Targeting FZD6 Sensitizes Advanced Prostate Cancer to Genotoxic Stress
Abstract
Identifying novel therapeutic target for advanced castration resistant prostate cancer is of substantial clinical significance. FZD6 is a membrane receptor for the Wnt ligands, which play critical roles in tissue development and homeostasis. In our preliminary data, we discovered that FZD6 is amplified in 22% of advanced prostate cancer and is highly expressed by prostate cancer cells. We showed that suppressing its expression inhibits the growth of prostate cancer cells in Petri dish. In addition, we showed that suppressing FZD6 impairs the DNA damage repair pathway, and this is likely mediated by ARID1A, a critical chromatin modeler. Based on these preliminary studies, we proposed in Aim 1 to test whether targeting FZD6 suppresses the growth of human patients-derived prostate tumor xenografts. In addition, we will use a novel nanoparticle-based technology to deliver FZD6-targeting agents specifically into prostate cancer xenografts in mouse hosts. This is a proof-of-principle preclinical study to demonstrate the feasibility of targeting FZD6 for prostate cancer treatment. In Aim 2, we will test the idea that targeting FZD6 will enhance the therapeutic efficacy of other therapeutic agents including cisplatin and PARP inhibitor. In Aim 3, we will investigate why targeting FZD6 can suppress the growth of prostate cancers. Our study will have a significant impact on prostate cancer treatment for several reasons. First, we will establish FZD6 as a novel therapeutic target for advanced prostate cancer. FZD6 is a component of the Wnt signaling transduction pathway. Although Wnt signaling has been known to play a critical role in prostate cancer progression, it has not been successfully targeted because pan-Wnt inhibitors cause dose-limiting toxicity due to depletion of the intestinal stem cells. Our strategy to target FZD6 will block only a portion of Wnt signaling, thereby it is a very promising therapeutic avenue without potential dose-limiting toxicity. Secondly, our finding that targeting FZD6 affects the DNA damage repair pathway will also have a significant impact on prostate cancer treatment. The PARP inhibitors such as Olaparib are only effective for patients with defects in a specific DNA damage repair pathway called homologous recombination repair (HRR). However, not all patients have mutations in genes associated with HRR. If targeting FZD6 impairs HRR, then it will also make those patients without HRR mutations respond to the PARP inhibitors. In the other word, this will expand the patient pool suitable for PARP inhibitor treatment. Finally, the basic mechanistic studies in Aim 3 will also inspire novel therapeutic strategies in the long run. In summary, our proposed studies will address two of the FY21 overarching challenges: Develop treatments that improve outcomes for men with lethal prostate cancer and Define the biology of lethal prostate cancer to reduce death.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210752
Entities
People
- Li Xin
Organizations
- United States Army
- University of Washington