HYPOXIA is a critical factor in tumour drug resistance, resulting in:
- poor penetration of conventional chemotherapy and immunotherapy - due to poor blood supply
- lack of oxygen to support effective radiotherapy
- amplification of Hypoxia Inducible Factor (HIF) mediated tumour cell survival and proliferation
In every solid tumour there are regions that are starved of oxygen. This happens because tumour cells divide rapidly and as they do so, some cells move away from the blood supply, creating low oxygen microenvironments. Most cells cannot survive without an oxygen supply, but some resistant cancer cells are able to switch their metabolism and effectively lie dormant in these hypoxic microenvironments.
The problem is that conventional chemotherapy, immunotherapy and radiotherapy do not treat hypoxic cancer cells, so unfortunately they lie waiting for an opportunity to reconnect to the blood supply. When they do, the presence of oxygen allows them to switch back to normal metabolism, whereupon they rapidly divide and spread.
unidirectional Hypoxia-Activated Prodrugs (uHAPs) given alongside conventional therapy:
- penetrate the whole tumour and in hypoxic tumour cells are converted to a known and highly effective anticancer agents known as Topo 2a inhibitors.
Our solution is to target the hypoxic microenvironment with a new class of pro-drugs. Our new pro-drugs are able to penetrate the whole tumour including the difficult to reach hypoxic regions. When they reach a hypoxic cancer cell, the prodrug is metabolised into a highly effective and persistent Topo 2a Isomerase inhibitor. So, by giving our unidirectional Hypoxia Activated Prodrugs alongside conventional chemotherapy, we are ensuring the effective treatment of the whole tumour.
Outside tumour cells, uHAPs demonstrate very low toxicity. However, inside hypoxic tumour cells they are irreversibly converted to a Topo 2a inhibitor which poisons a critical enzyme (DNA topoisomerase 2- alpha) - vital for tumour cell proliferation and survival.
Importantly uHAPs are designed to exert persistent anticancer effects at multiple levels and to complement the failure of standard treatments to deal with hypoxia-associated resistance.
To advance two significantly de-risked oncology assets in two key indications:
AQ4N: a unidirectional Hypoxia Activated Prodrug (uHAP) “Phase II Ready” for evaluation in pancreatic cancer. 10-year market exclusivity though a verifiable Orphan Drug Strategy with probable follow for glioblastoma multiforme and diffuse intrinsic pontine glioma (together Glioma). Significantly de risked because
- it has already been tested in >120 patients (Phase I clinical trials) and demonstrates an excellent safety record
- it is now possible to select patients most likely to be susceptible to these uHAP therapies using novel hypoxia biomarkers
- Hypoxia Activated Pro-Drugs are being actively sought by key opinion leaders who believe that treating hypoxic tumour cells will yield clinical success
OCT1002: a second-generation uHAP “Pre-Clinical Ready” for the treatment of prostate cancer, related to AQ4N which has been extensively evaluated.