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Context-Dependent Effects of PARP Inhibitors on Breast Cancer Bone Metastasis

PARP 抑制剂对乳腺癌骨转移的背景依赖性影响

基本信息

批准号：
9987293
负责人：
WILLIAM Lee KRAUS
金额：
$ 37.06万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-10 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9987293
关键词：
Antibodies Antineoplastic Agents Attenuated BRCA mutations Binding Proteins Biochemical Bone Diseases Bone Pain Bone Resorption Breast Cancer therapy Cancer Etiology Cell Death Cells ChIP-seq Chromatin Clinical Clinical Trials Collaborations Communities DNA Binding DNA Repair DNA-Binding Proteins Drug resistance Environment FDA approved Family member Gene Expression Regulation Genetic Genetic Transcription Genetic study Genomics Goals Hypercalcemia In Vitro Investigation Knockout Mice Life Malignant Bone Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Metastatic Neoplasm to the Bone MicroRNAs Molecular Molecular Target Mus Mutagenesis Nature Neoplasm Metastasis Osteoclasts Pathological fracture Patients Pharmaceutical Preparations Pharmacology Pharmacology Study Play Poly(ADP-ribose) Polymerases Primary Neoplasm Proteins Proteomics Regulation Resistance Role Scheme Series Skeleton TNFSF11 gene Testing Therapeutic Time advanced breast cancer analog base bisphosphonate bone cancer cell cancer complication cancer therapy cell type chemical genetics clinical development clinically relevant design genetic approach in vivo individualized medicine inhibitor/antagonist innovation insight knock-down loss of function malignant breast neoplasm mortality neoplastic cell novel osteoclastogenesis overexpression palliative personalized medicine skeletal spinal cord compression tool transcriptome sequencing tumor tumor growth

项目摘要

Bone metastasis is a frequent, debilitating and essentially incurable cancer complication. More than 70% of patients with advanced breast cancer have metastatic bone disease, leading to severe bone pain, pathological fracture, life-threatening hypercalcemia, spinal cord compression, limited mobility and increased mortality. During bone metastasis, cancer cells and osteoclasts form a vicious cycle so that cancer cells promote osteoclast differentiation and osteoclasts in turn facilitate cancer cell seeding and proliferation in the skeletal environment. Nonetheless, the current understanding of the intricate mechanisms underlying this malicious cycle is still limited, and the existing osteoclast inhibitor drugs confer no survival benefit. Our overarching goal is to discover new and better treatment for cancer bone metastasis that simultaneously suppresses both cancer cell and osteoclast. In December 2014, an inhibitor of Poly (ADP-ribose) polymerase (PARP), Olaparib, was approved by the FDA for treating elapsed BRCA-defective ovarian cancer. Since then, two more PARP inhibitors have also received FDA approval. Several PARP1/2 dual inhibitors are also currently in clinical trials as breast cancer therapy. Despite these clinical efforts on PARP inhibitors in cancer treatment, little is known about the roles of PARPs in metastasis. Moreover, it is unclear whether and how different PARP family members display distinct functions. In our preliminary studies, we have found that PARP2 loss, but not PARP1 loss, promotes bone metastasis by acting in both osteoclast and tumor cell to enhance osteoclastogenesis; olaparib treatment exacerbates bone metastasis in a manner that is dependent on modifiers such as BRCA status and drug resistance. We hypothesize that PARP2 is a powerful dual suppressor of bone metastasis by regulating key targets in osteoclast and tumor cell to synergistically impede breast cancer malignancy. Here we propose to perform a series of comprehensive analyses to test this hypothesis, combining genetic and pharmacological, gain- and loss-of-function, in vitro and in vivo strategies. In Aim 1, we will determine how PARPs in osteoclast regulate bone metastasis. In Aim 2, we will determine how PARPs in cancer cell regulate bone metastasis. In Aim 3, we will elucidate the molecular and biochemical mechanisms for PARP regulation of bone metastasis by identifying and functionally characterizing key PARP targets. This investigation is highly significant and clinically relevant because it will identify PARP2 as a novel dual suppressor of breast cancer bone metastasis, uncover potential deleterious yet context-dependent effects of current PARP1/2 dual inhibitor cancer drugs to exacerbate skeletal metastasis, reveal important functional distinctions between PARP2 and PARP1, suggest PARP1-specific inhibitors as possibly safer options, highlight the exciting therapeutic potential of PARP2 activation to mitigate breast cancer bone metastasis, and provide crucial insights for personalized medicine and tailored treatment to better design and utilize PARP inhibitors as cancer drugs.

骨转移是一种常见的、使人衰弱的、基本上无法治愈的癌症并发症。超过70%的