Studying Intratumor Heterogeneity in the Evolution of Metastatic Hormone-Naive Prostate Cancer to Castration Resistance After Intensified Hormonal Therapy
Abstract
Metastatic prostate cancer (mPC) is the advanced form of prostate cancer, when the disease has spread to other organs. mPC growth is primarily dependent on androgens. Intense targeting of the androgen signaling pathway, combining anti-hormone injections and drugs targeting the androgen receptor protein in the tumor cell, is the new standard of care for men with newly diagnosed mPC. However, a lethal form of the disease (castration-resistant) eventually emerges. We hypothesize that understanding the drivers of this resistance would be critical to further improve the outcome of men with newly diagnosed metastatic prostate cancer. To do so, we plan to study biopsies acquired from mPC patients at initial diagnosis, once they have started therapy and after their disease has become resistant. We will use novel molecular techniques to assess the heterogeneity within the tumor, with regards to the emergence of resistance mechanisms by providing a map of how changes occur in different tumor areas. These techniques will also give us information on how the tumor can evade the immune system by co-mapping the expression of immune checkpoints and the presence of immune cells in the tumor and exploring differences between organs where prostate cancer spreads. Some of these samples will come from men participating in a clinical trial that combines hormonal therapies with PARP inhibitors, a new family of drugs being investigated in prostate cancer. We have also generated tumor mice models using biopsies from these patients, allowing us to test different treatments in the same tumor; we will use these models to study in the laboratory how the tumor reacts when we give these treatments either together or sequentially, to better understand biological drivers of drug resistance. Contributions to the PCRP Overarching Challenges: This project will contribute to improving our understanding of the biology behind progression to lethal metastatic castration-resistant prostate cancer. Moreover, we aim to support the development of new treatment combinations that can prevent, or at least significantly delay drug resistance, to improve outcomes of men with lethal prostate cancer. What types of patients will it help and how will it help them? About half of men with metastatic prostate cancer present with distant metastasis at first diagnosis. These are the ones more likely to receive these therapies but unfortunately the tumor will relapse over time. They would be the first target population where a better understanding of resistance can be leveraged towards designing new therapies. Furthermore, this knowledge will also be applicable to treatments given to men in later stages of lethal prostate cancer. What is the projected time it may take to achieve a patient-related outcome? We will be testing the impact of drug combinations that are already being used in clinical practice and/or in late-stage clinical trials, so we anticipate a rapid translation of our findings into clinical trials that can improve outcomes of men with prostate cancer at the completion of this 4-year project. The Investigator: Joaquin Mateo is a prostate cancer physician-scientist who studies how mPC patients have distinct tumor molecular profiles and how these differences can guide personalized treatment selection. He has now launched his own laboratory, where he will carry out this project. He will be supported by co-mentors, Professor Johann de Bono, a world-renowned prostate cancer investigator, and Professor Josep Tabernero. They will ensure the applicant has all the necessary resources to conduct this project and provide scientific guidance and career-development support. Understanding intra-tumor heterogeneity and drug resistance is key to delivering precision medicine; this award would enable the applicant to expand his molecular testing and computational analysis skills and to consolidate his emerging independent group.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310209
Entities
People
- Joaquin Mateo
Organizations
- United States Army