Single-cell transcriptomics and in vitro characterization of the molecular causes of immunotherapy failure in advanced prostate cancer

• Grant number: 21/15011-4
• Support Opportunities: Research Projects - Thematic Grants
• Start date: October 01, 2023
• End date: September 30, 2028
• Field of knowledge: Health Sciences - Medicine - Surgery
• Principal Investigator: Jeremy Andrew Squire
• Grantee: Jeremy Andrew Squire
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Pesquisadores principais: Rodolfo Borges dos Reis
• Associated researchers: Eleni Efstathiou ; Fabiano Pinto Saggioro ; Jane Bayani ; Larissa Dias da Cunha ; Leticia Fröhlich Archangelo ; Luciano Neder Serafini ; Tamara L Lotan ; Thiago Mattar Cunha ; Thiago Vidotto ; Valdair Francisco Muglia
• Associated scholarship(s): 25/00553-7 - How changes in gene expression in immune and stromal cells are affect by PTEN loss?, BP.PD; 24/05784-4 - Establish patient-derived organoid models for pre-clinical study and interaction of Prostate Cancer (PCa) with the tumor microenvironment (TME), BP.PD

Abstract

The therapeutic landscape of advanced prostate cancer has considerably broadened in recent years. With the implementation of sensitive functional imaging techniques, advanced prostate cancer is no longer limited to metastatic castrate-resistant disease, but now also includes metastatic hormone-sensitive prostate cancer and some localized tumors that have previously unrecognized occult metastatic disease. These improved descriptions of the breadth of advanced disease coincide with a better understanding of the underlying genomic complexity of advanced cancers. However, resistance to chemotherapy, hormonal therapy, and immunotherapy in the metastatic setting remains a significant cause of morbidity and mortality in advanced prostate cancer. Initial results with immunotherapy indicate less than 10% of patients have responses to these treatments. Thus, it is critical to understand the molecular mechanisms that lead to variation in therapeutic responses in advanced prostate cancer. We will test the following related hypotheses to explain why a large percentage of metastatic prostate cancers fail current treatments: 1) we postulate that metastatic prostate tumors that have acquired inactivating mutations of PTEN express novel pathways related to immunotherapy evasion; 2) that organoid cultures of metastatic tumors will provide a functional platform to evaluate the role of tumor-intrinsic gene expression changes on immune and drug response in both castrate-sensitive and resistant-disease; and 3) downstream pathways activated in drug-resistant tumors will open avenues for investigating new combinatorial approaches to immunotherapy. The overall goal of this proposal is to use single-cell genomics and spatial profiling combined with in vitro approaches to model and improve the success of immunotherapy in metastatic prostate cancer. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GAZOLA, ANTONIA A.; LAUTERT-DUTRA, WILLIAM; ARCHANGELO, LETICIA FROHLICH; DOS REIS, RODOLFO B.; SQUIRE, JEREMY A.. Precision oncology platforms: practical strategies for genomic database utilization in cancer treatment. MOLECULAR CYTOGENETICS, v. 17, n. 1, p. 18-pg., 2024-11-14. (21/15011-4, 21/12271-5)