Posted September 11, 2018
David Bowtell, Ph.D., University of Melbourne

High-grade serous ovarian cancer (HGSC) is the most frequent type of ovarian cancer and also the most malignant. Defects in the homologous recombination (HR) pathway occur in 50% of HGSC. HR is required for appropriate repair of DNA breaks; a deficiency in HR can result in gene mutations that contribute to cancer. Effective therapies have been developed that target HR-defective ovarian cancer. The other 50% of HGSC patients with HR proficient tumors, on the other hand, do not respond to these therapies and thus constitute a particularly vulnerable clinical population. This patient population is the focus of Dr. Bowtell's research.

An increase in Cyclin E1 (encoded by CCNE1) is often found in HR-proficient HGSC. CCNE1 plays a role in the cell cycle progression, and its amplification and overexpression can result in chromosome instability, contributing to tumorigenesis. Previous studies by Dr. Bowtell's laboratory indicated a dependency on cyclin-dependent kinase 2 (CDK2) in CCNE1-amplified cell lines. Building on these studies, and with support from an Ovarian Cancer Research Program fiscal year 2014 Investigator-Initiated Research Award, Dr. Bowtell explored methods of targeting CDK2 in CCNE1-amplified HGSC in vivo.

Dr. Bowtell's laboratory developed patient derived xenograft models of CCNE1-amplified HGSC as a preclinical platform for testing CCNE1 therapies in mice as a prelude to studies in women with ovarian cancer. In studies led by Dr. George Au-Yeung in Dr. Bowtell's laboratory, they confirmed that suppression of CDK2 by shRNA suppressed tumor cell growth in a mouse model of CCNE1-amplified HGSC. It was also determined that the CDK2 inhibitor, dinaciclib, demonstrated modest tumor growth inhibition in the CCNE1-amplified mouse model. Drs. Bowtell and Au-Yeung were interested in finding more effective inhibitor combinations, so they designed a high-throughput screen to identify those drug combinations with dinaciclib that are most effective in treating CCNE1-amplified cancer. MK-2206, an inhibitor of AKT (a protein kinase that plays a key role in multiple cellular processes such as apoptosis and cell proliferation), was identified as producing a synergistic effect with dinaciclib in CCNE1-amplified cancer cell lines. When examined in vivo, the combination treatment caused inhibition of cell proliferation and induction of apoptosis, which led to significant tumor regression in CCNE1-amplified HGSC. This combination treatment was more effective than either agent alone, and no significant improvement was seen from using the combination therapy in CCNE1-unamplified ovarian cancer mouse models.

These findings promote CDK2 as a likely target in CCNE1-amplified HGSCs. They also indicate an interaction between CCNE1 and AKT in CCNE1-amplified tumors. These results identify dinaciclib and MK-2206 as a potential combination treatment for patients with CCNE1-amplified HGSC. Future work exploring CDK2 and AKT inhibitors in combination in clinically relevant models is the next step in validating the combination treatment. To advance these research directions, Dr. Jessica Beach in Dr. Bowtell's laboratory has generated transgenic mice conditionally over expressing the CCNE1 gene in an attempt to generate models of CCNE1-driven tumors in animals with intact immune systems. These mice will be evaluated in collaboration with Dr. Ronny Drapkin at the University of Pennsylvania.

In addition to the animal studies Drs. Au-Yeung and Bowtell are exploring novel agents targeting CCNE1-amplified tumors in a clinical trial expected to commence in late 2018 or early 2019. This work could provide much needed therapeutic strategies for ovarian cancer patients who have limited options.

Publication:

Au-Yeung G, Lang F, Azar W, et al. 2017. Selective Targeting of Cyclin E1 Amplified High-Grade Serous Ovarian Cancer by Cyclin-Dependent Kinase 2 and AKT Inhibition. Clin Cancer Res. 23:7.

Link:

Public and Technical Abstracts: Cyclin E1 as a Therapeutic Target in Women with High-Grade Serous Ovarian Cancer and Primary Treatment Failure

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