The most lethal type of prostate cancer is called metastatic castration resistant prostate cancer, with a 5-year survival rate of only 28%. One of the biggest challenges in managing this disease is that many patients will inevitably develop resistance to the current "standard-of-care" Androgen Receptor (AR) targeted therapies within 2 years. Therefore, there is an overwhelming need to understand the biology of resistance, develop new measurable biological markers to predict resistance, and create a new therapeutic approach to fight against resistance.

We have found, through a technology called "library screening", that the loss of a gene called IWS1, is a key factor leading to therapy resist...

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The most lethal type of prostate cancer is called metastatic castration resistant prostate cancer, with a 5-year survival rate of only 28%. One of the biggest challenges in managing this disease is that many patients will inevitably develop resistance to the current "standard-of-care" Androgen Receptor (AR) targeted therapies within 2 years. Therefore, there is an overwhelming need to understand the biology of resistance, develop new measurable biological markers to predict resistance, and create a new therapeutic approach to fight against resistance.

We have found, through a technology called ""library screening", that the loss of a gene called IWS1, is a key factor leading to therapy resistance. The survival of tumors without IWS1 relies on the increase of a protein called CPS1, which enables the tumors to reprogram their metabolism and adapt to the challenge of therapy. This revelation has uncovered a new subtype of lethal prostate cancer which responds poorly to current therapy. It suggests that proper clinical intervention targeting the protein CPS1 may be an effective avenue to combat resistance and improve the clinical outcome of patients.

We proposed to examine how resistance occurs, using cutting-edge technologies, including "3D organoid culture", "single cell RNA sequencing", "NanoString", and "Spatial Transcriptomics". Importantly, we will develop an original and measurable biological marker, called the IWS1-loss signature, to predict patients' responses to current AR targeted therapies and to employ this new tool to guide the practice of precision oncology. Finally, we will examine how well a novel class of drugs targeting CPS1 and its metabolic program could reduce therapy resistance. The combined results of these experiments will provide the rationale for direct follow-up clinical trials with this novel biomarker and the innovative CPS1 inhibitor, needed to remarkably improve the clinical outcome and survival for men with lethal prostate cancer.

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