Katie Olson

Abstract 1217: Development of a spontaneous in vivo cachexia model using the Champions TumorGraft™ platform

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Cachexia is present in the majority of patients with advanced cancer progression and is not reversible through nutritional supplementation, leading to loss of skeletal muscle and adipose tissue. There are a lack of quality pre-clinical models for cachexia research. Previously, Champions Oncology reported a mouse cachexia model derived from a primary human renal cell carcinoma tumor implanted in immunocompromised mice. This model, CTG-0804, was developed using the innovative Champions TumorGraft™ platform, which preserves the biological properties of the original human tumor. The Champions TumorGraft platform demonstrated dramatic weight loss in these mice as the tumor grew. Plasma from these mice also showed elevated levels of human IL-6. We have now further characterized this TumorGraft model by evaluating standard of care (SOC) agents for renal cell carcinoma and anti-IL-6 compounds to determine the mechanism of cachexia. The SOC evaluation revealed that sorafenib, sunitinib, temsirolimus and bevacizumab as single agents provided a survival advantage by inhibiting tumor growth and preventing weight loss in these mice. Blockade of human IL-6 with tocilizumab or ALD518 did not inhibit tumor growth and weight loss still occurred, demonstrating the possibility of other pathways involved in the cachexia mechanism. In addition, the SOC data for sunitinib showed significant tumor growth inhibition, but no regression at the study end point. This correlated with the clinical profile, where sunitinib could not prevent metastasis and the patient eventually progressed. The TumorGraft model was molecularly characterized and mutation analysis revealed a KIT V530I mutation. This mutation has been reported in extra-abdominal aggressive fibromatosis (desmoid tumor) and acute myeloid leukemia patients that have responded to c-kit targeting therapies, such as imatanib and dasatinib. Further characterization of this TumorGraft is ongoing to include additional bioinformatics using gene expression and mutation pathway analyses. In summary, we have continued development of this cachexia model using the Champions TumorGraft platform, along with molecular evaluation, to produce a robust and well-characterized approach for cachexia investigation which can also be applied to other areas of drug development and cancer research. Citation Format: Nathan Anderson, Tin Khor, Andrew Feldhaus, Andreya Gatling, Katie Olson, John Latham, David Sidransky, Elizabeth M. Bruckheimer. Development of a spontaneous in vivo cachexia model using the Champions TumorGraft™ platform. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1217. doi:10.1158/1538-7445.AM2014-1217

Abstract 2792: Characterization of spontaneous in vivo cachexia models in Champions TumorGraft™ models.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Cachexia, defined as a loss of adipose tissue and skeletal muscle mass not reversible by nutritional support, is present in the majority of patients with advanced cancer progression. This reduces the patients quality of life and impacts their ability to function normally and undergo treatments. Reversing cachexia has been problematic due to a lack of quality pre-clinical models. Traditional xenograft models using cell lines are limited due to their inability to accurately replicate the whole body response to cancer. Champions Oncology overcomes this challenge through the use of its innovative Champions TumorGraft™ platform, where primary human tumors are implanted into immunocompromised mice in a manner that preserves the biological properties of the original human tumor. Champions has identified a panel of three TumorGraft models which spontaneously induce cachexia when implanted subcutaneously into nude mice: 1) CTG-0282, a pancreatic cancer model, 2) CTG-0765, a NSCLC model, and 3) CTG-0804, a renal cell carcinoma model. All three models have shown a greater than 90% cachexia rate, as demonstrated by lost body weight, over multiple passages. In addition, loss of body weight correlates with an increase in tumor volume size. Mice that have little or no tumor growth show no loss of body weight. Past studies have indicated a function for pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin 1 (IL-1), interleukin 6 (IL-6) and interferon gamma (IFNγ), in the cachexia process. Champions is currently investigating the roles of these possible tumor-mediated factors in the aforementioned models. Principle among these factors is IL-6, which has been shown to be required in the regulation of cachexia in tumor-bearing mice and is correlated with weight loss and survival in patients. Preliminary results from our studies suggest a correlation between IL-6 levels and spontaneous cachexia in Champions TumorGraft models. In summary, we demonstrate that the Champions TumorGraft platform preserves the biological properties of the original human tumor, including spontaneous cachexia behavior in these models, and is therefore ideal for oncology drug development programs focused on the inhibition of cachexia. Citation Format: Nathan Anderson, Tin Oo Khor, Andrew Feldhaus, Katie Olson, John Latham, David Sidransky, Elizabeth M. Bruckheimer. Characterization of spontaneous in vivo cachexia models in Champions TumorGraft™ models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2792. doi:10.1158/1538-7445.AM2013-2792