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Immune checkpoints are known to contribute to tumor progression by enhancing cancer's ability to evade the immune system and metastasize. Immunotherapies, including monoclonal antibodies, have been developed to target specific immunosuppressive molecules on the membranes of cancer cells and have proven revolutionary in the field of oncology. Recently, small molecule inhibitors (SMIs) have gained increased attention in cancer research with potential applications in immunotherapy. SMIs have desirable benefits over large-molecule inhibitors, such as monoclonal antibodies, including greater cell permeability, organ specificity, longer half-lives, cheaper production costs, and the possibility for oral administration. This paper will review the mechanisms by which noteworthy and novel immune checkpoints contribute to tumor progression, and how they may be targeted by SMIs and epigenetic modifiers to offer possible adjuvants to established therapeutic regimens. SMIs target immune checkpoints in several ways, such as blocking signaling between tumorigenic factors, building immune tolerance, and direct inhibition via epigenetic repression of immune inhibitory molecules. Further investigation into combination therapies utilizing SMIs and conventional cancer therapies will uncover new treatment options that may provide better patient outcomes across a range of cancers., Competing Interests: None.

Dysregulated metabolism in the form of aerobic glycolysis occurs in many cancers including breast carcinoma. Here, we report PDK4 (pyruvate dehydrogenase kinase 4) as key enzyme implicated in the control of glucose metabolism and mitochondrial respiration is relatively highly expressed in breast cancers, and its expression correlates with poor patient outcomes. Silencing of PDK4 and ectopic expression of miR-211 attenuates PDK4 expression in breast cancer cells. Interestingly, low miR-211 expression is significantly associated with shorter overall survival and reveals an inverse correlation between expression of miR-211 and PDK4. We have found that depletion of PDK4 by miR-211 shows an oxidative phosphorylation-dominant phenotype consisting of the reduction of glucose with increased expression of PDH and key enzymes of the TCA cycle. miR-211 expression causes alteration of mitochondrial membrane potential and induces mitochondrial apoptosis as observed via IPAD assay. Further, by inhibiting PDK4 expression, miR-211 promotes a phenotype shift towards a pro-glycolytic state evidenced by decreased extracellular acidification rate (ECAR); increased oxygen consumption rate (OCR); and increased spare respiratory capacity in breast cancer cell lines. Taken together this data establishes a molecular connection between PDK4 and miR-211 and suggests that targeting miR-211 to inhibit PDK4 could represent a novel therapeutic strategy in breast cancers., Competing Interests: None.

Immunometabolism has recently emerged on the forefront of cancer research as a new avenue to potentially develop more effective and targeted treatment options. Several pathologically altered metabolic targets across various cancer types have been identified, including lactate in aerobic glycolysis; tryptophan in amino acid metabolism; and arginine in the urea cycle. Numerous advancements have improved our understanding of the dual function of these targets in influencing immune functions as an auxiliary function to their well-established metabolic role. This paper provides a comprehensive overview of immunometabolism research and attempts to provide insight into potential immunometabolic targets in glioblastoma for the purpose of future development and study of targeted therapies.

Medulloblastoma is one of the most prevalent pediatric brain malignancies, accounting for approximately 20% of all primary CNS tumors in children under the age of 19. OTX2 is the member of a highly conserved family of bicoid-like homeodomain transcription factors responsible for the regulation of cerebellar development and of current investigational interest in the tumorigenesis of medulloblastoma. Recent studies have revealed that Group 3 and Group 4 medulloblastomas show marked overexpression of OTX2 with a concurrent amplification of the MYC and MYCN oncogenes, respectively, correlating with anaplasticity and unfavorable patient outcomes. More recent attempts at elucidating the mechanism of OTX2-driven oncogenesis at the cellular level has also revealed that OTX2 may confer stem-cell like properties to tumor cells via epigenetic regulation. The review seeks to define the interaction pathways and binding partners involved in OTX2 function, its usefulness as a molecular marker for risk stratification and prognosis, and the mechanism by which it drives tumor maintenance. Additionally, it will preview unpublished data by our group highlighting the unanticipated involvement of OTX2 in the control of cellular metabolism.

GLUT1, and to a lesser extent, GLUT3, appear to be interesting targets in the treatment of glioblastoma multiforme. The current review aims to give a brief history of the scientific community's understanding of these glucose transporters and to relate their importance to the metabolic changes that occur as a result of cancer. One of the primary changes that occurs in cancer, the Warburg Effect, is characterized by an extreme shift toward glycolysis from the usual reliance on oxidative phosphorylation and is currently being investigated to target the upstream and downstream factors responsible for Warburg-induced changes. Further, it aims to explain the differential expression of GLUT1 and GLUT3 in glioblastoma tissue, and how these modulations in expression can serve as targets to restore a more normal metabolism. Additionally, hypoxia-induced factor-1α's (HIF1α) role in a number of transcriptional changes typical to GBM will be discussed, including its role in GLUT upregulation. Finally, the four known subtypes of GBM [proneural, neural, mesenchymal, and classical] will be characterized in order to discuss how metabolic changes differ in each subtype. These changes have the potential to be selectively targeted in order to provide specificity to the clinical treatment options in GBM.