What We Did: During the current grant period we developed an innovative therapeutic approach to induce chronic states of tumor dormancy. It consists of integrating continuous low-dose chemotherapy (called """"""""metronomic"""""""" dosing/scheduling) with molecular targeted antiangiogenic agents such as anti-VEGF receptor antibodies. This treatment concept, which has moved rapidly into clinical trial testing, may have the potential to change some of the prevailing paradigms of chemotherapy treatment, and to render various cancers currently considered untreatable using chemotherapy, susceptible to such drugs, but in a way that avoids the more acute and serious side effects generally associated with standard chemotherapy. What We Want To Do Next: This revised renewal application is designed to address a number of fundamental questions regarding mechanisms of antiangiogenic metronomic chemotherapy, answers to which could have a significant impact on improving its anti-tumor effects, the design of future clinical trials, as well as achieving a better understanding of the role of angiogenesis in tumor dormancy. These include: i) why does low dose metronomic chemotherapy appear to be selective for activated endothelial cells and not damage other types of normal dividing cells, and, in this regard, is an underlying mechanism induction of the endogenous inhibitor, thrombospondin-l? ii) how can optimum low-doses of particular drugs and drug combinations be determined? iii) does the treatment strategy have efficacy on advanced (high volume), drug resistant, metastatic disease?; iv) what mechanisms might compromise the efficacy of metronomic antiangiogenic therapies over time, and how can relapses be significantly delayed? Significance: The proposed basic research program has a high probability of significant translational impact, Le., to influence the implementation, and guide the design, of future clinical trials testing the metronomic antiangiogenic therapy concept. It also has the potential to uncover the basis of response versus resistance to antiangiogenic therapies, how tumor microenvironmental changes, e.g. hypoxia can alter response to antiangiogenic drugs, and point out new ways of integrating various molecular targeted therapies with conventional chemotherapeutic drugs so as to significantly enhance prolongation of survival without sacrificing quality of life.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA041233-18A1
Application #
6679318
Study Section
Pathology B Study Section (PTHB)
Program Officer
Song, Min-Kyung H
Project Start
1992-06-01
Project End
2008-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
18
Fiscal Year
2003
Total Cost
$203,040
Indirect Cost
Name
Sunnybrook & Women's Coll Health Sciences Center
Department
Type
DUNS #
200466345
City
Toronto
State
ON
Country
Canada
Zip Code
M4 3-M5
Finer-Moore, Janet S; Lee, Tom T; Stroud, Robert M (2018) A Single Mutation Traps a Half-Sites Reactive Enzyme in Midstream, Explaining Asymmetry in Hydride Transfer. Biochemistry 57:2786-2795
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
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
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
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
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
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
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-2R?(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
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

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