Posted May 29, 2019
Dr. Panagiotis Konstantinopoulos, Dana-Farber Cancer Institute
Dr. Rugang Zhang, The Wistar Institute
Dr. Dipanjan Chowdhury, Dana-Farber Cancer Institute

The Ovarian Cancer Research Program (OCRP) formed the Ovarian Cancer Academy to bring together talented and highly committed Early-Career Investigators (ECIs) along with experienced mentors to help establish the ECIs as successful and highly respected ovarian cancer researchers. To create an opportunity for the ECIs to form meaningful and productive collaborations both within the Academy and in the ovarian cancer research community, the OCRP offered the Ovarian Cancer Academy Collaborative Award in fiscal year 2014 (FY14). The award stipulated that the proposed collaboration be led by an Initiating Principal Investigator (PI) from the Academy and a team consisting of Partnering PIs, which could be other ECIs or independent investigators not affiliated with the Academy.

A team led by Dr. Panagiotis Konstantinopoulos was awarded the FY14 Ovarian Cancer Academy Collaborative Award. The other members of the team include fellow ECI Academy member Dr. Rugang Zhang and Dr. Dipanjan Chowdhury, who was not a member of the Academy.  The project aimed to develop strategies against cyclinE1 (CCNE1) amplified ovarian cancer, the most deadly ovarian cancer due to a lack of responsiveness to standard chemotherapy. Excitingly, the team has had success in identifying and validating heat shock protein 90 (HSP90) as a novel therapeutic target. 

The functional homologous recombination (HR) in CCNE1 amplified cells allows them to repair the DNA damage caused by chemotherapy, making them chemoresistant. HSP90 is a chaperone protein that assists proteins, including CCNE1 and those involved in HR, to fold properly. The team hypothesized that the inhibition of HSP90 would interfere with HR and downregulate CCNE1, and, alone or in combination with other DNA damage inducing drugs, may induce lethality in CCNE1 amplified cells.

The team’s results revealed that HSP90-inhibition downregulates HR DNA repair in CCNE-1 amplified cell lines and induces significant cell death. They determined that an HSP90-inhibitor, AT13387, synergized with DNA damage inducing agents, such as PARP-inhibitors, and enhanced cell death in CCNE1-amplified cell lines. Next, the team assessed the effects of the combination treatment of HSP90-inhibitors and PARP-inhibitors in patient derived CCNE1-amplified ovarian cancer tumors in a mouse model. They determined that the combination treatment inhibited tumor growth and was more effective than either treatment alone, suggesting that HSP90 inhibitors in combination with PARP-inhibitors may be an effective treatment for CCNE1-amplified ovarian cancer.

These impressive results supported by the OCRP have led to the initiation of a Phase 1 clinical trial of the PARP inhibitor, olaparib, and HSP90 inhibitor, AT13387, for the treatment of recurrent ovarian cancer and other metastatic solid tumors. If successful, this trial could validate this novel therapeutic strategy to treat patients with CCNE1-amplified ovarian cancer tumors who have poor outcomes due to the ineffectiveness of standard treatment.

Links:

Public and Technical Abstracts: Therapeutic Strategies against Cyclin E1-Amplified Ovarian Cancers

Clinical Trial:  NCT02898207

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