ID #154 Alternating MAPK and mTOR Signaling Pathway Inhibition in Refractory Pediatric Low-Grade Glioma: A Case Series Review
Nathaniel Zaroban, Adam EsbenshadeAbstract
Background and Objective
Pediatric low-grade gliomas (pLGGs) are most commonly generated by aberrations in the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) or the PI3K/AKT/TSC/RHEB/mTOR (mTOR) cell signaling pathways. Pre-clinical studies show that the MAPK and mTOR pathways are intricately interconnected with bidirectional regulation and are heavily sensitive to influences in the other. We aimed to report cases that suggest this biochemical signaling interplay may be clinically relevant in medical pLGG management.
Methods
This is a retrospective case series review of three patients. Selected patients were diagnosed with pLGGs that proved refractory to numerous traditional chemotherapies plus or minus surgical debulking and radiation therapy before sequentially receiving chemotherapy agents targeting MAPK and mTOR inhibition in variable order. After demonstrating sustained response to initial targeted inhibition of one signaling pathway, selected patients then eventually experienced tumor progression and subsequently responded to targeted inhibition of the other signaling pathway.
Case Descriptions
Patient one has a thalamic BRAF V600E positive desmoplastic infantile ganglioglioma that sustained partial response to selumetinib (MEK inhibitor) for 13 months before on-therapy progression. The patient then demonstrated a sustained five-year partial response to sirolimus (mTOR inhibitor) before on-therapy progression. Afterward they sustained two-year partial response to combination dabrafenib (BRAF V600E inhibitor) and trametinib (MEK inhibitor) and are now stable off therapy. Patient two has neurofibromatosis type 1 and an optic nerve pilocytic astrocytoma that partially responded to repeat courses of sirolimus over nine years before on-therapy progression. They are currently sustaining a one-year partial response to selumetinib. Patient three has a thalamic BRAF V600E positive ganglioglioma that sustained a three-year partial response to dabrafenib and trametinib before on-therapy progression. They then demonstrated a sustained two-year response to sirolimus and are now stable off therapy.
Conclusions
Each patient demonstrated response to inhibition of one pathway, progressed, then subsequently responded to inhibition of the other pathway. Together, these cases suggest that bidirectionally, inhibition of one pathway could cause upregulation of the other, leading to progression, and subsequent response to inhibition of the newly upregulated pathway. These findings warrant clinical investigation to assess potential benefit of standardly alternating MAPK and mTOR inhibition in refractory pLGG.