Exploiting the HIF pathway to tackle kidney cancer

01 August, Tim Burton 

Sarah Welsh is a consultant in medical oncology at Addenbrooke’s Hospital in Cambridge and an Academic Clinical Lecturer in Renal Oncology. Thanks to TUF Sarah has been able to determine the potential of a new drug to slow the growth of kidney cancer.

The HIF Pathway

HIF (Hypoxia-Inducible Factor) is a complex of different proteins which switches on over 100 different genes involved with promoting the survival of cells, preventing the death of cells, and lots of factors which promote the growth of new blood vessels. Constitutive activation of the HIF pathway drives the cancer to grow and makes kidney cancer resistant to traditional chemotherapy.

Sarah’s alternative

Previous research studies have shown that kidney cancers rely on HIF for their survival, and if HIF is blocked (for example by removing or blocking any of the components that make up the HIF complex), kidney cancers stop growing, do not spread, and act less aggressively.

Sarah’s previous research has identified a drug called CL67, which binds to, and inhibits, two of the components of the HIF complex (called HIF-1alpha and HIF-2alpha). Her previous studies, using kidney cancer cells grown in the lab, have shown that CL67 stops the growth of the cells and kills them, suggesting that it may be a potential future treatment for kidney cancer in humans.

TUF research

Thanks to TUF Sarah was able to run experiments in both cancer cells grown in dishes in the lab, as well as kidney cancer cells grown in mice, to confirm that CL67 only binds to the components of the HIF complex that we think it does, and to perform further testing of CL67 in animal models to check that it works to shrink tumours in animals and is not toxic or damaging to other organs or body systems.  For example, if CL67 bound to other proteins not involved with HIF, this could cause toxic side effects. 

The results

The research has shown that CL67 only binds tightly to components of HIF and that it is not toxic to mammals.  CL67 also slowed the growth of kidney cancer cells in a range of different kidney cancer cells when grown both in the laboratory in dishes, as well as in animals.

CL67 reduced the levels of HIF-1alpha and HIF-2alpha in tumours, as well as reducing the numbers of blood vessels seen in those tumours. It also reduced levels of those other genes that the HIF complex switches on.

What’s next?

These are very encouraging results and further experiments are planned to see whether CL67 is good enough to be tested in humans. If the drug can eventually be used to treat kidney cancer, it could become a substantial part of the arsenal we use to fight the disease. Put simply, it could save lives.

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