NEW YORK (GenomeWeb) – London-based startup My Personal Therapeutics (MPT) has developed a targeted therapeutic recommendation platform based on whole-exome sequencing data and fruit fly "avatars," which it said will hopefully minimize the amount of toxic drugs needed during treatment.
The firm now plans to commercialize a personalized treatment advisory service based on the platform called "TuMatch" for cancer patients, starting with colorectal cancer (CRC), by the end of the year.
Invented by Mount Sinai Center for Personalized Cancer Therapeutics researcher Ross Cagan, the personal discovery process (PDP) technology integrates artificial intelligence and personalized fruit fly avatars to model individual patients' cancer conditions and potentially offer targeted and less toxic drug treatments.
Founded in August 2018, London-based MPT was started by CEO Laura Towart. Cofounder and a director of personalized women's health firm Celmatix, Towart began collaborating with Cagan in 2014 as tested the technology in US clinical trials. Â
Towart explained that PDP service would begin with a patient and an appointment at their oncologist office. After extracting a tumor biopsy and blood sample from the patient, the oncologist sends the samples to a sequencing center for whole exome sequencing. The center then mails the whole-exome sequencing data to MPT for interpretation and to create fly models.
By performing a proprietary analysis on the sequenced data, MPT researchers select up to 15 genes — including known oncogenes like KRAS, BRAS, PIK3CA, as well as other known and possibly unknown cancer-related genes— driving the patient's tumor and build a construct containing the mutations. They then microinject the construct into Drosophila melanogaster embryos.
Monitoring up to 500,000 flies that develop a similar tumor to the patient, the MPT team screens the entire US Food and Drug Administration's approved drug list — about 1,200 — by using robotic tools to add them to the fruit flies' food source. The researchers identify a targeted cocktail — usually consisting of one chemotherapy and two non-cancer drugs — and select ones that rescue the fly from lethality. They then generate a treatment recommendation report for patients, generally for combination therapy.
In addition to PDP, MPT will also offer targeted PDP (tPDP) for CRC, which involves screening with a subset of the US Food and Drug Administration-approved drug library. According to Towart, dozens of previous PDPs have provided enough information for the firm to intelligently edit the library and eliminate drugs that are not as effective.
Towart noted that while full PDP screening can take up to seven months, tPDP for colorectal cancer only requires about four months.
Mount Sinai's Cagan declined to be interviewed for this article, but Towart explained that the main benefit of developing the PDP method in flies over other animals such as mice is their rapid and unbiased therapeutic response.
"The benefit of using flies as a tool for exploring solid tumors is that they are a whole animal model that we can use with speed and low cost," Towart explained. In contrast, "You can't do this type of high-throughput screening in mice, [as] it just isn't possible."
Towart said that Cagan's team is publishing a proof-of-concept case study using the technology in an upcoming edition of Science Advances She emphasized that MPT is confident in fruit fly model because flies have been extensively used and explored for cancer and other genetic disease research and drug development,
Baylor College of Medicine professor Hugo Bellen — who is not associated with MPT or Mount Sinai — agreed that testing approved drugs in fruit flies for cancer-related issues is ideal because of the ease, speed, effectiveness, and low cost. His team's own research explores the usage of fruit fly models for treating rare diseases including multiple sclerosis.
"The technology is extremely sophisticated in fruit flies, so you can ask very precise questions relatively quickly since their lifetime is very short," Bellen explained. "No other animal comes close besides Caenorhabditis elegans, but they don't have as much of the same biology and are limited in what can be tested."
Bellen explained that researchers can conserve a substantial amount of the fruit fly's biology when they "knock out" a gene and replace it with a functioning human gene. He argued that "at least 50, if not 70 percent of fly genes" could therefore be "rescued" with human genes.
"If the patient has a mutation in the gene, but if you're not sure if the mutation in the human gene affects the protein, you can [insert] the wild type gene into the fly that lacks the human gene homologue and observe it," Bellen said. "If the normal human gene rescues the loss of the gene in the fly, then the [condition] is due to the fact there's a mutation in the gene. However, if the variant found in the human rescues, then you can argue that the point mutation does affect the protein's function"
When asked by clinicians to track therapeutic response to a specific genetic disease, Bellen said that the overall time his team needs to produce results can range anywhere from three to six months depending on available reagents.
