SBIR Topic #446 Phase I -Development of Senotherapeutic Agents for Cancer Treatment

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Cancer therapies that harness the immune system are best positioned to improve long-term survival, but current immunotherapeutics suffer from nonresponse, resistance, and toxicity. Thus, conventional therapies such as radiation remain the standard-of-care for most patients. A major drawback of radiation therapy (RT) is the creation of therapy induced senescent (TIS) cells that exhibit a pro-tumor senescence-associated secretory phenotype (SASP) state. However, RT could be transformed into anti-tumor targeted immunotherapy using DNA damage response (DDR) inhibitors and/or senotherapeutic drugs. The pharmaceutical industry is pursuing DDR inhibitor + radiation combination therapies. But, current DDR inhibitors lack precise cancer targeting and are often too toxic to normal tissue. The drug we will advance with this proposal will be a first-in-class irreversible inhibitor of telomerase reverse transcriptase (TERT), a uniquely cancer-specific DDR target that’s in ~90% of tumors but negligible in normal tissue. In a proof-of-concept study, the TERT inhibitor will be demonstrated as a potent radiosensitizer and senomorphic agent that induces an anti-tumor immune response in non-small cell lung cancer (NSCLC) in vivo. This should justify the full preclinical development of our TERT inhibitor, which may eventually bring cancer-specific therapy sensitizers to the clinic for not just NSCLC, but potentially most cancers.