Merkel Cell Carcinoma (MCC) is an increasingly common skin cancer associated with ultraviolet exposure and immune suppression. Compared with malignant melanoma, MCC is twice as likely to be lethal. The landmark discovery of an MCC-associated polyomavirus offers hope of substantial progress in pathogenesis, prognostic markers, and treatment. Dr. Nghiem is a recognized leader and as of 2008, a funded patient-oriented researcher in the area of MCC. This K24 proposal will take advantage of an extensive and unique set of clinical data, tissues, and blood. This program will provide outstanding training opportunities for young clinical investigators to develop into patient-oriented researchers and allow Dr. Nghiem to focus a minimum of 50% effort on patient-oriented research and mentoring. Dr.Nghiem is a co-director of research in Dermatology and of a newly awarded NIH Training Grant in Dermatology. To provide optimal mentoring of Patient Oriented Research - trainees, Dr. Nghiem works closely with an established team of medical, surgical, and radiation oncologists at the UW and Fred Hutchinson Cancer Research Center. Of the 34 trainees that Dr. Nghiem has mentored over the past ten years, 33 remain involved in their training or have already taken a faculty position (12 trainees) at five different universities. The University of Washington provides a rich source of potential trainees for patient-oriented research and facilitates their funding, coursework and mentoring through an extensive NIH-funded Institute of Translational Health Sciences. Extensive collaborative mentoring relationships have been established to ensure effective training of mentees from various clinical disciplines in patient-oriented research. Mentees will have direct patient contact including consenting patients for tissue/blood donation and contacting them later for follow-up data. Their training will also involve the genetic, immunologic, and biostatistical outcomes analyses needed to improve our understanding of this lethal skin cancer. Although these projects focus on MCC, the training will be broadly applicable to human disease.
Three Aims (1-3) are funded through 2012 via an American Cancer Society grant:
Aim 1. Define key genetic aberrations that are recurrent in MCC, Aim 2. Develop a consensus staging system for MCC, Aim 3. Integrate clinical, histologic and molecular features into a nomogram to predict survival for MCC.
Aims 4 -6 will leverage our unique MCC resources to study the newly discovered Merkel cell polyomavirus:
Aim 4. Correlate viral status and outcome in MCC, Aim 5. Develop and employ a serologic assay to determine the prevalence of MCPyV in MCC patients and controls, and Aim 6. Define the cell-mediated immune response against the MCC-associated polyomavirus. Data from Aims 4-6 will support an application for a new NIH R01 grant to be submitted during the K24 award period.

Public Health Relevance

This proposal takes advantage of a unique collection of tissues and clinical data from an uncommon cancer, Merkel cell carcinoma (MCC), to provide an outstanding vehicle for training patient-oriented researchers. Dr. Nghiem has a proven history of commitment to and success in mentoring clinician investigators. The recent discovery of a new virus associated with MCC, combined with extensive clinical resources provide a superb opportunity to improve understanding, prognosis and therapy for MCC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24CA139052-05
Application #
8534545
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lim, Susan E
Project Start
2009-09-29
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$185,016
Indirect Cost
$12,964
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Chapuis, Aude G; Afanasiev, Olga K; Iyer, Jayasri G et al. (2014) Regression of metastatic Merkel cell carcinoma following transfer of polyomavirus-specific T cells and therapies capable of re-inducing HLA class-I. Cancer Immunol Res 2:27-36
Paulson, Kelly G; Iyer, Jayasri G; Simonson, William T et al. (2014) CD8+ lymphocyte intratumoral infiltration as a stage-independent predictor of Merkel cell carcinoma survival: a population-based study. Am J Clin Pathol 142:452-8
Paulson, Kelly G; Tegeder, Andrew; Willmes, Christoph et al. (2014) Downregulation of MHC-I expression is prevalent but reversible in Merkel cell carcinoma. Cancer Immunol Res 2:1071-9
Blom, Astrid; Bhatia, Shailender; Pietromonaco, Stephanie et al. (2014) Clinical utility of a circulating tumor cell assay in Merkel cell carcinoma. J Am Acad Dermatol 70:449-55
Iyer, Jayasri G; Storer, Barry E; Paulson, Kelly G et al. (2014) Relationships among primary tumor size, number of involved nodes, and survival for 8044 cases of Merkel cell carcinoma. J Am Acad Dermatol 70:637-43
Moshiri, Ata S; Nghiem, Paul (2014) Milestones in the staging, classification, and biology of Merkel cell carcinoma. J Natl Compr Canc Netw 12:1255-62
Asgari, Maryam M; Sokil, Monica M; Warton, E Margaret et al. (2014) Effect of host, tumor, diagnostic, and treatment variables on outcomes in a large cohort with Merkel cell carcinoma. JAMA Dermatol 150:716-23
Afanasiev, Olga K; Yelistratova, Lola; Miller, Natalie et al. (2013) Merkel polyomavirus-specific T cells fluctuate with merkel cell carcinoma burden and express therapeutically targetable PD-1 and Tim-3 exhaustion markers. Clin Cancer Res 19:5351-60
Paulson, Kelly G; Iyer, Jayasri G; Byrd, David R et al. (2013) Pathologic nodal evaluation is increasingly commonly performed for patients with Merkel cell carcinoma. J Am Acad Dermatol 69:653-4
Stetsenko, Galina Y; Malekirad, Jacqueline; Paulson, Kelly G et al. (2013) p63 expression in Merkel cell carcinoma predicts poorer survival yet may have limited clinical utility. Am J Clin Pathol 140:838-44

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