Abstract B125: Identification and characterization of a panel of B-Raf wildtype and mutant patient-derived low passage tumor models.
Authors: Wick Michael J. , Nieves Francis E. , Thangasamy Amalraj , Tolcher Anthony W. , Patnaik Amita , Smith Lon S. , Miller Alexander , Beeram Murali , Drengler Ronald L. , Papadopoulos Kyriakos P. 
Published: June 2012

Activating mutations of the BRAF gene occurs in approximately 60% of melanomas, most often resulting in a V600E mutant. Other substitutions at this and adjacent residues are known to exist, resulting in constitutive B-raf kinase activity and poor clinical prognosis. B-raf mutations may also play a role in the pathogenesis of a number of other malignancies including colorectal, lung, thyroid and hematopoietic cancers. Due to the importance of this target in cancer progression, several potential therapies targeting B-raf are currently in preclinical and clinical development.

To better understand the role of B-raf in melanoma and other cancers we have established and characterized a panel of wildtype and mutated B-raf melanoma, colorectal, ovary and biliary cancer patient-derived tumor models. For each model, tissue was implanted into immune-deficient mice and once established, each model was confirmed by histologic analysis and linked with donor patient treatment and outcome data. In addition, model characterization including mutation profiling and drug sensitivity studies were performed and results compared with clinical information. Finally we evaluated relevant B-raf wildtype and mutant models with the B-raf inhibitor vemurafenib.

Eighteen low passage melanoma models have been established, nine with confirmed mutated BRAF genes. Four additional mutant B-Raf tumor models include two colorectal one ovary and one biliary cancer. Model information and identified mutations are as follows:

Additional gene mutations identified include KRAS (9%), NRAS (9%), TP53 (14%) and CTNNB1 (5%). Differential activity was reported for single agent temozolomide, carboplatin and paclitaxel in melanoma model studies. In the majority, there was no correlation between mutation status and cytotoxic drug sensitivity. However, two B-raf models with identical mutations demonstrated sensitivity to irinotecan with sustained partial tumor regressions. Additional drug screens of two multi-mutated models, ST004 and ST054, showed resistance to all evaluated therapies. The ST274 (BRAF-D594G) melanoma model was found insensitive to vemurafenib; results from other models are pending.

Conclusion: We have generated and a panel of patient-derived tumor models which include B-raf wildtype and mutated melanoma, colorectal, ovary and biliary cancers possessing differential mutation status and drug sensitivity profiles. Expansion of this panel of tumors is planned and should further enhance its utility in development of useful agents towards melanoma and other B-raf mutant cancers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B125.