Drs Bernstein, Kamrava, Camphausen and Hodge at the National Institutes of Health, Bethesda, Maryland, US, explain why good things come in threes when it comes to cancer therapy 

Using several concurrent approaches to treat a single disease is not a novel concept anymore. When treating some of the most common illnesses affecting people today, the best outcomes are often achieved with more than one therapy or medication, especially when those therapies have different mechanisms of action. 

For instance, treatment for hypertension frequently starts with a diuretic to decrease the fluid volume in the blood stream, and so lower the arterial pressure. If blood pressure remains uncontrolled, a beta-blocker may be added to the regimen. This lowers the blood's force as it is pumped through the vessels. Along with this, an angiotensin-converting enzyme (ACE) inhibitor may be prescribed to dilate the arteries. Similarly, controlling hyperglycemia in diabetic patients often requires combining one medication to stimulate the pancreas to release more insulin with another medication to prevent the liver from releasing stored sugar. This approach of targeting different aspects of a disease with different drugs often succeeds because the actions of one agent complement, or even enhance, the actions of the second or third. 

This approach is now being applied in the challenging field of cancer treatment. Because some single therapies have shown limited clinical benefit, oncologists are increasingly using combination therapies to try to improve outcomes for cancer sufferers. For example, many patients first have their tumours removed surgically, then go on to receive postoperative chemotherapy, radiation therapy, or a combination of both. Unfortunately, while this and other advances in cancer treatment have shown promising results, malignancy has remained the second most common cause of death for decades, making cancer research one of the most dynamic fields in medicine. 

Combining radiation therapy, immunotherapy, and antiangiogenesis exploits weaknesses in cancer cell defences

 

In one potential approach, three different treatments - radiation therapy, immunotherapy (harnessing the immune system), and antiangiogenesis (reorganising the tumour's blood supply) - could be applied to treat cancer. The rationale is the same as for the combinatorial approach to treating hypertension and diabetes. Each of these three cancer therapies affects a different aspect of a tumour's biology and microenvironment, which could facilitate and enhance the actions of the other two. 

Cancer cells can grow and replicate stealthily, without setting off the usual alarms that activate the host's immune system. Besides its traditional role of directly killing tumour cells, radiation can also be used to sound these alarms and activate an immune response. Exposing a tumour to radiation can break the silent barrier and cause the tumour to release unique proteins. A rich supply of tumour-specific antigens is then presented to the immune system, which stimulates a tumour-specific immune response. Furthermore, radiation can change a cancer cell's biochemical appearance, making it more readily recognisable by immune cells. 

In addition to evading an immune response, tumours have other weapons against effective eradication. Tumour cells create a hypoxic (low oxygen) environment that can limit the effect of various therapies. This has spurred research into angiogenesis inhibitors, which normalise blood vessels in the tumour and limit hypoxia. By increasing oxygen availability and blood supply, antiangiogenic agents can both enhance the effects of radiation therapy and facilitate immune cells' access to the tumour.

Preclinical and clinical studies support the rationale for combining antiangiogenic agents with radiation and immunotherapy in cancer treatment. This particular combination of therapies not only exploits weaknesses in cancer cell defences, but also boosts the strengths of the individual methods. We are just beginning to recognise the potential benefits of this combination, but the evidence suggests that it provides a reasonable option for cancer patients and deserves further investigation. 

Read more in the review 'Combining radiation, immunotherapy, and antiangiogenesis agents in the management of cancer: the Three Musketeers or just another quixotic combination?' in Molecular BioSystems.

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