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：
10551902
负责人：
WILLIAM Lee KRAUS
金额：
$ 36.32万
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/10551902
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 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 Study Play Poly(ADP-ribose) Polymerase Inhibitor Poly(ADP-ribose) Polymerases Primary Neoplasm Proliferating Proteins Proteomics Regulation Resistance Role Scheme Series Skeleton TNFSF11 gene Testing Therapeutic Time advanced breast cancer analog bisphosphonate bone cancer cell cancer complication cancer therapy candidate identification cell type chemical genetics clinical development clinically relevant design gain of function genetic approach in vivo individualized medicine inhibitor inhibitor therapy innovation insight knock-down loss of function malignant breast neoplasm mortality neoplastic cell novel osteoclastogenesis overexpression palliative personalized medicine pharmacologic 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.

骨转移是一种频繁的，令人衰弱的癌症并发症。超过70％晚期乳腺癌患者患有转移性骨病，导致严重的骨痛，病理学断裂，威胁生命的高钙血症，脊髓压缩，迁移率有限和死亡率增加。在骨转移期间，癌细胞和破骨细胞形成恶性循环，使癌细胞促进破骨细胞分化和破骨细胞反过来促进癌细胞播种和骨骼增殖环境。但是，当前对这种恶意基础的复杂机制的理解周期仍然有限，现有的破骨细胞抑制剂药物赋予没有生存益处。我们的总体目标是为了发现癌症骨转移的新的，更好的治疗方法，同时抑制两者癌细胞和破骨细胞。 2014年12月，聚（ADP-核糖）聚合酶（PARP）的抑制剂，Olaparib，被FDA批准用于治疗经过的BRCA缺陷性卵巢癌。从那以后，又有两个parp 抑制剂也已获得FDA批准。目前，几种PARP1/2双重抑制剂也在临床试验中作为乳腺癌疗法。尽管在癌症治疗中对PARP抑制剂进行了临床努力，但知之甚少关于Parps在转移中的作用。而且，目前尚不清楚PARP家族是否以及如何不同成员显示不同的功能。在我们的初步研究中，我们发现PARP2损失，但没有PARP1 损失，通过在破骨细胞和肿瘤细胞中作用来促进骨转移，从而增强骨质质质质发生。 Olaparib处理以依赖于修饰符（例如BRCA）的方式加剧了骨转移状态和耐药性。我们假设PARP2是通过调节破骨细胞和肿瘤细胞中的关键靶标有协同障碍乳腺癌恶性肿瘤。我们在这里建议进行一系列全面分析，以检验这一假设，结合遗传和药理，功能丧失功能，体外和体内策略。在AIM 1中，我们将确定如何破骨细胞中的PARP调节骨转移。在AIM 2中，我们将确定癌细胞中的PARP如何调节骨转移。在AIM 3中，我们将阐明PARP调控的分子和生化机制通过识别和功能表征关键PARP靶标的骨转移。这项调查很高显着且在临床上相关，因为它将识别PARP2是一种新型的乳腺癌双重抑制剂骨转移，发现当前PARP1/2双重抑制剂的潜在有害但依赖上下文依赖性效应癌症药物加剧了骨骼转移，揭示了PARP2和 PARP1建议PARP1特异性抑制剂可能是更安全的选择，突出显示令人兴奋的治疗潜力 PARP2激活以减轻乳腺癌的骨转移，并为个性化提供关键见解药物和量身定制的治疗方法可以更好地设计并利用PARP抑制剂作为癌症药物。