CXCL5/CXCR2 axis as a therapeutic vulnerability of breast cancer metastasis to bone

项目概要/摘要 大多数乳腺癌表达雌激素受体a（ER+），这是一种典型的促进细胞凋亡的分子。 当被其配体雌激素激活时增殖。尽管在治疗ER+乳腺癌患者方面取得了成功， 在接受内分泌治疗的肿瘤患者中，约33%的患者会发生复发性转移 内分泌治疗后的肿瘤这些复发性肿瘤主要转移到骨，对化疗无反应。 目前的治疗方案。骨是乳腺癌最常见也是最危险的部位之一 转移性肿瘤生长。在死亡时，大约73%的乳腺癌女性患有骨转移。骨 血管窦状隙的结构和普遍存在提供了骨的可及性和容易的退出，以增加 转移性骨肿瘤在体内的扩散骨微环境释放细胞因子， 抑制癌细胞在健康骨中定植或支持定植的趋化因子和生长因子 在癌症中。这些因素也可以创造一个免疫抑制环境，阻止正常的免疫反应。 对免疫疗法的反应或应答。 在这项研究中，我们将研究趋化因子Cxc 15，其诱饵受体Ackr 1，及其受体Ackr 1， 受体Cxcr 2有助于ER+乳腺癌骨转移定植。我们还将研究CXCR 2 抑制剂作为单一药剂和作为组合疗法（与二膦酸盐或 免疫疗法）以抑制乳腺癌转移到骨。CXCR 2抑制剂是有吸引力的治疗剂 其可有效治疗转移性骨肿瘤的形成 依赖于CXCL 5：CXCR 2信号传导轴并且对当前疗法有抗性。由于患者 这些肿瘤目前几乎没有治疗选择，而且往往是无法治愈的，这项研究可能具有重要意义。 平移势值得注意的是，如果靶向或抑制这些因子可以减少骨转移， 临床前动物模型，那么我们将在资助期结束时提出， 这些化合物可用于ER+肿瘤转移至骨的乳腺癌患者的临床试验。以来 这些复发性肿瘤通常对目前的治疗反应不佳，这种治疗策略将 影响重大，为患者带来了巨大的希望。未来发展的补充 优化的CXCL 5/CXCR 2的小分子或肽抑制剂将扩大可用的治疗选择 临床医生在乳腺癌转移性疾病患者的护理。

PROJECT SUMMARY/ABSTRACT The majority of breast cancers express estrogen receptor a (ER+), a molecule that typically promotes cell proliferation when activated by its ligand estrogen. Despite successes seen in treating patients with ER+ breast tumors with endocrine therapies, approximately 33% of these treated patients will develop recurrent metastatic tumors after endocrine treatment. These recurrent tumors primarily metastasize to bone and do not respond to current treatment options. Bone is the most common and one of the most dangerous sites for breast cancer metastatic tumor growth. At death, roughly 73% of women with breast cancer have bone metastasis. The bone architecture and the ubiquity of vascular sinusoids provide accessibility to and easy exit from bone to increase the spread through the body from the metastatic bone tumor. The bone microenvironment releases cytokines, chemokines, and growth factors that inhibit colonization of cancer cells in healthy bone or support colonization in cancer. These factors also can create an immunosuppressive environment that prevents a normal immune response or response to immunotherapy. In the proposed research, we will investigate how the chemokine Cxcl5, its decoy receptor Ackr1, and its receptor Cxcr2 contribute to ER+ breast cancer metastatic colonization of bone. We also will examine CXCR2 inhibitors for their efficacy as single agents and as a combination therapy (with bisphosphonates or immunotherapy) to inhibit breast cancer metastasis to bone. CXCR2 inhibitors are attractive therapeutics against metastatic breast cancer that may have efficacy in treating the formation of metastatic bone tumors that are dependent on the CXCL5:CXCR2 signaling axis and resistant to current therapies. Since patients with these tumors currently have few treatment options and often are incurable, this study could have significant translational potential. Significantly, if targeting or inhibiting these factors can reduce bone metastasis in preclinical animal models, then we will be in a position at the end of the grant period to propose that these compounds be used in a clinical trial in breast cancer patients with ER+ tumors metastasized to bone. Since these recurrent tumors typically do not respond well to current therapies, this treatment strategy would be significantly impactful and bring significant hope for patients with this disease. Future development of additional optimized small molecules or peptide inhibitors of CXCL5/CXCR2 will expand the therapeutic options available to clinicians in the care of breast cancer patients with metastatic disease.