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

项目摘要/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生长的分子 当被其配体雌激素激活时，细胞增殖。尽管治疗ER+乳房的患者取得了成功 使用内分泌治疗的肿瘤，大约33%的接受治疗的患者会发生复发转移 内分泌治疗后的肿瘤。这些复发的肿瘤主要转移到骨骼，对 目前的治疗方案。骨骼是乳腺癌最常见和最危险的部位之一。 转移性肿瘤生长。在死亡时，大约73%的乳腺癌女性患者有骨转移。这块骨头 建筑和无处不在的血管窦提供了接近和容易退出骨骼的机会，以增加 从转移性骨肿瘤扩散到全身。骨骼微环境会释放细胞因子， 抑制癌细胞在健康骨骼中定植或支持定植的趋化因子和生长因子 在癌症中。这些因素还可以创造一种免疫抑制环境，阻止正常的免疫。 对免疫疗法的反应或反应。 在拟议的研究中，我们将研究趋化因子CXCL5、其诱骗受体Ackr1和它的 受体CXCR2参与ER+乳腺癌的骨转移定植。我们还将研究CXCR2 作为单一药物和联合治疗(与双磷酸盐或 免疫疗法)，以抑制乳腺癌的骨转移。CXCR2抑制剂是有吸引力的治疗药物 抗转移性乳腺癌，可能对转移性骨肿瘤的形成有疗效 它们依赖于CXCL5：CXCR2信号轴，对当前的治疗方案耐药。由于患者患有 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 翻译潜力。值得注意的是，如果靶向或抑制这些因素可以减少骨转移 临床前动物模型，那么我们将在资助期结束时提出这些 化合物用于ER+肿瘤转移到骨的乳腺癌患者的临床试验。自.以来 这些复发的肿瘤通常对目前的治疗方法反应不佳，这种治疗策略将是 显著的影响，并为这种疾病的患者带来了巨大的希望。附加服务的未来发展 优化的CXCL5/CXCR2小分子或多肽抑制剂将扩大现有的治疗选择 为临床医生在护理乳腺癌转移性疾病患者提供帮助。

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.