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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要聚（二磷酸腺苷 [ADP]）核糖聚合酶抑制剂（PARPi）单药治疗方案具有在临床上证明了对转移性实体瘤的明显功效，其中观察到的最大活性同源重组缺陷 HRD 癌症，但对非 HRD 癌症的活性有限。因此，人们对将 PARPi 与其他全身疗法（包括化疗）相结合非常感兴趣。临床研究表明 PARPi 和 DNA 损伤之间具有微妙的协同作用化疗，包括烷化剂替莫唑胺 (TMZ) 此外，PARPi 与 PARPi 组合。 TMZ 有潜力大大增强针对非 HRD 癌症的抗肿瘤活性。当 PARPi 与化疗联合使用时，骨髓抑制是治疗效果的主要障碍，这大大降低了治疗效果，因此，对于实现更安全、更有效的治疗存在着巨大的未满足的需求。在这项快速 SBIR 提案中，Cybrexa 是结合 PARPis 与常规化疗的有效方法。 Therapeutics（“Cybrexa”）将使用专有的药物输送技术来创建全新的一类药物肿瘤靶向 PARPi，将 (a) 解决脱靶毒性问题，(b) 增强治疗效果与化疗联合使用时，对 HRD 和非 HRD 癌症均有效。因此，特定（TSD）药物的治疗指数将大大提高，我们的技术基于一种新颖的技术。 pH 低插入肽 (pHLIP) 的变体最初是在耶鲁大学发现的。 ~36 个氨基酸肽，可被低 pH (≤ 6.5-7.0) 触发，将其 C 末端插入细胞中附着在 pHLIP C 末端的货物可以被靶向并输送到细胞质中。基于肿瘤微环境酸度的癌细胞。现在世界已经证明 pHLIP 是一个高度选择性和有效的肿瘤靶向平台。建立了一套全面的协议和流程来创建 TSD，并在体外表征它们，然后验证它们的体内活性。我们已经成功地缀合了多种结构独特的化合物。迄今为止，PARPi 已发展到 pHLIP，我们的初步结果表明 PARPi-TSD 具有以下功能： (1) pH 依赖性功能活性药物在体外递送至肿瘤细胞 (2) 在体内持续且选择性； (3)药物的靶点参与特别是在肿瘤组织中，其水平与用游离药物观察到的水平相似；(4) 预防骨髓；与游离药物相比，与 TMZ 联合使用时的毒性也得到了强有力的支持。我们推进 PARPi-TSD 开发的目标的可行性如果成功，我们的方法将会实现。大大提高了 PARPi 与化疗联合使用的安全性和有效性，并将扩大其应用范围最后，这些研究将构成更广泛的 HRD 和非 HRD 实体瘤类型的基础。 Cybrexa 未来将开发一系列基于 TSD 的治疗组合。