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 i nvolves 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 i s 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA041233-27
Application #
8403497
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Song, Min-Kyung H
Project Start
1992-06-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
27
Fiscal Year
2013
Total Cost
$180,805
Indirect Cost
$13,393
Name
Sunnybrook & Women's Coll Health Sciences Center
Department
Type
DUNS #
200466345
City
Toronto
State
ON
Country
Canada
Zip Code
M4 3-M5
Kuczynski, Elizabeth A; Lee, Christina R; Man, Shan et al. (2015) Effects of Sorafenib Dose on Acquired Reversible Resistance and Toxicity in Hepatocellular Carcinoma. Cancer Res 75:2510-9
Kerbel, Robert S (2015) A Decade of Experience in Developing Preclinical Models of Advanced- or Early-Stage Spontaneous Metastasis to Study Antiangiogenic Drugs, Metronomic Chemotherapy, and the Tumor Microenvironment. Cancer J 21:274-83
Cruz-Muñoz, William; Di Desidero, Teresa; Man, Shan et al. (2014) Analysis of acquired resistance to metronomic oral topotecan chemotherapy plus pazopanib after prolonged preclinical potent responsiveness in advanced ovarian cancer. Angiogenesis 17:661-73
Hackl, Christina; Man, Shan; Francia, Giulio et al. (2013) Metronomic oral topotecan prolongs survival and reduces liver metastasis in improved preclinical orthotopic and adjuvant therapy colon cancer models. Gut 62:259-71
Guerin, Eric; Man, Shan; Xu, Ping et al. (2013) A model of postsurgical advanced metastatic breast cancer more accurately replicates the clinical efficacy of antiangiogenic drugs. Cancer Res 73:2743-8
Milsom, Chloe C; Lee, Christina R; Hackl, Christina et al. (2013) Differential post-surgical metastasis and survival in SCID, NOD-SCID and NOD-SCID-IL-2Rγ(null) mice with parental and subline variants of human breast cancer: implications for host defense mechanisms regulating metastasis. PLoS One 8:e71270
Kuczynski, Elizabeth A; Sargent, Daniel J; Grothey, Axel et al. (2013) Drug rechallenge and treatment beyond progression--implications for drug resistance. Nat Rev Clin Oncol 10:571-87
Kerbel, Robert S; Guerin, Eric; Francia, Giulio et al. (2013) Preclinical recapitulation of antiangiogenic drug clinical efficacies using models of early or late stage breast cancer metastatis. Breast 22 Suppl 2:S57-65
Cruz-Muñoz, William; Jaramillo, Maria L; Man, Shan et al. (2012) Roles for endothelin receptor B and BCL2A1 in spontaneous CNS metastasis of melanoma. Cancer Res 72:4909-19
Francia, Giulio; Shaked, Yuval; Hashimoto, Kae et al. (2012) Low-dose metronomic oral dosing of a prodrug of gemcitabine (LY2334737) causes antitumor effects in the absence of inhibition of systemic vasculogenesis. Mol Cancer Ther 11:680-9

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