Screening Ion Channels in Cancer Cells

Ion channels are critical for cell development and maintaining cell homeostasis. The perturbation of ion channel function contributes to the development ...

University of Cincinnati College of Medicine

Brain tumors make up over a quarter of pediatric malignancies. Depending on the age of presentation and treatment, pediatric brain tumor survivors experience varying degrees of treatment induced morbidity and sequelae. Epigenetic mechanisms play a critical role in silencing of tumor suppressor genes and activation of driver genes involved in oncogenesis in different types of brain tumors. Epigenetic modifications in pediatric brain tumor patients may influence long-term survival and may refine the molecular response to treatment induced morbidity and sequelae. However, there is a dearth of studies on how epigenetics of pediatric brain tumors is connected with neurocognition and other treatment related sequelae in survivors.

Epigenetics and survivorship in pediatric brain tumor patients.

Most patients with metastatic melanoma show variable responses to radiation therapy and do not benefit from immune checkpoint inhibitors. Improved strategies for combination therapy that leverage potential benefits from radiation therapy and immune checkpoint inhibitors are critical.

Melanoma Cell Intrinsic GABA Receptor Enhancement Potentiates Radiation and Immune Checkpoint Inhibitor Response by Promoting Direct and T Cell-Mediated Antitumor Activity.

Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor. The current standard of care for GBM is the Stupp protocol which includes surgical resection, followed by radiotherapy concomitant with the DNA alkylator temozolomide; however, survival under this treatment regimen is an abysmal 12-18 months. New and emerging treatments include the application of a physical device, non-invasive 'tumor treating fields' (TTFs), including its concomitant use with standard of care; and varied vaccines and immunotherapeutics being trialed. Some of these approaches have extended life by a few months over standard of care, but in some cases are only available for a minority of GBM patients. Extensive activity is also underway to repurpose and reposition therapeutics for GBM, either alone or in combination with the standard of care. In this review, we present select molecules that target different pathways and are at various stages of clinical translation as case studies to illustrate the rationale for their repurposing-repositioning and potential clinical use.

Reuse of Molecules for Glioblastoma Therapy.

γ-aminobutyric acid or GABA is an amino acid that functionally acts as a neurotransmitter and is critical to neurotransmission. GABA is also a metabolite in the Krebs cycle. It is therefore unsurprising that GABA and its receptors are also present outside of the central nervous system, including in immune cells. This observation suggests that GABAergic signaling impacts events beyond brain function and possibly human health beyond neurological disorders. Indeed, GABA receptor subunits are expressed in pathological disease states, including in disparate cancers. The role that GABA and its receptors may play in cancer development and progression remains unclear. If, however, those cancers have functional GABA receptors that participate in GABAergic signaling, it raises an important question whether these signaling pathways might be targetable for therapeutic benefit. Herein we summarize the effects of modulating Type-A GABA receptor signaling in various cancers and highlight how Type-A GABA receptors could emerge as a novel therapeutic target in cancer.

Therapeutically leveraging GABA receptors in cancer.

Pediatric cerebellar tumors: transcriptionally distinct but developmentally heterogeneous.

Glioblastoma, or glioblastoma multiforme (GBM, WHO Grade IV), is a highly aggressive adult glioma. Despite extensive efforts to improve treatment, the current standard-of-care (SOC) regimen, which consists of maximal resection, radiotherapy, and temozolomide (TMZ), achieves only a 12-15 month survival. The clinical improvements achieved through immunotherapy in several extracranial solid tumors, including non-small-cell lung cancer, melanoma, and non-Hodgkin lymphoma, inspired investigations to pursue various immunotherapeutic interventions in adult glioblastoma patients. Despite some encouraging reports from preclinical and early-stage clinical trials, none of the tested agents have been convincing in Phase III clinical trials. One, but not the only, factor that is accountable for the slow progress is the blood-brain barrier, which prevents most antitumor drugs from reaching the target in appreciable amounts. Herein, we review the current state of immunotherapy in glioblastoma and discuss the significant challenges that prevent advancement. We also provide thoughts on steps that may be taken to remediate these challenges, including the application of ultrasound technologies.

Article	Year
Epigenetics and survivorship in pediatric brain tumor patients. Journal of neuro-oncology\| PubMed ID: 32451770	2020
Melanoma Cell Intrinsic GABA Receptor Enhancement Potentiates Radiation and Immune Checkpoint Inhibitor Response by Promoting Direct and T Cell-Mediated Antitumor Activity. International journal of radiation oncology, biology, physics\| PubMed ID: 33289666	2021
Reuse of Molecules for Glioblastoma Therapy. Pharmaceuticals (Basel, Switzerland)\| PubMed ID: 33525329	2021
Therapeutically leveraging GABA receptors in cancer. Experimental biology and medicine (Maywood, N.J.)\| PubMed ID: 34649481	2021
Pediatric cerebellar tumors: transcriptionally distinct but developmentally heterogeneous. Translational cancer research\| PubMed ID: 35117480	2020
Advances in Immunotherapy for the Treatment of Adult Glioblastoma: Overcoming Chemical and Physical Barriers. Cancers\| PubMed ID: 35406398	2022

Debanjan Bhattacharya

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