Host Cell Assisted Primary and Metastatic Tumor Regrowth after Chemotherapy

描述(申请人提供)：针对肿瘤血管生成的VEGF-VEGFR-2途径的抗体，如贝伐单抗，在晚期转移性疾病的治疗中影响很小或没有影响。相反，当与标准化疗方案联合使用时，有时会获得临床益处。然而，即使在这种情况下，生存的好处也是有限的。抗血管生成治疗的化学增敏能力的基础尚不清楚；改进可能来自于对相关机制的更好理解。假设：在某些情况下，常规化疗可以诱导骨髓(BM)来源细胞的急性动员，包括VEGFR-2循环内皮祖细胞(CEP)，这些细胞是大量药物治疗肿瘤的宿主和定植，从而改变肿瘤血管生成微环境并刺激肿瘤重新生长；这种全身宿主反应可以通过联合使用药物(如VEGFR-2靶向抗体)或小剂量的节拍(抗血管生成)化疗而显著阻断。具体目标：首先，将测试一些化疗药物对CEP的急性动员和肿瘤归巢的诱导作用，以及在这些药物中，是否通过使用药理学和遗传学方法阻断这种宿主反应来增强其抗肿瘤效果。第二个目标涉及分析化疗诱导的骨髓来源细胞在原位和异位原发移植瘤以及肝、肺或脑中生长的晚期转移瘤中的定植。第三个目的是分析化疗诱导的骨髓来源细胞动员和肿瘤定植的分子机制，包括G-CSF、A4？1整合素和CXCR4趋化因子受体及其配体SDF-1的作用。第四个目标将评估其他骨髓来源的促血管生成CD45细胞群具有血管白细胞特性，例如Gr1 CD11b髓系细胞或表达Tie-2的单核细胞等。最后，第五个目标旨在评估化疗是否会在癌症患者中诱导CEP激增，包括MTD紫杉烷，如果是，贝伐单抗是否会钝化这种宿主反应。意义/影响：这项研究以一种新的方式将化疗、肿瘤血管生成、抗血管生成治疗和肿瘤微环境联系起来；它将为联合化疗时抗癌治疗指明新的靶点，但可能会因转移环境而异，并为包括CEP在内的骨髓来源细胞在肿瘤生物学和治疗中的贡献提供新的视角。公共卫生相关性：拟议研究对公共健康的相关性在于它有可能改善接受化疗和抗血管生成药物或治疗的联合治疗的癌症患者的治疗结果。这一点至关重要，因为与单独化疗相比，这种联合疗法目前的好处非常有限，而且是以副作用增加和财务成本迅速上升为代价的。这项拟议的研究概述了通过利用全身骨髓和血液环境的各个方面以及局部肿瘤微环境(包括肝、肺和脑等不同器官部位的转移)来获得此类改善的策略。

DESCRIPTION (provided by applicant): Antibodies such as bevacizumab targeting the VEGF-VEGFR-2 pathway of tumor angiogenesis have little or no impact in the treatment of advanced metastatic disease. Instead, clinical benefit is sometimes attained when used in combination with standard chemotherapy regimens. However, even in such cases, the survival benefits are modest. The basis for the chemosensitizing ability of antiangiogenic therapy remain unclear; improvements are likely to come from a better understanding of the mechanisms involved. Hypothesis: Conventional chemotherapy can, in some cases, induce an acute mobilization of bone marrow (BM)-derived cells, including VEGFR-2+ circulating endothelial progenitors (CEPs) which home to and colonize drug treated tumors in large numbers, thus altering the tumor angiogenic microenvironment and stimulating tumor regrowth; this systemic host response can be significantly blocked by co-treatment with a drug such as VEGFR-2 targeting antibodies, or low-dose `metronomic' (antiangiogenic) chemotherapy. Specific Aims: First, a number of chemotherapy drugs will be tested for induction of acute mobilization and tumor homing of CEPs, and whether among those that do, their anti-tumor efficacy is increased by blockade of this host response, using both pharmacologic and genetic approaches. The second aim involves an analysis of chemotherapy-induced BM-derived cell colonization of orthotopic versus ectopic primary transplanted tumors as well as advanced metastases growing in the liver, lungs, or brain. The third aim is devoted to analyzing molecular mechanisms mediating chemotherapy-induced BM-derived cell mobilization and tumor colonization including role of G-CSF, a4¿1 integrin and the CXCR4 chemokine receptor and its ligand SDF-1. The fourth aim will evaluate the contribution of other BM-derived pro-angiogenic CD45+ cell populations having `vascular leukocyte properties', e.g. Gr1+CD11b+ myeloid cells or tie-2 expressing monocytes, among others. Finally, the fifth aim is designed to assess whether surges in CEPs are induced in cancer patients by chemotherapy, including MTD taxanes, and if so, whether bevacizumab blunts such host responses. Significance/Impact: The research links chemotherapy, tumor angiogenesis, antiangiogenic therapy, and the tumor microenvironment in a new way; it will indicate new targets to consider for anti-cancer therapy when combined with chemotherapy, but which may vary with the metastatic environment, and provide new perspectives for the contribution of BM-derived cell populations, including CEPs, in tumor biology and therapy. PUBLIC HEALTH RELEVANCE: The relevance to public health of the proposed research lies in its potential to improve therapeutic outcomes in cancer patients receiving combination treatments of chemotherapy and an antiangiogenic drug or treatment. This is critical since the current benefits of such combination therapies, compared to chemotherapy alone, are very modest, and moreover, come at the expense of increased side effects and rapidly escalating financial costs. The proposed research outlines strategies for obtaining such improvements by exploiting aspects of the systemic bone marrow and blood environments, as well as the local tumor microenvironment, including metastases in different organ sites such as the liver, lung, and brain.