Figure 4

Targeting of hypoxic cells in cancer treatment. Hypoxic cells can be quantitated in situ by staining for antibodies that measure uptake of nitroimidazole compounds (which are reduced in hypoxic environments and bind to SH-containing molecules such as glutathione and proteins); one such compound is pimonidazole (PIMO). These studies, in addition to direct measurements of pO₂, have linked the proportion of hypoxic cells to aggressive tumor cell variants that are resistant to radiotherapy, chemotherapy and have an increased propensity for metastases. Direct targeting with agents that create DNA damage solely under hypoxic conditions (e.g. TH-302) or inhibit selective pathways activated in hypoxic cells (e.g. HIF1α and mTOR signaling) may improve the overall cell kill within a tumor volume when used alone or with radiotherapy or chemotherapy. Hypoxia may also lead to differential transcription or translation of DNA repair or replication genes which can reduce the function of the repair pathway. These repair-deficient hypoxic cells can be killed by agents that target remaining back-up pathways leading to cell death. Given the repair defect is secondary to the effects of hypoxia as opposed to a primary somatic or germline defect, this type of cell kill is denoted, “contextual synthetic lethality” given it is contextual on the local tumor microenvironment and varies depending on the metabolic state of the cancer cell.