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Liquid Biopsy Test to Guide Prostate Cancer Treatment Being Developed With £5M Award

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NEW YORK (360Dx) –  A group of international researchers is developing a new test that could be used to guide prostate cancer treatment selection, particularly among advanced cases.

Led by investigators at the University of Trento in Italy, the team received a five-year, £5 million ($6.4 million) award recently to advance its work. The grant was made through the Accelerator Award program, which is funded by Cancer Research UK, the Spanish Association Against Cancer, and the Italian Association for Cancer Research. The trio announced a total of £30 million in funding for European cancer research in September.

According to Principal Investigator Francesca Demichelis, the envisioned test, called PRIME, will be run using liquid biopsies obtained from patient samples, and will rely on genomic, methylomic, and transcriptomic markers to arrive at personalized results. PRIME stands for prostate cancer plasma integrative multimodal evaluation.

Demichelis, an investigator at the Center of Integrative Biology (CIBIO) at the University of Trento, has for years been working on developing a test that could be used to monitor treatment response in prostate cancer patients, especially those with resistant disease. The new CRUK award, though, could provide a platform for her team's research to eventually reach the clinic.

"This award changed our mindset because it gave us the support to develop the framework to deliver a tool into the hands of clinicians that can be used in their own research," she said.

Demichelis and colleagues have run their analysis of cell-free DNA on targeted sequencing panels. She said that they have used Illumina technology in the past and continue to use Illumina instruments in their work, though they have tried other technologies. They have also used Agilent Technologies, Roche's NimbleGen products, and other approaches for panel design. She did not elaborate.

The core concept behind the test is a multi-model design that queries the genomics of the cell-free DNA in addition to its epigenomics and transcriptomics, data all obtained from the targeted sequencing panel. "Our idea is to develop the test in such a way that the three components can be used together and integrated from an analysis perspective," said Demichelis. She noted that PRIME is being developed so that each component can be run in a standalone manner. "That should provide wider flexibility for future use in the clinic by oncologists who want to use this tool to characterize the molecular features of their patients," she said.

Demichelis declined to elaborate on the specific content of the test. She said that during the course of the next five years, the team hopes to run the analysis on samples drawn from its networks in Italy as well as the UK. Gert Attard, a clinical scientist at University College London Cancer Institute, is the co-PI on the new project. Attard said that the team will run PRIME on multiple cohorts totaling 1,000 patients.

Attard has long been motivated to develop new approaches for treating cancer patients. "The way we treat cancer is that we give patients drug A, wait for responses, and by that time there are several million cancer cells and the chance of there not being a resistant clone is exceedingly low," he said. "So we see either primary resistance to treatment or an initial response that is shallow and often short lived."

Attard said the concepts that he and Demichelis are introducing via PRIME — looking at a variety of omics data points to arrive at results that can guide treatment — should not be "too controversial" for the clinical research community, though validating such a test presents the team with a number of challenges.

"We have a lot of experience with obtaining information from DNA, but we can make further improvements," said Attard. He added there is a need to "think outside the box" to expand analysis of cell-free DNA to earlier disease, when the fraction of cancer cells is less. By casting a wider net — looking at sequence data, methylation, and expression — the team hopes to overcome these obstacles in its development of PRIME.

"We have a number of exploratory aspects of the test," noted Attard. "If successful with the data we generate in the next 18 months, we would continue developing all three aspects. Clearly there is important information in transcripts that is not captured by DNA. We want to make the most of blood. To do that, we need very robust assays."

The future availability of PRIME is unclear. Demichelis said that once PRIME is validated, the team will offer the test to a number of sites in Italy that are part of a wider, 55-member cancer network called Meet-URO, the Italian Network for Research in Urologic Oncology. That in turn could help drive adoption of PRIME as a free tool for clinical research.

"The tool is a combined solution where one part includes all the optimized protocol for collection and processing for every single component," said Demichelis. "We envision that the data generation can be done either locally using an NGS facility or by third party, while the computation will be done in a cloud solution," she said. "The molecular features [of the patient sample] would then be delivered to the site directly."

The investigators also believe the tool could be used as a stratification tool in ongoing clinical trials. "There are more than 200 open trials for metastatic prostate cancer," Demichelis noted. "Patients are most commonly assessed using tissue biopsy, which is a big impediment."

Yet there could be a commercial aspect to the PRIME story as well.

"Neither of us wants to run the test on large-scale samples once our work is done," said Attard. "That would swamp what we do," he said. Attard suggested that the mechanism for the test to receive a wider vetting on even more samples would be through a partnership with either an established commercial player in the space or a spinoff company that provides that service.

A number of companies have already invested in liquid biopsy-based tests for prostate cancer, though with differing applications. Genomic Health, for instance, earlier this year launched Oncotype DX AR-V7, which is run using an assay designed by its partner, Epic Sciences. That test can be used to specifically determine which patients are more likely to respond to treatment with an androgen receptor-signaling inhibitor therapy, and which would be better served by chemotherapy.

MDNA Life Sciences last month announced the UK release for its PCR-based Mitomic Prostate Test, a liquid biopsy assay that developers claim can be used to detect prostate cancer in advance of biopsy. In August, Laboratory Corporation of America obtained a license to MDNA's technology to develop a test for patients with elevated PSA levels to determine their risk of having clinically significant prostate cancer.

So far, it is unclear what form of a commercial test PRIME could take, given its multi-modal approach. Attard underscored that developing and validating the test is the research team's current priority. "We are undertaking analytical development of these three approaches, and once we have analytically robust, fit-for-purpose tests, we will be implementing them in a number of cohorts," he said.

"Once the test is qualified, we also need to think about commercially what is most desirable to increase access to the test," he added. We are just starting, but when we scan the horizon, that's what we need to get to."