Nonacus, a provider of genetic testing products for precision medicine and liquid biopsy, and the University of Birmingham have partnered to develop a non-invasive urine test for bladder cancer. The test, which is expected to be available by mid-2022, will use highly sensitive liquid biopsy technology developed by Nonacus, and a panel of biomarkers validated by Dr Rik Bryan and Dr Douglas Ward from the university’s Bladder Cancer Research Centre, to diagnose the disease from urine samples.

Chris Sale, CEO of Nonacus, commented: “We expect this partnership to deliver better care and outcomes for patients by reducing the number of invasive procedures, providing earlier diagnosis and speeding up access to treatment for people with bladder cancer.”

Haematuria

Bladder cancer is the seventh most common cancer in the developed world [1]. In the UK, over 100,000 people a year are referred to hospital clinics that investigate for bladder cancer, usually after passing blood in their urine (haematuria). The first stage of investigation is usually cystoscopy, which involves inserting a camera into the bladder. Of these 100,000 patients, around 12% are subsequently diagnosed with bladder cancer, normally after a second invasive procedure to extract a biopsy.

Dr Bryan, Director of the Bladder Cancer Research Centre, commented: “While blood visible in the urine should always be investigated, over 80% of people who have a cystoscopy at a haematuria clinic are diagnosed with non-malignant conditions or have no abnormality. Unfortunately, the remaining 20% will need a further invasive procedure to confirm diagnosis. What is required is a highly sensitive and specific, non-invasive test that can rapidly determine those who need a biopsy and those who do not, and a urine test is the obvious place to start.”

While the ‘liquid biopsy’ approach is attractive, the low levels of tumour DNA in a background of DNA from normal tissues requires highly sensitive analytical techniques to obtain accurate results. However, researchers at the University of Birmingham started their work in the knowledge that Nonacus had successfully pioneered commercial non-invasive prenatal tests to identify low-levels of foetal DNA in maternal blood samples. Moreover, the company was developing methods to allow confident and sensitive calling of mutations from as little as 10ng of DNA.

Deep sequencing of tumour DNA

The researchers used ‘deep sequencing’ of tumour DNA to identify mutations that are present in the majority of urothelial bladder cancers (UBCs). Their work, which was funded by Cancer Research UK and an MRC Confidence in Concept grant, involved sequencing 23 genes from tumour samples collected from 956 newly diagnosed, treatment-naïve patients. This deep sequencing of genes identified 451 unique mutations that were present in over 96% of tumours. The researchers also demonstrated that these mutations were identifiable in urine samples collected at the same time as tumour sampling [2].

As the researchers have shown, mutated DNA in a urine sample can be extracted from cancer cells shed into the urine from the lining of the urinary tract, or can be found as cell-free DNA fragments [2]. However, extracting DNA from the cancer cells provides more reliable amounts of DNA for the test, especially when only small volumes of urine may be available. Coupling the mutation panel with the unique molecular identifiers and the proprietary target capture technology provided by the Nonacus Cell3 Target™ will provide a much more sensitive test than the existing PCR-based approach. The researchers are already working on validating this combination in a further 600 cases (including non-cancer cases) and they expect to publish data on sensitivity and specificity within six months.

Nonacus intends to launch the new bladder cancer test within 12 months, and the final product will include access to bioinformatics software to help with analysis. The company expects the test will provide high sensitivity for all stages and grades of disease, and will ensure the test is available worldwide to laboratories, hospitals and clinics.

Influence of  mutations on cancer progression

Promisingly, the original research also determined the influence of the mutations on cancer progression, time to recurrence, and overall and disease-specific survival in patients with non-muscle-invasive bladder cancer (NMIBC), and disease-specific survival in patients with muscle-invasive bladder cancer (MIBC), raising the possibility that the test could be used to stratify patients according to risk.

Allen Knight, Chair of Trustees, Action Bladder Cancer UK, said: “This really is very exciting and has the potential to make an incredible difference for patients and for Bladder Cancer treatment. Currently urine tests do not accurately pick up bladder cancer, and invasive tests are required to confirm a diagnosis. A urine test that can rapidly determine who needs these tests will be a very welcome development. Many patients, myself included, find cystoscopies very uncomfortable at best, and they can have lasting side effects. This research could pave the way for routine screening, common in other cancers, but unavailable at present for Bladder Cancer.”

References

[1] Antoni, S. et al. Bladder cancer incidence and mortality: a global overview and recent trends. Eur Urol 2017; 71: 96–108.

[2] Bryan RT et al. Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA: a 23 gene panel with utility for non-invasive diagnosis and risk stratification. BJU Int 2019: 124; 532-544.

Selux Diagnostics, which is leading a new era in personalized diagnostics to combat superbug infections and fight antibiotic resistance, has been awarded an additional $14.6 million in funding from the Biomedical Advanced Research and Development Authority (BARDA), part of Office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services.

BARDA modified the cost sharing contract, raising the Government’s cost share of $45 million to a total level of $60.8 million if all options are exercised. This additional funding will allow Selux to continue implementing its microbiology roadmap and commercialize its Next Generation ‘Phenotyping’ (NGP) platform for rapid antimicrobial susceptibility testing (AST).

Selux received the latest round of funding after successfully achieving a key milestone: completion of its first clinical trial. The trial confirmed the platform’s ability to accurately provide rapid AST results from cultured isolates with a broad antibiotic menu all within the same shift – the patient’s most vulnerable window and critical period of infection. Selux will now submit the clinical trial results to the U.S. Food and Drug Administration (FDA), the next step in clearing the way for the commercialization of the innovative NGP platform.

Antibiotic resistance

“A global crisis of antibiotic resistance requires innovation to save lives, and we believe this next generation technology represents the future backbone of microbiology,” said Steve Lufkin, CEO of Selux. “Our plan is to build on the success of this first clinical study and turn our attention to the next phase of product development to speed the time to targeted antibiotic treatment further, preserving the lifesaving power of antibiotics for future generations.”

The Centers for Disease Control and Prevention calls antibiotic resistance one of the “biggest public health challenges of our time” – a growing problem that is not only deadly but extremely costly. According to a January report by the CDC and the University of Utah, multi-drug resistant pathogens are estimated to cost the U.S. more than $4.6 billion annually.

The proprietary Selux technology uniquely provides targeted therapy results days faster than the current standard of care providing actionable information to inform patient treatment for all Infectious Diseases. Selux’s NGP platform provides unprecedented speed-to-results and breadth of menu while meeting the accuracy, throughput, and cost effectiveness requirements of clinical microbiology laboratories and integrated healthcare systems.

The Selux platform is an investigational device, limited by U.S. federal law to investigational use.