Targeting Wnt signaling in therapy-resistant ovarian cancer

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.

Grant Number: 3R37CA261987-05S1
NIH Institute/Center: NIH
Principal Investigator: Benjamin Bitler