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

SBIR主题

• 批准号: 10929719
• 负责人: Grant B Frost
• 金额: $ 40万
• 依托单位: RIPTIDE THERAPEUTICS LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2024-09-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10929719
• 关键词: Active Sites; Binding; Biological; Breast Cancer Cell; CT26; Cancer Model; Cancer cell line; Cells; Clinic; Colon Carcinoma; Combined Modality Therapy; DNA Damage; Data; Development; Dose; Drug Industry; Exhibits; Immune system; Immunotherapeutic agent; Immunotherapy; In Vitro; MCF7 cell; Malignant Neoplasms; Modeling; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenotype; Positioning Attribute; Proteomics; RNA-Directed DNA Polymerase; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Resistance; Reverse Transcriptase Inhibitors; Small Business Innovation Research Grant; Stimulator of Interferon Genes; Telomerase; Telomerase Inhibitor; Toxic effect; anti-tumor immune response; cancer therapy; cancer type; conventional therapy; immune activation; immunogenic; improved; in vivo; inhibitor; lung cancer cell; preclinical development; response; senescence; standard of care; tumor

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.

利用免疫系统的癌症疗法最有可能提高长期存活率，但目前的免疫疗法存在无反应、耐药和毒性。因此，放射等传统疗法仍然是大多数患者的标准护理。放射治疗(RT)的一个主要缺点是产生的治疗诱导衰老(TIS)细胞表现出促肿瘤衰老相关的分泌表型(SASP)状态。 然而，RT可以转化为使用DNA损伤反应(DDR)抑制剂和/或老年治疗药物的抗肿瘤靶向免疫治疗。制药业正在寻求DDR抑制剂+放射联合疗法。但是，目前的DDR抑制剂缺乏精确的癌症靶向，而且往往对正常组织毒性太大。我们将在这项提案中推进的药物将是一种一流的端粒酶逆转录酶(TERT)不可逆抑制物，TERT是一种独特的癌症特异性DDR靶点，在约90%的肿瘤中存在，但在正常组织中可以忽略不计。在一项概念验证研究中，TERT抑制剂将被证明是一种有效的放射增敏剂和变形剂，可在体内诱导非小细胞肺癌(NSCLC)的抗肿瘤免疫反应。这应该证明我们的TERT抑制剂的全面临床前开发是合理的，它可能最终将癌症特异性治疗增敏剂引入临床，不仅适用于非小细胞肺癌，而且可能适用于大多数癌症。