M6L1 Hypoxia targeted therapies

  • The definition of hypoxia varies for different tissues

  • Hypoxia causes - tumour growth/survival, angiogenesis, Warburg effect and low pH, metastasis, genetic changes, immune evasion, stem-like phenotypes

  • More hypoxia = worse response of tumours, regardless of the type of treatment

    • Chemotherapies are less effective

    • Tumour is more likely to have spread at time of surgery

    • x3 less DNA damage during radiotherapy

    • Resistance to immunotherapies

  • Strategies to target hypoxia:

    • Hyperbaric oxygen - increased radiotherapy toxiciuty, oxygen seizures, difficult to provide for all patients/cumbersome

    • Oxygen mimics

      • Electron affinic chemicals that mimic oxygen in fixing free-radical damage

      • Not metabolised by tumour cells through which they diffused

      • Can penetrate further than oxygen

      • Matronidazole - more active, toxic, benefit in some cancer sub groups

      • Etanidazole - equal activity to miso, less toxic, no clinical benefit

      • Nimorazole - less active, much less toxic, benefit in HNSCC (Denmark, no change found in combination with RT in UK studies)

    • CARGOGEN (95% O2, 5% CO2) - thought to influence chronic (diffusion limited) hypoxia only, limited benefit unless combined with radiosensitiser (nicotinamide)

      • Comparable toxicity

      • Positive improvements in regional contral

      • More effective in highly hypoxic tumours, confirmed by 26-gene hypoxia signature

    • Hypoxia activated prodrugs/cytotoxins

      • In hypoxic conditions, prodrug is reduced and fragmented to produce the active agent

      • Drug delivery issues

      • Some may require very high hypioxia

      • Relevant enzymes must be expressed, and there is high level of reductase in liver which may cause side effects if this is not the site of interest

      • Tirapazamine - no evidence of benefit in HNSCC, poor radiotherapy delivery, drug toxicity, no selection of patients based on tumour hypoxia in trials

      • Evofosamide - little/no advantage in pancreatic and soft tissue sarcoma, no selection of patients based on tumour hypoxia in trials

      • Molecularly targeted hypoxia activated prodrugs - inhibits a molecular target only under hypoxia (conventional HAPs release a cytotoxic agent/chemotherapy)

      • Proteolysis targeting chimeras (PROTACs)/hypoxia activated PROTAC (HAP-TAC) - allows degradation of protein of interest in hypoxic regions specifically

      • Modifying existing therapies (eg oxaliplatin) for use in hypoxia

    • Modulating oxygen consumption

      • Atovaquone - antimalarial drug which inhibits complex III in ETC

      • Papaverine - phosphodiesterase 10A inhibitor, inhibits complex I of ETC

    • Targeting hypoxia induced biological response, eg DDR

  • None of these approaches have made it to clinic

    • In clinical trials, there is rarely stratification for hypoxic tumours

    • We need to pick the right patients - needle electrodes, hypoxia signatures, tissue based biomarkers, serological markers, imaging

    • However this is difficult to do as there is different levels of hypoxia at different parts of the tumour

    • Need to come up with a method to quickly and cheaply provide a picture of the full tumour landscape of hypoxia, not just the few parts being sampled

    • Preclinical testing has not been good enough, for example only choosing highly hypoxic cell lines and not others which is not representative of patients in clinic