Details

Autor(en) / Beteiligte

• Khor, Tin Oo
• Tiruchinapalli, Dhanrajan
• Friedman, Jay
• Anderson, Nathan
• Sidransky, David
• Bruckheimer, Elizabeth M.

Titel

Abstract 2781: Champions TumorGraft™ models possess PIK3CA mutations - A great tool to explore the PI3K/AKT pathway

Ist Teil von

• Cancer research (Chicago, Ill.), 2013-04, Vol.73 (8_Supplement), p.2781-2781

Erscheinungsjahr

2013

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Abstract Phosphatidylinositol 3-kinase (PI3K) is an important intracellular signal transducer that is involved in many cellular functions such as cell growth, proliferation, and differentiation. PI3K is a heterodimeric molecule composed of a regulatory and a catalytic subunit. PIK3CA, which encodes the p110α catalytic subunit, is often mutated in a range of human cancers, such as colorectal and non-small-cell lung cancers. Increasing our understanding of the biological implications of these mutations and the role of PI3K pathway in cancer proliferation or survival may lead to potential new therapeutic opportunities targeting PI3K signaling. Champions Oncology focuses on the development of TumorGraft models derived from the direct implantation of patient tumors into immunocompromised mice. Compared to traditional cell line-based xenograft models, the patient derived Champions TumorGraft™ models maintain stable gene-expression patterns and mutational status and correlate to clinical predictability. Through extensively characterization, Champions has identified 19 TumorGraft models with PIK3CA mutations. Out of these 19 models, there are 11 colorectal cancers, 3 non-small cell lung cancers, 3 pancreatic cancers, 1 gastric cancer and 1 melanoma. Genomics analyses using the Ampliseq platform identified the majority of PIK3CA mutations in exon 9 and 20. Mutations in these regions of PIK3CA are known to confer resistance to some anti-cancer agents, such as HER2 antibodies. Additionally, it has been reported that PIK3CA mutations frequently coexist with RAS and BRAF mutations in patients with advanced cancers. Upon further analysis, we identified the same pattern in Champions TumorGraft models where∼70% (13 out of 19) of the PIK3CA mutant models possess either concurrent RAS or BRAF mutations. Notably, PI3K activates the downstream kinase AKT which ultimately triggers the mTOR pathway. Mutations in cancer often result in constitutive activation of this pathway. Given the role of the PI3K/AKT signaling in cancer and the presence of these specific mutations in the Champions TumorGraft bank, utilization of Champions’ TumorGraft models in oncology drug development allows for greater insight into new therapeutic opportunities targeting the inhibition of PI3K/AKT signaling and offers new promise for patients with these activated pathways. Citation Format: Tin Oo Khor, Dhanrajan Tiruchinapalli, Jay Friedman, Nathan Anderson, David Sidransky, Elizabeth M. Bruckheimer. Champions TumorGraft™ models possess PIK3CA mutations - A great tool to explore the PI3K/AKT pathway. [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 2781. doi:10.1158/1538-7445.AM2013-2781