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article imageQ&A: How fruit flies aid personalized cancer treatments Special

By Tim Sandle     Jun 24, 2019 in Science
London - London-based startup My Personal Therapeutics are pioneering the use of fruit fly avatars and big data to create fully personalized cancer treatments for patients. To find out more, we've interviewed founder Laura Towart.
The unusual treatment, based on the fruit fly avatars, was developed by Mount Sinai Hospital over four years of clinical research with technical input from the U.S. Food and Drug Administration (FDA). Following this success, My Personal Therapeutics has an exclusive license to commercialize its treatment and already has $500,00 in seed funding.
My Personal Therapeutics has a good record in developing novel and pioneering treatments. The company leadership previously built Celmatix, which is known within healthcare as the “Uber of fertility”. Company founder Laura Towart explains more.
Digital Journal: Why are traditional fruit flies a model organism for biological research?
Laura Towart: The fruit fly Drosophila melanogaster has been used for more than a century to understand basic principles of biology, including those that govern cell growth and proliferation both in physiological and pathological conditions. Their short life cycle and their numerous offspring let research progress rapidly and to get fast results. In addition, their relatively small genome, with only four pairs of chromosomes, alongside the development of an impressive array of genetic tools allows for easy manipulation of their genome to conduct a great variety of experiments.
The decodification of the fly and human genomes in the early 2000s exposed beyond all expectations an amazing conservation of most cellular pathways implicated in human diseases. It showed that an estimated of 75 percent of known human disease genes have a match in the fly genome. These striking genetic and molecular similarities between Drosophila and humans and the possibility to create flies mimicking human disease conditions (avatars) redirected several Drosophilists toward biomedical research.
DJ: What advantages do fruit fly avatars present over the biological model?
Towart: Different avatar models have been created using other animals, such as mice and fish. High-throughput drug screening platforms in mammals are impractical due to technical and financial pitfalls, a hindrance circumvented by the use of flies. They can be bred large-scale using a minimum amount of drugs. One of the main advantages of fly avatars is that the transgenic model can be established in less than three months. This becomes crucial when a patient is waiting for therapy, giving the fly model a time-scale advantage.
Their small size additionally permits thousands of fly stocks to be stored cost-efficiently in a reduced space. Most importantly, Drosophila offers the possibility to explore cancer biology in the context of an entire animal at a level of genetic sophistication not available for any other biological model. The current techniques allow for creating animals carrying about 20 gene alterations, better mimicking a patient's specific tumor mutations, a complexity that can only be achieved in flies.
A microscopic photo of a fruit fly retina  by Dr. W. Ryan Williamson
A microscopic photo of a fruit fly retina, by Dr. W. Ryan Williamson
Via Nikon Small World
DJ: What types of medical research are fruit fly avatars being used for?
Towart Most diseases with a genetic basis can be modeled in Drosophila, including a broad spectrum of illnesses such as neurodegenerative diseases, metabolic syndromes, rare genetic conditions, and even sleep disorders. But so far the best possibilities that fly avatars offer are the design and further creation of precise tumorigenic conditions that recapitulates specific types of human cancers.
The avatar can be then used for in vivo-based drug screenings to identify the best drug cocktail tailored for a patient. In this way, tumor progression can be measured within the complexity of a whole organism. Therefore drug pharmacokinetic metrics like absorption, distribution, metabolization, and elimination can be adequately weighted. The list of cancers that can be recreated in flies includes gastrointestinal (colorectal, oesophagus, etc.), thyroid, brain, lung, leukemia, and epithelial cancers, among others.
DJ: How was the technology developed?
TowartA fly avatar carries three decades of continuous advances in biotechnological techniques, built brick by brick by several groups around the globe. The generation of a binary expression system in the 90s allowed fly researchers to insert a specific gene into a defined set of cells, and activate or deactivate a gene (or a set of genes) in demarcated tissues at a precise moment. More recently, the advent of genome-wide RNA libraries that allow interfering with each gene of the fly genome boosted research into the engineering of complex genetic combinations and the creation of avatars.
Simultaneously, the demonstration that flies can respond to chemical treatments similarly to humans led to the design of drug screening platforms for the identification of compounds with medical relevance. Finally, next generation sequencing technology, together with better access to human data and new bioinformatics tools, partnered with Drosophila know-how to create patient specific tumors and to solve medically relevant problems.
DJ: What were the major challenges?
Towart An important challenge of preclinical evaluation and screening of new anti-cancer drug combinations was to understand the extent that genetically modified animals recapitulate cancer progression and, crucially, whether the response to anti-cancer therapies observed in fly models would be effective as target therapies for human patients.
Nonetheless, one of the most important challenges to establish the fly avatar model for biomedical research were probable not technical, but to set our minds into a new way of thinking and to realise that we can transfer all the basic knowledge generated during several years studying a simple organism into human treatments. Another challenge was creating a multi-disciplinary team of research and health professionals, including Drosophila biologists, human geneticists, bioinformaticians, and clinicians.
A microscopic photo of fruit fly larvae  pic by Dr. Andrew Woolley
A microscopic photo of fruit fly larvae, pic by Dr. Andrew Woolley
Via Nikon Small World
DJ: Are there any research successes that you’d like to share using the new technology?
Towart Scientists from the Icahn School of Medicine at Mount Sinai (NY) recently reported (Science Advances, 2019) a personalized treatment for a KRAS+ colorectal cancer patient developed using a fly avatar bearing multiple genetic tumorigenic alterations. Whole-exome sequencing of the patient tumor exposed the presence of dozens of mutations, including several likely to be cancer drivers.
Subsequently, a genetic fly model bearing the specific patient tumor mutations targeted to the fly gut was created, and the engineered flies were then used to screen a library of FDA approved drugs. The platform used 400,000 flies, an impossible scale for any other animal model. They found a combination of drugs that showed activity in the fly and when given to the patient led to a substantial decrease in tumor size, significantly improving the patient’s quality of life and extending his lifespan.
DJ: How is investment in the project proceeding?
Towart We finalized our seed round in April 2019 and have been actively expanding our team, including stellar cancer biologists and geneticists, and building a state of the art lab facility in central London. Preliminary discussions with VCs are in process as we prepare for our Series A in the Fall.
DJ: What has the responses and support been from regulatory agencies?
Towart The Personal Discovery Process (PDP) offers personalized drug treatment recommendations that include only FDA approved drugs in combination. Our services don’t require regulatory approval. When our AI/big data product TuMatch is available (early 2020) we will pursue regulatory review and reimbursement.
More about Fruit flies, Cancer, Personalized medicine, precision medicine, Medical
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