Targeting Wnt signaling in therapy-resistant ovarian cancer

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PROJECT SUMMARY PARP inhibitor (PARPi) use in the clinic is expanding into multiple cancer types, and consequently, PARPi resistance is a growing clinical problem. High grade serous ovarian cancer (HGSOC) tumors and cells remain an optimal model system to assess PARPi response and resistance. We have developed a panel of unique isogenic PARPi sensitive and resistance HGSOC cell lines and patient-derived xenograft (PDX) models. We published that hyperactivation of the Wnt/-catenin pathway promotes PARPi resistance. Through the current literature and our preliminary investigation, we have discovered that Wnt-mediated PARPi resistant HGSOC cells have increased expression of the immune checkpoint, PD-L1, and reduced expression of the tumor suppressor, interferon regulatory factor 1 (IRF1). Further, Wnt/-catenin signaling directly inhibits effector T cell differentiation and promotes a tumor-promoting, M2-like macrophage. We will continue to collaborate with MD2 Biosciences to investigate a first-in-class allosteric -catenin inhibitor, 1525. We hypothesize that Wnt-dependent PARPi resistance inhibits anti-tumor immunity, and combining ICB with Wnt inhibition will promote immune activation to eradicate PARPi resistant HGSOC. We are proposing to use both in vitro and in vivo models to determine the role of PARPi resistance and Wnt signaling in promoting an immune-suppressive environment. In Aim 1, we will use our unique PARPi resistant cell line models to establish -catenin regulation of PD-L1 (gene – CD274) and IRF1. In Aim 2, we will determine whether secreted factors from PARPi resistant cells attenuates T cell activation and promotes macrophage M2 differentiation. In Aim 3, we will use our novel syngeneic and humanized mouse models to assess the 1525 - catenin inhibitor combined with anti-PD-1. The proposed work has the potential for a high impact on understanding ovarian cancer biology and improving therapeutic options. We anticipate combining -catenin inhibition with an immune checkpoint blocker will overcome PARPi resistance and provide a therapeutic option for those who are no longer responding to PARP inhibitors. Thus, the proposed work's long-term goal is to develop an investigator-initiated clinical trial at the University of Colorado.