"When physicians approach me to model a fruit fly gene to test if the variant they've identified in the patient is causing a malfunction in the protein, we can usually respond in three to four months with knockouts made and have gene inserted into the fly," Bellen said.
University of Trento associate genetics professor Paola Bellosta, also unaffiliated with MPT and Mount Sinai, agreed that fruit flies are advantageous as human drug response models. Like Bellen, she highlighted that flies have high progeny, are relatively cheap to raise, and are easy to manipulate genetically. She therefore believes that flies provide a strong model to test the effect and function of mutations that are found in certain types of cancers like has CRC.
In her own lab, Bellosta's team examines the role in growth of Drosophila myc — the homologue of human c-myc proto-oncogene — that is involved in more than 80 percent of cancers. By looking at genetic factors linked to tumor growth in fruit flies, Bellosta and her team can genetically manipulate the animals in order to identify key components that regulate uncontrolled growth.
While noting that MPT does not require additional US regulatory approval since the firm is already using FDA approved drugs, Towart said her team is tackling state and government insurance coverage in the US and the UK. The group is therefore partnering with Genomics England and Medicines Discovery Catapult to apply for funding and perform studies to produce UK National Health Services-quality data.
"Through the NHS, oncologists can only offer drugs that are currently used for patients with cancer," Towart explained. "Many of our personalized drug combinations will include drugs not normally prescribed for cancer patients."
Earlier this month, Towart and her team received an exclusive worldwide license from Mount Sinai to commercialize the PDP technology. The firm also secured an undisclosed amount of initial funding in a seed funding round led by London-based Startup Funding Club, in addition to independent international firms that Towart mentioned are "major investors in the healthcare industry."
According to Towart, MPT will partner with US, UK, Middle Eastern, and European medical centers to make PDP available to oncologists interested in the service. The firm currently offers the PDP services to private oncology practices for patients who are interested in using the tool.
Towart said that Cagan's lab was recently awarded a grant from the National Institutes of Health to build a database of CRC PDPs using de-identified sequencing data from The Cancer Genome Atlas. MPT is now using the genetic database — along with PDPs conducted by Mount Sinai and the firm — to develop and commercialize TuMatch.
While Baylor's Bellen noted that startups have popped up in the past and used flies as models, few have survived because of lack of funding
"People pour in a lot of money and effort into cell modeling, especially into human cells, but human cells can't replace the actual organism," Bellen explained. He argued that model organisms should be the driving force to explore new biology because most cells in human and animal bodies communicate with each other and control their functions.
"When you find a pathway in the fly that is affected, and you think 'this drug affects a certain gene, and this gene is in my pathway, maybe I should test this drug that is commercially available," Bellen said. "If it works in the fly, you can immediately jump to using it in the patient because it's a clinically approved drug."
Bellen noted that using fruit fly models to study basic biological signaling process has greatly benefitted cancer research. He said that several pathways had been studied before researchers found they also caused cancer in humans. In terms of gene discovery and mechanisms for rare diseases, his team is currently testing numerous approved drugs in flies.
In contrast to other cancer therapy recommendation methods, Towart argued that PDP is "the world's most comprehensive, high-throughput drug screening for patients with cancer." In addition, she claims that the approach is unique because her team takes an unbiased, whole-animal screening approach when searching for actionable genes.
However, Bellen said that the predictive reliability of fruit fly models depends on the exact medication, as "in some cases they are very reliable" and "in others much less so." While researchers can work relatively quickly with fly models, he said that clinical data will take years to produce actionable results.
In terms of pricing, Towart noted that PDP costs about $30,000 per patient because it examines the whole gamut of US FDA-approved drugs for therapy recommendation. The firm's targeted screening tool, which examines specific US FDA-approved drugs, costs patients about $15,000 per run. However, Towart anticipates that TuMatch will only cost $5,000 because the group will not need to perform any drug screening. Â
"We make treatment recommendations based on the patient's cancer, but the oncologists ultimately make the final decision," Towart explained.
While her team expects to apply for reimbursement from health insurance companies in the future, Towart said her team is initially offering PDP to patients that can pay out of pocket or through private oncology practices.
According to Towart, MPT aims to offer TuMatch for patients with CRC by the end of the year, followed by other genetically driven tumor types in the future. Following the CRC application, Towart said that oncologists will be able to request targeted PDP reports for lung cancer, adenocarcinoma, medullary thyroid carcinoma, and rare genetic cancers.