the cancer, said Gottfried E. Konecny, M.D., a UCLA assistant professor of hematology/oncology, a Jonsson Comprehensive Cancer Center researcher, and first author of the study.

“I think Sprycel® could be a potential additional drug for treating patients with Src dependent ovarian cancer,” Konecny said. “It is important to remember that this work is only on cancer cell lines, but it is significant enough that it should be used to justify clinical trials to confirm that women with this type of ovarian cancer could benefit.”

Recent gene expression studies have shown that approximately one-third of women have ovarian cancers with activated Src pathways, so the drug could potentially help 7,000 ovarian cancer patients every year. Notably, a gene expression study published in 2007 reported Src activation in approximately 50% of the ovarian cancer tumors examined.

In the dasatinib study, the UCLA team tested the drug against 34 ovarian cancer cell lines and conducted genetic analysis of those lines. Through these actions, the researchers were able to identify genes that predict response to dasatinib. If the work is confirmed in human studies, it may be possible to test patients for Src activation and select those who would respond prior to treatment, thereby personalizing their care.

“We were able to identify markers in the pre-clinical setting that would allow us to predict response to Sprycel®,” Konecny said. “These may help us in future clinical trials in selecting patients for studies of the drug.”

Dasatinib is referred to as a “dirty” kinase inhibitor, meaning it inhibits more than one cellular pathway. Konecny said it also inhibits the focal adhesion kinase (FAK) and ephrin receptor, also associated with ovarian cancer, in addition to the Src cellular pathway.

The next step, Konecny said, would be to test the drug on women with ovarian cancer in a clinical trial. The tissue of responders would then be analyzed to determine if the Src and other pathways were activated. If that is confirmed, it would further prove that dasatinib could be used to fight ovarian cancer. In studies, women would be screened before entering a trial and only those with Src dependent cancers could be enrolled to provide further evidence, Konecny said, much like the studies of the molecularly targeted breast cancer drug Herceptin® enrolled only women who had HER-2 positive disease.

“Herceptin® is different because we knew in advance that it only worked in women with HER-2 [gene] amplification,” he said. “In this case, we don’t clearly know that yet. The data reassures us that the drug works where the targets are over-expressed but we need more testing to confirm this.”

The tests combining the drug with chemotherapy are significant because chemotherapy, namely carboplatin and paclitaxel, is considered the standard first line treatment for ovarian cancer patients following surgery. Because dasatinib proved to have a synergistic effect when combined with chemotherapy, it may be possible to add this targeted therapy as a first line treatment if its efficacy is confirmed in future studies.

Dasatinib Study Significance

The dasatinib study is potentially significant to the area of ovarian cancer treatment for several reasons.

First, although this study only tested dasatinib in vitro against ovarian cancer cell lines, the drug is already FDA-approved.  Accordingly, the general safety of the drug has already been established by the FDA.

Second, 71% of the ovarian cancer lines were highly sensitive to dasatinib.

Third, dasatinib was additive to, or synergistic with, the standard of care chemotherapy drugs used in first line ovarian cancer treatment, i.e., carboplatin and paclitaxel.

Fourth, the study established molecular markers that may be predictive of dasatinib effectiveness in particular patients.  In theory, a patient’s tumor biopsy could be tested for the presence of those molecular markers to determine whether a patient will benefit from dasatinib.

Fifth, one of the dasatinib study authors is Dennis J. Slamon, M.D. Ph.D. Dr. Slamon is the director of Clinical/Translational Research, and director of the Revlon/UCLA Women’s Cancer Research Program, at the UCLA Jonsson Comprehensive Cancer Center. Dr. Slamon is also the co-discoverer of Herceptin®, a targeted therapy that revolutionized the treatment of HER-2 positive breast cancer.  Herceptin® is a targeted therapy that kills HER-2 positive breast cancer cells while leaving normal cells unaffected.  The potential use of dasatinib to treat select ovarian cancer patients who test “positive” for specific molecular markers (e.g., Src cellular pathway activation) is similar to the extremely successful drug development approach used for Herceptin®.

Open Clinical Trials Testing Dasatinib (Sprycel®) Against Ovarian Cancer & Solid Tumors

As of this writing, there are several open (i.e., recruiting) clinical trials that involve testing dasatinib against ovarian cancer and solid tumors.

For a list of open clinical trials that involve testing dasatinib against ovarian cancer, CLICK HERE.

For a list of open clinical trials that involve testing dasatinib against solid tumors, CLICK HERE.

All potential volunteers must satisfy the clinical trial entrance criteria prior to enrollment.  Depending on the drug combination being tested, one or more of the solid tumor clinical trials may not be appropriate for an ovarian cancer patient.

About the UCLA Jonsson Comprehensive Cancer Center

UCLA’s Jonsson Comprehensive Cancer Center (JCCC) 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, JCCC is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2009, JCCC was named among the top 12 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 10 consecutive years. For more information on JCCC, visit the website at http://www.cancer.ucla.edu.

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