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

SBIR主题

基本信息

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
项目类别：
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

项目摘要

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适合改善长期生存，但目前的免疫疗法存在无反应、耐药性和毒性等问题，因此，放射线等传统疗法仍然是大多数患者的标准治疗方法。放射治疗 (RT) 的关键是产生治疗诱导衰老 (TIS) 细胞，这些细胞表现出促肿瘤衰老相关分泌表型 (SASP) 状态。然而，RT 可以转化为使用 DNA 损伤反应 (DDR) 抑制剂和/或治疗药物的抗肿瘤靶向免疫疗法。制药行业正在寻求 DDR 抑制剂 + 放射组合疗法，但目前的 DDR 抑制剂缺乏精确的癌症靶向性。我们将通过此提案推进的药物将是端粒酶逆转录酶 (TERT) 的一流不可逆抑制剂，端粒酶逆转录酶是一种独特的癌症特异性 DDR 靶点。约 90% 的肿瘤，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基因剂，可在非小细胞肺癌 (NSCLC) 中诱导抗肿瘤免疫反应。）））这应该证明我们的TERT抑制剂的全面临床前开发是合理的，这可能最终将癌症特异性治疗敏化剂带入临床，不仅适用于非小细胞肺癌，而且可能适用于大多数癌症。