A terminally ill colon cancer patient has received a bespoke chemotherapy recipe following drug screens in Drosophila engineered to mimic the complexity of the man’s disease, according to a paper in Science Advances today (May 22). The drug combination significantly shrunk the patient’s tumors, which remained small for several months, paving the way for further investigations into such genetically personalized fly models.
“It is an exciting study. Nothing like this has been done before,” says cancer and Drosophila expert Tin Tin Su of the University of Colorado who was not involved in the work. “Whether the approach will work, how applicable it is, that of course remains to be seen—it’s one patient. But you’ve got to start somewhere and this is an exciting start.”
Despite immense efforts to develop new and better chemotherapy drugs, “one of the key challenges has been that therapeutics that work very well in our model systems don’t translate very well into the clinic, and it’s not exactly clear why,” says Ross Cagan, a developmental and cancer biologist at the Icahn School of Medicine at Mount Sinai who led the study.
In colorectal cancer, for example, approximately 40 percent of patients have increased expression of an oncogene called RAS. Yet, drugs specifically designed to inhibit RAS, which have worked well in preclinical experiments, often “don’t succeed” in patients, says Cagan.
For such RAS-positive patients, if their cancer resists therapy, recurs after therapy, or is already metastatic, “there isn’t really a set treatment,” says colorectal cancer researcher Owen Sansom of Cancer Research UK who was not involved with the project. “It’s such an unmet need.”
There are a number of reasons why some initially promising drugs are ultimately unsuccessful, says Cagan. “[Animal] models generally capture one or two mutations,” he explains, while a patient’s tumor may have tens or hundreds of mutations that may alter the response to a drug. Capturing the full genetic complexity of a tumor can be achieved by removing and culturing cells during patient surgery, however, such in vitro modeling does not recapitulate the physiological influences of the body—such as oxygenation, a blood supply, and the effects of surrounding healthy tissues.
To accomplish both genetic and physiological complexity, patients’ cells can be grown within a mouse. But these xenografted animals take several months to generate and are expensive to keep.
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Cagan’s team thus turned to a cheaper, faster animal model—fruit flies—which, through genetic tinkering of hindgut cells, model several aspects of human colorectal cancer including hyperproliferation, layering within the tumor, and metastasis-like migration to distant sites. The team ramped up the model’s genetic complexity to recapitulate, at least in part, the mutational landscape of a patient’s tumor.
Whole-exome sequencing of DNA taken from the primary tumor of a 53-year-old man with stage 4 colorectal cancer revealed the presence of more than 100 cancer-associated mutations. By examining these for the most likely driver mutations—those that alter protein function, affect known cancer genes, or participate in pathways linked to cancer—the team narrowed the list to six. They also identified a number of mutations the patient had inherited, picking the three most likely to have contributed to the disease.
It is a little difficult to know to what extent the drug treatment has really helped the patient, because there is actually no control—it is only one patient—and we don’t know how he would have done on a single drug, for example.—Norbert Perrimon, Harvard Medical Schoo
These nine genetic anomalies were then recreated in the hindgut epithelial cells of fruit fly embryos. The engineered flies were then used to screen a panel of 121 FDA-approved drugs indicated either for cancer or a cancer-associated target, or were not indicated for cancer but had a reported anti-tumor effect. The drugs were mixed into the insects’ food and the scientists tracked their survival.
With no drugs, less than 20 percent of the embryos made it to pupation or adulthood and, when each of the 121 drugs was tested individually, survival rates did not rise. Further screens involving drug combinations, however, revealed that two particular drugs given together—trametinib (a KRAS inhibitor) and a bisphosphonate drug (for treating osteoporosis)—increased fly survival to between 30 percent and 60 percent.
When this combination of drugs was then given to the patient, his tumors shrank by 45 percent. The tumors remained small for the next 11 months, though after the first three months, they had slightly increased in size and two new tumors had emerged. After this time, the patient switched to a different chemotherapy drug and the researchers no longer followed the patient.
While the results in the patient seem encouraging, “it is a little difficult to know to what extent the drug treatment has really helped the patient, because there is actually no control—it is only one patient—and we don’t know how he would have done on a single drug, for example,” says developmental geneticist Norbert Perrimon of Harvard Medical School who did not participate in the study.
However, “I think the strength of the paper is in the overall approach,” Perrimon says, referring to the benefits of using a genetically complex in vivo model for drug screens.
“It’s a really great proof-of-concept study,” adds Sansom. “It’s going to be really interesting going forward to see . . . whether this is going to be an exciting new way to discover new drug combinations.”
E. Bangi et al., “A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer,” Sci Adv, 5:eaav6528, 2019.