Metabolic Imaging Biomarkers of Response to Signaling Inhibition Therapy in Melanoma
Pradeep Kumar Gupta1, Stepan Orlovskiy1, Fernando Arias-Mendoza1,2
1Molecular Imaging Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Abstract:
Dabrafenib therapy for metastatic melanoma focuses on blocking growth-promoting signals produced by a hyperactive BRAF protein. We report the metabolic differences of four human melanoma cell lines with diverse responses to dabrafenib therapy (30 mg/kg; oral): WM3918 < WM9838BR < WM983B < DB-1. Our goal was to determine if metabolic changes produced by the altered signaling pathway due to BRAF mutations differ in the melanoma models and whether these differences correlate with response to treatment. We assessed metabolic changes in isolated cells using high-resolution proton magnetic resonance spectroscopy (1H MRS) and supplementary biochemical assays. We also noninvasively studied mouse xenografts using proton and phosphorus (1H/31P) MRS. We found consistent changes in lactate and alanine, either in isolated cells or mouse xenografts, correlating with their relative dabrafenib responsiveness. In xenografts, we also observed that a more significant response to dabrafenib correlated with higher bioenergetics (i.e., increased βNTP/Pi). Notably, our noninvasive assessment of the metabolic status of the human melanoma xenografts by 1H/31P MRS demonstrated early metabolite changes preceding therapy response (i.e., tumor shrinkage). Therefore, this noninvasive methodology could be translated to assess in vivo predictive metabolic biomarkers of response in melanoma patients under dabrafenib and probably other signaling inhibition therapies.
Insights
Metabolic changes in melanoma cells and xenografts, including lactate and alanine levels, correlate with response to dabrafenib therapy. Noninvasive magnetic resonance spectroscopy (MRS) can predict treatment outcomes in melanoma patients.
Area of Science:
- Oncology
- Biochemistry
- Medical Imaging
Background:
- Metastatic melanoma treatment often involves targeting hyperactive BRAF protein signaling with drugs like dabrafenib.
- Understanding metabolic alterations in melanoma is crucial for predicting treatment response.
- Diverse responses to dabrafenib highlight the need for biomarkers to guide therapy.
Purpose of the Study:
- To investigate metabolic differences in melanoma cell lines with varying dabrafenib responses.
- To determine if metabolic changes correlate with BRAF mutation-driven signaling pathway alterations and treatment efficacy.
- To explore the potential of noninvasive magnetic resonance spectroscopy (MRS) for predicting dabrafenib response.
Main Methods:
- Assessed metabolic profiles of four human melanoma cell lines using proton magnetic resonance spectroscopy (1H MRS) and biochemical assays.
- Utilized noninvasive proton and phosphorus (1H/31P) MRS to study mouse xenografts.
- Correlated metabolic findings with dabrafenib treatment response and tumor bioenergetics.
Main Results:
- Consistent changes in lactate and alanine levels were observed in both isolated cells and xenografts, correlating with dabrafenib responsiveness.
- In xenografts, a higher bioenergetic status (increased beta-nucleoside triphosphate/inorganic phosphate ratio) correlated with a significant response to dabrafenib.
- Noninvasive 1H/31P MRS detected early metabolic changes in xenografts preceding observable tumor shrinkage.
Conclusions:
- Metabolic profiles, particularly lactate and alanine levels, can serve as predictive biomarkers for dabrafenib response in melanoma.
- Noninvasive 1H/31P MRS is a promising tool for assessing in vivo metabolic status and predicting treatment outcomes.
- This methodology holds potential for clinical translation in monitoring melanoma patients undergoing dabrafenib or similar targeted therapies.
