Correlation of a tivozanib response biomarker identified in a preclinical model with clinical activity in a phase II study in renal cell carcinoma (RCC).

Abstract

e13564 Background: A population-based, genetically engineered breast tumor model comprising 107 tumors was developed, characterized, and used to test the efficacy of tivozanib, a VEGFR-1, 2, and 3 kinase inhibitor that has shown clinical activity in RCC (ASCO 2009, abstract #5032). Methods: Propagated HER2/INK4A(−/−) murine breast tumor isolates were dosed daily with 5mpk tivozanib, tumor volume measurements were taken twice weekly, followed by histological characterization of tumors at end of study. Hypoxia markers were also monitored in a subset. Bioinformatics analysis of RNA microarray expression profiles identified a gene signature associated with resistance. Immunohistochemical (IHC) analysis using a murine myeloid marker was also conducted on pretreatment samples to correlate the gene based marker with the myeloid IHC marker. IHC using a human myeloid marker was conducted on available formalin fixed paraffin embedded tumor samples Results: Tivozanib treatment of 25 propagated murine tumors identified both sensitive and resistant tumors among the population (40% responders, 60% resistant). Bioinformatics analysis of pre-treatment tumor microarray data identified a 42 gene resistance signature representing components of hematopoietic gene expression. IHC quantitation of myeloid markers in the tumors identified the presence of infiltrating myeloid cells, whose percentage composition in the tumor correlated with both the 42 gene signature and resistance to tivozanib. Examination of both the signature and myeloid infiltration in human tumor samples indicated that this resistant phenotype is present in a significant subset of all human tumor datasets examined. IHC analysis of infiltrating myeloid cells in 21 patient samples demonstrated a significant correlation between the percent myeloid cell composition in the tumors and maximum tumor shrinkage by RECIST. Conclusions: These observations define two distinct angiogenesis mechanisms in both murine and human solid tumors and demonstrate the utility of this population based preclinical model in predicting response in humans. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AVEO No significant financial relationships to disclose.