Adamantinomatous craniopharyngioma: moving toward targeted therapies

Abstract

<jats:p>The evolving characterization of the biological basis of adamantinomatous craniopharyngioma (ACP) has provided insights critical for novel systemically delivered therapies. While current treatment strategies for ACP are associated with low mortality rates, patients experience severely lowered quality of life due to high recurrence rates and chronic sequelae, presenting a need for novel effective treatment regimens. The identification of various dysregulated pathways that play roles in the pathogenesis of ACP has prompted the investigation of novel treatment options. Aberrations in the <jats:italic>CTNNB1</jats:italic> gene lead to the dysregulation of the Wnt pathway and the accumulation of nuclear β-catenin, which may play a role in tumor invasiveness. While Wnt pathway/β-catenin inhibition may be a promising treatment for ACP, potential off-target effects have limited its use in current intervention strategies. Promising evidence of the therapeutic potential of cystic proinflammatory mediators and immunosuppressants has been translated into clinical therapies, including interleukin 6 and IDO-1 inhibition. The dysregulation of the pathways of mitogen-activated protein kinase/extracellular signal–regulated kinase (MAPK/ERK), epidermal growth factor receptor (EGFR), and programmed cell death protein 1 and its ligand (PD-1/PD-L1) has led to identification of various therapeutic targets that have shown promise as clinical strategies. The Sonic Hedgehog (SHH) pathway is upregulated in ACP and has been implicated in tumorigenesis and tumor growth; however, inhibition of SHH in murine models decreased survival, limiting its therapeutic application. While further preclinical and clinical data are needed, systemically delivered therapies could delay or replace the need for more aggressive definitive treatments. Ongoing preclinical investigations and clinical trials of these prospective pathways promise to advance treatment approaches aimed to increase patients’ quality of life.</jats:p>

Radiologic response to MEK inhibition in a patient with a WNT‐activated craniopharyngioma

“…WNT signaling pathway–targeted therapies could be potentially useful for reducing morbidity and mortality from ACPs. Unfortunately, WNT/beta‐catenin–targeted agents have not been well studied in children 5,7,8,9 …”

“…Molecular pathway–targeted therapies such as vemurafenib/dabrafenib and trametinib/binimetinib—BRAF V600E and MEK inhibitors, respectively—have been used successfully in controlling tumor growth and progression. WNT/beta‐catenin–targeted agents have not been well studied or used in children; despite the absence of WNT/beta‐catenin–targeted agents, MEK inhibitors are potentially beneficial in WNT‐activated tumors 5,7 …”

“…Beta-catenin is a transcriptional coactivator that is stabilized in the presence of Unfortunately, WNT/beta-catenin-targeted agents have not been well studied in children. 5,7,8,9 Mitogen-activated protein kinase/extracellular signal-regulated inhibitors are potentially beneficial in WNT-activated tumors. 5,7 This case presentation provides evidence that MEK inhibitors (binimetinib) have therapeutic potential in patients with WNTactivated tumors such as ACPs.…”

“…5,7,8,9 Mitogen-activated protein kinase/extracellular signal-regulated inhibitors are potentially beneficial in WNT-activated tumors. 5,7 This case presentation provides evidence that MEK inhibitors (binimetinib) have therapeutic potential in patients with WNTactivated tumors such as ACPs. Our patient had years of tumor progression and recurrences with secondary morbidities despite surgery, chemotherapy, radiation, and radiosurgery.…”

“…When dysregulation occurs, cancer cells proliferate and grow uncontrollably. Molecules such as EGFR, Ras, Raf, and MEK are involved in the regulation of the MAPK/ERK pathway and are targets for therapeutic interventions.The MAPK/ERK activation has recently been shown to be activated in beta-catenin-dependent ACP tumor cells, with preclinical efficacy of MEK inhibitors reported 2,3,5,9. Current therapies such as vemurafenib/dabrafenib and trametinib/binimetinib-BRAF V600E and MEK inhibitors, respectively-have been used for adult malignancies such as melanomas and non-small cell lung cancers and pediatric gliomas.…”