Abstract 1585: Novel human renal medullary carcinoma mouse model to evaluate chemotherapy efficacy and tumor biology

Abstract

Abstract Renal medullary carcinoma (RMC) is a rare disease with only ∼100 cases having been reported to date with the majority of these patients also having the sickle cell disease or trait. Multiple therapies, including chemotherapy, radiation, and resection, have been tried; however, this disease is almost uniformly fatal. We developed new mouse models of RMC that were created using patient derived tumor xenografts in the NOD SCID IL2 receptor γ chain null (NSG) mouse. RMC was diagnosed in a 9 year old male with sickle cell trait and multiple metastases in liver and lungs. The patient was treated by resection of the renal tumor, followed by chemotherapy, including bortezomib, paclitaxel/carboplatin/ bevacizumab, doxil/bevacizumab, and sunitinib. The patient showed partial or no response to each regimen and developed malignant pleural effusion and died 9 months p=0.0043 from diagnosis. NSG xenograft models were formed from both the patient primary renal tumor specimen and malignant pleural effusion. Comparative microarray gene expression data collection, genomic SNP data collection for copy number variance (CNV), and histology analyses were performed with the original patient renal tumor specimen and the two xenograft models for determining predictive chemotherapy responses for therapeutic efficacy. Additionally, the xenograft tumors were used for chemotherapy efficacy studies for using these models for future predictive efficacy studies. Both primary renal tumor and the metastatic pleural effusion developed large mouse xenograft tumors (P0) that were passaged into secondary mouse passages (P1). H & E histology showed that both the patient renal tumor and the renal tumor-derived xenograft tumors were moderately differentiated and morphologically similar. The malignant pleural effusion xenograft tumors were highly differentiated and not morphologically similar to the primary patient renal tumor or the renal tumor-derived xenograft. Sunitinib and temsirolimus were evaluated in comparison to vehicle control for tumor growth delay in P1 malignant pleural effusion xenografted mice and sunitinib efficacy was established vs. vehicle controls. Sunitinib demonstrated was highly efficacious compared to vehicle control with 110% tumor growth delay (p=0.0043) and temsirolimus tumor growth delay was not efficacious (p>0.05). Since RMC is a rare disease for which there is currently no effective therapy, these new mouse models will be a useful for developing new treatments for this lethal disease. Furthermore, with a series of samples (normal, sickle cell trait kidney, RMC at diagnosis, and tumor cells from pleural effusion), we expect to understand molecular mechanisms underlying the disease progression pathway (pathogenesis). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1585. doi:10.1158/1538-7445.AM2011-1585