Faculty Bibliography

Association of aberrant glycosylation with melanoma progression is based mainly on analyses of cell lines. Here we present a systems-based study of glycomic changes and corresponding enzymes associated with melanoma metastasis in patient samples. Upregulation of core fucosylation (FUT8) and downregulation of alpha-1,2 fucosylation (FUT1, FUT2) were identified as features of metastatic melanoma. Using both in vitro and in vivo studies, we demonstrate FUT8 is a driver of melanoma metastasis which, when silenced, suppresses invasion and tumor dissemination. Glycoprotein targets of FUT8 were enriched in cell migration proteins including the adhesion molecule L1CAM. Core fucosylation impacted L1CAM cleavage and the ability of L1CAM to support melanoma invasion. FUT8 and its targets represent therapeutic targets in melanoma metastasis.

Despite increasing amounts of experimental evidence depicting the involvement of non-coding RNAs in cancer, the study of BRAFV600E-regulated genes has thus far focused mainly on protein-coding ones. Here, we identify and study the microRNAs that BRAFV600E regulates through the ERK pathway.By performing small RNA sequencing on A375 melanoma cells and a vemurafenib-resistant clone that was taken as negative control, we discover miR-204 and miR-211 as the miRNAs most induced by vemurafenib. We also demonstrate that, although belonging to the same family, these two miRNAs have distinctive features. miR-204 is under the control of STAT3 and its expression is induced in amelanotic melanoma cells, where it acts as an effector of vemurafenib's anti-motility activity by targeting AP1S2. Conversely, miR-211, a known transcriptional target of MITF, is induced in melanotic melanoma cells, where it targets EDEM1 and consequently impairs the degradation of TYROSINASE (TYR) through the ER-associated degradation (ERAD) pathway. In doing so, miR-211 serves as an effector of vemurafenib's pro-pigmentation activity. We also show that such an increase in pigmentation in turn represents an adaptive response that needs to be overcome using appropriate inhibitors in order to increase the efficacy of vemurafenib.In summary, we unveil the distinct and context-dependent activities exerted by miR-204 family members in melanoma cells. Our work challenges the widely accepted "same miRNA family = same function" rule and provides a rationale for a novel treatment strategy for melanotic melanomas that is based on the combination of ERK pathway inhibitors with pigmentation inhibitors.

Purpose To identify MR imaging features of melanoma brain metastases (MBM) that correlate with genetic profile of melanoma and patient survival. Materials and methods Patients with newly diagnosed melanoma metastases were identified from institutional database A retrospective review of brain MRI was performed focusing on lesion number, size, T1-, T2- and diffusion-weighted signal characteristics, hemorrhage, necrosis, enhancement pattern and edema. Genomic (BRAF status), treatment and survival data was collected. Results 98 patients were included in final analysis. A strong correlation was found between size of the largest lesion and the percent of lesions with T1-weighted hyperintense signal (R = 0.49), percent of lesions with size >1 cm (0.55), and the lesions that are clearly hemorrhagic (0.43). The analyzed imaging parameters were found to be independent of BRAF mutation status. The median survival of subjects with single lesion (9.1 months) was significantly higher than the median survival of subjects with more than 1 lesion (4.9 months) (p = 0.002). Patients with 2-18 lesions had significantly longer survival (5.6 months) than with >18 lesions (2 months) (p < 0.001). Other imaging parameters such as lesion size, T1-weighted hyperintensity, number of lesions with edema and hemorrhage were not found to be significantly related to survival. BRAF inhibitor treatment was found to be the most significant prognostic factor (p = 0.002) among patients with multiple lesions. Conclusion There is a statistically significant correlation between number of brain metastases and survival. In patients with multiple lesions, BRAF inhibitor treatment was the most significant prognostic factor.

Patients with stage IB melanoma have a 10% risk of melanoma-specific mortality within five years. The current prognostic paradigm, however, is insufficient to predict which of these patients are most likely to recur. Additional prognostic characteristics of stage IB melanoma are needed to identify this patient subset who are at highest risk of recurrence, and may benefit from closer follow-up. We evaluated a prospective cohort of stage IB patients (n = 655) treated at NYU Langone Medical Center. In a research subset (n = 149) composed of patients with recurrent (n = 63) and nonrecurrent (n = 86) disease matched for age, sex, thickness, ulceration and mitoses, primary tumors were independently reviewed for digitally calculated area, manually calculated area (depth x width), width, and conformation (contiguous versus noncontiguous) using computer-assisted histopathological analysis (Aperio, Vista, CA USA). We tested the association between histologic variables and recurrence-free survival (RFS) using Cox univariate analysis. Increasing digital area (HR 1.08, P < 0.01), tumor width (HR 1.17, P = 0.01), and non-contiguous conformation (HR 0.57, P = 0.05) were independently prognostic of RFS. Linear regression analysis showed a significant correlation between the manual and digital area (estimate 0.64, P < 0.01), which became even stronger when restricted to patients with contiguous tumors (estimate 0.75, P < 0.01), suggesting manually calculated tumor area may also provide useful prognostic information for providers without access to similar software. Computer-assisted measurement of cross-sectional tumor area, width, and contiguity may help risk-stratification in stage IB patients. Independent validation of these primary tumor characteristic is needed to fully comprehend their prognostic role in stage IB melanoma

