NEW YORK – Biotech company My Personal Therapeutics announced last week that it has received a £476,791 ($607,357) grant from the governmental research funding body Innovate UK, with which it intends to evaluate its personalized therapy matching technology in patients with gastrointestinal cancers.
The company's personalized discovery process (PDP) uses sequencing data, artificial intelligence, and tumor modeling with fruit fly "avatars" to sort through a library of drugs and predict which therapies cancer patients are most likely to benefit from.
My Personal Therapeutics CEO Laura Towart said the company is focusing on studying the utility of its technology in GI cancers, especially upper GI tract cancers like esophageal cancer, because many of the latest treatment advances in cancer, such as immunotherapies, don't work that well in these tumors. "We wanted to focus on where there was a great need," Towart said.
The recently acquired funds will support a study assessing the PDP's ability to inform treatments in GI cancer patients. The study will be done in collaboration with the London In Vitro Diagnostics Co-operative, which is one of four National Institute for Health Research-funded centers in England that generate evidence used to develop diagnostics.
According to Towart, most of the study participants will be enrolled at Hammersmith Hospital, but patients could also come from private centers, such as Sarah Cannon Research Institute-UK. Since My Personal Therapeutics also partnered with Genomics England on this study, a few cancer patients from the Genomics England tumor database, who have had their samples sequenced, may also be included in the trial.
George Hanna, director of the London IVD Co-operative, and others at the center will lead the study, monitor patient outcomes, and publish the results. The study, which has already started enrollment, will initially evaluate the PDP in approximately 20 patients who are recommended by their oncologists. The endpoints of the study will include treatment response, progression-free survival, and cost/savings analysis.
Ultimately, My Personal Therapeutics is hoping to submit the evidence generated from this study to the UK's National Institute for Health and Care Excellence for a cost-effectiveness appraisal. If deemed cost-effective and recommended by NICE, then the PDP could become broadly available to patients within the National Health Service.
At this time, the PDP is only available through the NHS in the UK within this clinical study, but My Personal Therapeutics also markets the technology to patients globally. The price for using the service is $15,000 for patients with gastrointestinal cancers.
The PDP technology was invented by Ross Cagan, a researcher at Mount Sinai Center for Personalized Cancer Therapeutics, and exclusively licensed to My Personal Therapeutics in 2019. Later that year, Cagan and colleagues published a case study in Science Advances on a patient with KRAS-mutated colorectal cancer who had cycled through several rounds of chemotherapy.
After using the model to conduct drug screening on a focused library of around 100 US Food and Drug Administration-approved drugs, the researchers homed in on trametinib (Novartis' Mekinist), which is effective against oncogenic RAS, combined with the biphosphate drug zoledronate. The combination demonstrated an anticancer effect and low lethality in the fly avatar model of the patient's cancer. After administering the drug combination in the patient, researchers observed a partial response in target lesions that lasted eight months, and up to a 45 percent reduction in some target lesions.
Towart noted that early evaluations of the PDP have been done on heavily pretreated patients, but in the study with the London IVD Co-operative the company is hoping to gauge the utility of the technology earlier in a patient's cancer journey. "We couldn't necessarily see the full potential of the technology and what the impact of the technology would be if a patient had access to it earlier," she said. "With this study, we're hoping to have that."
After patients are first diagnosed, at their oncologists' discretion, they would learn about the PDP technology and decide if they want to enroll. Once patients are enrolled, their tumor and blood samples would be sent to Genomics England for whole-genome sequencing. Once this analysis is available, My Personal Therapeutics will use the PDP technology to parse the sequence data and identify 15 to 20 driver mutations that will also characterize the tumors modeled in the fruit fly avatars. Around 400,000 avatars will be generated for each patient, through which researchers can perform high-throughput screening of drugs and combinations approved by the FDA and the European Medicines Agency.
Because all the avatar flies will have lethal tumors that mimic the patients', only the flies that receive the right drug cocktail will survive. Based on this, My Personal Therapeutics will identify drugs that patients' tumors are likely to respond to and these recommendations will be sent to the treating oncologists and tumor board.
While My Personal Therapeutics has decided to use flies in their drug screening model, mice are also commonly used as "avatars" to model precision oncology options for patients. For example, another group from Mount Sinai in 2014 tested the feasibility of using mouse avatars to assess responses in breast cancer patients.
However, there are certain advantages to using flies. Cagan and colleagues from Mount Sinai acknowledged in their Science Advances paper that while preclinical mammalian models, including patient-derived xenografts and organoid cultures, are important parts of the drug discovery pipeline, "success rates for growing patient-derived tumor tissue in mice or in three-dimensional culture are generally low and highly variable, and the cost and time frame are generally prohibitive."
Another advantage, they noted in the paper, is that fruit fly models can be made with isolated tumor tissues, including formalin-fixed tissues, while mammalian models usually require live tumor specimen from patients. They recognized, however, that mammalian models could possibly be combined with fruit fly models for drug screening in the future and be used to test the most promising drugs or combination therapies that emerge from the fruit fly models.
Another limitation of mouse avatars, according to Towart, is that only a few genetic alterations can be induced at a time in mice, whereas up to 20 gene alterations can be modeled in a fly. Compared to mice, flies can also be grown quickly and don't take up as much space.
It takes around 18 months to create an animal with only two or three genetic alterations, and only around 3 months to create flies with up to 20 genetic alterations, she explained. Mouse avatars also cannot be expanded the same way that fly avatars can. Around 100 mouse avatars can be created for each patient compared to the 400,000 fly avatars that My Personal Therapeutics can generate. These factors allow flies to be a useful vehicle for testing many more drugs quickly than would be possible with mice, she noted.
"Flies have been used for almost a century for cancer studies, many of the original oncogenes were found and identified in flies," added Towart.
An example is the discovery of the NOTCH oncogene, as well as other genes in the NOTCH signaling pathway. A more recent example includes the discovery of genes in the Hippo pathway of flies, which also plays a role in human cancers.
One of the reasons that My Personal Therapeutics wanted to test the technology out in GI cancers was because there is a well-conserved GI tract between the Drosophila fly and humans.
In the fly, genetic engineering is used to introduce the cancerous mutations found in the patient tumor into the intestinal cells of flies. The fly intestinal cells became oncogenic and grow genetically similar tumors to that of the patient. These genetic modifications are introduced in a subset of cells of the fly hindgut, which is analogous to the colorectal portion of the human intestine, explained Towart. Whereas in creating mouse avatars, tumors are often created subcutaneously under the skin of the animal no matter the tissue of origin of the tumor in the human.
"When you're really trying to create the most personalized model, you want to try to direct the tumor to the most similar place," she said.
My Personal Therapeutics is working with other medical centers around the world to conduct feasibility studies on the PDP technology. The company in April announced that it was collaborating with the Association for Health Research and Development (ACINDES), which will make the PDP technology available to oncologists and oncology centers in Latin America. The firm will also collaborate with the King Abdullah International Medical Research Center in Saudi Arabia to sequence and analyze five colorectal cancer patients in a pilot study.
My Personal Therapeutics is certainly not alone in its efforts to model tumor behavior and test out precision oncology treatment options before giving them to patients. For example, Israeli personalized medicine company Curesponse is planning to launch clinical trials for its cResponse technology, which models patients' cancers on an ex vivo organ culture in order to predict response to chemotherapy or targeted drugs.
California-based Notable Labs is another firm currently validating its ex vivo drug sensitivity platform, which uses flow cytometry to evaluate cancer cell behaviors in the presence of different treatments in blood cancer patients.