Abstract B143: Distinct antitumor mechanisms of VEGFR inhibitor tivozanib (AV-951) and mTOR inhibitor rapamycin support rational combination for solid tumors to overcome drug resistance
Authors: Lin Jie , Sun Xiaojian , Jiang Feng , Chiu Isabel , Robinson Murray 
Published: June 2012

Abstract
The approval of an increasing number of molecularly targeted therapies in cancer creates an opportunity to contemplate combinations of such agents. This is particularly important because single agents typically exhibit limited activity and very often drug resistance in clinic. A current challenge is to identify appropriate rational combinations that combine distinct mechanisms to elicit maximal anti-tumor activity and to overcome drug resistance.
Tivozanib (formerly AV-951 or KRN951) is a small molecule VEGFR inhibitor that has been shown to be active in a phase 2 clinical trial in RCC. Tivozanib inhibits VEGFR 1, 2 and 3 activity at picomolar concentrations (IC50 of 0.21, 0.16 and 0.24 nM respectively), Rapamycin targets mTOR, a protein involved in integrating nutrient availability with cellular functions, including proliferation. mTOR is also known to promote hypoxia inducible factor (HIF1) activity, which in turn drives angiogenesis, such that in some settings, rapamycin is thought to elicit anti-tumor activity through an anti-angiogenic mechanism.
We studied the activity of tivozanib and rapamycin as single agents and in combination in a genetically engineered HER2 driven breast adenocarcinoma model where multiple primary tumors have been expended in vivo for mechanisms of response and drug resistance biomarker exploration. These tumors exhibit significant variation in response to tivozanib. In one group of tumors, tivozanib as a single agent induced complete tumor growth inhibition persisting for at least 6 weeks. Rapamycin at a clinically relevant dose also induced complete tumor growth inhibition. However, histological analysis after short (5 days) or longer (35 days) term treatment revealed distinct mechanisms of action, i.e., anti-VEGF for tivozanib but direct antiproliferation for rapamycin. Combination of tivozanib and rapamycin resulted in substantially greater overall tumor reduction with evidence of both anti-angiogenic and anti-proliferation activities. Importantly, after 6 weeks of treatment, regions of drug resistance start to emerge in either rapamycin or tivozanib monotherapy tumors. However no evidence of drug resistance was observed with the tivozanib/rapamycin combination. To further explore the combination activity in resistant tumors, we established a resistant sub-line by long term tivozanib treatment. Both tivozanib and rapamycin as single agents resulted in only partial tumor growth inhibition. The combination treatment induced complete growth inhibition with evidence of both angiogenesis inhibition and direct antitumor effect.
The distinct mechanisms of action of these two agents, along with the apparent suppression of drug resistance suggest that tivozanib and mTOR inhibitors may represent an attractive rational combination treatment for solid malignancies. At this point, an on-going phase 1B trial in RCC has shown that tivozanib can be combined with temsirolimus at full doses of both agents. An all oral combination of tivozanib and everolimus, an oral mTOR inhibitor, is also being developed for RCC and other tumors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B143.