Patients with thick (>4 mm) primary melanomas have highly variable outcomes. Current staging criteria for these patients are based primarily on the presence of nodal disease, which often serves as the basis for adjuvant trial eligibility. Identification of novel biomarkers could help identify patients who may benefit from promising, new adjuvant therapies or, alternatively, spare patients with good prognoses the cost and potential toxicity of these drugs. We examined patients with thick primary melanoma to determine whether proliferation markers (mitotic index and Ki- 67) and other clinicopatholgical features were associated with survival. We studied 171 patients with thick primary melanomas; median thickness was 6.0 mm (median follow-up, 3.0 years). In clinically node-negative patients, Ki-67 expression was an independent predictor of worse RFS (HR 2.19, P = 0.024) and OS (HR 2.49, P = 0.028). In a separate model, moderate (>1 to <5 per mm²) and many (>5 per mm²) mitoses were each significantly associated with RFS (HR = 9.97, P = 0.035 and HR = 11.93, P = 0.025, respectively); and OS (HR = 12.79, P = 0.033 and HR = 18.68, P = 0.017, respectively). In the same model, natural log-transformed tumor thickness was also significantly associated with worse OS (HR 2.37, P = 0.009). In sum, we identified cell proliferation markers Ki-67 and mitotic index as independent predictors of survival in clinically nodenegative patients with thick primary melanoma. Greater tumor thickness was also an independent predictor of survival in this cohort. With further investigation, these measures may improve risk-stratification for patients with thick primary melanoma

BACKGROUND: Metastatic melanoma of unknown primary (MUP) is uncommon, biologically ill defined, and clinically understudied. MUP outcomes are seldom reported in clinical trials. In this study, we analyze responses of MUP patients treated with systemic therapy in an attempt to inform treatment guidelines for this unique population. METHODS: New York University (NYU)'s prospective melanoma database was searched for MUP patients treated with systemic therapy. PubMed and Google Scholar were searched for MUP patients treated with immunotherapy or targeted therapy reported in the literature, and their response and survival data were compared to the MUP patient data from NYU. Both groups' response data were compared to those reported for melanoma of known primary (MKP). RESULTS: The MUP patients treated at NYU had better outcomes on immunotherapy but worse on targeted therapy than the MUP patients in the literature. The NYU MUP patients and those in the literature had worse outcomes than the majority-MKP populations in 10 clinical trial reports. CONCLUSIONS: Our study suggests that MUP patients might have poorer outcomes on systemic therapy as compared to MKP patients. Our cohort was small and limited data were available, highlighting the need for increased reporting of MUP outcomes and multi-institutional efforts to understand the mechanism behind the observed differences.

OBJECTIVES: Since 2011, metastatic melanoma treatment has evolved with commercial approval of BRAF- and MEK-targeted therapy and CTLA-4- and PD-1-blocking antibodies (immune checkpoint inhibitors, ICI). While novel therapies have demonstrated improved prognosis in clinical trials, few studies have examined the evolution of prognosis and toxicity of these drugs among an unselected population. We assess whether survival and toxicity reported in trials, which typically exclude most patients with brain metastases and poor performance status, are recapitulated within a commercial access population. METHODS: 182 patients diagnosed with stage IV melanoma from July 2006 to December 2013 and treated with BRAF- and/or MEK-targeted therapy or ICI were prospectively studied. Outcomes and clinicopathologic differences between trial and commercial cohorts were assessed. RESULTS: Patients receiving commercial therapy (vs. on trial) had poorer prognostic features (i.e., brain metastases) and lower median overall survival (mOS) when assessed across all treatments (9.2 vs. 17.5 months, p = 0.0027). While toxicity within trial and commercial cohorts did not differ, patients who experienced toxicity had increased mOS (p < 0.001), irrespective of stratification by trial status or therapy. CONCLUSION: Metastatic melanoma patients receiving commercial treatment may represent a different clinical population with poor prognostic features compared to trial patients. Toxicity may prognosticate treatment benefit.