The unmet need of treatment for therapy-resistant tumours is being met with a hypoxia-beating new drug
Hypoxia is a common pathophysiological characteristic of solid tumours, known to be a driver of malignancy and metastatic spread and tumours resistant to both chemo- and radiotherapy.
The use of hypoxia-activated prodrugs (bioreductive cytotoxic drugs) is an attractive approach to kill therapy-resistant hypoxic cells. However, despite the development of a range of structurally diverse agents, there is no well-defined clinical success. The major reason for this is off-target toxicity.
The effectiveness of bioreductive drugs would be greatly improved if selective tumour delivery can be achieved while at the same time minimising exposure and toxicity towards normal tissues. To achieve this, The University of Manchester have created a hyaluronic acid (HA)/bioreductive drug conjugate.
This soluble polymer is designed to preferentially target and accumulate in tumours via CD44 binding (and internalization). An attractive feature of this approach is that CD44, a cell surface protein which binds HA, is widely expressed in many cancer types and is known to be a marker for cancer cell stemness, therapy resistance and poor prognosis.
The novelty of this approach is to conjugate the cytotoxic payload to HA via a boronic acid linker. This linkage is pH sensitive with the result of releasing the payload at a pH of 6.5 (a pH commonly found in solid tumours). The cytotoxic entity released is a bioreductive drug that is selectively toxic to the therapy resistant hypoxic cells.
Thus, the technology has three components leading to tumour selectivity and the sparing of damage to normal tissues: 1) selective targeting via CD44; 2) local pH sensitive release of the cytotoxic payload, and 3) hypoxia-selectivity for toxicity.
This approach is suitable to treat solid tumours expressing CD44 and those tumours known to be hypoxic. The treatment could be used to augment the anti-tumour effects of radiotherapy. This would be particularly useful for the treatment of lung cancer where there is a major unmet clinical need and other solid tumours where radiotherapy is the standard of care.
The team are carrying out preclinical studies to show proof of concept and are seeking partners to collaborate on commercialising this technology.
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