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A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
Targeted molecular therapy in melanoma
Igor Puzanov1, Keith T Flaherty
1Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA.
Abstract:
Immunotherapy and chemotherapy benefit few patients with metastatic melanoma, and even fewer experience durable survival benefit. These poor results may come from treating all melanomas as though they are biologically homogeneous. Recently, it has been shown that targeting specific activated tyrosine kinases (oncogenes) can have striking clinical benefits in patients with melanoma. In 2002, a V600E mutation of the BRAF serine/threonine kinase was described as present in more than 50% of all melanomas. The mutation appeared to confer a dependency by the melanoma cancer cell on activated signaling through mitogen-activated protein kinase pathway. The frequency and focality of this mutation (>95% of all BRAF mutations being at V600 position) suggested its importance in melanoma pathophysiology and potential as a target for therapy. The recent results of a phase 1 study with PLX4032/RG7204, a small molecule RAF inhibitor, confirm this hypothesis. Mucosal and acral-lentiginous melanomas, comprising 3% of all melanomas, frequently harbor activating mutations of c-kit and drugs targeting this mutation seem to confer similar benefits for these types of tumors. Here we provide an overview of the targeted therapy development in melanoma with emphasis on BRAF inhibition because of its prevalence and possibility of transforming the care of many melanoma patients.
Insights
Targeted therapies, particularly BRAF inhibitors, show promise for metastatic melanoma. Targeting specific mutations like BRAF V600E offers a new avenue for effective melanoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Metastatic melanoma treatments like immunotherapy and chemotherapy offer limited durable survival benefits.
- Melanoma heterogeneity suggests a need for targeted treatment strategies.
- Activating tyrosine kinase mutations, such as BRAF V600E, are key drivers in melanoma.
Purpose of the Study:
- To provide an overview of targeted therapy development in melanoma.
- To emphasize the significance of BRAF inhibition due to its prevalence.
- To highlight the potential of targeted therapies to transform melanoma patient care.
Main Methods:
- Review of scientific literature on targeted therapy in melanoma.
- Focus on the role of BRAF V600E mutations and their targeted inhibition.
- Discussion of c-kit mutations in specific melanoma subtypes.
Main Results:
- BRAF V600E mutation is present in over 50% of melanomas, driving MAPK pathway signaling.
- A small molecule RAF inhibitor (PLX4032/RG7204) shows positive clinical results.
- Targeting c-kit mutations in mucosal and acral-lentiginous melanomas also demonstrates benefit.
Conclusions:
- Targeted therapies, especially BRAF inhibitors, represent a significant advancement in melanoma treatment.
- Understanding specific genetic mutations allows for personalized and more effective therapeutic strategies.
- BRAF inhibition holds the potential to dramatically improve outcomes for a large subset of melanoma patients.
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