“I’m about two months away from finding out if there are other drugs and combinations that could actually save my life,” says Silverman, who has been taking a targeted therapy based on the detection of a mutation in the PIK3CA gene. It’s not clear if that drug is diminishing the lung lesions. “If they could stop what’s going on in my lung, my life is saved—or at least prolonged,” he says of Vivan Therapeutics.
The basic science underlying Vivan Therapeutics dates back to 1918, when Mary Stark, a little-known scientist in biologist Thomas Hunt Morgan’s famous Fly Room at Columbia University, identified tumors in Drosophila larvae and experimented with transplanting pieces of them into healthy larvae. Over the decades, the lowly fruit fly became 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, from 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 genome was sequenced in 2000 (three years before the human genome), new possibilities arose for probing the genetic origins of disease. Developmental biologist Ross Cagan was studying the mechanisms of cancer in fruit flies, but in 2010 he turned the question around: Could the flies reveal cancer-killing drugs, even if the science wasn’t fully worked out?
He created the drug testing process in his lab at Mount Sinai Medical Center in New York City that 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 moved his work to the University of Glasgow in Scotland.
First, scientists analyze the patient’s tumor, comparing its exome with the whole exome sequencing of the patient’s blood to identify the tumor’s protein-coding alterations. They select the changes most likely to drive the growth or proliferation of the tumor, based on their function or location. (A single tumor can contain hundreds of genetic alterations, but typically only five to 15 of them drive its growth.)
“There are many, many tumors that are not caused by one mutation. Or one mutation is compounded with two or three others that allow the cancer to grow, proliferate, and stay alive,” says Marshall Posner, a Mount Sinai oncologist specializing in head and neck cancer who has conducted fly research with Cagan but is not affiliated with the company.
Scientists next inject strands of synthetic bacterial DNA into fruit fly larvae to integrate the mutations into the genome. The location is precise; a colorectal cancer will be expressed in the fly’s gut, for example. Then they calibrate larvae development by altering the temperature of their environment, so the tumor is timed to kill the larvae in seven days. (Larvae typically metamorphose into flies in 10 to 11 days.)
Then these fruit fly “avatars” must propagate. Vivan Therapeutics uses about a half million fly larvae to test about 2,000 drugs and drug combinations, encompassing a version of most FDA-approved drugs that are currently in use, says the company’s chief scientific officer, Nahuel Villegas. For example, an anti-inflammatory or anti-hypertensive drug might have unexpected cancer-fighting properties when used with a tumor suppressor.
The larvae live in tubes in groups of 35—half with the tumor, half without to serve as the control group—feeding on drug-laced food. The healthy larvae have been tweaked with genetic alterations that make them shorter and fatter, so they can be distinguished from those carrying tumors. After seven days, their survival rates are compared. Every drug is tested on at least 300 larvae, and promising drug combinations are retested. The top candidates are ranked based on the survival rates, but ultimately the selection takes into account the human patient’s clinical history and their oncologist’s judgment. For example, a patient with an underlying cardiac problem might steer clear of a drug associated with cardiac concerns, Villegas says.