Molecular Medicine Israel

Targeted therapy: An elusive cancer target

Advanced tumours may have met their match with new drugs, but why have these treatments proved ineffective at stopping early-stage tumours from coming back?

Kidney cancer has frustrated the best efforts of clinicians. The disease is notoriously resistant to chemotherapy, and is often caught only after it has metastasized. As recently as 2013, survival for people with advanced cancer who were treated in clinical trials was two and a half years on average.

“I’ve been here taking care of people with kidney cancer for over 25 years,” says Robert Motzer, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York City. “When I started here in the 1980s, the average survival on chemotherapy was less than a year.

Treatment advances were modest over the intervening decades. But in the past year, three new drugs have brought hope. These therapies represent the “first big revolution that is going to change survival and the way we are going to treat our patients”, says Bernard Escudier, a kidney-cancer specialist at Gustave Roussy near Paris. The key developments revolve around research on the genetic changes that allow kidney tumours to create their own blood supply and grow. The new drugs target the specific pathways in the process, and hold promise for personalized therapy that is more effective, and has fewer side effects, than previous treatments. “The paradigm has changed with these new drugs all coming in within a year,” says Motzer.

But it is a revolution that seems to have passed by early-stage kidney cancer. Targeted therapies do not prevent initial tumours from recurring and can have serious toxic effects. This ‘good news, bad news’ story, however, is teaching researchers more about how the disease works.

Ambushing cancer pathways

Targeted therapy arose from the discovery that a gene called VHL is inactivated in most people with clear-cell renal cell carcinoma (RCC), which accounts for about 70% of kidney cancers. When it is functioning, VHL suppresses tumours by regulating angiogenesis — the formation of new blood vessels. Tumours need their own blood supply to grow, the loss of VHL allows this angiogenesis.

Researchers have been exploring the promise of drugs that treat cancer by stopping angiogenesis since the process was first proposed in 1971 by the US vascular researcher Judah Folkman. The first antiangiogenesis drug for any type of cancer, bevacizumab, was approved in 2004 for metastatic colon cancer. The drug has since been approved for a variety of cancers, including advanced RCC. The first antiangiogenesis drugs approved specifically for RCC, sorafenib and sunitinib, were approved in 2005 and 2006. “It changed the way we treated this disease, away from chemotherapy and towards these targeted drugs,” says Motzer. “It opened up a whole new era of treatment.”

Sorafenib and sunitinib opened the floodgates. In the next ten years came pazopanib and axitinib (see ‘A new era of treatment’). Each of these drugs targets the tyrosine kinase receptors of an enzyme involved in the growth of blood vessels, vascular endothelial growth factor receptors (VEGFRs). In spring 2016, two more VEGFR inhibitors, cabozantinib and lenvatinib (in combination with everolimus), were approved by the US Food and Drug Administration (FDA) for the treatment of RCC. These newly approved drugs are more effective than their predecessors, increasing the time before the cancer progresses as well as improving survival. This might be because the drugs target other pathways in addition to VEGFR, says Motzer.


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