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.
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.
|Qin, Jie; Rajaratnam, Rajathees; Feng, Li et al. (2015) Development of organometallic S6K1 inhibitors. J Med Chem 58:305-14|
|Bastian, Boris C (2014) The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. Annu Rev Pathol 9:239-71|
|Simpson, R Mark; Bastian, Boris C; Michael, Helen T et al. (2014) Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma. Pigment Cell Melanoma Res 27:37-47|
|Vultur, A; Villanueva, J; Krepler, C et al. (2014) MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. Oncogene 33:1850-61|
|Wähler, Kathrin; Ludewig, Anja; Szabo, Patrick et al. (2014) Rhenium Complexes with Red-Light-Induced Anticancer Activity. Eur J Inorg Chem 2014:807-811|
|Wiesner, Thomas; He, Jie; Yelensky, Roman et al. (2014) Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun 5:3116|
|Yeh, Iwei; Mully, Thaddeus W; Wiesner, Thomas et al. (2014) Ambiguous melanocytic tumors with loss of 3p21. Am J Surg Pathol 38:1088-95|
|Wang, Tao; Ge, Yingbin; Xiao, Min et al. (2014) SECTM1 produced by tumor cells attracts human monocytes via CD7-mediated activation of the PI3K pathway. J Invest Dermatol 134:1108-18|
|Dörr, Markus; Meggers, Eric (2014) Metal complexes as structural templates for targeting proteins. Curr Opin Chem Biol 19:76-81|
|Botton, Thomas; Yeh, Iwei; Bastian, Boris C (2014) Melanoma BRAF fusions--letter. Clin Cancer Res 20:6631|
Showing the most recent 10 out of 331 publications