Abstract 1219: Patient-derived Tumor Models of Resistant Metastatic Melanoma

Despite recent advances in the therapy of metastatic melanoma, patients have a poor prognosis and die from their disease, with a 5-year survival rate of less than 20%. Metastatic melanoma remains mainly chemoresistant, therefore novel therapeutic strategies to overcome primary or acquired resistance are required. In order to more reliably predict clinical activity of novel compounds in melanoma patients, we have established a series of patient-derived tumor xenograft models (PDTX). Surgically resected tumors samples were obtained from patients with metastatic melanoma before or after treatment. Twenty-three samples from 9 patients and representative of various stages of disease progression were implanted onto immunocompromised NSG mice. A high take rate of 56% (13/23 samples) was observed, corresponding to the samples from 8/9 patients. Tumor take was independent of tumor size, histologic parameters and B-RAF status. The first tumor generation (graft) harbouring the patient-derived sample (G1), as well as the subsequent generations were characterized for each PDTX. The pattern of expression of the melanoma differentiation markers S100, melanosome, tyrosinase and melan-A were maintained over the serial transplantations. These models also closely recapitulated the heterogeneity of patient tumors in terms of cell morphology over the first generations (G1-G5), but this heterogeneity tended to decrease with the number of generations. One of these primary PDTXs, MEL-11 exhibited metastatic spread in axillary lymph nodes. Furthermore 2 other primary melanoma PDTXs, MEL-1 and MEL-3, established from primary refractory patient metastatic melanoma retained complete resistance to temozolomide and vemurafenib, the two reference drugs for melanoma. The MEL-3 model was selected to assess the anti-melanoma activity of F-RK-4, a novel multi-kinases inhibitor (including inhibition of mutated B-RAF). Multiple i.p. administrations of F-RK-4 resulted in a significant antitumor activity, as reflected by a tumor growth inhibition of 50%. Overall these results suggest that these patient-derived melanoma xenografts represent a useful preclinical tool to identify novel anti-melanoma therapeutics. Citation Format: Bruno Gomes, Céline ROBICHON, Arnaud Pillon, Jean-Philippe Annereau, Sandrine Pourtau, Jean-Christophe Blanchet, Aline Stennevin, Karim Bedjeguelal, Philippe Rochaix, Ignacio Garrido-Stowhas, Laurence Lamant, Nicolas Meyer, Nicolas Guilbaud, Christian Bailly, Anna Kruczynski. Patient-derived tumor models of resistant metastatic melanoma. [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 1219. doi:10.1158/1538-7445.AM2014-1219