Marked progress in the treatment of patients with advanced stage melanoma has occurred over the past two years. Along with vemurafenib, a targeted BRAF inhibitor, ipilimumab was recently approved for use in patients with metastatic disease. Ipilimumab therapy has potential to provide benefit to all melanoma patients because it acts systemically on the innate immune system via anti-CTLA-4 activity. Although ipilumimab therapy has shown a survival benefit, only a minority of patients derives durable responses, and an equivalent proportion of patients develop significant immune related adverse events (irAEs). In order to maximize the clinical utility of ipilimumab, it is critically important to identify potential biomarkers capable of delineating patients most likely to respond to therapy and those at increased risk for developing irAEs. However, no such biomarkers currently exist. Multiple lines of evidence suggest that inherited genetic variation may play a role in response to immunotherapies, such as ipilimumab, but also in the development of irAEs. Our preliminary data from a small genome-wide association (GWA) study examining outcomes related to ipilimumab therapy provide additional strong supportive evidence. To address our hypothesis that inherited variation is a determinant of both response and irAEs, we have identified patients treated on ipilimumab clinical trials from 10 academic contributing sites, two ECOG clinical trials and Bristol-Myers Squibb for a total of 716 and 1035 patients treated with 3mg/kg and 10mg/kg, respectively. We propose to determine the association of inherited variation with 1) irAEs and 2) overall survival at 1 and 2 years.
In Aims 1 and 2, we will perform candidate-based gene and pathway analyses of genes involved in lymphocyte activation, cytokines, cytokine receptors and within the MHC region, as well as an agnostic genome-wide SNP-based approach to discover novel genetic markers associated with our outcomes of interest.
In Aim 3, we will replicate our findings in an independent sample set. Our long term goal is to identify inherited variation that can inform clinical decision making for patients treated with ipilimumab. Of note, our results may have implications for other immunomodulatory immunotherapies and for other cancer types in which ipilimumab currently is being studied.
Ipilimumab is an FDA approved drug for the treatment of metastatic melanoma. Currently no biomarkers are known which predict either response to therapy or immune associated adverse events (irAEs). Based on various lines of evidence, inherited genetic variation may play a role in determining response and irAEs, which we will evaluate in this study. The ultimate goal is to identify markers that allow us to select patients who will derive the most benefit from treatment with ipilimumab.
|Kaur, Amanpreet; Webster, Marie R; Marchbank, Katie et al. (2016) sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 532:250-4|
|Lu, Hezhe; Liu, Shujing; Zhang, Gao et al. (2016) Oncogenic BRAF-Mediated Melanoma Cell Invasion. Cell Rep 15:2012-24|
|Amaravadi, Ravi; Kimmelman, Alec C; White, Eileen (2016) Recent insights into the function of autophagy in cancer. Genes Dev 30:1913-30|
|Fatkhutdinov, Nail; Sproesser, Katrin; Krepler, Clemens et al. (2016) Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma. Mol Cancer Res 14:767-75|
|Kumar, Vinit; Cheng, Pingyan; Condamine, Thomas et al. (2016) CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation. Immunity 44:303-15|
|Shannan, Batool; Chen, Quan; Watters, Andrea et al. (2016) Enhancing the evaluation of PI3K inhibitors through 3DÂ melanoma models. Pigment Cell Melanoma Res 29:317-28|
|Gimotty, Phyllis A; Shore, Ronald; Lozon, Nancy L et al. (2016) Miscoding of Melanoma Thickness in SEER: Research and Clinical Implications. J Invest Dermatol 136:2168-2172|
|Natale, Christopher A; Duperret, Elizabeth K; Zhang, Junqian et al. (2016) Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors. Elife 5:|
|Krepler, Clemens; Xiao, Min; Sproesser, Katrin et al. (2016) Personalized Preclinical Trials in BRAF Inhibitor-Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies. Clin Cancer Res 22:1592-602|
|Wang, Joshua X; Fukunaga-Kalabis, Mizuho; Herlyn, Meenhard (2016) Crosstalk in skin: melanocytes, keratinocytes, stem cells, and melanoma. J Cell Commun Signal 10:191-196|
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