Modeling and Tumor-Stromal Cotargeting for Lethal Castration-Resistant Prostate Cancer Metastases
Abstract
Prostate cancer metastasis is lethal. Tumor-directed therapies remain the mainstay therapy for metastatic castration-resistant prostate cancer (mCRPC), but tumor cells evolve rapidly to evade monotherapy, leading to disease recurrence. Our studies and others have reported that tumors cells not only evolve, but also educate the tumor microenvironment (TME) to support tumor growth and evade therapy. This functionally important tumor-TME ecosystem should be therapeutically exploited to develop effective strategies for currently incurable mCRPC. Study on tumor and metastatic TME (mTME) interaction has not been feasible due to the limited availability of specimens, animal models, and technologies, creating a huge knowledge gap in developing targeted therapy to effectively treat mCRPC. Liver metastasis represents the worst prognosis among all mCRPC (6-13 months survival). Importantly, the number has increased from 53% to 71% in mCRPC patients who participated in our prostate cancer rapid autopsy program since the introduction of abiraterone and enzalutamide. This suggests liver metastasis is likely to affect more patients when abiraterone and enzalutamide is moving earlier to the diseases course and needs immediate therapeutic discovery. In this project, we will (1) target TGF-beta (the major mTME factor for liver metastasis; galunisertib) with docetaxel to inhibit CRPC progression in the liver using intrahepatic tumor injection into mouse liver, (2) systemically define pharmacologically targetable interactions between CRPC and mTME and directly perturb mTME-derived factors in live culture of clinical metastases in the form of tissue slices that ideally preserve the native interaction between prostate cancer cells and its mTME, and (3) determine the penetrance of druggable targets including TGF-beta in clinical mCRPC specimens to inform biomarker-driven therapy. By introducing the combination therapy, we aim to not only lower the dose of docetaxel for improved tolerance, but also to achieve durable treatment response. We anticipate that galnunisertib plus docetaxel, if proven effective in this proposal, will inhibit the progression of liver metastases in patients. The combination therapy would be most effective in prostate cancer patients who are newly diagnosed with liver metastasis because, at this early stage, the tumor heavily relies on its microenvironment for growth. Since both galunisertib with docetaxel are clinically available, transition to clinical trials is immediate. In contrast to the standard-of-care tumor-directed therapy, this study will provide critical evidence to support the first tumor-TME co-targeting in prostate cancer. Furthermore, defining the tumor and its mTME landscape will for the first time uncover druggable mTME targets that may be shared across different metastatic sites. Finally, our novel animal model recapitulating liver metastasis/patient live mCRPC culture will provide unprecedented opportunity for faithful therapeutic testing in tumor’s native TME. Metastatic biopsy provides limited specimen for biological discovery; we will leverage our large mCRPC biorepository containing >130 mCRPC specimens from the prostate cancer rapid autopsy program and our long-standing preclinical testing expertise to develop and test therapy. This study addresses overarching challenges on defining the biology and developing treatments for men with lethal mCRPC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110750
Entities
People
- Hung-ming Lam
Organizations
- United States Army
- University of Washington