Development of tumor-targeted PARP inhibitors for the treatment of solid cancers

开发用于治疗实体癌的肿瘤靶向 PARP 抑制剂

• 批准号: 10158804
• 负责人: ROBERT J AIELLO
• 金额: $ 117.94万
• 依托单位: CYBREXA, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158804
• 关键词: Acidity; Address; Adenosine Diphosphate; Adenosine Diphosphate Ribose; Advanced Development; Alkylating Agents; Amino Acids; BRCA1 gene; BRCA2 gene; Blood Circulation; Bone Marrow; Bone Marrow Suppression; Cancer Patient; Cell membrane; Chemistry; Clinic; Clinical Trials; Cytosol; DNA Damage; DNA Repair; DNA Repair Pathway; Data; Defect; Development; Dose; Drug Delivery Systems; Drug Kinetics; FDA approved; Freedom; Future; Goals; In Vitro; Laboratories; Lead; Legal patent; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Maximum Tolerated Dose; Monkeys; Mutation; Oncology; Patients; Peptides; Pharmaceutical Preparations; Phase; Poly(ADP-ribose) Polymerases; Polymerase; Prevention; Process; Protocols documentation; Rattus; Regimen; Resistance; Safety; Small Business Innovation Research Grant; Solid; Solid Neoplasm; Structure; Systemic Therapy; Technology; Testing; Therapeutic; Therapeutic Index; Time; Tissues; Toxic effect; Toxicology; Treatment Efficacy; Tumor Tissue; Tumor-Derived; Universities; Variant; barrier to care; base; cancer cell; chemotherapy; drug testing; homologous recombination; improved; in vitro activity; in vivo; inhibitor/antagonist; interest; meetings; neoplastic cell; new technology; novel; preclinical development; preclinical study; success; synergism; temozolomide; tumor; tumor microenvironment; tumor xenograft

PROJECT SUMMARY Monotherapy regimens of poly(adenosine diphosphate [ADP]) ribose polymerase inhibitor (PARPi) have demonstrated clear efficacy in the clinic against metastatic solid tumors, with the greatest activity observed in homologous recombination deficient HRD cancers, but have limited activity against non-HRD cancers. As such, there is great interest in combining PARPi's with other systemic therapies, including chemotherapy. Pre- clinical studies indicate the potential for exquisite synergy between PARPi's and DNA-damaging chemotherapies, including the alkylating agent, temozolomide (TMZ). Furthermore, PARPi combinations with TMZ have the potential to greatly enhance anti-tumor activity against non-HRD cancers. However, bone marrow suppression is a major barrier to treatment efficacy when PARPi's are combined with chemotherapy, which substantially reduces treatment efficacy. Hence, there is a great unmet need to enable safer and more effective means to combine PARPis with conventional chemotherapy. In this fast-track SBIR proposal, Cybrexa Therapeutics (“Cybrexa”) will use a proprietary drug delivery technology to create an entirely new class of tumor-targeted PARPi's, which will (a) address the issues of off-target toxicity, and (b) increase treatment efficacy against both HRD and non-HRD cancers, when used in combination with chemotherapy. These tumor- specific drugs (TSDs) thus will have a greatly enhanced therapeutic index. Our technology is based on a novel variant of pH-low insertion peptides (pHLIPs), which were originally discovered at Yale University. pHLIP is a ~36-amino acid peptide that can be triggered by low pH (≤ 6.5-7.0) to insert its C-terminus across the cell membrane into the cytosol. Cargoes attached to the C-terminus of pHLIP can be targeted and delivered into cancer cells based on the acidity in the tumor microenvironment. Multiple independent laboratories across the world have now shown that pHLIP is a highly selective and effective tumor targeting platform. Our team has established a comprehensive set of protocols and process-flows to create TSDs, characterize them in vitro, and then validate their activity in vivo. We have successfully conjugated a diverse range of structurally unique PARPi's to pHLIPs thus far, and our preliminary results indicate that PARPi-TSDs are capable of the following: (1) pH-dependent delivery of functionally active drug into tumor cells in vitro; (2) sustained and selective in vivo tumor localization, without free drug detection in systemic circulation; (3) target engagement by the drug specifically in tumor tissue, at levels similar to that observed with free drug; and (4) prevention of bone marrow toxicity when combined with TMZ, again compared with free drug. These preliminary results strongly support the feasibility of our objective to advance the development of a PARPi-TSD. If successful, our approach will greatly increase the safety and efficacy of PARPi's in combination with chemotherapy, and will expand their use into a wider range of HRD and non-HRD solid tumor types. Finally, these studies will form the basis for a wide range of TSD-based therapeutic combinations that Cybrexa will develop in the future.

项目摘要 聚（腺苷二磷酸腺苷[ADP]）核糖聚合酶抑制剂（PARPI）的单一疗法方案 在临床中证明了针对转移性实体瘤的明确效率，在 同源重组不足的HRD癌症，但针对非HRD癌症的活性有限。作为 这样的是将PARPI与其他系统性疗法（包括化学疗法）相结合的人们非常感兴趣。 pre 临床研究表明，PARPI和DNA破坏性之间的独家协同作用 化学疗法，包括烷基化剂替莫唑胺（TMZ）。此外，PARPI与 TMZ有可能大大增强针对非HRD癌症的抗肿瘤活性。但是，骨头 当Parpi与化学疗法结合时，骨髓抑制是治疗效率的主要障碍， 这大大降低了治疗效率。因此，有巨大的未满足需要使更安全和更多 将PARPI与常规化学疗法相结合的有效方法。在这个快速的SBIR提案中，Cybrexa Therapeutics（“ Cybrexa”）将使用专有的药物输送技术来创建全新的类别 针对肿瘤的PARPI，它将（a）解决靶向毒性的问题，以及（b）增加治疗 与化学疗法结合使用时，对HRD和非HRD癌的功效均具有疗效。这些肿瘤 - 因此，特定药物（TSD）将具有大大增强的治疗指数。我们的技术是基于小说 最初在耶鲁大学发现的pH-低插入肽（PHLIP）的变体。 phlip是一个 〜36-氨基酸肽可以由低pH（≤6.5-7.0）触发，以将其C末端插入细胞 膜进入细胞质。可以将附着在phlip的C端附在的货物进行瞄准并交付到 癌细胞基于肿瘤微环境中的酸度。多个独立实验室 世界现在已经表明，Phlip是一个高度选择性且有效的肿瘤靶向平台。我们的团队有 建立了一组全面的协议和过程流程，以创建TSD，在体外表征它们， 然后在体内验证其活性。我们成功地结合了各种结构独特的范围 到目前为止，Parpi到Phlips，我们的初步结果表明PARPI-TSD能够以下内容： （1）在体外将功能活性药物递送到肿瘤细胞中； （2）体内持续和选择性 肿瘤定位，没有全身性循环中的免费药物检测； （3）药物的目标参与 特别是在肿瘤组织中，在类似于自由药物的水平上； （4）预防骨髓 与免费药物相比，与TMZ结合使用时的毒性。这些初步结果强烈支持 我们目标推进PARPI-TSD的可行性。如果成功，我们的方法将 大大提高了PARPI与化学疗法结合的安全性和效率，并将扩大其 用于更广泛的HRD和非HRD实体瘤类型。最后，这些研究将构成 Cybrexa将来会发展出广泛的基于TSD的治疗组合。