The observation of aerobic glycolysis by tumor cells in 1924 by Otto Warburg, and subsequent innovation of imaging glucose uptake by tumors in patients with PET-CT, has incited a renewed interest in the altered metabolism of tumors. As tumors grow in situ, a fraction of it is further away from their blood supply, leading to decreased oxygen concentrations (hypoxia), which induces the hypoxia response pathways of HIF1α, mTOR, and UPR. In normal tissues, these responses mitigate hypoxic stress and induce neoangiogenesis. In tumors, these pathways are dysregulated and lead to decreased perfusion and exacerbation of hypoxia as a result of immature and chaotic blood vessels. Hypoxia selects for a glycolytic phenotype and resultant acidification of the tumor microenvironment, facilitated by upregulation of proton transporters. Acidification selects for enhanced metastatic potential and reduced drug efficacy through ion trapping. In this review, we provide a comprehensive summary of preclinical and clinical drugs under development for targeting aerobic glycolysis, acidosis, hypoxia and hypoxia response pathways. Hypoxia and acidosis can be manipulated, providing further therapeutic benefit for cancers that feature these common phenotypes.

/pdf/targeting-the-metabolic-microenvironment-of-tumors-3bqug4nvnp.pdf

Targeting the Metabolic Microenvironment of Tumors

The interferons (IFNs) were identified and named for their interference with viral infections of eukaryotic cells (1,2). They were divided into three categories, based on the predominant cells of origin: leukocytes (now known collectively as IFN-α), fibroblasts (now known as IFN-β), and T-cells (immune or IFN-γ). These interferons also had important differences in acid stability, molecular size, and activity. IFN-α and IFN-β, and the similar IFN-ω, share similar biochemical properties, gene proximity, induction, receptor, and signaling pathways and are collectively referred to as type I interferons. In contrast, IFN-γ is quite distinct in many of these features and is referred to as a type II interferon. However, all of the interferons have certain parts of the signaling pathways in common, and they all interfere with viral replication.

Interferon-γ in the Management of Infectious Diseases

Interferon-y in the Management of Infectious Diseases

Because of its immunomodulatory and anticancer activities, IFNgamma has been used as an anticancer drug in several clinical studies, unfortunately with modest results. Attempts to increase the response by increasing the dose or by repeated continuous injection often resulted in lower efficacy, likely due to counterregulatory effects. We show here that targeted delivery of low doses of IFNgamma to CD13, a marker of angiogenic vessels, can overcome major counterregulatory mechanisms and delay tumor growth in two murine models that respond poorly to IFNgamma. Tumor vascular targeting was achieved by coupling IFNgamma to GCNGRC, a CD13 ligand, by genetic engineering technology. The dose-response curve was bell-shaped. Maximal effects were induced with a dose of 0.005 microg/kg, about 500-fold lower than the dose used in patients. Nontargeted IFNgamma induced little or no effects over a range of 0.003 to 250 microg/kg. Studies on the mechanism of action showed that low doses of targeted IFNgamma could activate tumor necrosis factor (TNF)-dependent antitumor mechanisms, whereas high doses of either targeted or nontargeted IFNgamma induced soluble TNF-receptor shedding in circulation, a known counterregulatory mechanism of TNF activity. These findings suggest that antitumor activity and counterregulatory mechanisms could be uncoupled by tumor vascular targeting with extremely low doses of IFNgamma.

https://cancerres.aacrjournals.org/content/canres/65/7/2906.full.pdf

Targeted Delivery of IFNγ to Tumor Vessels Uncouples Antitumor from Counterregulatory Mechanisms

