Project Details
Projekt
Analysis and therapeutic targeting of the metabolic and proliferative tumor heterogeneity in malignant melanoma
Applicant
Professor Dr. Alexander Roesch
Subject Area
Dermatology
Term
from 2010 to 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 190767923
Malignant melanoma is an aggressive tumor with dramatically reduced patient survival when disseminated to distant organs. Despite the historic response rates that have been lately seen for signaling targeted therapies in BRAFV600E mutant melanomas, relapses recur within ~6 months indicating gradually developing therapy resistance, e.g. via adaptive and acquired (re-) activation of MAKP and PI3K signaling. However, it has been unclear so far, how melanoma cells survive the very first contact with drugs (early intrinsic resistance). Cytotoxic drugs but also modern targeted therapies principally affect rapidly dividing cells. Thus, particularly slow-cycling cell subpopulations may escape therapy a priori and irrespective of their genetic origin. In our most recent experiments, we confirmed that slow-cycling melanoma cells of various genotypes are resistant to therapeutic attacks irrespective of the pharmacologic agents used. Our quest for the molecular basis of this intrinsic therapy resistance surprisingly revealed that no common oncogenic or therapeutic resistance mechanisms are involved. Instead, our preliminary data indicate a possible role of bioenergetic proteins such as mitochondrial ATP synthase. Following the basic hypothesis that rapidly growing cancer cells are characterized by high glycolysis, whereas slow-cycling, therapy resistant cells more rely on mitochondrial oxidative phosphorylation (OXPHOS), we plan to further dissect the different bioenergetic states of melanoma cell subpopulations in vitro and in vivo under changing microenvironmental conditions. Next, we intend to overcome the intrinsic therapy resistance of melanoma cell subpopulations in vitro and in vivo using novel therapeutic OXPHOS inhibitors or new inhibitors of the slow cycling phenotype. We will combine these new strategies with established therapeutics known to eliminate the rapidly proliferating tumor mass, such as BRAFV600E inhibitors or cytotoxic drugs. The final aim will be to determine the ideal temporal sequence for the combination of both therapeutic modules (e.g. simultaneous vs. alternating). The groundbreaking nature of the proposed work lies in the historic chance to overcome the notorious therapeutic resistance of melanoma right where it begins, i.e. in intrinsically resistant tumor subpopulations.
DFG Programme
Research Grants
International Connection
Austria, USA
