Abstract #2343: Establishing primary human tumor xenografts for use in oncology drug discovery

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO In an effort to generate tumor xenograft models that may better reflect human disease, we developed a collection of primary human tumor xenografts (PHTX). These models have the advantage of i) retaining complex heterotypic interactions between the epithelium and stroma, ii) maintaining tissue-specific histology and iii) expressing particular genetic lesions and mutations associated with clinical disease. The National Disease Research Interchange and Cooperative Human Tissue Network provide Millennium with fresh primary human tumor tissue from surgical resections. On arrival, tumor tissue is subcutaneously (SC) implanted in the right dorsal flank of immuno-deficient SCID-Nod mice and is serially passaged to develop a new PHTX line. Overall take rate, across multiple tissue types has been approximately 23%. Initial model development studies determine the growth kinetics of the various tumor models. Once established, further characterization is performed by examining tissue histology, analyzing DNA for specific genetic mutations including genes involved in cell survival and proliferation (e.g. Ras, B-raf, AKT, NF\#954;B, EGFR, PDGFR\#945;, cKit, p16 and p53) and chromosomal amplifications and deletions. Thus far, several PHTX models have been established and have been used in efficacy studies. Here we describe efficacy results of two separate studies: the first tests the activity of the proteasome inhibitors bortezomib and MLN9708 (Millennium\#8217;s second generation proteasome inhibitor) in a primary colon tumor model and the second uses MLN8237, a novel Aurora protein kinase inhibitor, in a primary lymphoma model. PHTX-24C is a xenograft model developed with tissue obtained from a patient with colon adenocarcinoma. Mice inoculated SC with PHTX-24C tumor fragments were treated with vehicle alone, bortezomib or MLN9708. MLN9708 immediately hydrolyzes to MLN2238, the biologically active form, upon exposure to aqueous solutions or plasma. MLN2238 was used for all preclinical studies. A significant anti-tumor response was seen in PHTX-24C tumors treated with MLN2238 dosed either at 4.0 mg/kg SC daily or intravenously (IV) at 14 mg/kg twice weekly (BIW). Weaker anti-tumor responses were seen in PHTX-24C tumors treated with bortezomib at 0.8 mg/kg IV BIW or dosed orally with MLN2238 at 11 mg/kg BIW. PHTX-22L is a xenograft model developed with tissue obtained from a patient with diffuse large B-cell lymphoma. Mice inoculated SC with PHTX-22L tumor fragments were treated with vehicle or MLN8237 at 10 or 20 mg/kg dosed orally twice a day. Significant anti-tumor response were seen in PHTX-22L tumors treated with MLN8237 at both doses. Our goal is to develop a collection of PHTX models with different sensitivities towards a given drug treatment and to look for a relationship between response and tumor genotype. Data generated from these studies may help identify patient populations more likely to respond to a specific drug treatment. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2343.