The SIK2 Inhibitor GRN-300 Enhances PARP Inhibitor Sensitivity and Cytotoxic T-Cell Function in Ovarian Cancer

University Of Tx Md Anderson Can Ctr, Houston TX

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Abstract

Ovarian cancer remains a major cause of morbidity and mortality, affecting nearly 300,000 women globally each year. Poor outcomes are primarily driven by delayed diagnosis and the development of resistance to standard chemotherapy with carboplatin and paclitaxel. In the previous SPORE cycle, we developed and initiated a firstin-human clinical trial of GRN-300, a first-in-class salt-inducible kinase 2 (SIK2) inhibitor that enhances sensitivity to both carboplatin and paclitaxel. Building on this progress, we now propose to complete the Phase IA trial of GRN-300, including additional dose escalation and dose expansion, to further evaluate its safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. Our preclinical studies demonstrate strong rationale for continued clinical development. GRN-300 enhances sensitivity to the PARP inhibitor olaparib in both homologous recombination (HR)-proficient and HR-deficient ovarian cancer cell lines and xenograft models. Mechanistically, GRN-300 increases olaparib sensitivity by (1) abolishing the class IIa histone deacetylase (HDAC4/5/7)-associated transcriptional activity of myocyte enhancer factor 2D (MEF2D); (2) reducing MEF2D binding at regulatory regions of DNA repair genes; and (3) suppressing expression of key genes involved in the DNA repair pathway. While PARP inhibitors (PARPi) have improved progression-free survival in HR-deficient ovarian cancers, most patients eventually develop resistance. Moreover, attempts to combine PARPi with other agents are often limited by additive myelosuppression. Notably, GRN-300 has demonstrated minimal bone marrow toxicity in patients treated to date, supporting its potential for future combination strategies. Beyond DNA repair modulation, GRN-300 also has significant immunomodulatory effects. It activates the cGAS/STING pathway by increasing TBK1 phosphorylation and promoting nuclear localization of IRF3 in murine ovarian cancer cells. GRN-300, alone or in combination with olaparib, increases PD-L1 expression in both human and murine ovarian cancer cells. Furthermore, GRN-300 combined with anti–PD-L1 enhances CD8+ T-cell infiltration and antitumor activity in syngeneic ovarian cancer models. These findings suggest that SIK2 inhibition not only sensitizes tumors to DNA damage but may also enhance antitumor immune responses. We propose three specific aims: 1) To determine the molecular mechanisms by which GRN-300 overcomes PARP inhibitor resistance in ovarian cancer cell lines, xenografts, and patient-derived xenografts (PDXs), 2) To elucidate how GRN-300 modulates innate and adaptive immunity, enhances T-cell cytotoxicity, and potentiates response to immune checkpoint blockade (ICB), and 3) To complete a Phase IA trial of GRN-300 in patients with recurrent ovarian, primary peritoneal, and fallopian tube cancers, including a final dose escalation and a dose expansion cohort in order to find the RP2D of GRN-300 in order to initate a phase 1B trial of GRN-300 and olaparib.