Host Cell Assisted Primary and Metastatic Tumor Regrowth after Chemotherapy

描述（由申请人提供）：针对肿瘤血管生成的VEGF-VEGFR-2途径的抗体，如贝伐单抗，对晚期转移性疾病的治疗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致敏能力的基础尚不清楚；改进可能来自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），这些细胞大量聚集并定植在药物治疗的肿瘤中，从而改变肿瘤血管生成微环境并刺激肿瘤再生；这种系统性宿主反应可以通过与VEGFR-2靶向抗体等药物或低剂量“节律”（抗血管生成）化疗共同治疗而显著阻断。具体目的：首先，将测试一些化疗药物诱导cep的急性动员和肿瘤归巢，以及是否在这些药物中，通过使用药理学和遗传学方法阻断这种宿主反应来增加其抗肿瘤功效。第二个目的是分析化疗诱导的原位与异位原发性移植肿瘤的脑转移细胞定植，以及肝、肺或脑的晚期转移瘤。第三个目标是分析介导化疗诱导的脑转移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bm来源的具有“血管白细胞特性”的促血管生成CD45+细胞群的贡献，例如Gr1+CD11b+骨髓细胞或表达tie-2的单核细胞等。最后，第五个目的是评估化疗（包括MTD紫杉烷）是否会诱导癌症患者cep的激增，如果是这样，贝伐单抗是否会减弱这种宿主反应。意义/影响：本研究将化疗、肿瘤血管生成、抗血管生成治疗与肿瘤微环境联系起来；这将为联合化疗的抗癌治疗提供新的靶点，但可能随着转移环境的变化而变化，并为包括cep在内的脑转移细胞群在肿瘤生物学和治疗中的贡献提供新的视角。

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.