Next-generation precision medicine for targeting recombination-deficient cancers

针对重组缺陷癌症的下一代精准医学

基本信息

批准号：
9909705
负责人：
Richard T Pomerantz
金额：
$ 29.9万
依托单位：
RECOMBINATION THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-10 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9909705
关键词：
Acute Myelocytic Leukemia Animal Model BRCA1 gene BRCA2 gene Base Excision Repairs Blood Breast Breast Cancer Cell Cells Characteristics Chemical Structure Chemicals Clinic Collaborations Combined Modality Therapy Crystallization Cytochrome P450 DNA DNA Damage DNA Double Strand Break DNA Polymerase I DNA Repair DNA Repair Pathway DNA Sequence Alteration DNA-Directed DNA Polymerase Data Development Docking Dose Double Strand Break Repair Drug Kinetics Drug Targeting Drug resistance Enzymes Epithelial ovarian cancer Escherichia coli Exhibits FDA approved FLT3 gene Generations Genetic Recombination Human Impairment In Vitro Intellectual Property Lead Leukemic Cell Malignant Neoplasms Malignant neoplasm of ovary Mediating Medicine Methods Modeling Mutate Normal Cell Ovarian Ovary Pancreas Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Phase III Clinical Trials Poly(ADP-ribose) Polymerases Polymerase Proliferating Property Prostate Research Solubility Structure Structure-Activity Relationship Survival Rate System Testing Therapeutic Tumor Suppressor Proteins Tyrosine Kinase Inhibitor X-Ray Crystallography Xenograft Model Xenograft procedure absorption base cancer cell cancer type cell killing chemical synthesis compound 30 design drug candidate efficacy testing gene product homologous recombination improved in silico in vivo inhibitor/antagonist leukemia malignant breast neoplasm new therapeutic target next generation novel personalized medicine phase 1 study pre-clinical precision medicine success therapy design triple-negative invasive breast carcinoma tumor tumor growth

项目摘要

Precision medicine is a revolutionary therapeutic approach in which therapies are designed and selected based on genetic mutations present in certain cancers. For example, treating patients with BRCA-deficient cancers with a medicine that inhibits a particular DNA repair pathway can result in selective killing of these cancer cells. This approach is based upon the concept of synthetic lethality whereby inactivation of a particular gene product selectively kills cells based on their genetic mutation, while sparing normal cells. Synthetic lethality has been used to target cancer cells mutated or deficient in the BRCA1 or BRCA2 tumor suppressor proteins which promote the homologous recombination (HR) DNA double-strand break (DSB) repair pathway. Because BRCA- deficient cancer cells are impaired in HR, they are susceptible to drugs that cause DNA damage and/or block DNA repair. Approximately 5-10% of breast cancers and ~50% of epithelial ovarian cancers are defective in the BRCA pathway. Thus, these cancer types have been used to develop first-generation personalized medicines that kill BRCA-deficient cells by inactivating Poly-ADP ribose polymerase 1 (PARP1) which promotes base excision repair. Despite the initial success of PARP inhibitors (PARPi), drug resistance has become a major problem in the clinic. Thus, it is important to identify and develop alternative drug targets involved in DNA repair as next-generation personalized medicines for BRCA-deficient cancers that increase patient survival rates and potentially reduce drug resistance. Recent studies have identified DNA polymerase theta (Polq) as a promising new precision medicine drug target in BRCA-deficient breast and ovarian cancers. We have identified selective Polq inhibitors (Polqi) that preferentially kill BRCA-deficient breast cancer cells and BRCA-deficient leukemia cells. These data demonstrate proof of concept that selective Polqi can be developed as pre-clinical drug leads that target BRCA-deficient cancer cells for killing. In Phase I research, we plan to optimize the potency and drug-like properties of our leading Polqi via structure-activity relationship (SAR) studies, and test the efficacy of our lead drug candidate as monotherapy and as combination therapy with PARPi in BRCA-deficient breast cancer xenografts in vivo. In summary, we anticipate that optimized Polqi will preferentially kill BRCA-mutated breast cancer cells in vitro and in vivo, while having little or no effects in normal cells.

精准医学是一种革命性的治疗方法，其中设计和选择疗法基于某些癌症中存在的基因突变。例如，治疗 BRCA 缺陷患者使用抑制特定 DNA 修复途径的药物可以选择性杀死这些癌症细胞。这种方法基于合成致死性的概念，即特定基因的失活该产品根据基因突变选择性杀死细胞，同时不伤害正常细胞。综合杀伤力有被用于靶向 BRCA1 或 BRCA2 肿瘤抑制蛋白突变或缺陷的癌细胞促进同源重组（HR）DNA双链断裂（DSB）修复途径。因为 BRCA- 缺陷癌细胞的 HR 受损，它们容易受到导致 DNA 损伤和/或阻断的药物的影响 DNA修复。大约 5-10% 的乳腺癌和约 50% 的上皮性卵巢癌在 BRCA 途径。因此，这些癌症类型已被用于开发第一代个性化药物通过灭活聚 ADP 核糖聚合酶 1 (PARP1) 来杀死 BRCA 缺陷细胞，而聚 ADP 核糖聚合酶 1 (PARP1) 可促进碱基切除修复。尽管 PARP 抑制剂（PARPi）取得了初步成功，但耐药性已成为一个主要问题诊所中的问题。因此，识别和开发参与 DNA 修复的替代药物靶点非常重要作为针对 BRCA 缺陷癌症的下一代个性化药物，可提高患者的生存率，可能降低耐药性。最近的研究发现 DNA 聚合酶 theta (Polq) 是一种有前途的新型精准医疗药物 BRCA 缺陷型乳腺癌和卵巢癌的靶标。我们已经鉴定出选择性 Polq 抑制剂 (Polqi) 优先杀死BRCA缺陷型乳腺癌细胞和BRCA缺陷型白血病细胞。这些数据表明概念证明选择性 Polqi 可以开发为针对 BRCA 缺陷的临床前药物先导药物用于杀死癌细胞。在第一阶段研究中，我们计划优化我们的药物的效力和类药特性通过构效关系 (SAR) 研究引领 Polqi，并测试我们的主要候选药物的功效体内 BRCA 缺陷乳腺癌异种移植物的单一疗法和与 PARPi 的联合疗法。在总之，我们预计优化后的 Polqi 将在体外优先杀死 BRCA 突变乳腺癌细胞，在体内，而对正常细胞几乎没有影响。