Dissecting the Role of Cancer Cell Chromatin Remodeling on the Landscape of Tumor Immune Microenvironment
Abstract
The prostate is a unique organ in its dependency from androgen receptor activity for its growth during development and in almost all stages of prostate cancer progression. That discovery is the basis for the long- standing treatment in prostate cancer targeting the synthesis of testosterone (the hormone binding the receptor) or the receptor itself. These treatments, together with early detection programs, better surgeries, and improved chemo and radiotherapies have resulted in impressive improvements in the prognosis and survival of prostate cancer patients. However, despite the advances, prostate cancer remains the most diagnosed and the third leading cause of cancer-related mortality among men in the USA. This evidences the fact that standard-of-care treatments are not curative in many cases and that, for a significant number of patients, tumors eventually progress to aggressive forms that are highly metastatic. Since novel antiandrogens have shown clinical benefit in earlier stages of prostate cancer, very often patients with these aggressive resistant tumors that have already been treated with antiandrogens face a scarcity of available treatment options. Fortunately, the development of immunotherapies such as Immune Check-Point Inhibitors has changed the prognostic of many aggressive cancers, including a small subset of prostate cancer patients. However, most patients will still not benefit from these new therapies because their tumors are resistant from day 1 of treatment. This is partly due to the scarcity of studies investigating how and when immune cells infiltrate the tumors, which specific immune cell types act as promoters of tumor growth, and which ones could be exploited to kill cancer cells, hindering the development of rational approaches to overcome primary immune-resistance. Our project is based on the idea that changes in how chromatin (the macromolecule containing DNA in the cell nucleus) is accessible to factors that regulate gene expression in cancer cells ultimately determines the amount and type of immune cells that infiltrate tumors and that those changes are triggered by genetic alterations and in response to cancer treatment. We found that Nsd2, a chromatin regulator, drives aggressive prostate cancer and therapy resistance and is associated with unique patterns of immune infiltration in prostate tumors. We have now generated a new prostate cancer mouse model recapitulating the effect of Nsd2 on prostate cancer progression to assess the relationship between accessible chromatin and immune cell infiltration during treatment response and resistance. Our proposal will use sophisticated, genetically engineered models of prostate cancer, advanced genomics profiling tools, and computational biology approaches to investigate how these mechanisms can be exploited as cancer vulnerabilities and potential pharmacological targets using genome-editing tools and drug screenings. Our proposal aims at utilizing sophisticated genetically engineered models of prostate cancer, advanced genomics profiling tools, and computational biology approaches to identify and validate new mechanisms in lethal prostate cancer. We will investigate how these mechanisms can be exploited as cancer vulnerabilities and potential pharmacological targets using genome-editing tools and test them in preclinical trials. Our excellent training in cancer biology and translational research at world-class institutions like Columbia University and the rich intellectual and technological environment at IDIBELL, together with the world-class group of collaborators engaged in this proposal, ensure that results and discoveries will be translated to preclinical and clinical settings shortly after completion. This will be also facilitated by our close collaboration with patients advocate groups such as The Prostate Net, UsToo, or the Movember Foundation, among others. We strongly believe that this project will provide key insights
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210960
Entities
People
- Alvaro Aytes
Organizations
- United States Army