Melanoma -- Clinical Research Program

Pictured: Paul Chapman
Video

Medical oncologist Paul Chapman of Memorial Sloan Kettering describes cutting-edge research to improve the treatment of metastatic melanoma.

(08:00)

Melanomas can arise in the skin, mucous membranes, or eyes. Members of our melanoma research team are leaders in the fields of immunology, medical oncology, pathology, radiology, radiation oncology, and surgery. We have participated in research studying families in which multiple members have been diagnosed with melanoma.

We are leaders in the development of immune therapies, vaccines, and targeted therapies for melanoma, and we were the first to show the effectiveness of monoclonal antibodies for the treatment of solid tumors. Our team also has developed surgical techniques and new radiation therapies, including brachytherapy and stereotactic radiosurgery, for the treatment of melanoma.

Among our recent research accomplishments:

Molecular Pathology

  • We found that neoadjuvant temozolomide can produce complete response in advance melanoma patients. Our initial analysis showed that expression of MMP-1 and S100(7) are associated with response to temozolomide, which merits further testing.

New Agents

  • Multiple experimental agents are being evaluated in melanoma patients, including: ipilimumab, IMC1121B, ADI-SS PEG, anti-CD 137, mouse gp100 DNA, tyrosinase DNA vaccine, TRP2 DNA vaccine, GD2-KLH and GD3-KLH, and 17-AAG.
  • We led a phase II trial 17-allylamino-17-demethoxygeldanamycin (17-AAG) in melanoma patients, with the strategy of blocking the heat-shock protein 90 (hsp90). No objective anti-melanoma responses were seen. The conclusion is that future trials in melanoma should focus on a more potent hsp90 inhibitor or a formulation that can be administered chronically for a more prolonged suppression of the MAPK pathway. Clin Cancer Res. 2008 Dec 15;14(24):8302-7. [PubMed Abstract]
  • A phase I/II trial studying the use of arginine deiminase (ADI-PEG 20) as a strategy for melanoma therapy is in progress, with careful attention being paid to pharmacodynamic endpoints (arginine and citrulline levels) and correlation with anti-ADI antibodies.

Targeted Therapies

  • A phase II trial that is testing imatinib as a c-Kit inhibitor and is open only to patients with either a c-kit mutation or c-kit amplification is the first melanoma trial limited to a specific genotype. The trial is based on preclinical data that were generated in part by our disease management team.
  • We were the leading center in the United States for the testing of AZD6244, which is resulting in a phase II trial in patients with inoperable melanoma who have mutations in the BRAF gene. AZD6244 is designed to block a protein called MEK, which melanomas depend on to grow — especially melanomas with BRAF mutations.
  • We are leading a phase I study to observe the effects of PLX4032, a new investigational drug designed to block the BRAF protein. Researchers are observing side effects of PLX4032 and finding the highest safe dose.

Immunotherapy

  • We have been the major investigative site for the anti-CTLA-4 antibody (ipilimumab) program in melanoma. In addition to clinical contributions, we have developed an extensive immunologic monitoring program for patients receiving this therapy. A member of our team was one of the first investigators to describe the delay in tumor responses seen with ipilimumab treatment. Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20410-5. [PubMed Abstract]
  • Our first clinical trial using a combination therapy of mouse and human tyrosinase DNA vaccines showed that 40 percent of melanoma patients injected with the xenogeneic DNA developed quantifiable CD8+ responses. Mol Ther. 2007 Nov;15(11):2044-50. [PubMed Abstract]
  • We showed in a phase I/II study that giving granulocyte-macrophage colony-stimulating factor (GM-CSF) DNA is an effective adjuvant for peptide vaccines, stimulating CD8+ T cell responses in about 45 percent of patients. Mol Ther. 2008 Dec;16(12):2022-9. [PubMed Abstract]

Behavioral Approaches

  • We found that family discussions about melanoma after diagnosis are guided by an implicit set of rules that determine what is discussed and when the conversations occur, as well as who is engaged. Women are likely to spread the word about diagnosis and the need for prevention and screening. Understanding how discussion rules operate within families may help guide physicians' recommendations to families with melanoma. Arch Dermatol. 2008 Apr;144(4):553-4. [PubMed Abstract]
  • Members of our team are involved in collaborations to identify a research agenda for behavioral issues in testing for genetic susceptibility to melanoma relevant to the general population.
  • We found that melanoma survivors do not consistently practice skin self-examination or sun protection behaviors at higher rates than the general population. Psychooncology. 2009 Jan 13. [Epub ahead of print] [PubMed Abstract]