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Novel therapies for pediatric low grade glioma
Dardan Demaliaj1, Sharon L Gardner
1New York University Langone Medical Center, New York, New York, USA.
Purpose Of Review:
Current biological findings provide new insights into the genetics driving growth of low-grade gliomas in pediatric patients. This has provided new targets for novel therapies. The purpose of this paper is to review novel therapies for pediatric low-grade gliomas that have been published in the past 24 months.
Recent Findings:
Low-grade gliomas are often driven by mitogen activated protein kinase (MAPK) alterations either with BRAF V600E point mutations or BRAF fusions. Current advances have also highlighted novel fusions of fibroblast growth factor receptor (FGFR), myeloblastosis family of transcription factors (MYB), meningioma 1 tumor suppressor (MN1), neurotrophic receptor kinase family of receptors (NTRK), Kristen RAS (Rat Sarcoma Virus) oncogene homolog in mammals (KRAS), Receptor tyrosine kinase ROS proto oncogene 1 (ROS1), protein kinase C alpha (PRKCA), and platelet derive growth factor receptor (PDGFR) amplification. Novel therapies have been employed and are showing encouraging results in pediatric low-grade gliomas. Current trials are underway with newer generation pan RAF inhibitors and mitogen activated protein kinase - kinase (MEK) inhibitors. Other early phase clinical trials have provided safety data in pediatric patients targeting FGFR fusion, NTRK fusion, PDGFR amplification and ROS1 mutations.
Summary:
Historical treatment options in pediatric low-grade gliomas have utilized surgery, radiation therapy and conventional chemotherapy. Recently greater insight into their biology has found that alterations in MAPK driven pathways are often the hallmark of tumorigenesis. Targeting these novel pathways has led to tumor control and shrinkage without the use of conventional chemotherapy. Caution should be taken however, since these treatment options are still novel, and we do not fully appreciate the long-term effects. Nonetheless a new era of targeted medicine is here.
Insights
Novel targeted therapies show promise for pediatric low-grade gliomas by targeting specific genetic alterations like MAPK pathway changes. These new treatments offer tumor control without traditional chemotherapy, marking a new era in pediatric cancer medicine.
Area of Science:
- Pediatric oncology
- Molecular genetics
- Drug development
Background:
- Pediatric low-grade gliomas (pLGGs) are heterogeneous tumors with complex genetic underpinnings.
- Historically, treatment relied on surgery, radiation, and chemotherapy, often with significant side effects.
- Recent advances have elucidated key genetic drivers, particularly alterations in the mitogen-activated protein kinase (MAPK) pathway.
Purpose of the Study:
- To review novel therapeutic strategies for pediatric low-grade gliomas.
- To highlight recent findings in the genetic drivers and targeted treatments for pLGGs.
- To summarize advancements published within the last 24 months.
Main Methods:
- Literature review of studies published in the past 24 months.
- Analysis of genetic alterations in pediatric low-grade gliomas.
- Evaluation of novel targeted therapies and ongoing clinical trials.
Main Results:
- pLGGs are frequently driven by MAPK pathway alterations, including BRAF V600E mutations and various fusions (FGFR, NTRK, KRAS, ROS1, etc.).
- Novel targeted therapies are demonstrating encouraging results, leading to tumor control and shrinkage.
- Early-phase clinical trials are investigating pan-RAF and MEK inhibitors, as well as agents targeting FGFR, NTRK, PDGFR, and ROS1 alterations.
Conclusions:
- Targeting MAPK-driven pathways represents a paradigm shift in treating pediatric low-grade gliomas.
- Novel therapies offer effective tumor control, potentially avoiding conventional chemotherapy.
- While promising, long-term effects of these novel treatments require further investigation, heralding a new era of precision medicine.
