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

项目3建立在DF/HCC广泛的基础、转化和正在进行的临床工作的基础上，并解决了一个临床紧迫问题：需要更有效的散发性三阴性乳腺癌治疗策略。它的目的是通过发展使brca精通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。将使用两种高度创新的治疗策略，都涉及同源重组的新认识方面。在Aim 1中，我们将专注于利用dinaciclib和veliparib开发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肿瘤异种移植模型中进行研究。最终，该组合将进入2期临床试验，以探索疗效和药效学终点。Aim 2利用了另一个先前未被认识到的同源重组方面的观察结果，表明蛋白酶体抑制导致同源重组缺陷，从而对PARP抑制敏感。我们将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进行类似的工作，重点是硼替佐米/维利帕里联合治疗。对于硼替佐米/veliparib组合的临床转化，该组合的推荐2期剂量将在u01支持的1期临床试验中确定。在完成剂量递增后，SPORE将支持三阴性乳腺癌队列的登记，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.