Avastin - Abstract 53: HPMA copolymer-TNP-470 (caplostatin) and Avastin show synergistic inhibition of human tumor growth in mice
Citation: European Journal of Cancer Supplements Volume 3, No. 2, October 2005, Page 14
R. Satchi-Fainaro, A.E. Birsner, C. Butterfield, L. Akslen, S.M. Short, J. Folkman
Children's Hospital Boston and Harvard Medical School, Vascular Biology Program, Boston, USA
Inhibition of angiogenesis, a concept proposed by Judah Folkman in 1971, is one of the most promising approaches for treating human tumors.
The formation of capillaries from preexisting blood vessels is now considered to be a key point for tumor growth beyond a critical size of approximately 1 mm3. Solid tumors can trigger this complex process by expression of angiogenic factors. Of particular clinical interest is the vascular endothelial growth factor (VEGF); its expression correlates with vessel density and poor prognosis in various tumors. Therapies directed against VEGF or its receptors are showing efficacy in cancer treatment.
Recently, this modality has received validation in a large, Phase III clinical trial in metastatic colorectal cancer patients.
Monoclonal antibody to VEGF, Avastin, plus chemotherapy resulted in a highly significant longer time to progression and greater survival than chemotherapy alone. Avastin is approved for clinical use in 28 countries.
TNP-470, a broad spectrum angiogenesis inhibitor, has also shown promise in clinical trials, however, doses necessary for tumor regression, showed signs of neurotoxicity.
We recently described the synthesis and characterization of a novel non-toxic, water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-TNP-470 conjugate, now called caplostatin [Nature Medicine 10, 255 (2004)].
Conjugation of TNP-470 to HPMA copolymer eliminated its neurotoxicity while retaining its antiangiogenic and anti-tumor activity.
Moreover, caplostatin has an improved pharmacokinetic profile, all of which could facilitate its return to clinical trials.
Here we describe the combination of two angiogenesis inhibitors, caplostatin and Avastin with the goal of augmenting the effects of either drug alone. Targeting the endothelial cell, rather than the tumor itself, avoids issues of accessibility to the tumor interior and drug resistance may be less likely.
We propose that the antitumor spectrum and efficacy of Avastin can further increase when administered in combination with caplostatin.
Our findings demonstrate the high antiendothelial/antitumoral efficacy of the concurrent administration of caplostatin and Avastin in vitro.
Furthermore, we show the synergistic effect of the combination on 6 different subcutaneous and orthotopic tumor models with a 50% of tumors undergoing complete regression in the COLO-205 human colon carcinoma model.
A potential explanation for the favorable combination would be that Avastin inhibits tumor growth by targeting VEGF while VEGF is only one of many angiogenesis stimulators.
TNP-470 which has the broadest spectrum of any known antiangiogenic/anti-cancer agent, may target multiple pathways.
Our data suggest that combining two non-toxic angiogenesis inhibitors can have increased synergistic anti-tumor effect and no toxicity.
The clinical translation of this novel combination is warranted.
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