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Host Cell Assisted Primary and Metastatic Tumor Regrowth after Chemotherapy

化疗后宿主细胞辅助原发性和转移性肿瘤再生

基本信息

批准号：
8403497
负责人：
ROBERT S KERBEL
金额：
$ 18.08万
依托单位：
SUNNYBROOK & WOMEN'S COLL HLTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-06-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403497
关键词：
Acute Adverse effects Angiogenesis Inhibitors Antibodies Area Blood Blood Vessels Bone Marrow Bone Marrow Cells Brain Breast Melanoma CSF3 gene CXCR4 gene Cancer Patient Cells Chemotherapy-Oncologic Procedure Cisplatin Clinic Clinical Collaborations Combined Modality Therapy Cyclophosphamide Disease Dose Drug Combinations Drug Efflux Drug usage Environment Financial cost Genetic Grant Health Home environment Homing Human ITGAM gene Immune response Integrins Leukocytes Ligands Link Liver Lung Malignant Neoplasms Maximum Tolerated Dose Mediating Mediator of activation protein Medical Oncologist Membrane Transport Proteins Metastatic malignant neoplasm to brain Molecular Monitor Mus Mutant Strains Mice Myeloid Cells Nature Neoplasm Metastasis Neoplasm Transplantation Oral Organ Outcome P-Glycoprotein PTPRC gene Paclitaxel Pathway interactions Patients Pharmaceutical Preparations Population Primary Neoplasm Property Public Health Research Role Site Stem cells Stromal Cell-Derived Factor 1 Taxane Compound Testing Therapeutic Time Toxic effect Tumor Angiogenesis Tumor Biology Tyrosine Kinase Inhibitor Variant Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors angiogenesis base bevacizumab cancer therapy cell type chemokine receptor chemosensitizing agent chemotherapy design docetaxel gemcitabine improved malignant breast neoplasm monocyte neutrophil peripheral blood progenitor receptor response success taxane tumor tumor growth tumor microenvironment

项目摘要

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.

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;这种系统性宿主反应可以通过与药物如VEGFR-2靶向抗体或低剂量“节拍”（抗血管生成）化疗的共同治疗而被显著阻断。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。

项目成果

期刊论文数量（111）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Analysis of acquired resistance to metronomic oral topotecan chemotherapy plus pazopanib after prolonged preclinical potent responsiveness in advanced ovarian cancer.

DOI：
10.1007/s10456-014-9422-9
发表时间：
2014-07
期刊：
Angiogenesis
影响因子：
9.8
作者：
Cruz-Muñoz W;Di Desidero T;Man S;Xu P;Jaramillo ML;Hashimoto K;Collins C;Banville M;O'Connor-McCourt MD;Kerbel RS
通讯作者：
Kerbel RS

Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis.

DOI：
10.1016/j.ccr.2009.01.021
发表时间：
2009-03-03
期刊：
Cancer cell
影响因子：
50.3
作者：
Ebos JM;Lee CR;Cruz-Munoz W;Bjarnason GA;Christensen JG;Kerbel RS
通讯作者：
Kerbel RS

Metronomic oral topotecan with pazopanib is an active antiangiogenic regimen in mouse models of aggressive pediatric solid tumor.

DOI：
10.1158/1078-0432.ccr-11-0078
发表时间：
2011-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Kumar S;Mokhtari RB;Sheikh R;Wu B;Zhang L;Xu P;Man S;Oliveira ID;Yeger H;Kerbel RS;Baruchel S
通讯作者：
Baruchel S

Reduction of TGF-beta activity abrogates growth promoting tumor cell-cell interactions in vivo.

TGF-β活性的降低消除了体内促进肿瘤细胞-细胞相互作用的生长。