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

• 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
• 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

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、使人衰弱且基本上无法治愈的癌症并发症。超过70% 晚期乳腺癌患者患有转移性骨病，导致严重的骨痛、病理性骨痛。 骨折、危及生命的高钙血症、脊髓受压、活动受限和死亡率增加。 骨转移过程中，癌细胞与破骨细胞形成恶性循环，使癌细胞促进骨转移。 破骨细胞分化和破骨细胞反过来促进骨骼中癌细胞的播种和增殖 环境。尽管如此，目前对这种恶意行为背后的复杂机制的理解 周期仍然有限，并且现有的破骨细胞抑制剂药物没有带来生存益处。我们的总体目标 是发现新的更好的癌症骨转移治疗方法，同时抑制 癌细胞和破骨细胞。 2014年12月，聚（ADP-核糖）聚合酶（PARP）抑制剂Olaparib， 经 FDA 批准用于治疗 BRCA 缺陷型卵巢癌。此后，又有两个 PARP 抑制剂也已获得 FDA 批准。多种PARP1/2双抑制剂目前也处于临床试验阶段 作为乳腺癌治疗。尽管在癌症治疗中 PARP 抑制剂有这些临床努力，但人们知之甚少 关于 PARP 在转移中的作用。此外，尚不清楚 PARP 家族是否以及如何不同 成员发挥不同的功能。在我们的初步研究中，我们发现 PARP2 丢失，但 PARP1 没有丢失 通过作用于破骨细胞和肿瘤细胞来增强破骨细胞生成，从而促进骨转移； 奥拉帕尼治疗会加剧骨转移，其方式依赖于 BRCA 等修饰因子 状态和耐药性。我们假设 PARP2 是骨转移的强大双重抑制剂 调节破骨细胞和肿瘤细胞的关键靶标，协同阻止乳腺癌恶性肿瘤。在这里我们 建议进行一系列综合分析来检验这一假设，结合遗传和 药理学、功能获得和丧失、体外和体内策略。在目标 1 中，我们将确定如何 破骨细胞中的 PARP 调节骨转移。在目标 2 中，我们将确定癌细胞中的 PARPs 如何调节 骨转移。在目标 3 中，我们将阐明 PARP 调节的分子和生化机制 通过识别关键 PARP 靶点并对其功能进行表征来研究骨转移。此次调查的高度 具有重要意义和临床相关性，因为它将确定 PARP2 是乳腺癌的新型双重抑制因子 骨转移，揭示当前 PARP1/2 双抑制剂的潜在有害但与环境相关的影响 癌症药物加剧骨骼转移，揭示了 PARP2 和 PARP2 之间的重要功能区别 PARP1，表明 PARP1 特异性抑制剂可能是更安全的选择，强调了令人兴奋的治疗潜力 PARP2 激活减轻乳腺癌骨转移，并为个性化治疗提供重要见解 药物和定制治疗，以更好地设计和利用 PARP 抑制剂作为抗癌药物。