Next-generation precision medicine for targeting recombination-deficient cancers

精确医学是一种革命性的治疗方法，它设计和选择了治疗方法 基于某些癌症中存在的基因突变。例如，治疗BRCA缺乏的患者 带有抑制特定DNA修复途径的药物的癌症可以导致选择性地杀死这些癌症 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 该产品根据细胞的基因突变选择性地杀死细胞，同时保留正常细胞。人工合成杀伤力 用于靶向BRCA1或BRCA2肿瘤抑制蛋白突变或缺失的癌细胞 促进同源重组(HR)DNA双链断裂(DSB)修复途径。因为BRCA- 有缺陷的癌细胞在HR中受损，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 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 通过灭活促进碱基的多聚ADP核糖聚合酶1(PARP1)来杀死BRCA缺陷细胞 切除修复。尽管PARP抑制剂(PARPI)取得了初步成功，但耐药性已成为主要 诊所里的问题。因此，确定和开发参与dna修复的替代药物靶点是很重要的。 作为治疗BRCA缺陷癌症的下一代个性化药物，可提高患者存活率和 有可能降低抗药性。 最近的研究发现dna聚合酶theta(Polq)是一种很有前途的精准药物。 BRCA缺陷型乳腺癌和卵巢癌的靶点。我们已经确定了选择性POLQ抑制剂(POLQI) 优先杀伤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 选择性波尔奇可被开发为临床前药物导致靶向BRCA缺陷的概念的证明 用于杀戮的癌细胞。在第一阶段的研究中，我们计划优化我们的药效和类药物特性 通过结构-活性关系(SAR)研究领导波尔奇，并测试我们的领先候选药物作为 BRCA缺陷型乳腺癌体内移植瘤的单一治疗和AS联合治疗。在……里面 综上所述，我们预计优化的Polqi在体外和体外将优先杀死BRCA突变的乳腺癌细胞 在体内，而对正常细胞几乎没有影响。

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.