To determine the role of the transcription factor signal transducer and activator of transcription (STAT) 1 on endothelial cell function, human umbilical vein endothelial cells (HUVEC) were treated with IFN-gamma, a potent activator of STAT1. IFN-gamma inhibited cell growth and tube formation of HUVECs. Although the potent proangiogenic protein vascular endothelial growth factor (VEGF) stimulated cell growth and tube formation, IFN-gamma could suppress these effects of VEGF. Transfection of HUVECs with short interfering RNA targeting STAT1 abrogated IFN-gamma-induced inhibition of HUVEC growth and tube formation, and suppressed the inhibition of VEGF-induced tube formation by IFN-gamma, indicating that STAT1 is critical for this process. IFN-gamma blocks the biological activity of VEGF through inhibition of genes necessary for the VEGF response, including angiopoietin-2, urokinase plasminogen activator, tissue inhibitor of matrix metalloproteinase-1, cyclooxygenase-2, and VEGF receptor 2. To extend these findings in vivo, the role of STAT1 in angiogenesis was examined in STAT1-deficient mice using the Matrigel in vivo angiogenesis assay. Substantial cellular infiltration and formation of vascular structures occurred in STAT1-/- mice compared with wild-type controls. These data indicate that STAT1 plays a key role in the inhibition of angiogenesis through its action within endothelial cells, and exploiting this process may be useful in treating cancers and vascular tumors.

https://cancerres.aacrjournals.org/content/canres/66/7/3649.full.pdf

Signal transducer and activator of transcription 1 activation in endothelial cells is a negative regulator of angiogenesis.

Interferon-γ for the treatment of metastatic renal cancer: Dose-dependent stimulation and downregulation of beta2 microglobulin and neopterin responses

The object of this study was to investigate the effects of different single doses of recombinant interferon-γ (rIFN-γ) on white blood cell counts, differential blood counts, and the relative composition of T-cell subsets in the peripheral blood of cancer patients. Sixteen patients suffering from metastasizing renal cell carcinoma received 10, 100, or 500 μg of rIFN-γ three times at weekly intervals. After a therapy-free interval of 2 weeks, the next dose level was applied. The order of dose levels was assigned randomly to each patient. White blood cells, differential blood counts, and the number of Leu1, Leu3, Leu2a, Leu7, and HLA DR+ cells were measured immediately before and at 4, 24, 48, 72, 96, and 168 h after the administration of single doses of rIFN-γ. Results indicated that white blood cells were transiently removed from the blood circulation after administration of IFN-γ. Monocytes, HLA DR+ cells, and Leu7+ cells were reduced to below 50% of pretreatment values 4 h after application of t...

Acute Effects of Single Doses of Recombinant Interferon-γ on Blood Cell Counts and Lymphocyte Subsets in Patients with Advanced Renal Cell Cancer

Interferon-γ for the Treatment of Metastatic Renal Cancer: Dose-Dependent Stimulation and Downregulation of Beta-2 Microglobulin and Neopterin Responses

Recently interferon- γ (IFN- γ) has been widely tested in clinical trials. These studies investigated not only efficacy but also several immunomodulatory properties of the cytokine [1–4]. In all studies published so far, IFN-γ was administered three to seven times weekly. The effects of single doses of IFN- γ have not been investigated in detail. The present study aimed at testing the effect that different dose levels of IFN- γ administered as a single dose have on white blood cell counts, number of T cell subsets, natural killer (NK) cells and human leukocyte antigen (Major histocompahibility antigens class II) (HLA) DR positive cells in the peripheral blood of patients treated for metastasizing renal cell cancer.

Acute Effects of Recombinant IFN-γ on White Blood Cell Counts and Lymphocyte Subsets in the Peripheral Blood of Cancer Patients

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Interferon-γ for the treatment of metastatic renal cancer: Dose-dependent stimulation and downregulation of beta2 microglobulin and neopterin responses

Acute Effects of Single Doses of Recombinant Interferon-γ on Blood Cell Counts and Lymphocyte Subsets in Patients with Advanced Renal Cell Cancer

Interferon-γ for the Treatment of Metastatic Renal Cancer: Dose-Dependent Stimulation and Downregulation of Beta-2 Microglobulin and Neopterin Responses

Acute Effects of Recombinant IFN-γ on White Blood Cell Counts and Lymphocyte Subsets in the Peripheral Blood of Cancer Patients