Multi-tyrosine kinase inhibitors (MTKIs) have thus far had limited success in the treatment of castration-resistant prostate cancer (CRPC). Here, we report a phase I-cleared orally bioavailable MTKI, ESK981, with a novel autophagy inhibitory property that decreased tumor growth in diverse preclinical models of CRPC. The anti-tumor activity of ESK981 was maximized in immunocompetent tumor environments where it upregulated CXCL10 expression through the interferon gamma pathway and promoted functional T cell infiltration, which resulted in enhanced therapeutic response to immune checkpoint blockade. Mechanistically, we identify the lipid kinase PIKfyve as the direct target of ESK981. PIKfyve-knockdown recapitulated ESK981’s anti-tumor activity and enhanced the therapeutic benefit of immune checkpoint blockade. Our study reveals that targeting PIKfyve via ESK981 turns tumors from cold into hot through inhibition of autophagy, which may prime the tumor immune microenvironment in advanced prostate cancer patients and be an effective treatment strategy alone or in combination with immunotherapies.

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Sickle cell disease (SCD) is common in tribal belt of Gujarat, but not addressed effectively as it should be with effective use of Hydroxyurea, supportive care and counseling. In our single centre study of 70 patients of SCD who were only on Folic acid and Blood transfusion support, were analyzed and followed up for 1 year in terms of their clinical symptoms, Blood transfusion requirement, laboratory parameters before and after Hydroxyurea therapy. We found statistically significant improvement in clinical symptoms and positive changes in laboratory parameters studied. This validates the well established role of Hydroxyurea in SCD as seen in the various international trials. Hence it is imperative that the well documented benefits of Hydroxyurea in various International studies should be translated into clinical practice. SCD should be treated like a chronic disorder needing preventive therapy in form of Hydroxyurea and counseling with regular follow up.