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

延长三阴性乳腺癌 DNA 修复疗法的新策略

基本信息

批准号：
8607755
负责人：
ALAN D. D'ANDREA
金额：
$ 30.94万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-17 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607755
关键词：
Accounting Address African American Aggressive behavior Androgen Receptor BRCA1 gene Biological Markers Biology Biopsy Bortezomib Breast Breast Cancer Cell Cancer Patient Cancer Therapy Evaluation Program Cancer cell line Classification Clinical Clinical Trials Correlative Study Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases DNA Damage DNA Repair Dana-Farber Cancer Institute Defect Development Diagnosis Disease Dose Drug Combinations Enrollment Fanconi Anemia-BRCA Pathway Future Genetic Transcription Goals Grouping Heterogeneity In Vitro Laboratories Malignant Neoplasms Mesenchymal Molecular Target Mus Normal tissue morphology Pathway interactions Patients Pharmacodynamics Phase Phase I Clinical Trials Phase II Clinical Trials Poly(ADP-ribose) Polymerases Population Primary Neoplasm Proteasome Inhibition Proteasome Inhibitor Safety Solid Neoplasm Testing Therapeutic Time Toxic effect Translating Translations Woman Work Xenograft Model base cancer cell chemotherapy cohort effective therapy homologous recombination in vivo inhibitor/antagonist innovation malignant breast neoplasm neoplastic cell novel strategies novel therapeutic intervention phase 1 study phase 2 study pre-clinical recombinational repair stem treatment strategy triple-negative invasive breast carcinoma tumor tumor xenograft

项目摘要

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.

项目 3 以 DF/HCC 内广泛的基础、转化和持续临床工作为基础，解决临床紧迫问题：散发性三阴性乳腺癌需要更有效的治疗策略。它旨在通过开发使 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。将使用两种高度创新的治疗策略，两者都涉及同源重组的新认识方面。在目标 1 中，我们将重点开发利用 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肿瘤异种移植模型中进行研究。最终，该组合将转化为二期临床试验，探索疗效和药效学终点。目标 2 利用了关于同源重组先前未被认识的方面的另一项观察结果，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进行类似的工作，重点关注硼替佐米/维利帕尼组合。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UO1支持的1期临床试验中确定。剂量递增完成后，SPORE 将支持三阴性乳腺癌队列的招募，以确认该人群的安全性并进行相关研究。