Current melanoma treatments are either completely ineffective or they elicit short-lived responses, i.e., initial tumor shrinkage followed by rapid relapse. Our overall hypothesis is that therapy resistance in melanoma is due to a 'biologic signature', which is characterized through differential expression and activation of proteins in biologically defined sub-populations. Our working hypothesis is that chemo-resistance in melanoma is initially due to a defined subpopulation of malignant cells that evades antagonistic threats through slow or complete lack of proliferation. In addition, melanoma cells can develop acquired resistance mechanisms. In preliminary studies we have characterized a small population that cycles ten to hundredfold slower than the main population but that maintains high proliferation potential. This cell population, identified by the expression of the histone 3 K4 demethylase JARID1B, appears to serve as a tumor reservoir responsible for melanoma recurrence after therapeutic intervention as most chemotherapeutic agents and signaling inhibitors affect only rapidly dividing cells. We therefore hypothesize that melanomas can be effectively killed through a dual-tiered therapeutic approach: a genetic-based treatment aiming to eradicate the bulk of melanoma growths plus targeting of the remaining slow-cycling, self-renewing subpopulation.
In Specific Aim 1, we will determine which signaling mechanisms slow-cycling self-renewing JARID1B+ cells apply to escape treatment with clinically used chemotherapeutic drugs and recently developed compounds targeting key signal transduction pathways. It is expected that slow-cycling, self-renewing JARID1B+ melanoma cells will remain largely unaffected whereas other populations are more sensitive.
In Specific Aim 2, we plan to eliminate all cellular populations responsible for the malignant phenotype of advanced melanoma through a two-tiered therapeutic approach whereby the bulk of the population is killed through genetic-based targeted therapies and the slow-cycling subpopulation by a JARIDIB-targeting approach. These studies will enable the rational development of therapeutic modalities whereby oncologists can eliminate all melanoma cells and prevent drug resistance or recurrence.

Public Health Relevance

This proposal has high translational significance because it deals with the mechanisms of drug resistance in melanoma, which continues to be a major challenge in this malignancy. Through the work in this proposal we begin to better understand why melanomas are highly resistant to therapies. We are then developing strategies to overcome resistance and expect that combination therapies will be most effective if they take into account all populations of malignant cells within a tumor.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA025874-32
Application #
8450869
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
32
Fiscal Year
2013
Total Cost
$340,035
Indirect Cost
$22,496
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Perego, M; Maurer, M; Wang, J X et al. (2018) A slow-cycling subpopulation of melanoma cells with highly invasive properties. Oncogene 37:302-312
Heppt, Markus V; Wang, Joshua X; Hristova, Denitsa M et al. (2018) MSX1-Induced Neural Crest-Like Reprogramming Promotes Melanoma Progression. J Invest Dermatol 138:141-149
Ca├▒adas, Israel; Thummalapalli, Rohit; Kim, Jong Wook et al. (2018) Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Nat Med 24:1143-1150
Jenkins, Russell W; Aref, Amir R; Lizotte, Patrick H et al. (2018) Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids. Cancer Discov 8:196-215
Liu, Shujing; Zhang, Gao; Guo, Jianping et al. (2018) Loss of Phd2 cooperates with BRAFV600E to drive melanomagenesis. Nat Commun 9:5426
Reyes-Uribe, Patricia; Adrianzen-Ruesta, Maria Paz; Deng, Zhong et al. (2018) Exploiting TERT dependency as a therapeutic strategy for NRAS-mutant melanoma. Oncogene 37:4058-4072
Chen, Gang; Huang, Alexander C; Zhang, Wei et al. (2018) Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560:382-386
Vitiello, Marianna; Tuccoli, Andrea; D'Aurizio, Romina et al. (2017) Context-dependent miR-204 and miR-211 affect the biological properties of amelanotic and melanotic melanoma cells. Oncotarget 8:25395-25417
Krepler, Clemens; Sproesser, Katrin; Brafford, Patricia et al. (2017) A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma. Cell Rep 21:1953-1967
Somasundaram, Rajasekharan; Zhang, Gao; Fukunaga-Kalabis, Mizuho et al. (2017) Tumor-associated B-cells induce tumor heterogeneity and therapy resistance. Nat Commun 8:607

Showing the most recent 10 out of 382 publications