Could fruit flies help match patients with cancer treatments?
“I’m about two months away to find out if there are other drugs and combinations that could actually save my life,” says Silverman, who is undergoing targeted therapy based on detecting a mutation in the PIK3CA uncomfortable. It is not known if this drug decreases lung damage. “If they could stop what’s going on in my lungs, my life is saved – or at least prolonged,” he says of Vivan Therapeutics.
The basic science behind Vivan Therapeutics dates back to 1918, when Mary Stark, a little-known scientist in the famous Fly Room of biologist Thomas Hunt Morgan at Columbia University, identified tumors in Drosophila larvae and experimented with transplanting pieces of them into healthy larvae. Over the decades, the humble fruit fly has become an exquisite model of human disease. (Morgan received a Nobel Prize for his Drosophila work in 1933.) The fruit fly reveals attributes and treatments for disorders ranging from amyotrophic lateral sclerosis to aging, epilepsy to eye disease – the source of enough discoveries to fill a book titled First in Fly. (The author, Harvard geneticist Stephanie Mohr, also contributes to an ongoing blog called Drosophila models of human disease.)
When the Drosophila melanogaster the genome was sequenced in 2000 (three years before the human genome), new possibilities have appeared to probe the genetic origins of the disease. Developmental biologist Ross Cagan was studying the mechanisms of cancer in fruit flies, but in 2010 he turned the question around: Could flies reveal anti-cancer drugs, even if the science wasn’t fully developed?
He created the drug testing process in his lab at Mount Sinai Medical Center in New York City, which has since been licensed by Vivan Therapeutics. “We’re exploring which drugs work, attacking the cancer network with a therapeutic network,” says Cagan, who recently transferred his work to the University of Glasgow in Scotland.
First, the scientists analyze the patient’s tumor, comparing its exome to the entire exome sequencing of the patient’s blood to identify alterations encoding the tumor proteins. They select the changes most likely to stimulate tumor growth or proliferation, based on their function or location. (A single tumor can contain hundreds of genetic changes, but usually only five to 15 of them are responsible for its growth.)
“There are many, many tumors that are not caused by a single mutation. Or one mutation is made worse by two or three others that allow cancer to grow, proliferate and stay alive, ”says Marshall Posner, a Mount Sinai oncologist specializing in head and neck cancer who has conducted researching flies with Cagan but is not affiliated with the company.
Scientists then inject synthetic bacterial DNA strands into fruit fly larvae to integrate the mutations into the genome. The location is precise; colorectal cancer is expressed for example in the intestine of the fly. Then, they calibrate the development of the larvae by changing the temperature of their environment, so that the tumor is programmed to kill the larvae in seven days. (The larvae usually metamorphose into flies within 10 to 11 days.)
Then these fruit fly “avatars” must spread. Vivan Therapeutics uses about half a million fly larvae to test about 2,000 drugs and drug combinations, encompassing a version of most of the FDA-approved drugs that are currently in use, said the company’s chief scientist Nahuel Villegas . For example, an anti-inflammatory or anti-hypertensive drug may have unexpected anti-cancer properties when used with a tumor suppressor.
The larvae live in tubes in groups of 35 people – half with the tumor, the other half without serving as a control group – feeding on foods containing drugs. Healthy larvae have been modified with genetic alterations that make them shorter and larger, so that they can be distinguished from those with tumors. After seven days, their survival rates are compared. Each drug is tested on at least 300 larvae and promising drug combinations are retested. The best candidates are ranked based on survival rates, but ultimately the selection takes into account the clinical history of the human patient and the judgment of their oncologist. For example, a patient with an underlying heart problem might avoid a drug associated with heart problems, Villegas says.