Full Projects
Current SPORE projects are described below. The grant also funds Career Enhancement Projects and Development Research Projects. Annual requests for proposals will be issued for CEP & DRPs.
ATR Inhibitor-Mediated Reversal of PARP Inhibitor Resistance in High-Grade Serous Ovarian Cancer (HGSOC)
Project Summary
More than half of high-grade serous ovarian cancers (HGSOCs) carry defects in homologous recombination (HR) repair, most commonly related to BRCA1 and BRCA2 alterations. Such alterations also compromise the stability of stalled replication forks in ovarian cancer cells. These features translate to sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition so that the introduction of PARP inhibitors has transformed the treatment paradigm for this disease. These agents are now approved for all stages of ovarian cancer treatment: newly diagnosed patients and those with recurrent cancer as well. Unfortunately, acquired resistance has emerged as a high unmet clinical need. Current data suggest that the two major mechanisms of PARP inhibitor resistance include (1) restoration of HR; and (2) replication fork stabilization. The work of Project 1 investigators has shown co-occurrence of these mechanisms in ovarian cancer cell line models of acquired PARP inhibitor resistance. Consequently, strategies that address both HR restoration and replication fork stability represent promising avenues for development. Our preliminary data in cell lines suggest that inhibition of Ataxia telangiectasia and Rad3-related (ATR) or checkpoint kinase 1 (CHK1) is capable of reversing both mechanisms. Here, we will confirm these results in primary ovarian organoid cultures, as well as in BRCA-mutated patient-derived xenograft (PDX) models with acquired PARP inhibitor resistance, followed by translation to a clinical trial of combined ATR and PARP inhibition.
In addition to the problem of acquired resistance in initially responsive tumors, subsets of HGSOC demonstrating a high degree of replication stress, such as those harboring CCNE1 amplification, are refractory to PARP inhibition but sensitive to ATR or CHK1 inhibition. We have completed a trial randomizing gemcitabine to gemcitabine combined with ATR inhibition in platinum-resistant HGSOC (NCT02595892) that demonstrated superiority of the combination, particularly in patients with a platinum-free interval < 3 months. We hypothesize that the gemcitabine/ATR inhibitor combination may be particularly useful in HGSOCs under high replication stress. We will test this hypothesis in both preclinical models and in biopsy samples procured during the trial, with the development of biomarkers that may define HGSOCs with replication stress that predict sensitivity to ATR or CHK1 inhibition alone or in combination with gemcitabine.
Combined Personal Neoantigen-Targeting Cancer Vaccines with Immune Checkpoint Blockade for Ovarian Cancer
Project Summary
Recent studies of immune checkpoint blockade (CPB) therapy have demonstrated its potent clinical activity across multiple tumor types but only modest effectiveness in ovarian cancer has been observed. Hence, the development of strategies to improve efficacy of CPB while minimizing immune-related toxicity is currently a high priority for ovarian cancer treatment. In parallel, large-scale cancer sequencing efforts have revealed the mutational landscape of tumors, which together with the maturation of predictive algorithms for binding of peptides to class I HLA molecules, have enabled the ability to systematically identify immunogenic epitopes arising from somatic mutations, called neoantigens. Unlike native proteins, neoantigens are not subject to the immune-dampening effects of central tolerance and yet exhibit exquisite tumor-specific expression. We and others have spearheaded efforts demonstrating the feasibility of using such computational tools to identify immunogenic candidate patient-specific mutated epitopes that are capable of stimulating tumor-specific T cell responses. This promising activity has led us to prospectively test the targeting of personal neopeptides as cancer vaccines. Recently, we demonstrated the proof-of-concept of the safety, feasibility and immunologic activity of immunizing patients with advanced melanoma and glioblastoma with personal vaccines consisting of up to 20 mutated epitopes per patient, delivered as synthetic long peptides (20-30mers) admixed with the potent immune adjuvant poly-ICLC, a TLR3 agonist (the combination of the neoantigen vaccine and poly-ICLC is termed Ott et al. Nature,2017 and Keskin et al. Nature 2019. Of note, the induced neoantigen-specific T cell responses could recognize autologous tumor cells.
Evaluation of the Efficacy of Trametinib + Navitoclax in Recurrent Ovarian Carcinoma
Project Summary
The overall objective of this project is to investigate the clinical efficacy of a combination therapy targeting the RAS-ERK pathway serine/threonine kinase MEK and two anti-apoptotic proteins, BCL-2 and BCL-XL in ovarian cancer. Epithelial ovarian cancer is comprised of several subtypes, the most common being high grade serous carcinoma (HGSC). While initially sensitive to platinum drugs and poly ADP ribose polymerase (PARP) inhibitors, HGSC becomes increasingly therapy resistant. Additionally, other ovarian cancer subtypes, such as low grade serous (LGSC) and mucinous ovarian cancers, many of which are RAS/RAF mutated, are often platinum refractory, and new treatment strategies are needed. We hypothesize that combined MEK and BCL-2/XL inhibition will be active in refractory/relapsed ovarian cancer based on: (i) evidence that the RAS-ERK pathway is activated in a large percentage of ovarian cancers, (ii) the efficacy of combined MEK and BCL-2/XL inhibition in preclinical PDX models of chemoresistant HGSC, (2) preclinical models of RAS mutant tumors, and (iii) a Phase I clinical trial showing safety and tolerability of combined treatment with the MEK inhibitor trametinib and BCL-2/XL inhibitor navitoclax.