Posted June 22, 2018
Fiona Simpkins, M.D., University of Pennsylvania

Ovarian cancer is one of the deadliest cancers in women. The lack of effective screening for early detection results in the majority of patients being diagnosed at an advanced stage, resulting in low survival rates. Ovarian cancer therapies targeting pathways that are indispensable for the cancer cells� survival have shown success in managing the disease. The poly(ADP-ribose) polymerase inhibitor (PARPi) is an example of a therapy that targets poly(ADP-ribose) polymerase (PARP) DNA repair. Its use can lead to lethality that is specific to the cancer cells that are more dependent on PARP DNA repair than regular cells are. The challenge with PARPi therapy is that not all ovarian cancers will respond, and there is no good indicator as to which will.

PARP-1 belongs to the PARP family of proteins, and is responsible for initiating and modulating multiple DNA repair pathways. It has emerged as the primary drug target of PARPi and thus, a possible biomarker for PARPi therapy; however, there is no mechanism for assessing PARP 1 levels in patients. A novel radiolabeled tracer, [¹⁸F]FluorThanatrace ([¹⁸F]FTT), has recently been developed that has been shown to correlate with PARP-1 expression. With support from a fiscal year 2016 Ovarian Cancer Research Program (OCRP) Clinical Development Award (CDA), Dr. Simpkins, in collaboration with other researchers from the University of Pennsylvania School of Medicine, confirmed that PARP-1 is the target of PARPi therapy and demonstrated the feasibility in imaging PARP-1 using the [18F]FTT tracer in epithelial ovarian carcinoma.¹

To accomplish this, Dr. Simpkins and colleagues first validated that PARP-1 expression was a requirement for PARPi sensitivity in ovarian cancer in vitro. Loss of PARP-1 in ovarian cancer cell lines caused a decrease in tracer binding and resulted in resistance to PARPi treatment. Next, the [¹⁸F]FTT tracer was assayed in a patient-derived xenograft mouse model of ovarian cancer. Administration of a conventional PARPi, olaparib, resulted in a reduction of the [18F]FTT tracer, demonstrating the specificity of the tracer for the molecular target. In a small clinical trial, positron-emission tomography (PET) imaging demonstrated that the [¹⁸F]FTT tracer localized to areas of epithelial ovarian cancer. PET imaging also revealed a positive correlation between the [¹⁸F]FTT tracer and PARP-1 expression in patient tumors. The results are promising, and the radiotracer provides a noninvasive means of profiling PARP-1 in ovarian cancer patients that could be used to guide clinical management.

With support from the OCRP CDA, Dr. Simpkins will continue to research the [¹⁸F]FTT tracer as a predictor of response to PARPi therapy through a small clinical trial aiming to validate and standardize methods for [¹⁸F]FTT PET as a measure of PARP-1 expression in ovarian cancer. Results from this trial will help provide the data needed to provide regulatory support for larger multicenter clinical trials with the goal of fully evaluating the importance of PARP-1 expression as a biomarker for cancer therapy and the use of the [¹⁸F]FTT tracer for measuring PARP-1 expression.

Publication

¹Makvandi M, Pantel A, Schwartz L, Schubert E, Xu K, Hsieh CJ, Hou C, Kim H, Weng CC, Winters H, Doot R, Farwell MD, Pryma DA, Greenberg RA, Mankoff DA, Simpkins F, Mach RH, and Lin LL. 2018. A PET imaging agent for evaluating PARP-1 expression in ovarian cancer. Journal of Clinical Investigation 128(5):2116-2126. doi: 10.1172/JCI97992. Epub 2018 Apr 16.

Link:

Public and Technical Abstracts: Investigation of a Novel PARP Inhibitor PET Tracer in Ovarian Carcinoma

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