Most anticancer agents, including cytotoxic chemotherapy and select small molecules, directly induce DNA damage, or impair the DNA damage response. DNA damage augments tumor immunogenicity that can improve immune checkpoint blockade (ICB) efficacy. However, most DNA damaging agents have significant adverse effects. We found that the FDA-approved antihypertensive angiotensin receptor blocking drug (ARB) telmisartan enhances G2/M arrest, augments DNA damage, and activates immunogenic tumor cGAS/STING to elicit IFNα/β, CXCL9, and CCL5 production. Telmisartan sensitizes tumors to doxorubicin, taxanes, and small molecules in vitro and in vivo and enhances ICB efficacy in mice. It also depleted tumor PDL1 that reduced stemness, which could be exploitable to reduce treatment resistance, but immunogenicity and DNA damage effects were PDL1-independent. DNA damaging and immune effects are also independent of its antihypertensive moiety, and no other FDA-approved ARBs tested increased DNA damage or improved chemotherapy efficacy. We started a phase I clinical trial in metastatic prostate cancer combining telmisartan with standard-of-care taxanes or PARP inhibitors based on preclinical data. Telmisartan is a broad-spectrum, clinically relevant anti-cancer drug that augments treatment sensitivity and tumor immunogenicity. As it is FDA-approved, inexpensive, relatively benign, and efficacious, it is optimal for rapid clinical translation.
Telmisartan augments DNA damage and tumor immunogenicity to improve cancer treatments
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Poster and Podium (Block Symposium)
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Date: May 4 Presentation Time: 03:15 PM to 04:30 PM Room: Exhibit Hall F1