Reciprocal Cross-Talk Between Notch Signaling and Hippo Pathway in the Tumor Microenvironment Mediates Castrate-Resistant Prostate Cancer
Abstract
Rationale of the Proposed Study: There are no effective therapeutic strategies for metastatic castrate-resistant prostate cancer. Prostate tumor cells constantly interact with the surrounding microenvironment in all stages of the metastatic cascade. A deeper understanding of the role of the surrounding tumor microenvironment in recent years has led to a paradigm shift in the clinical treatment of the advanced disease as it is now widely appreciated that the evolution of novel therapies require further understanding of two critical facets of the biology of prostate cancer metastasis: (a) the vicious cycle with which prostate cancer cells interact with the metastatic microenvironment leading to tumor proliferation and (b) the immune evasive strategies deployed by the prostate cancer cells to escape the body s natural immune response against the tumor. The Hippo and Notch signaling are two crucial pathways that have been reported to be dysregulated in advanced prostate cancer by multiple investigations. Our novel preclinical findings demonstrate a vicious cycle of cross-talk between Hippo signaling in prostate cancer cells and Notch pathway in the tumor microenvironment and that this vicious cycle results in fueling tumor proliferation. Another crucial and concomitant process that relies on the tumor cell-microenvironment interaction and critically aids in the multi-step metastatic cascade is the immune escape mechanisms deployed by the tumor cells against the body s immune response. A crucial immune escape strategy mediated by the tumor cells involves the induction of programmed death-1 (PD-1) receptor expressed on exhausted T cells, also called PD-1/PD-L1 immune checkpoint. Disruption of this interaction or checkpoint through therapeutic antibodies facilitates the T-cell-mediated immune response, and this strategy has led to recent success in the clinic in multiple cancers including melanoma, renal, and lung cancer patients. Despite its success in other cancers, PD-1 blockade in men with metastatic castrate-resistant prostate cancer has not been effective, likely due to low expression of PD-L1 on prostate tumor cells. Our novel findings demonstrate that inhibition of Notch signaling in the tumor microenvironment of prostate cancer bone metastases increases PD-L1 expression, thereby pointing to the effectiveness of a co-targeting strategy that involves the concomitant inhibition of Notch and PD-1/PD-L1 interaction in metastatic prostate cancer. Objective of the Proposed Study: The overall objective of the study is to tease apart the Hippo/Notch cross-talk in castrate-resistant prostate cancer and elucidate the effect of this cross-talk on the immune response mounted by the tumor microenvironment. Further, based on our data and previous reports that Hippo and Notch pathways are overexpressed/dysregulated in human prostate cancer, we propose to develop a biomarker panel of Hippo/Notch signaling axis to predict disease progression and survival in human prostate cancer bone metastasis patients. In Aim 1, we will elucidate the cross-talk between Hippo and Notch signaling in human primary castrate-resistant prostate cancer. In Aim 2a and 2b respectively, using novel prostate cancer mouse models that have an intact immune system, we will evaluate the efficacy of co-targeting Notch and PD-L1 in primary and metastatic castrate-resistant prostate cancer. Clinical Relevance of the Proposed Study: Optimizing the tumor microenvironment for checkpoint inhibition is now in the forefront of therapeutic development in medical oncology. We propose using a double-pronged strategy to treat metastatic castrate-resistant prostate cancer through: (a) targeting tumor proliferation by the inhibition of Notch signaling (by using anti-Notch-1 antibody) and (b) facilitating the T-cell-mediated immune response by blocking PD-1/PD-L1 immune checkpoint (through the use of PD-L1 antibody). This strategy is more holistic and effective tha
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710353
Entities
People
- Manisha Tripathi
Organizations
- Cedars-Sinai Medical Center
- United States Army