THE seemingly alarming discovery that some chemotherapies speed up the growth and spread of tumours in mice is prompting new approaches to the way these drugs are administered. The new approaches might completely destroy cancers that right now can only be delayed by drugs.
Many cancer drugs prolong people鈥檚 lives for months but don鈥檛 provide a cure. Most researchers assumed that this is because a few rogue cancer cells find ways to circumvent the drugs before the whole tumour has been killed off.
Now several studies in animals suggest that certain doses or combinations of drugs may actually speed up cancer growth, encourage cancer cells to invade deeper into surrounding tissue and prompt them to break free of the main tumour and spread around the body.
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As depressing as this sounds, it doesn鈥檛 mean people should stop taking the drugs, which clearly prevent fatal tumour growth in the short term and therefore prolong lives. In fact, as a result of these findings, researchers are now experimenting with new ways to administer existing drugs that would dodge these problems. 鈥淚 suspect that this is going to have a fairly major impact on how we think about chemotherapy,鈥� says , a cancer researcher at the Lawrence Berkeley National Laboratory in California.
The chemotherapies in question are anti-angiogenesis drugs 鈥� many still experimental 鈥� which are designed to cut off the growth of new blood vessels to the tumour, starving it of the oxygen and nutrients it needs to grow.
In one study, Andrew Reynolds at the (ICR) in London and his colleagues looked at experimental drugs that inhibit integrins 鈥� molecules that help new blood vessels grow. The drugs have shown promise in treating a type of brain tumour called glioma, for which they are in the final phases of clinical trials, but results with other cancers have proved disappointing.
Now Reynolds says the team may have figured out why. They found that although high doses of integrin inhibitors reduced tumour growth in mice implanted with a variety of human cancers, at low doses they appeared to enhance growth and increase angiogenesis, the exact process of blood vessel formation that they are supposed to prevent (Nature Medicine, ). 鈥淚t was completely unexpected,鈥� says , also at the ICR, who supervised the study. 鈥淭hese drugs have a dark side.鈥�
鈥淎t low doses the drugs seemed to enhance tumour growth and increase blood vessel formation鈥�
Integrin inhibitors are given at a high dose once every three days, so tumours experience an initial blast of the drug that then tails off. These low levels may therefore be undoing much of the good work the drug initially achieved 鈥� perhaps explaining why integrin inhibitors don鈥檛 always work.
They are now working to establish why a low dose encourages angiogenesis, which should allow them to refine dosing so as to avoid both toxicity and the promotion of blood vessel formation.
Meanwhile, two independent groups report similarly surprising findings in studies of a different class of anti-angiogenesis drugs called VEGF inhibitors. One of them, sunitinib, has been approved for renal cell carcinoma and gastrointestinal stromal tumour, and is under investigation for breast, lung and colorectal cancer.
The teams, led by at the University of Toronto in Canada and Oriol Casanovas at the Catalan Institute of Oncology in L鈥橦ospitalet de Llobregat, Spain, found that while VEGF inhibitors initially suppress tumour growth in mice, they increase both tumour invasiveness into the surrounding tissue and metastasis 鈥� the spread of a tumour to other parts of the body (Cancer Cell, and ).
Casanovas suspects that in response to a loss of oxygen supply, caused by the shortage of blood vessels feeding them, cancer cells expend extra effort in moving to regions that still have a blood supply. 鈥淚t鈥檚 as if they are trying to escape,鈥� he says. Kerbel鈥檚 group showed that treating mice with a VEGF inhibitor before they are injected with cancer cells promotes metastasis, suggesting that the drug also affects non-cancer cells in a way that creates a more permissive environment for tumour growth.
The Casanovas and Kerbel teams are now investigating whether the molecular changes that lead to 鈥渢umour escape鈥� can be inhibited with other drugs, such as existing ones that target metastasis. The goal is to combine both therapies.
In the meantime, the researchers emphasise that patients should continue to take VEGF inhibitors until further research has been carried out. 鈥淭hese drugs are not approved for no reason, they鈥檙e approved because they work,鈥� says John Ebos, a member of the University of Toronto team. 鈥淚 think the major question is why don鈥檛 they work better and what can we do to improve their efficacy?鈥