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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Developmental Therapeutics Study Section (DT)
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Forry, Suzanne L
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Boston University
Schools of Arts and Sciences
United States
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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
Doloff, Joshua C; Chen, Chong-Sheng; Waxman, David J (2014) Anti-tumor innate immunity activated by intermittent metronomic cyclophosphamide treatment of 9L brain tumor xenografts is preserved by anti-angiogenic drugs that spare VEGF receptor 2. Mol Cancer 13:158
Doloff, Joshua C; Waxman, David J (2014) Adenoviral vectors for prodrug activation-based gene therapy for cancer. Anticancer Agents Med Chem 14:115-26
Jia, Li; Waxman, David J (2013) Thrombospondin-1 and pigment epithelium-derived factor enhance responsiveness of KM12 colon tumor to metronomic cyclophosphamide but have disparate effects on tumor metastasis. Cancer Lett 330:241-9
Manley Jr, Eugene; Waxman, David J (2013) Impact of tumor blood flow modulation on tumor sensitivity to the bioreductive drug banoxantrone. J Pharmacol Exp Ther 344:368-77
Zhang, Kexiong; Waxman, David J (2013) Impact of tumor vascularity on responsiveness to antiangiogenesis in a prostate cancer stem cell-derived tumor model. Mol Cancer Ther 12:787-98
McGuire, Mary F; Enderling, Heiko; Wallace, Dorothy I et al. (2013) Formalizing an integrative, multidisciplinary cancer therapy discovery workflow. Cancer Res 73:6111-7
Doloff, Joshua C; Waxman, David J (2012) VEGF receptor inhibitors block the ability of metronomically dosed cyclophosphamide to activate innate immunity-induced tumor regression. Cancer Res 72:1103-15

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