Project

Development of Novel Nanocarriers and Immunotherapies for the Treatment of Prostate Cancer

Short Summary

Patients with metastatic prostate cancer, specifically those with disease progression following primary androgen ablation therapy, are generally considered to be refractory to hormonal therapy. The treatment of castration-resistant prostate cancer (CRPC) remains unsatisfactory. Unfortunately, chemotherapy can only marginally improve patient survival, providing a palliative benefit in this setting. Therefore, there is an urgent need to develop novel effective targeted therapies to improve the outcome of patients with androgen refractory diseases. Moreover, chemo-/radiotherapy or targeted therapies can cause cellular senescence, a stable cell growth arrest that occurs in tumor cells subjected to different stresses which can promote chronic inflammation, tumor progression or treatment relapse when accumulated. The elimination of senescent cells has therefore emerged as a promising therapeutic strategy. By performing proteomic analysis of murine and human prostate tumor samples treated with different senescence-inducing therapies, we have identified a transmembrane protein (SENO-1) that is selectively upregulated in senescent prostate tumor cells. Thus, we now aim at generating novel nanocarriers and immunotherapies for the treatment of prostate cancer targeting SENO-1.

Goals

The current project aims at the generation of novel therapies targeting senescent prostate tumour cells. Therefore, we will both develop immunoliposomes and TanCAR T cells construct specific for SENO1 and PSMA and we will assess their efficacy and safety in preclinical models of prostate cancer.

Significance

This project will shed light on the complex interactions between senescent cells and the immune response, with the overarching goal to design new strategies to defeat therapy-induced senescence, which is responsible for tumor relapse and the anti-tumor capacity of the immune microenvironment.

Background

Despite recent progress, prostate cancer (PCa) still represents a major cause of cancer-related mortality and morbidity in men. Treatment of prostate cancer is usually based on androgen deprivation therapy (ADT), which is achieved either pharmacologically or by surgical castration. However, despite initial response, the majority of patients invariably progress and eventually develop metastatic castration-resistant prostate cancer (mCRPC). Patients affected by mCRPC that do not respond to second-generation ADT (enzalutamide or abiraterone) are eventually treated with either chemotherapy or targeted therapy with limited benefit for their survival. Different clinically available prostate cancer therapies, including ADT and chemotherapy, induce cellular senescence, a state of stable arrest of the cell cycle, preventing old, damaged, or precancerous cells from dividing. Senescent cells secrete a complex cocktail of factors that drive a response called the senescence-associated secretory phenotype (SASP). This recruits T cells and NK cells of the immune system, promoting the removal of the senescent cells. Under these conditions, senescence is transient, which benefits the organism. However, when senescent cells linger, they can promote chronic inflammation resulting in tumor progression or treatment relapse. The elimination of senescent cells has therefore emerged as a promising therapeutic strategy. One possible way to target senescent cells is with so-called senolytic drugs, that kill them selectively. However, the current armamentarium of effective senolytics includes only a small number of effective compounds that are not suitable for clinical trials. Moreover, many currently available senolytics are only partially effective in prostate cancer. Therefore, there is the need to identify novel senolytic strategies that selectively target tumor cells in patients treated with therapies that enhance senescence, significantly reducing therapy resistance.

iDoc

Co-Investigators

Migliorini Denis, MD, University of Geneva
de Bono Johann, MD, The Institute of Cancer Research

Consortium

The Institute of Cancer Research

Status

In Progress

5th Call, iDoc