Abstract C10: Establishment and characterization of melanoma patient-derived xenograft (PDX) model sets: correlation with clinical response and progression using serial biopsy sampling.

Abstract

Abstract Background: Recent FDA approval of B-Raf and Mek inhibitors has improved treatment outcomes for patients with BRAFV600E/K metastatic melanoma. However, most patients receiving these agents progress within a year and are left with limited treatment options. Few validated screening tools exist to evaluate potentially beneficial therapies for these resistant/refractory patients. To address this deficiency we have established patient-derived xenograft (PDX) model sets by collecting serial samples at timepoints when patients demonstrated sensitivity and resistance to B-Raf and Mek inhibitors and characterized each by mutation, receptor and ligand density and drug sensitivity. Methods: Paired, sensitive/insensitive PDX melanoma models from three patients were established in athymic nude mice from primary or metastatic patient tissue. Baseline samples for each paired model were collected from patients who subsequently reported clinical response to a therapy and again once the patient progressed on that therapy. Established models were confirmed by histologic comparative analysis and linked with patient treatment and outcome data. For each model DNA was extracted and subjected to exon sequencing of 207 known oncogenes; growth factor receptor and ligand densities were interrogated using immunohistochemistry and quantitative RNA in situ hybridization. Drug sensitivity studies were performed evaluating and comparing each model following treatment with oral vemurafenib, trametinib or dabrafenib. Study endpoints included tumor volume and time from treatment initiation, with tumor growth inhibition, delay and regression reported at study completion. Results: The B-RafV600E models ST052, ST052B, ST052C and ST052D reported sensitivity or resistance to vemurafenib correlative with clinical response and progression. Trametinib but not vemurafenib was active towards the ST361 B-RafV600R model while the ST361B model was found insensitive to both agents. Trametinib sensitivity to the ST697 and ST697B H-RasQ61K models was correlative with clinical response and progression. Dabrafenib sensitivity was similar to vemurafenib in evaluated models. Expression of HER3, a mechanism of possible adaptive resistance to targeted therapies, but not EGFR or HER2 was reported in all models and was relatively unchanged in serial models sets; heregulin expression was also determined in each model. Conclusion: We have established patient-derived xenograft (PDX) model sets with sensitivity and resistance to B-Raf and Mek inhibitors correlative with clinical response and progression. Receptor and ligand expression was identified and maintained in serial models. Based on these results this panel can serve as a valuable screening tool to evaluate potentially beneficial therapies for patients resistant/refractory to B-Raf and Mek inhibitors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C10. Citation Format: Michael J. Wick, Justin Meade, Jennifer Brown, Teresa L. Vaught, Anthony W. Tolcher, Lizette Gamez, Drew Rasco, Amita Patnaik, Ronald Drengler, Kyriakos P. Papadopoulos. Establishment and characterization of melanoma patient-derived xenograft (PDX) model sets: correlation with clinical response and progression using serial biopsy sampling. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C10.