Addressing Treatment Resistance in Models of Lethal Prostate Cancer by Identifying Novel Targets for Drug Discovery

Rationale: Lethal prostate cancer is often a result of treatments failure. Novel drugs developed for patients with advanced prostate cancer can prolong their survival for a few years, yet ultimately patients succumb to the disease. The main reason is because a more aggressive variation of prostate cancer arises as a consequence of treatment failure. This variant is termed neuroendocrine prostate cancer, and there are no approved therapies to cure this lethal disease. Therefore, a better understanding of neuroendocrine prostate cancer emergence, as well as novel therapeutic strategies, are sorely needed to improve patient outcomes. In the past decade, Dr. Andrea Califano's laboratory developed several systems biology approaches to systematically unravel cellular mechanisms that drive and control tumor initiation and progression. These molecular drivers are often proteins, termed Master Regulators, and their aberrant activity is responsible for orchestrating tumor states. Dr. Califano and his collaborators successfully validated several Master Regulators associated with prostate cancer malignancy, drug resistance mechanisms, and other neuroendocrine tumors such as the metastatic gastroenteropancreatic tumor. Lately, collaborators of Dr. Califano generated very promising data about preclinical models of neuroendocrine prostate cancer that can be investigated using Master Regulator analysis and other technologies developed by Dr. Califano and collaborators.

Objectives: Based on several factors, such as the research experience I acquired across three different institutions in Italy, Germany and the United States; Dr. Andrea Califano's and Dr. Michael Shen's laboratory track records, and strong preliminary data, I propose a systems biology approach for the identification of lethal prostate cancer molecular drivers and the identification of drugs that kill the tumor by selectively targeting the molecular resources the drivers need for their activity. Specifically, the approach I intend to use is twofold. First, I will identify the key drivers that are responsible for the lethal variant of advanced prostate cancer associated with drug resistance. Second, I will use molecular data from drug screenings to identify/predict which drug is able to significantly change Master Regulator activity while killing tumor cells. A similar approach used by Dr. Califano and collaborators has already identified a drug for metastatic gastroenteropancreatic neuroendocrine tumors, and a clinical trial has already started. Additionally, I will focus on the mechanistic elucidation of drug action to identify existing drugs that selectively target the molecular dependencies needed by tumor drivers to control cellular proliferation.

Principal Investigator's Career Goals: The development of this project under the guidance of Dr. Califano will enable me to acquire the necessary knowledge and expertise to dissect biological mechanisms responsible for prostate cancer and its lethal variants by using sophisticated and successful computational methods for biological data analysis. Likewise, the mentorship of Dr. Shen will be instrumental to my initial training in prostate cancer research and the successful completion of my project aims. Moreover, the collaborative network provided by the mentors, the numerous training opportunities available at Columbia University Medical Center, and the ones that this award will provide by allowing me to present research results to international meetings and prepare manuscripts for peer-reviewed journals are setting the basis for acquiring independence as investigator in prostate cancer research, which is my ultimate goal.

Contributions of this Study to Advancing the Field of Prostate Cancer Research: The prostate cancer research field will tremendously benefit the outcomes of this project, both in terms of novel insights into biological mechanisms related to the emergence of lethal prostate cancer and the identification of drugs that can impinge on those mechanisms to selectively kill tumor cells while sparing all the others.

Ultimate Applicability of the Research: While novel therapies have clearly prolonged survival in men affected by advanced prostate cancer, resistance invariably emerges, and an increasing number of patients are diagnosed with the neuroendocrine variant of lethal prostate cancer. These men are left with no treatment options apart from the highly toxic chemotherapy regimen that is very poorly tolerated in older patients and can prolong their survival for only less than 2 years. This project is intended to improve the outcome of those patients left with no other alternatives. Certainly, the identification of drugs that mechanistically and selectively kill lethal prostate cancer tumor cells can directly benefit the above-mentioned patients.

Definitely, with this study, we anticipate finding several novel candidate biomarkers of lethal prostate cancers and drugs that can be used as starting point for in vivo validation and clinical trials.