Melanoma models for the next generation of therapies

Abstract

There is a lack of appropriate melanoma models that can be used to evaluate the efficacy of novel therapeutic modalities. Here, we discuss the current state of the art of melanoma models including genetically engineered mouse, patient-derived xenograft, zebrafish, and ex vivo and in vitro models. We also identify five major challenges that can be addressed using such models, including metastasis and tumor dormancy, drug resistance, the melanoma immune response, and the impact of aging and environmental exposures on melanoma progression and drug resistance. Additionally, we discuss the opportunity for building models for rare subtypes of melanomas, which represent an unmet critical need. Finally, we identify key recommendations for melanoma models that may improve accuracy of preclinical testing and predict efficacy in clinical trials, to help usher in the next generation of melanoma therapies.

Keywords: animal models; drug discovery; immunotherapy; melanoma; targeted therapy; therapeutics; tumor microenvironment.

Figure 1.. Timeline of treatment approvals by the US Food and Drug Administration for advanced melanoma patients

Thirteen new treatments, including both single agents and combination therapies, have been approved since 2011. 2011 also marked the first approval of an immune checkpoint inhibitor, ipilimumab, which ushered in the modern era of cancer immunotherapy. Several of these new treatments have also been approved in the adjuvant setting (after surgery). Credit: Heather McDonald, Nancy R. Gough, BioSerendipity.

Figure 2.. Timeline of melanoma models and opportunities for addressing key challenges

A brief selection of models from mouse, zebrafish, human, and other species that have made major contributions to our understanding of melanoma biology and in the discovery of new therapies. Such models are critical to address the most pressing challenges in melanoma, including metastasis, drug resistance, immune response, aging and the microenvironment, and rare forms of melanoma. Due to space constrictions, unfortunately only a subset of available melanoma models is presented. Species are indicated by colored circles, and challenges are indicated by letters in colored circles. Credit: Heather McDonald, Nancy R. Gough, BioSerendipity.

Figure 3.. Schematic representation of current melanoma models and the many ways they can be employed to develop new therapies

Animal models are first generated to resemble their human counterparts as closely as possible, but are also constantly being improved through genetic engineering, environmental intrusions, and/or technical advances. In general, in vitro models are more amenable to mechanistic analysis, while in vivo models help capture the complex microenvironment and immune responses that contribute to melanoma outcomes. A critical evolving aspect to all animal models is that “omics” data generated from their study can now be compared directly with comparable human datasets, providing powerful validation of relevance. The establishment of in vitro cultures generated from the models and directly from patients (such as organoids) provides additional layers of experimental possibilities. 2D, two-dimensional; GEM, genetically engineered mouse; GDA, GEM-derived allograft; NSG, NOD/SCID/IL-2rγ^null immunodeficient mouse; PDX, patient-derived xenograft; TME, tumor microenvironment; WT, wild-type.