Computer artwork of white blood cells attacking a cancerous cell
Low tissue oxygen levels, known as hypoxia, are a common feature of solid tumours and may provide an opportunity for the development of effective anti-cancer drugs. I have many years of experience working in this field as both a research scientist and as a physician and recently authored a book exploring the biology of tumour hypoxia and how this can be translated into novel cancer therapies.
As a tumour grows, blood supply to the cancer cells often becomes inadequate due to dysfunctional and leaky tumour vasculature, leading to poor or irregular oxygen delivery and tumour hypoxia. Normal cells would eventually die under extreme hypoxic conditions, however, cancer cells have genetic alterations that enable them to adapt and thrive in the hypoxic tumour microenvironment. In this way the cancer cells are able to “hijack” the adaptive mechanisms used to cope with hypoxia by activating a number of pathways that favour their survival.
Hypoxic cancers have a number of hallmarks that make them very difficult to cure. Typically, hypoxic cancer cells are invasive and can metastasise away from the primary location to other sites. They are often resistant to therapies like chemotherapy and radiation therapy. What’s more, they include the so-called ‘cancer stem cells’ that are believed to be the engine driving continuous production of cancer cells.
However, all is not lost! The presence of hypoxia in tumour tissue may also be an opportunity to develop novel therapeutic approaches that selectively target cancer cells and spare normal cells. This is an area that I have personally spent time examining during my oncology research and drug development career.
Whilst tumour hypoxia is an established area of research, new and exciting developments continue to provide a lot of interest in the field. The hypothesis behind my team’s work was to target the cancer’s adaptive mechanisms. To do this we attempted to target Hypoxia-inducible factor 1 (HIF-1), which is responsible for turning on a number of genes that are critical for the cancer’s adaptive mechanism. Preclinical and clinical studies have shown that HIF-1 plays a critical role in angiogenesis and tumour progression. If we are able to block HIF-1 then we believe we may be able to halt the downstream functions and stop tumour angiogenesis.
Currently, many investigators are developing specific agents to target HIF-1 and are investigating several different approaches, including antisense technology and small molecules. As with all current drug development it is necessary to identify compounds highly selective for the therapeutic target. Using a high throughput screening assay we have identified and described a number of HIF-1 inhibitors. Others are also investigating novel delivery technologies such as nanoparticles, targeting to overcome off target issues.
This is an exciting new area for the development of cancer therapeutics. Previous approaches for exploiting tumour hypoxia have centred on developing anti-cancer drugs that are activated in a hypoxic environment. The aim of our research has been to develop a therapeutic approach that more directly targets tumour hypoxia.
Targeting tumour hypoxia may be an attractive hypothesis but in reality there have been many difficulties to overcome. Established hurdles, such as the difficulties associated with modulating protein-protein interactions, mean that many pharmaceutical companies are reluctant to invest in what is seen to be a high risk investment.
As a physician-scientist I can see both aspects of the work that we have been doing in this field. I believe that broad perspectives are important so that clinicians understand the basic science and scientists have an appreciation of the clinical impact of their work. After all, the ultimate outcome of the work that we do in science is to provide benefit to patients.