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

骨转移是一种常见的、使人衰弱的和基本上不可治愈的癌症并发症。70%以上 晚期乳腺癌患者有转移性骨病，导致严重的骨痛，病理性 骨折、危及生命的高钙血症、脊髓压迫、活动受限和死亡率增加。 在骨转移过程中，癌细胞和破骨细胞形成恶性循环，使得癌细胞促进骨转移。 破骨细胞分化和破骨细胞反过来促进癌细胞在骨骼中的种植和增殖， 环境尽管如此，目前对这种恶意软件背后复杂机制的理解 周期仍然有限，现有的破骨细胞抑制剂药物不能带来生存益处。我们的总目标 是发现新的更好的治疗癌症骨转移的方法，同时抑制 癌细胞和破骨细胞。2014年12月，聚（ADP-核糖）聚合酶（PARP）抑制剂奥拉帕尼， 被FDA批准用于治疗复发的BRCA缺陷卵巢癌。此后，又有两名PARP 抑制剂也已获得FDA批准。几种PARP 1/2双重抑制剂目前也在临床试验中 as breast乳腺cancer癌症therapy治疗.尽管在癌症治疗中对PARP抑制剂进行了这些临床努力，但知之甚少。 PARP在转移中的作用此外，目前还不清楚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PARP 2的丢失，而不是PARP 1 丢失，通过作用于破骨细胞和肿瘤细胞以增强破骨细胞生成来促进骨转移; 奥拉帕尼治疗以依赖于诸如BRCA的修饰剂的方式加重骨转移 状态和耐药性。我们假设PARP 2是一个强大的骨转移双重抑制因子， 调节破骨细胞和肿瘤细胞中的关键靶点以协同阻止乳腺癌恶性。这里我们 我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PARP如何调节 骨转移在目标3中，我们将阐明PARP调控的分子和生化机制 通过识别和功能性表征关键PARP靶点来研究骨转移。这项调查是高度 因为它将PARP 2鉴定为乳腺癌的新型双重抑制因子 骨转移，揭示了当前PARP 1/2双重抑制剂的潜在有害但依赖于环境的作用 癌症药物加剧骨转移，揭示了PARP 2和 PARP 1，建议PARP 1特异性抑制剂作为可能更安全的选择，突出了令人兴奋的治疗潜力 PARP 2激活可减轻乳腺癌骨转移，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抑制剂作为癌症药物。

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.