The NYU Cancer Institute's Melanoma Research Program focuses its efforts on the diagnosis, development, and treatment of melanoma. Investigators are focusing on the following areas of study:
Melanoma Diagnosis and Prognosis
One of the main focuses of the NYU Cancer Institute's Interdisciplinary Melanoma Cooperative Group is to identify better ways to diagnose patients and predict their prognosis. Below are examples of current research:
IMCG investigators aimed to identify primary tumor characteristics and clinical features predictive of brain metastases (B-Met) development and post-B-Met survival. They studied a prospectively accrued cohort of 900 melanoma patients to identify clinicopathologic features of primary melanoma that are predictive of B-Met development and survival after a diagnosis of B-Met. The results of the study suggested that patients with ulcerated primary tumors should be prospectively studied to determine whether heightened surveillance for B-Met can improve clinical outcome (Zakrzewski J et al., Cancer 2010). Dr. Eva Hernando's group recently reported that specific miRNAs may be important mediators of melanoma dissemination to the brain (AACR 2010).
Several IMCG investigators worked together to explore the potential of a melanoma microRNA (miRNA) expression signature to be predictive of outcome, and its potential to improve risk stratification when added to the standard-of-care staging criteria. They identified a signature of 18 miRNAs whose overexpression was significantly correlated with longer survival (defined as more than 18 months post-recurrence survival). Subsequent cross-validation showed that a small subset of these miRNAs can predict post-recurrence survival in metastatic melanoma with an estimated accuracy of 80.2 percent (CI: 79.8-80.6). In contrast to standard-of-care staging criteria, a six-miRNA signature significantly and independently stratified stage III patients into "better" and "worse" prognostic categories (Segura MF et al., Clinical Cancer Research 2010).
IMCG investigators collaborated to investigate the mechanisms of altered expression of proto-oncogene SKP2 in metastatic melanoma and its clinical relevance in patients with metastatic melanoma. The genomic status of SKP2 was assessed, as were SKP2 protein levels in human metastatic tissues. No mutations were identified in SKP2. Increased copy number at the SKP2 locus was observed in metastatic cell lines and in human metastatic tissues which was associated with overexpression of SKP2 protein. Overexpression of the SKP2 protein in human tissues (due mostly to copy number gain) was associated with worse survival in a multivariate model controlling for the site of metastasis. Results may have implications for the development of therapeutics that target SKP2 (Rose AE et al., Pigment Cell & Melanoma Research 2010).
Molecular Biology of Melanoma
Many IMCG investigators are involved in discovering the molecular mechanisms behind melanoma. Below are some examples of current initiatives:
The IMCG and Dr. Julide Celebi (Columbia University) are working on a project to dissect the melanoma genome. Together they will define and functionally characterize candidate oncogenes and tumor-suppressor genes to determine correlations with clinical and pathological parameters.
Using data showing that miR-182 is commonly overexpressed in human melanoma cell lines and tissue samples, IMCG investigators found that miR-182 overexpression stimulates migration of melanoma cells in vitro and their metastatic potential in vivo by directly repressing MITF-M and Foxo3, whereas miR-182 downregulation impedes invasion and triggers apoptosis. These data provide a mechanism for invasion and survival in melanoma that could prove applicable to the metastasis of other cancers, and suggest that miRNA silencing may be a worthwhile therapeutic strategy. (Segura MF et al., Proceedings of the National Academy of Sciences of the United States of America 2009).
In collaboration with Dr. Emily Bernstein (Mount Sinai School of Medicine), IMCG investigators are studying the epigenetic profiling of malignant melanoma and examining the role of histone variants on tumor progression.
Novel Immunotherapeutic Approaches to Melanoma Treatment
IMCG scientists are leaders in the development and evaluation of novel immunotherapeutic approaches to melanoma. Below are a few of our recent projects:
DC vaccines: Dendritic cell (DC) vaccines have been widely used in clinical trials to treat cancer; however, their immunogenicity compared to conventional vaccine adjuvants has not been well examined. IMCG investigators received a $1 million grant from the Melanoma Research Foundation to evaluate improved methods of generating DC using Toll-like receptor (TLR) agonists such as poly I:V, alongside montanide. Dr. Bhardwaj, a member of the IMCG and Director of the Tumor Vaccine Program, recently published data showing that DC vaccines function as vehicles for antigens rather than directly priming T-cell immunity (Yewdall AW et al., PLos One 2010). Her group showed that following vaccination with DC, the cells are acquired by endogenous DC populations and that antigens are subsequently cross-presented to T cells. This finding suggests that DC vaccinations should be accompanied by systemically delivered maturation agents to enhance the capacity of endogenous DC to present antigens from phagocytosed DC, a concept the investigators will be testing in the clinic shortly.
TLR agonists as vaccine adjuvants: TLR agonists are potent activators of DC and prime melanoma-specific T cells. Clinical trials using the cancer testis antigen NY-ESO-1 with CpG and montanide showed the development of high levels of antigen-specific CD4+ and CD8+ T cells and strong antibody responses (Valmori D et al., Proceedings of the National Academy of Sciences of the United States of America 2007). The NY-ESO-1 protein elicited immunodominant HLA-DR52b-restricted CD4+ T-cell responses with a conserved T-cell receptor repertoire (Bioley G et al., Clinical Cancer Research 2009), and revealed an HLA class I-associated immunodominance for CTL responsiveness restricted to Cw3 and B35 (Bioley G et al., Clinical Cancer Research 2009).
