bims-malgli 2022-01-30 papers

Issue of 2022–01–30
six papers selected by
Oltea Sampetrean, Keio University

Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdab186

Prospective biomarker study in newly diagnosed glioblastoma: Cyto-C clinical trial.

Background: Glioblastoma (GBM) has a 5-year survival rate of 3%-5%. GBM treatment includes maximal resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ). Cytochrome C oxidase (CcO) is a mitochondrial enzyme involved in the mechanism of resistance to TMZ. In a prior retrospective trial, CcO activity in GBMs inversely correlated with clinical outcome. The current Cyto-C study was designed to prospectively evaluate and validate the prognostic value of tumor CcO activity in patients with newly diagnosed primary GBM, and compared to the known prognostic value of MGMT promoter methylation status.
Methods: This multi-institutional, blinded, prospective biomarker study enrolled 152 patients with newly diagnosed GBM who were to undergo surgical resection and would be candidates for standard of care. The primary end point was overall survival (OS) time, and the secondary end point was progression-free survival (PFS) time. Tumor CcO activity and MGMT promoter methylation status were assayed in a centralized laboratory.
Results: OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of MGMT promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and MGMT promoter methylation in tumors may be predictive of long-term survival.
Conclusions: Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated MGMT promoter may reveal a subgroup of GBM patients with improved long-term survival that warrants further evaluation. Our work also demonstrates the importance of performing large, multi-institutional, prospective studies to validate biomarkers. We also discuss lessons learned in assembling such studies.

Keywords: MGMT; biomarker; cytochrome C oxidase; glioblastoma; prospective clinical trial

DOI: https://doi.org/10.1093/noajnl/vdab186

Sci Rep. 2022 Jan 27. 12(1): 1464

CD97 is associated with mitogenic pathway activation, metabolic reprogramming, and immune microenvironment changes in glioblastoma.

Michael M Safaee, Elaina J Wang, Saket Jain, Jia-Shu Chen, Sabraj Gill, Allison C Zheng, Joseph H Garcia, Angad S Beniwal, Y Tran, Alan T Nguyen, Melissa Trieu, Kevin Leung, Jim Wells, James M Maclean, Keith Wycoff, Manish K Aghi.

Glioblastoma (GBM) is the most common primary brain tumor with a median survival under two years. Using in silico and in vitro techniques, we demonstrate heterogeneous expression of CD97, a leukocyte adhesion marker, in human GBM. Beyond its previous demonstrated role in tumor invasion, we show that CD97 is also associated with upregulation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathways in GBM. While CD97 knockout decreased Akt activation, CD97 targeting did not alter MAPK/Erk activation, did not slow GBM cell proliferation in culture, and increased levels of glycolytic and oxidative phosphorylation metabolites. Treatment with a soluble CD97 inhibitor did not alter activation of the MAPK/Erk and PI3K/Akt pathways. Tumors with high CD97 expression were associated with immune microenvironment changes including increased naïve macrophages, regulatory T cells, and resting natural killer (NK) cells. These data suggest that, while CD97 expression is associated with conflicting effects on tumor cell proliferative and metabolic pathways that overall do not affect tumor cell proliferation, CD97 exerts pro-tumoral effects on the tumor immune microenvironment, which along with the pro-invasive effects of CD97 we previously demonstrated, provides impetus to continue exploring CD97 as a therapeutic target in GBM.

DOI: https://doi.org/10.1038/s41598-022-05259-y

Front Neurosci. 2021 ;15 648476

Adenosinergic Signaling as a Key Modulator of the Glioma Microenvironment and Reactive Astrocytes.

Gabriela N Debom, Dominique S Rubenich, Elizandra Braganhol.

Astrocytes are numerous glial cells of the central nervous system (CNS) and play important roles in brain homeostasis. These cells can directly communicate with neurons by releasing gliotransmitters, such as adenosine triphosphate (ATP) and glutamate, into the multipartite synapse. Moreover, astrocytes respond to tissue injury in the CNS environment. Recently, astrocytic heterogeneity and plasticity have been discussed by several authors, with studies proposing a spectrum of astrocytic activation characterized by A1/neurotoxic and A2/neuroprotective polarization extremes. The fundamental roles of astrocytes in communicating with other cells and sustaining homeostasis are regulated by purinergic signaling. In the CNS environment, the gliotransmitter ATP acts cooperatively with other glial signaling molecules, such as cytokines, which may impact CNS functions by facilitating/inhibiting neurotransmitter release. Adenosine (ADO), the main product of extracellular ATP metabolism, is an important homeostatic modulator and acts as a neuromodulator in synaptic transmission via P1 receptor sensitization. Furthermore, purinergic signaling is a key factor in the tumor microenvironment (TME), as damaged cells release ATP, leading to ADO accumulation in the TME through the ectonucleotidase cascade. Indeed, the enzyme CD73, which converts AMP to ADO, is overexpressed in glioblastoma cells; this upregulation is associated with tumor aggressiveness. Because of the crucial activity of CD73 in these cells, extracellular ADO accumulation in the TME contributes to sustaining glioblastoma immune escape while promoting A2-like activation. The present review describes the importance of ADO in modulating astrocyte polarization and simultaneously promoting tumor growth. We also discuss whether targeting of CD73 to block ADO production can be used as an alternative cancer therapy.

