Single Punches Don't Knock Out Advanced Cancers

Advanced colorectal cancers become resistant to single therapies

(RxWiki News) Once cancer starts to move, it's hard to take out. A single punch isn't going to knock it out. All is not lost, though. Combination therapies may deliver the blow that starts the count down.

While single therapies usually are effective in shrinking advanced tumors, the drugs can sometimes stop working and the cancer can returns.

New research suggests that combination therapies can be developed to attack the pathways to recurrence.

"Ask about available combination therapies."

Johns Hopkins researchers have confirmed that advanced cancers are predestined to return.

Working with 28 advanced colon cancer patients, the team found that five to seven months after treatment with the standard chemotherapy -- panitumumab -- drug-resistant tumor cell mutations start to appear in the blood.

Low levels of these mutant cells are seen in nearly all tumors before treatment begins, the researchers found, making recurrence a near certainty.

“These resistance mutations develop by chance as cancer cells divide so that tumors always contain thousands of resistance cells,” says Luis Diaz, MD, associate professor of oncology and director of the Swim Across America laboratory at Johns Hopkins. He adds that these findings probably apply to any targeted anti-cancer

Bert Vogelstein, MD, professor and co-director of the Ludwig Center at Johns Hopkins and, Howard Hughes Medical Institute investigator, says, “The best chance for a cure is when a tumor is very small, but when the cancer is advanced, our research quantifies the probability that we can achieve cures with single-agent targeted therapies.”

“Long-term remissions of advanced cancers will be nearly impossible with single targeted agents,” Dr. Vogelstein adds.

To reach these conclusions, the scientists analyzed blood samples from the 28 individuals with advanced colorectal cancers.

The Johns Hopkins scientists analyzed blood samples taken from 28 patients with advanced colorectal cancers enrolled in a clinical trial of panitumumab.

This agent is in a class of drugs known as monoclonal antibodies that zero in on the growth pathways of cancer cells. Panitumumab targets the growth-factor receptor called EGFR. Patients who respond to the drug have normal copies of the KRAS gene found in their tumors.

In this study, 24 of the 28 patients had normal KRAS genes, and the control group was made up of four people who had mutations in this gene.

Blood samples were taken before therapy began and at four-week intervals throughout treatment.

Researchers found that nine of the 24 patients with normal KRAS genes developed mutations in the gene within five to seven months of beginning treatment.

Using mathematical models to figure out when these mutations started, Martin Nowak, PhD, and his team from Harvard University determined that the KRAS mutations were present before treatment began.

“The probability that the mutations were absent at the beginning of treatment is exceedingly low,” says Dr. Vogelstein. This means that drug resistance is bound to occur -- it's only a matter of time.

For longer remissions, the team sees combination therapies as the best opportunity.

“The good news is that there is a limited number of pathways that go awry in cancer, so it should be possible to develop a small number of agents that can be used in a large number of patients,” says Dr. Vogelstein.

He adds, “However, I hope this research will help stimulate the testing of new drugs as combination therapies much earlier in the drug approval process than the current norm.”

The study was published online June 13, 2012 in the journal Nature.

The research was funded by the Virginia and D.K. Ludwig Fund for Cancer Research, the National Colorectal Cancer Research Alliance, Swim Across America, and National Institutes of Health (NIH).

Conflicts of interest were not disclosed publicly. 

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Review Date: 
June 13, 2012