Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment

Abstract

Hypoxia exists to some degree in most solid tumors due to inadequate oxygen delivery of the abnormal vasculature which cannot meet the demands of the rapidly proliferating cancer cells. The levels of oxygenation within the same tumor are highly variable from one area to another and can change over time. Tumor hypoxia is an important impediment to effective cancer therapy. In radiotherapy, the primary mechanism is the creation of reactive oxygen species; hypoxic tumors are therefore radiation resistant. A number of chemotherapeutic drugs have been shown to be less effective when exposed to a hypoxic environment which can lead to further disease progression. Hypoxia is also a potent barrier to effective immunotherapy in cancer treatment. Because of the recognition of hypoxia as an important barrier to cancer treatment, a variety of approaches have been undertaken to overcome or reverse tumor hypoxia. Such approaches have included breathing hyperbaric oxygen, artificial hemoglobins, allosteric hemoglobin modifiers, hypoxia activated prodrugs and fluorocarbons (FCs). These approaches have largely failed due to limited efficacy and/or adverse side effects. Oxygen therapeutics, based on liquid FCs, can potentially increase the oxygen-carrying capacity of the blood to reverse tumor hypoxia. Currently, at least two drugs are in clinical trials to reverse tumor hypoxia; one of these is designed to improve permeability of oxygen into the tumor tissue and the other is based upon a low boiling point FC that transports higher amounts of oxygen per gram than previously tested FCs.

Clinicopathological Analysis of HIF-1alpha and TERT on Survival Outcome in Glioblastoma Patients: A Prospective, Single Institution Study

“…There are various factors responsible for treatment resistance in glioblastomas (Table 4) [8][9][10][11][12][13][14][15]. Hypoxia has been correlated with poor prognosis in cervical cancers, head & neck cancers, soft tissue sarcomas, hepatocellular, gastric and invasive breast cancer [16][17][18][19][20][21].…”

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

“…The often observed abundant, highly cross-linked ECM further aggravates the supply situation, leading to hypoxia and metabolic stress. Hypoxia again is directly linked to resistance vs. various forms of cytotoxic therapy and radiotherapy (Moeller and Dewhirst, 2004;Doublier et al, 2012;Jain, 2014;Horsman and Overgaard, 2016;Graham and Unger, 2018).…”

“…The effect of ionizing radiation on cells is also strongly dependent on their oxygenation status. Hypoxia significantly impairs the effectiveness of radiotherapy (reviewed in Griffioen et al, 2001;Horsman and Overgaard, 2016;Graham and Unger, 2018). Consequently, strategies to improve oxygenation status, in tumors before radiotherapy-e.g., by pretreatment with antiangiogenic drugs-have been devised and tested.…”

Hypoxia potentiates the capacity of melanoma cells to evade cisplatin and doxorubicin cytotoxicity via glycolytic shift

“…We demonstrate that similarly to other types of cancer cells [1], B16F10 and YUMM1.7 cells exhibit metabolic plasticity and under hypoxia readily shift to glycolytic metabolism. Importantly, in agreement with salient ability of cancer cells to evade toxicity of chemotherapeutic drugs in hypoxic tumors [14], B16F10 and YUMM1.7 cell lines better withstand exposures to DNA damaging drugs under hypoxic conditions.…”