Immunomodulatory agents for melanoma: Dr. Anna Pavlick, Director of the IMCG Clinical Trials Program, has acquired extensive experience treating metastatic melanoma with anti-CTLA-4 agents (ipilimumab and tremelimumab), treating more than 150 patients and managing their immune-related adverse events. As a result of this vast experience, she was the first to document complete hair depigmentation (similar to B16-bearing mice treated with TRP-2/GM-CSF vaccines and anti-CTLA-424), as a clinical biomarker heralding a complete and durable response to therapy. This observation was seen with both tremelimumab and ipilimumab. The IMCG is analyzing immune responses in these patients to determine the underlying etiology, and tumor tissue is being analyzed for TILs and miRs. The IMCG has also acquired funding from the Cancer Research Institute for testing the combination of anti-CTLA-4 and cytoxan in patients with metastatic melanoma, with approval pending from Bristol-Myers Squibb.
Novel tumor antigens: Melanoma patients can develop disabling Th2 responses for unclear reasons. Members of the IMCG showed that CD4+ TILs from melanoma patients recognize matrix metalloproteinase 2 (MMP-2) and have a Th2 inflammatory profile producing IL-4 and TNF. MMP-2, abundant in tumors, modulates DC function through inhibition of IL-12 production, thereby causing Th2 responses to develop in default (Godefroy et al., Cancer Cell 2011). MMP-2 is the first endogenous immune modulator discovered to date.
A Broad Clinical Trial Program
At the IMCG, patients at risk for melanoma recurrence and those diagnosed with advanced disease are referred whenever possible to a clinical trial. Because of our large patient population, we have the ability to conduct multiple clinical trials for multiple patients at multiple stages of the disease. The IMCG is conducting several clinical trials for patients with melanoma, evaluating new therapies to target the disease from different angles. Many of those studies stem from ideas generated by basic science researchers who share them with clinicians via the bimonthly IMCG meetings. We offer investigator-initiated, Eastern Cooperative Oncology Group, National Cancer Institute, and industry-supported clinical trials evaluating novel biologics, inhibitors, and chemotherapeutic combinations.
Dr. Anna Pavlick, an oncologist in the IMCG who directs our Clinical Trials program, is overseeing an immunotherapy-based GlaxoSmithKline-sponsored phase III trial incorporating TLR4 and -9 agonists: DERMA Adams, which combines MPL and CpG with the cancer-testis antigen MAGE-A3 in melanoma. She has also negotiated with companies to evaluate IL-18, GM-CSF, type I interferon, IL-2 and anti-integrins in clinical trials. In collaboration with Dr. Richard Carvajal (Memorial Sloan-Kettering Cancer Center), Dr. Pavlick is also participating in a clinical trial called "A Phase II Study of Imatinib Mesylate (STI571; NSC #716051; IND 61135) in Patients with Inoperable AJCC Stage III or IV Melanoma Harboring Somatic Alterations of C-KIT."
Dr. Nina Bhardwaj, Director of the NYUCI Tumor Vaccine Program, is the principal investigator for a clinical trial studying poly IC:LC, a TLR3 agonist plus/minus montanide ISA-51 as adjuvants for NY-ESO-1 protein vaccine in patients with resected melanoma (NYU 09-0007). Dr. Pavlick is a co-investigator. Collaborators at the Ludwig Institute for Cancer Research (LICR) and the Cancer Vaccine Collaborative (CVC) (Drs. Lloyd Old, Sacha Gnajtic, and Jedd Wolchok) are also participating in this study.
A jointly-proposed trial of ipilimumab and poly IC/NY-ESO-1/montanide vaccine has been pre-approved for drug supply by BMS. NYU and Memorial Sloan-Kettering Cancer Center will work together in an attempt to augment the clinical activity of CTLA-4 blockade using vaccination. Finally, IMCG investigators will collaborate with Dr. Jedd Wolchok on a clinical trial comparing improved DC vaccines with montanide in a study recently funded by the Melanoma Research Foundation.
The IMCG is also currently conducting phase II trials of RO4929097, an inhibitor of Notch pathway signaling in tumor cells. In addition to the trial, IMCG investigators are evaluating the effects of the drug on melanoma tumorigenesis by studying its effect on many downstream targets. This information will elucidate how the drug is working and interacting with other known players in melanoma genesis.
Other areas of scientific investigation include:
- NY-ESO-1 expression in melanoma prognosis and survival
- Immunologic potential of NY-ESO-1 as a treatment target
- Overexpression of NEP in the progression of cutaneous melanoma
- BRAF and N-RAS mutations in metastatic melanoma
- Novel imaging approaches for the early detection of melanoma, including the MoleSafe total skin imaging program, and dermoscopic analysis of individual skin lesions to differentiate early melanomas from benign growths. Investigators are also exploring the use of these tools to calculate a patient's overall risk for developing melanoma or multiple primary melanomas.