Ecologically Informed Treatment of the Polyaneuploid Cancer Cell (PACC) State to Halt the Emergence of Castrate-Resistant Prostate Cancer
Abstract
Scientific Objective and Rationale: Cancer is lethal because tumors evolve resistance to all forms of systemic therapy. That is, after a series of attempts, cancer eventually solves the resistance puzzle. For prostate cancer patients, this is apparent by resistance to hormone therapy, marked by the development of castrate-resistant tumor growth. Yet, the evolutionary path that cancer follows to solve the resistance puzzle remains broadly undefined. Likewise, the ecological features that define the path to resistance are poorly understood. Specifically, it is unclear whether uncertainty and volatility in oxygen availability accelerates the search for a resistant solution through the accession of a transient cell state, the Polyaneuploid Cancer Cell (PACC) state. The PACC state is accessed by cancer cells in response to stress (including in the tumor microenvironment or due to therapy) that is impervious to conventional therapeutics, e.g., hormonal therapy and chemotherapy. Once the stress subsides, the cancer cells can then exit from the PACC state and repopulate the tumor(s) within a treated patient, which is clinically observed as cancer recurrence following treatment failure. As a result, we hypothesize that, unless cells that enter the PACC state are eliminated, cancer will recur in treated patients and continue to lead to the deaths of men with prostate cancer. The overarching goal of this proposal is to determine the effect of oxygen availability on the evolutionary path to castrate-resistant growth via accession of the PACC state and to test the effectiveness of a novel PACC-targeted therapy. In Aim 1, we will quantify the effect of evolutionary impact of changes in oxygen availability on the emergence of castrate-resistant growth via accession of the PACC state. In short, we will test whether continual fluctuations in oxygen availability accelerate the search for a resistant solution. In Aim 2, we will evaluate the use of a novel therapeutic approach in which we force cells to prematurely exit the PACC state, making them vulnerable once again to hormonal therapy. By achieving these aims, we will address two of the PCRP overarching challenges to define the biology of prostate cancer progression to lethal prostate cancer to reduce death and to develop treatments that improve outcomes for men with lethal prostate cancer. Furthermore, the findings from this project will be applicable to drugs that are already FDA-approved for other purposes and therefore have the potential for rapid translation and impact for high-risk patients. Principal Investigator Career Goals in Prostate Cancer Research: I plan to eventually lead a multidisciplinary research lab to characterize the different evolutionary paths that drive the emergence of lethal and incurable metastatic prostate cancer and to identify vulnerabilities that can be exploited with targeted therapies. My Ph.D. in Mathematical Biology focused on understanding the individual traits that make a cell likely to successfully metastasize. My postdoctoral work builds upon my quantitative background while also honing my practical cell and molecular biology lab skills to understand how individual cellular traits and behaviors evolve to drive the emergence of lethal cancer. Combining my unique mathematical background in single cell modeling with my postdoctoral research in prostate cancer therapy resistance provides me with a powerful skillset to build a successful multidisciplinary research program centered around understanding the evolutionary dynamics of prostate cancer resistance. In addition to rigorous training, I have developed a bespoke individual Researcher Development Plan that includes specific training in translation research (e.g., attending weekly Tumor Board meetings at Johns Hopkins), research leadership and laboratory management (e.g., involved in go/no-go decisions regarding the continuation of low-productivity projects within the wider la
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310157
Entities
People
- George Butler
Organizations
- Johns Hopkins University
- United States Army