Keywords: A2-like astrocyte; CD73; adenosine; glioblastoma; tumor microenvironment; tumor-associated astrocyte

DOI: https://doi.org/10.3389/fnins.2021.648476

Dev Cell. 2022 Jan 24. pii: S1534-5807(21)01040-6. [Epub ahead of print]57(2): 260-276.e9

Regulation of reverse electron transfer at mitochondrial complex I by unconventional Notch action in cancer stem cells.

Rani Ojha, Ishaq Tantray, Suman Rimal, Siddhartha Mitra, Sam Cheshier, Bingwei Lu.

Metabolic flexibility is a hallmark of many cancers where mitochondrial respiration is critically involved, but the molecular underpinning of mitochondrial control of cancer metabolic reprogramming is poorly understood. Here, we show that reverse electron transfer (RET) through respiratory chain complex I (RC-I) is particularly active in brain cancer stem cells (CSCs). Although RET generates ROS, NAD+/NADH ratio turns out to be key in mediating RET effect on CSC proliferation, in part through the NAD+-dependent Sirtuin. Mechanistically, Notch acts in an unconventional manner to regulate RET by interacting with specific RC-I proteins containing electron-transporting Fe-S clusters and NAD(H)-binding sites. Genetic and pharmacological interference of Notch-mediated RET inhibited CSC growth in Drosophila brain tumor and mouse glioblastoma multiforme (GBM) models. Our results identify Notch as a regulator of RET and RET-induced NAD+/NADH balance, a critical mechanism of metabolic reprogramming and a metabolic vulnerability of cancer that may be exploited for therapeutic purposes.

Keywords: NAD(+)/NADH; Sirtuin; Warburg effect; glioblastoma multiforme; inflammation; metabolic reprogramming; mitochondrial complex I; non-canonical Notch signaling; reactive oxygen species; reverse electron transport

DOI: https://doi.org/10.1016/j.devcel.2021.12.020

Sci Rep. 2022 Jan 24. 12(1): 1275

An oncogenic splice variant of PDGFRα in adult glioblastoma as a therapeutic target for selective CDK4/6 inhibitors.

Taiji Hamada, Toshiaki Akahane, Seiya Yokoyama, Nayuta Higa, Mari Kirishima, Kei Matsuo, Michiko Shimokawa, Koji Yoshimoto, Akihide Tanimoto.

Understanding human genome alterations is necessary to optimize genome-based cancer therapeutics. However, some newly discovered mutations remain as variants of unknown significance (VUS). Here, the mutation c.1403A > G in exon 10 of the platelet-derived growth factor receptor-alpha (PDGFRA) gene, a VUS found in adult glioblastoma multiforme (GBM), was introduced in human embryonal kidney 293 T (HEK293T) cells using genome editing to investigate its potential oncogenic functions. Genome editing was performed using CRISPR/Cas9; the proliferation, drug sensitivity, and carcinogenic potential of genome-edited cells were investigated. We also investigated the mechanism underlying the observed phenotypes. Three GBM patients carrying the c.1403A > G mutation were studied to validate the in vitro results. The c.1403A > G mutation led to a splice variant (p.K455_N468delinsN) because of the generation of a 3'-acceptor splice site in exon 10. PDGFRA-mutated HEK293T cells exhibited a higher proliferative activity via PDGFRα and the cyclin-dependent kinase (CDK)4/CDK6-cyclin D1 signaling pathway in a ligand-independent manner. They showed higher sensitivity to multi-kinase, receptor tyrosine kinase, and CDK4/CDK6 inhibitors. Of the three GBM patients studied, two harbored the p.K455_N468delinsN splice variant. The splicing mutation c.1403A > G in PDGFRA is oncogenic in nature. Kinase inhibitors targeting PDGFRα and CDK4/CDK6 signaling should be evaluated for treating GBM patients harboring this mutation.

DOI: https://doi.org/10.1038/s41598-022-05391-9

Adv Drug Deliv Rev. 2022 Jan 22. pii: S0169-409X(22)00005-9. [Epub ahead of print] 114115

Nanomedicine for Brain Cancer.

Sabina Quader, Kazunori Kataoka, Horacio Cabral.

CNS tumors remain among the deadliest forms of cancer, resisting conventional and new treatment approaches, with mortality rates staying practically unchanged over the past 30 years. One of the primary hurdles for treating these cancers is delivering drugs to the brain tumor site in therapeutic concentration, evading the blood-brain (tumor) barrier (BBB/BBTB). Supramolecular nanomedicines (NMs) are increasingly demonstrating noteworthy prospects for addressing these challenges utilizing their unique characteristics, such as improving the bioavailability of the payloadsviacontrolled pharmacokinetics and pharmacodynamics, BBB/BBTB crossing functions, superior distribution in the brain tumor site, and tumor-specific drug activation profiles. Here, we review NM-based brain tumor targeting approaches to demonstrate their applicability and translation potential from different perspectives. To this end, we provide a general overview of brain tumor and their treatments, the incidence of the BBB and BBTB, and their role on NM targeting, as well as the potential of NMs for promoting superior therapeutic effects. Additionally, we discuss critical issues of NMs and their clinical trials, aiming to bolster the potential clinical applications of NMs in treating these life-threatening diseases.

DOI: https://doi.org/10.1016/j.addr.2022.114115