Chemical modulation of autophagy as an adjunct to chemotherapy in childhood and adolescent brain tumors

Abstract

Brain tumors are the leading cause of cancer-related death in children and are the most challenging childhood cancer in relation to diagnosis, treatment, and outcome. One potential novel strategy to improve outcomes in cancer involves the manipulation of autophagy, a fundamental process in all cells. In cancer, autophagy can be thought of as having a “Janus”-like duality. On one face, especially in the early phases of cancer formation, autophagy can act as a cellular housekeeper to eliminate damaged organelles and recycle macromolecules, thus acting as tumor suppressor. On the other face, at later stages of tumor progression, autophagy can function as a pro-survival pathway in response to metabolic stresses such as nutrient depravation, hypoxia and indeed to chemotherapy itself, and can support cell growth by supplying much needed energy. In the context of chemotherapy, autophagy may, in some cases, mediate resistance to treatment. We present an overview of the relevance of autophagy in central nervous system tumors including how its chemical modulation can serve as a useful adjunct to chemotherapy, and use this knowledge to consider how targeting of autophagy may be relevant in pediatric brain tumors.

Autophagy in cancers including brain tumors: role of MicroRNAs

“…The poor response of malignant brain tumors to conventional therapies, many of which work by inducing apoptosis, makes it attractive to target autophagy as an alternative mechanism for triggering glioma cell death [185,186]. Alterations or mutations that are commonly found in brain tumors, include p53, PTEN, AKT, NF1 and EGFR, and some of these are accepted to be implicated in the modulation of autophagy [185,186]. Considering the frequencies of mutations in EGFR, p53, PTEN, NF1, and PDGFR, the Cancer Genome Atlas consortium categorized glioblastoma (GBM) tumors into four molecular sub-types, including neural, classical, mesenchymal, and proneural [187].…”

Autophagy Machinery as a Promising Therapeutic Target in Endometrial Cancer

“…Intriguingly, if autophagy continues beyond reversibility of cell viability, autophagy can result in apoptosis of tumor cells (17). The dual role of autophagy during carcinogenesis difficult the efforts to understand how to modulate it to achieve successful treatments, suggesting that genetic mutational background and tumor cell type specific knowledge should be required (18).…”