Malignant melanoma initiating cells (MMICs) are minority subpopulations in which clinical virulence resides as a consequence of unlimited self-renewal capacity, resulting in inexorable tumor progression and potential metastasis. Our laboratories have recently identified human MMICs and shown them to express the targetable biomarker and multidrug resistance transporter, ABCB5 (Nature, Jan 17, 2008). In this study, proof of principle of immune-mediated MMIC destruction and consequent inhibition of tumor growth was demonstrated. More recently, we have shown that MMICs employ mechanisms to thwart endogenous anti-tumor immunity via the B7-2 and PD1 pathways (Cancer Res, Jan 15, 2010). This proposal seeks to further advance these findings in a translationally-relevant manner with the goal of accelerating progress toward clinical application of anti- melanoma immune therapies specifically targeting MMICs.
The specific aims of this proposal are: (1) Characterization of ABCB5+ MMIC response to immunotherapy in human patients and assessment/prediction of MMIC therapeutic response;(2) In vivo dissection of antitumor immunity pathway interactions with MMIC in a novel humanized xenotransplantation model, melanoma to hu-PBMC NOD-scid IL2r3null mice;and (3) Preclinical immunomodulatory/MMIC-targeted combination therapies. This initiative should enhance the rapid development and refinement of targeted immunotherapies directed against MMICs, and thus holds great promise for rapid evolution to clinical testing.

Public Health Relevance

Malignant melanoma, a form of cancer that is increasing faster than any other cancer worldwide, becomes deadly once it spreads from a primary skin tumor (sometimes no larger than a grain of rice) to the body's vital organs. Until now, there is no effective therapy for metastatic melanoma, in large part because the most virulent melanoma cells, called cancer stem cells, are resistant to treatment. We have successfully identified these virulent melanoma stem cells, and have developed strategies to immunologically target and eliminate them, and this grant proposal advances this research to a point whereby patients with otherwise incurable disease may significantly benefit.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA158467-02
Application #
8532856
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Welch, Anthony R
Project Start
2012-09-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$377,059
Indirect Cost
$116,640
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Luke, Jason J; Lezcano, Cecilia; Hodi, F Stephen et al. (2015) Antitumor granuloma formation by CD4+ T cells in a patient with rapidly progressive melanoma experiencing spiking fevers, neuropathy, and other immune-related toxicity after treatment with ipilimumab. J Clin Oncol 33:e32-5
Lezcano, Cecilia; Lee, Chung-Wei; Larson, Allison R et al. (2014) Evaluation of stromal HGF immunoreactivity as a biomarker for melanoma response to RAF inhibitors. Mod Pathol 27:1193-202
Wilson, Brian J; Saab, Karim R; Ma, Jie et al. (2014) ABCB5 maintains melanoma-initiating cells through a proinflammatory cytokine signaling circuit. Cancer Res 74:4196-207
Murphy, George F; Wilson, Brian J; Girouard, Sasha D et al. (2014) Stem cells and targeted approaches to melanoma cure. Mol Aspects Med 39:33-49
Larson, Allison R; Dresser, Karen A; Zhan, Qian et al. (2014) Loss of 5-hydroxymethylcytosine correlates with increasing morphologic dysplasia in melanocytic tumors. Mod Pathol 27:936-44
Ksander, Bruce R; Kolovou, Paraskevi E; Wilson, Brian J et al. (2014) ABCB5 is a limbal stem cell gene required for corneal development and repair. Nature 511:353-7
Lee, Jonathan J; Murphy, George F; Lian, Christine G (2014) Melanoma epigenetics: novel mechanisms, markers, and medicines. Lab Invest 94:822-38
Lee, Chung-Wei; Zhan, Qian; Lezcano, Cecilia et al. (2014) Nestin depletion induces melanoma matrix metalloproteinases and invasion. Lab Invest 94:1382-95
Hodi, F Stephen; Lawrence, Donald; Lezcano, Cecilia et al. (2014) Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res 2:632-42
Volpicelli, Elgida R; Lezcano, Cecilia; Zhan, Qian et al. (2014) The multidrug-resistance transporter ABCB5 is expressed in human placenta. Int J Gynecol Pathol 33:45-51

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