Novel Strategies to Extend DNA Repair Therapies for Triple Negative Breast Cance

项目3建立在DF/HCC内广泛的基础、转化和正在进行的临床工作的基础上，并解决了一个临床上紧迫的问题：需要更有效的治疗策略来治疗散发性三阴性乳腺癌。其目的是通过开发使BRCA-熟练的三阴性乳腺癌细胞对PARP抑制敏感的方法来改变当前的范式。两个高度创新的治疗策略将被使用，都涉及同源重组的新认识方面。在目标1中，我们将专注于开发利用dinaciclib和veliparib的CDK抑制剂/PARP抑制剂组合。该药物组合将在三阴性乳腺癌细胞系和原位原发性肿瘤异种移植模型中进行研究。最终，该组合将转化为II期临床试验，该试验将探索疗效和药效学终点。目的2利用了关于同源重组的先前未被认识到的方面的另一个观察结果，该观察结果表明蛋白酶体抑制导致同源重组缺陷，从而导致对PARP抑制的敏感性。我们将通过在三阴性乳腺癌细胞系、患者来源的原位异种移植模型和早期临床试验中的工作进行类似的研究，重点是硼替佐米/维利帕尼组合。对于硼替佐米/维利帕尼组合的临床转化，将在UO 1支持的I期临床试验中确定该组合的推荐II期剂量。完成剂量递增后，SPORE将支持三阴性乳腺癌队列的入组，以确认该人群的安全性并进行相关研究。

Project 3 builds upon extensive basic, translational and ongoing clinical work within DF/HCC, and addresses a clinically pressing issue: the need for more effective treatment strategies for sporadic triple negative breast cancer. It aims to shift current paradigms by the development of approaches that will sensitize BRCA-proficient triple negative breast cancer cells to PARP inhibition. Two highly innovative therapeutic strategies will be used, both involving newly appreciated aspects of homologous recombination. In Aim 1, we will focus on the development of a CDK inhibitor/PARP inhibitor combination utilizing dinaciclib and veliparib. The drug combination will be studied in triple negative breast cancer cell lines and orthotopic primary tumor xenograft models. Ultimately, the combination will be translated to a Phase 2 clinical trial that will explore efficacy and pharmacodynamic endpoints. Aim 2 takes advantage of another observation regarding previously unappreciated aspects of homologous recombination indicating that proteasome inhibition leads to a defect in homologous recombination, and thus sensitivity to PARP inhibition. We will proceed similarly through work in triple negative breast cancer cell lines, patient-derived orthotopic xenograft models and early phase clinical trial, focusing on the bortezomib/veliparib combination. For the clinical translation of the bortezomib/veliparib combination, the recommended phase 2 doses of the combination will be established in a UO1-supported phase 1 clinical trial. Following completion of the dose escalation, the SPORE will support enrollment of a triple negative breast cancer cohort in order to confirm safety in this population and to perform correlative studies.