Project Summary/Abstract - UTMDACC Ovarian SPORE Project 1 Ovarian cancer is a significant cause of morbidity and mortality that affects nearly 300,000 women worldwide each year (1). Its poor outcomes relate to delayed diagnosis and development of resistance to conventional therapy with carboplatin and paclitaxel (2). In the last SPORE cycle, we evaluated a novel inhibitor of salt-induced kinase 2 (SIK2) GRN-300 that enhances sensitivity to both carboplatin and paclitaxel (3,4). With the support of the SPORE, we initiated a first-in-human phase IA/B trial to define the maximum tolerated dose of GRN-300 alone and in combination with weekly paclitaxel. We also conducted preclinical studies to demonstrate that GRN- 300 enhanced olaparib sensitivity in homologous recombination (HR)-proficient and deficient ovarian cancer cell lines and xenografts. We have demonstrated that GRN-300 enhances olaparib sensitivity by 1) abolishing the class IIa histone deacetylase 4/5/7-associated transcriptional activity of myocyte enhancer factor 2D (MEF2D), 2) decreasing MEF2D binding to regulatory regions with high chromatin accessibility in DNA repair genes, and 3) repressing critical gene expression in the DNA repair pathway. Whereas poly (ADP-ribose) polymerase inhibitors (PARPi) have played a large part in maintaining progression-free survival in patients with HR-deficient ovarian cancers, the majority of patients will have resistance to PARPi and experience relapse (5). Moreover, combining conventional or other targeted agents with PARPi has been limited by additive myelosuppression (6). To date, GRN-300 has had no significant marrow toxicity in our phase I clinical trial. GRN-300 enhanced olaparib activity in both olaparib-sensitive and acquired olaparib-resistant ovarian cancer cells. Cancer immunotherapy, including immune checkpoint blockade (ICB), has shown great promise for cancers at multiple sites, but the frequency and duration of response of ovarian cancer has been limited (7). Recent studies suggest that a deficiency in DNA repair is associated with increased response of cancer cells to immunotherapy (8,9). We have found that GRN-300 increases phosphorylation of TBK1 and nuclear localization of IRF3 in murine ovarian cancer cells. Both TBK1 and IRF3 are downstream targets of the cGAS/STING pathway. GRN-300 or GRN-300 combined with olaparib increases the expression of programmed death-ligand 1 (PD-L1) in human and murine ovarian cancer cells. GRN-300 combined with anti-PD-L1 enhances CD8+ T-cell infiltration and antitumor activity in a syngeneic ovarian cancer model. The goal of our project is to determine whether GRN-300 overcomes resistance to PARPi and enhances PARPi sensitivity and whether GRN-300 promotes adaptive T-cell function and enhances immune checkpoint therapy. We will pursue three aims: 1) To determine the underlying mechanisms of olaparib resistance that can be overcome with the SIK2 inhibitor GRN-300 in combination with olaparib in ovarian cancer cell lines and PDXs,2) To identify the mechanism(s) by which the SIK2 inhibitor GRN- 300, alone and in combination with olaparib, sensitizes ovarian cancer cells to immune checkpoint blockade (ICB) and enhances T-cell cytotoxicity in human ovarian cancer cells and syngeneic murine models, and 3) To perform a phase IB trial of the SIK2 inhibitor GRN-300 in combination with olaparib.

NARRATIVE Ovarian cancer is a significant cause of morbidity and mortality that affects nearly 300,000 women worldwide each year, and its poor outcomes are related to delayed diagnosis and development of resistance to conventional therapy with carboplatin, paclitaxel and PARP inhibitors. We have discovered that GRN-300, a SIK-2 inhibitor, enhances PARP inhibitor olaparib activity. The proposed research will improve outcomes for women with ovarian cancer by understanding the underlying mechanisms by which GRN-300 overcomes olaparib resistance in ovarian cancer and will provide initial proof-of concept for a novel therapeutic approach.