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

• 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
• 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

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.

精准医疗是一种革命性的治疗方法，在这种方法中， 基于某些癌症中存在的基因突变例如，治疗BRCA缺乏的患者 使用抑制特定DNA修复途径的药物的癌症可导致选择性杀死这些癌症 细胞这种方法是基于合成致死性的概念，即特定基因的失活 该产品基于基因突变选择性地杀死细胞，同时保留正常细胞。合成杀伤力 已被用于靶向突变或缺乏BRCA 1或BRCA 2肿瘤抑制蛋白的癌细胞， 促进同源重组（HR）DNA双链断裂（DSB）修复途径。因为BRCA- 缺乏HR的癌细胞受损，它们对导致DNA损伤和/或阻断的药物敏感。 DNA修复大约5-10%的乳腺癌和~50%的上皮性卵巢癌在免疫缺陷方面存在缺陷。 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 其通过灭活聚ADP核糖聚合酶1（PARP 1）杀死BRCA缺陷细胞， 切除修复尽管PARP抑制剂（PARPi）最初取得了成功，但耐药性已成为主要的耐药因素。 诊所里的问题。因此，识别和开发参与DNA修复的替代药物靶标是重要的 作为治疗BRCA缺陷癌症的下一代个性化药物，可提高患者生存率， 潜在地降低耐药性。 最近的研究已经确定DNA聚合酶theta（Polq）是一种有前途的新型精准医学药物 靶向BRCA缺陷乳腺癌和卵巢癌。我们已经确定了选择性Polq抑制剂（Polqi）， 优先杀死BRCA缺陷乳腺癌细胞和BRCA缺陷白血病细胞。这些数据证明 概念证明，选择性Polqi可开发为靶向BRCA缺陷的临床前药物先导 杀死癌细胞。在第一阶段的研究中，我们计划优化我们的药物的效力和药物性质。 通过结构-活性关系（SAR）研究领导Polqi，并测试我们的主要候选药物的疗效， 单药治疗以及与PARPi联合治疗BRCA缺陷乳腺癌体内异种移植物。在 总之，我们预期优化的Polqi将在体外优先杀死BRCA突变的乳腺癌细胞， 在体内，而在正常细胞中几乎没有影响。