Host Cell Assisted Primary and Metastatic Tumor Regrowth after Chemotherapy

描述（由申请方提供）：靶向肿瘤血管生成的VEGF-VEGFR-2途径的抗体（如贝伐珠单抗）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增敏能力的基础尚不清楚，改善可能来自对所涉及机制的更好理解。假设：在某些情况下，常规化疗可诱导骨髓（BM）衍生细胞的急性动员，包括大量归巢并定殖于药物治疗的肿瘤的VEGFR-2+循环内皮祖细胞（CEP），从而改变肿瘤血管生成微环境并刺激肿瘤再生长;这种全身性宿主反应可以通过与VEGFR-2靶向抗体或低剂量“节拍”（抗血管生成）化疗等药物联合治疗来显着阻断。具体目标：首先，将使用药理学和遗传学方法测试一些化疗药物诱导CEP的急性动员和肿瘤归巢，以及在那些药物中，是否通过阻断这种宿主反应来增加其抗肿瘤疗效。第二个目标涉及原位与异位原发性移植肿瘤以及在肝、肺或脑中生长的晚期转移瘤的化疗诱导的BM衍生细胞定植的分析。第三个目标是致力于分析介导化疗诱导的BM源性细胞动员和肿瘤定植的分子机制，包括G-CSF、α 4 <$1整联蛋白和CXCR 4趋化因子受体及其配体SDF-1的作用。第四个目标将评价具有“血管白细胞特性”的其他BM衍生的促血管生成CD 45+细胞群的贡献，例如Gr 1 + CD 11b+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紫杉烷类）是否会诱导癌症患者的CEP激增，如果是，贝伐单抗是否会减弱这种宿主反应。意义/影响：该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;它将指出与化疗联合使用时抗癌治疗的新靶点，但可能会随转移环境而变化，并为BM衍生细胞群（包括CEP）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：拟议研究与公共卫生的相关性在于其有可能改善接受化疗和抗血管生成药物或治疗联合治疗的癌症患者的治疗结果。这是至关重要的，因为与单独的化疗相比，这种联合疗法的当前益处非常有限，而且是以增加的副作用和迅速上升的财务成本为代价的。拟议的研究概述了通过利用全身骨髓和血液环境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.