While organ-confined prostate cancer can be treated and cured, late stages of the disease often progress to a treatment-resistant form known as castration-resistant prostate cancer (CRPC). Currently available treatments for CRPC are only marginally effective. The goal of this research is to develop new drugs that will be effective against CRPC or delay its development. To develop new therapies, a therapeutic target must be known. Recently we have proposed that the protein monocarboxylate transporter 4 (MCT4) on the cancer cell surface is a promising therapeutic target for treatment of CRPC. We suggest that cancer cells use MCT4 to excessively secrete lactic acid to ensure survival (through suppressing the anticancer immune response) and progression to treatment-resistance. To date we have been the leaders in identifying a unique set of therapeutic MCT4-targeting agents (antisense oligonucleotides; ASOs) and in showing their therapeutic effect in cancer cell cultures and animal models for prostate cancer. Here we propose 1) to design and select ASOs with chemical modifications that make them even more effective, 2) to study the anticancer effect of modified ASOs in animal models that closely reflect patient situations, and 3) to investigate in more detail how the ASOs work against cancer, especially focusing on cancer cell metabolism, the acidic tumour environment, and the anticancer immune response. Because this new therapeutic strategy can potentially impact multiple aspects fundamental to cancer growth and survival, completion of this research project will identify important compounds that can be used to develop new drugs potentially effective against CRPC or delay its development.