Chemotherapy using cytotoxic drugs is presently the most commonly used weapon in the treatment of advanced cancer. However, the therapeutic efficacy of cancer chemotherapeutic agents is limited by factors such as tumor heterogeneity, host toxicity and drug resistance. Recent advances in drug development have provided new opportunities to improve cancer therapy using drugs that target the tumor vasculature and inhibit tumor angiogenesis. To date, however, the survival benefit of these angiogenesis inhibitors has been rather modest and efforts to improve activity by combination with conventional chemotherapeutic drugs have been only partially successful. The overall goal of this project is to develop novel, more effective approaches to combining angiogenesis inhibitors with traditional cancer chemotherapeutics, building on progress made in the last project period in studies using the VEGF receptor-selective tyrosine kinase inhibitor axitinib and the liver cytochrome P450-activated anti-cancer prodrug cyclophosphamide. The major aims of this proposal are: 1) to elucidate the mechanism whereby anti-angiogenic drug treatment blocks tumor regression induced by metronomic cyclophosphamide treatment and then devise alternative therapeutic approaches that circumvent this block;2) to investigate the use of provascular strategies to enhance tumor delivery of cancer chemotherapeutic drugs given in conjunction with anti-angiogenesis;3) to harness the anti-vascular effects of anti-angiogenic drugs so as to increase tumor cell exposure to cytotoxic drugs administered intratumorally via an intratumoral 'trapping'(enhanced drug retention) mechanism;and 4) to investigate the impact of changes in tumor microvessel density, neovascularization and vascular maturity on responsiveness to the combination of anti-angiogenic drug treatment with chemotherapy. Together, these studies will elucidate ways to increase responsiveness to anti-angiogenic drugs by combination with conventional chemotherapeutic agents in a way that improves overall therapeutic activity, and will thereby advance the development of anti-cancer therapies.

Public Health Relevance

This project investigates ways to increase responsiveness to anti-angiogenic drugs by combination with conventional cancer chemotherapeutic agents. These studies may identify strategies that can be used to improve the therapeutic effectiveness of anti-angiogenic drugs in the clinic, and thereby advance the development of anti-cancer therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA049248-23
Application #
8391071
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Forry, Suzanne L
Project Start
1991-07-16
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
23
Fiscal Year
2013
Total Cost
$308,545
Indirect Cost
$118,671
Name
Boston University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
Jordan, Marie; Waxman, David J (2016) CpG-1826 immunotherapy potentiates chemotherapeutic and anti-tumor immune responses to metronomic cyclophosphamide in a preclinical glioma model. Cancer Lett 373:88-96
Haery, Leila; Mussakhan, Sultan; Waxman, David J et al. (2016) Evidence for an oncogenic modifier role for mutant histone acetyltransferases in diffuse large B-cell lymphoma. Leuk Lymphoma 57:2661-71
Wu, Junjie; Jordan, Marie; Waxman, David J (2016) Metronomic cyclophosphamide activation of anti-tumor immunity: tumor model, mouse host, and drug schedule dependence of gene responses and their upstream regulators. BMC Cancer 16:623
Diep, Phuong; Pannem, Sanjana; Sweer, Jordan et al. (2015) Three-dimensional printed optical phantoms with customized absorption and scattering properties. Biomed Opt Express 6:4212-20
Kareva, Irina; Waxman, David J; Lakka Klement, Giannoula (2015) Metronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance. Cancer Lett 358:100-6
Doloff, Joshua C; Waxman, David J (2015) Transcriptional profiling provides insights into metronomic cyclophosphamide-activated, innate immune-dependent regression of brain tumor xenografts. BMC Cancer 15:375
Wu, Junjie; Waxman, David J (2015) Metronomic cyclophosphamide eradicates large implanted GL261 gliomas by activating antitumor Cd8(+) T-cell responses and immune memory. Oncoimmunology 4:e1005521
Wu, Junjie; Waxman, David J (2014) Metronomic cyclophosphamide schedule-dependence of innate immune cell recruitment and tumor regression in an implanted glioma model. Cancer Lett 353:272-80
Chen, Chong-Sheng; Doloff, Joshua C; Waxman, David J (2014) Intermittent metronomic drug schedule is essential for activating antitumor innate immunity and tumor xenograft regression. Neoplasia 16:84-96
Manley Jr, Eugene; Waxman, David J (2014) H460 non-small cell lung cancer stem-like holoclones yield tumors with increased vascularity. Cancer Lett 346:63-73

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