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、翻译和正在进行的临床工作的基础上，并解决了一个临床紧迫的问题：需要对零星的三阴性乳腺癌采取更有效的治疗策略。它的目的是通过开发使精通BRCA的三阴性乳腺癌细胞对PARP抑制敏感的方法来改变目前的范式。将使用两种高度创新的治疗策略，都涉及到新认识的同源重组方面。在目标1中，我们将重点开发利用地奈西利和维利帕利的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肿瘤异种移植模型中进行研究。最终，这一组合将转化为第二阶段临床试验，探索疗效和药效终点。目的2利用另一个关于同源重组以前未被认识的方面的观察，表明蛋白酶体抑制导致同源重组的缺陷，从而对PARP抑制敏感。我们将通过三重阴性乳腺癌细胞系、患者来源的原位异种移植模型和早期临床试验进行类似的工作，重点是bortezomib/veliparib组合。对于bortezomib/veliparib组合的临床翻译，该组合的推荐2期剂量将在UO1支持的1期临床试验中确定。在完成剂量升级后，孢子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.