Project 2: Next Generation TOP1 Inhibition for the Treatment of Ovarian Cancer

摘要-项目2

ABSTRACT – PROJECT 2 Inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP1) are highly active in homol- ogous recombination (HR)-deficient ovarian cancers, especially those with BRCA1 or BRCA2 (BRCA1/2) muta- tions. Even in this setting, however, 40-80% of cases become PARP inhibitor (PARPi) resistant, most often as a result of genetic or biochemical changes that restore HR. Among other genomic subsets of ovarian cancer, PARPi resistance is even more prevalent. The observation that most common mechanisms of acquired PARPi resistance do not result from a failure to inhibit PARP1 raises the possibility that PARPis can potentially be utilized as chemosensitizing agents in this setting if suitable combinations can be identified. Accordingly, the present project seeks to enhance the efficacy of the PARPi rucaparib and extend its use by combining it with a 3rd generation topoisomerase I (TOP1) inhibitor (TOP1i). Recent studies have shown that nanoparticle formulations such as PLX038, a polyethylene glycol-conjugated ultra-long acting form of the TOP1i 7-ethyl-10- hydroxycamptothecin (SN-38), exhibit less marrow toxicity and greater efficacy than conventional TOP1is in preclinical cancer models. Our preliminary studies show that sustained release TOP1is, including PLX038, are active against five of seven PARPi-resistant ovarian cancer patient-derived xenografts (PDXs) tested. Moreover, using a unique antibody that detects TOP1-DNA covalent complexes (TOP1ccs), which are intermediates in the TOP1i-induced killing process, we have shown that TOP1ccs are diminished or undetectable in PDXs that are resistant to the TOP1i/PARPi combination, providing a starting point for understanding ovarian cancer resistance to this treatment. Collectively, these results lead to the hypothesis that a readily identifiable subset of HR- proficient ovarian cancers will exhibit sustained antitumor effects when treated with a next generation TOP1i alone or in combination with a PARPi. To test this hypothesis, we now propose to i) assess the efficacy of PLX038, alone and in combination with the PARPi rucaparib, in a cohort of genomically profiled high grade serous ovarian cancer PDXs with intrinsic or acquired resistance to single agent PARPis to identify the spectrum of ovarian cancers that could potentially benefit from PLX038 or the combination; ii) identify mechanisms of resistance to the TOP1i/PARPi combination in PDXs and cell lines; and iii) examine the association between the formation of drug-stabilized TOP1-DNA covalent complexes in tumor cells and the response of ovarian cancer patients to the PLX038/rucaparib combination in a phase II clinical trial. Collectively, these studies will not only provide insight into the genomic and biochemical factors that affect response to a 3rd generation TOP1i in ovarian cancer, but also determine whether it is possible to use PARPis as chemosensitizing agents in settings where they are no longer active as single agents. If successful, this project will point to a new therapy for the growing number of women with PARPi-resistant ovarian cancer.