Fruit fly "cancer avatars" recreate mutations in tumors for personalized treatment
Using fruit flies to mirror the tumors of patients can help with difficult to treat cancers
"John" (not their real name) has a tumor on the left side of his face near his nose – it is adenoid cystic carcinoma (ACC), a rare cancer with very few therapeutic options. He has already undergone extensive surgery to remove the tumor and had his face reconstructed. When the cancer starts to spread, he receives multiple rounds of radiotherapy. Yet the cancer keeps on spreading. This is when he is given the option to recruit some unlikely helpers who can identify new drug treatments personalized for him – fruit flies.
Fruit flies are common in scientific research. For almost a century, scientists have been using these humble little flies to uncover the basic principles of biology, and more recently, in drug screening for various medical conditions, including cancer.
Cancer is a complex disease – a cancer patient's tumor can often contain dozens to hundreds of mutations. These mutations allow the cancer to grow and stay alive, posing a challenge in identifying the best treatment for a specific person's cancer. An ideal scenario is to screen for drugs in a whole living animal ('in vivo') containing the same combination of mutations as a cancer patient has. Typical animal models such as mice can only recreate one or two mutations. To capture the full genetic complexity of the cancer, cells from the patient’s tumor can be removed and cultured in a dish (called ‘in vitro’ experiments). More recently, tumor cells derived from patients can even be grown into complex 3D, self-organizing microtissues called organoids.
However, all of these methods hinge on cancer cells grown outside of their normal biological environment. Influences from a cancer cell's usual surroundings in the body – blood vessels, immune cells, and so on – cannot be fully replicated in a dish. “This is a particular problem when modelling diseases like cancer, where the microenvironment plays such a key role,” says Kyra Campbell from the University of Sheffield, a developmental and cancer biologist who uses fruit flies as cancer models for research. All these external factors can influence whether the cancer cells respond to a drug or not. The ideal situation is therefore to screen drugs in a whole animal, taking into account the surrounding influences on the cancer.
This is why scientists recruited fruit flies to help John. Scientists behind a recent study were able to generate fruit flies that carry the same mutations found in John's tumor, which they called personalized "cancer avatars." These avatars were then used to screen for drug combinations that were able to stop the flies from dying. The identified drug treatment helped stabilize John's cancer for 12 months. This "fly-to-bedside" approach was built upon a previous study where drugs identified from personal avatars stabilized the condition of a colorectal cancer patient for 11 months.
Fruit flies are particularly suited to mimicking the complex combinations of mutations in a human’s tumor. Over the past several decades, fruit fly scientists have assembled an impressive array of genetic tools for research purposes. To generate the personal fruit fly avatars, the scientists first analyzed the genome of John's tumor and identified major gene mutations that can drive tumor growth. They then used a series of genetic tricks to generate flies containing the same mutations found in his tumor. More impressively, to mimic tumor initiation in humans, the scientists used a clever system to "switch on" these mutations only at a later time and in a specific organ in the fly.
There are many advantages in using fruit flies for drug screening. Their life cycle is short, just ten days, and it is easy to produce large number of flies with little genetic variation among individuals, crucial considerations when a cancer patient is urgently waiting for personalized treatment options. Each drug is tested in a large number of avatars, and the efficacy of each drug can be analyzed in a reliable and cost-effective way. This personalized approach can be adapted to various types of cancers, pushing it beyond the current method of developing targeted treatments based on a single biomarker or a common mutation.
But this fly-to-bedside therapy platform has its limitations. The ACC and colorectal cancer studies centered on just one patient each, and it is impossible to compare their results to a scenario where the patient did not receive the selected drug combination, making it difficult to judge to what extent the treatment helped them. And crucially, this approach does not provide a cure. The personalized treatment stabilized the John's cancer for almost a year, but as new mutations evolved, the drugs no longer worked. A potential follow-up was to treat with the second-line drug cocktail discovered from the screening; however, unfortunately John's condition declined so rapidly that such treatment was too risky.
Nevertheless, the future of fruit flies avatars in cancer treatment looks promising. “This work brings flies much closer to the center of the action than ever before,” says Campbell. “Moving directly from fly avatars to treating patients is a huge step forwards. In some ways it is not surprising, because the relevance of fruit fly research to human health has been proven again and again.”
For John, these fruit fly avatars offer a glimmer of hope. His type of cancer is rare and he has limited therapy options. Thanks to decades of work from fly scientists building a wealth of genetic tools, the fruit fly avatars are in a unique position to recreate the mutations found in John’s cancer, providing a chance to find drug treatments tailored specifically for him.