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.

精密医学是一种设计和选择疗法的革命性治疗方法 基于某些癌症中存在的基因突变。例如，治疗BRCA缺陷患者 用抑制特定DNA修复途径的药物的癌症会导致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，在该概念中，特定基因失活 产品根据其基因突变选择性杀死细胞，同时避免正常细胞。合成致死性 用于靶向BRCA1或BRCA2抑制蛋白突变或缺乏的癌细胞，该蛋白 促进同源重组（HR）DNA双链断裂（DSB）修复途径。因为brca- 缺乏癌细胞在人力资源中受损，它们容易受到造成DNA损伤和/或阻滞的药物 DNA修复。大约5-10％的乳腺癌和约50％的上​​皮卵巢癌在 BRCA途径。因此，这些癌症类型已用于开发第一代个性化药物 通过灭活多聚ADP核糖聚合酶1（PARP1）来杀死BRCA缺陷型细胞，该细胞促进碱 切除维修。尽管PARP抑制剂（PARPI）最初取得了成功，但耐药性已成为主要 诊所的问题。因此，重要的是要识别和开发与DNA修复有关的替代药物靶标 作为用于BRCA缺陷癌症的下一代个性化药物，以提高患者的存活率和 有可能降低耐药性。 最近的研究已将DNA聚合酶theta（POLQ）确定为一种有希望的新精密药物药物 靶向BRCA缺乏的乳腺癌和卵巢癌。我们已经确定了选择性POLQ抑制剂（POLQI） 优先杀死缺乏BRCA的乳腺癌细胞和BRCA缺乏性白血病细胞。这些数据证明了 概念证明可以作为临床前药物铅的选择性POLQI，以靶向BRCA缺陷 癌细胞杀死。在第一阶段的研究中，我们计划优化我们的效力和类似药物的特性 通过结构活性关系（SAR）研究领导POLQI，并测试我们的主要药物候选者的功效 单一疗法和作为BRCA缺陷乳腺癌异种移植体的PARPI组合疗法在体内。在 总而言之，我们预计经过优化的POLQI将优先杀死Brca突变的乳腺癌细胞，并 在体内，虽然在正常细胞中几乎没有影响。