EPIGENETIC ALTERATIONS IN GENES FROM LIQUID BIOPSIES PROVIDE INSIGHT INTO DRUG RESISTANCE IN NON-SMALL LUNG CANCER PATIENTS
Longitudinal analysis of paired samples of CTCs and ctDNA shows important differences in epigenetic biomarkers at disease progression
Study supports analysis of CTCs captured by Parsortix, together with ctDNA, from serial liquid biopsies to provide information on disease progression and drug resistance
GUILDFORD, SURREY / ACCESSWIRE / January 10, 2022 / ANGLE plc (AIM:AGL)(OTCQX:ANPCY), a world-leading liquid biopsy company, is pleased to announce that the world-class research team led by Prof. Evi Lianidou at the National and Kapodistrian University of Athens (Greece), has published results of a further study undertaken in non-small cell lung cancer (NSCLC) patients with an EGFR mutation being treated with the tyrosine kinase inhibitor (TKI), Osimertinib (AstraZeneca's Tagrisso®), which demonstrates the benefit of longitudinal analysis of epigenetic alterations in circulating tumour cells (CTCs), in addition to circulating tumour DNA (ctDNA), to assess possible drug resistance mechanisms in patients.
The aim of the study was to analyse increased DNA methylation in the promoters of six selected genes that result in loss of gene expression and are implicated in drug resistance in lung cancer. The analysis was performed using ctDNA and paired CTCs from a single blood sample. The study used the Parsortix® system to harvest CTCs in blood samples from 42 metastatic NSCLC patients before treatment with Osimertinib and again at disease progression.
After harvesting from the Parsortix system, captured CTCs were lysed and the genomic DNA extracted. Once DNA integrity had been evaluated, the DNA was amplified and expression levels assessed using real-time methylation specific PCR (MSP) assays for the targeted genes. CTC-derived DNA was analysed in 74 samples and DNA methylation assessed before treatment and at disease progression. For the first time, direct comparison of the CTC results with 70 paired results from 80 ctDNA samples has revealed significant differences in DNA methylation indicating that CTCs and ctDNA give complementary information and demonstrate a high level of heterogeneity between patients even at the DNA methylation level.
Moreover, the combined results from CTC and ctDNA methylation analysis indicated that methylation rates for all genes tested were significantly elevated at progression of disease after treatment with Osimertinib compared to before treatment, indicating that DNA methylation of these genes may be associated with resistance to Osimertinib during therapy. As a result, identifying the differences between DNA methylation in ctDNA and CTCs in longitudinal studies could help guide therapy decisions and provide an important enhancement to monitoring patient response in cancer drug trials.
In the United States, lung cancer is the second most common cause of cancer and the leading cause of cancer related mortality, responsible for 22% of all cancer related deaths. In 2021, The National Cancer Institute predicts that there will be a total of 236,000 new cases and 132,000 deaths - NSCLC accounts for 84% of all lung cancer cases. Whilst the overall 5-year survival rate for NSCLC is 25%, 60% of patients are diagnosed with metastatic (stage IV) disease for which the 5-year relative survival rate is just 5%.
However, lung tissue biopsy required for biomarker assessment is associated with significant risks. Due to adverse events following the procedure, a mean cost of US$14,600 per biopsy has been estimated. Liquid biopsy offers the potential for safe, cost-effective longitudinal monitoring of tumour evolution and disease progression to track mutations responsible for therapy resistance and identify biomarkers for targeted treatment selection.
Precision medicine has transformed cancer care in NSCLC. There are 34 FDA approved therapeutics for NSCLC, 24 of these are targeted therapies including PD-L1/PD-1 inhibitors which can induce durable and long lasting antitumour immunity. Patient response to PD-L1 or PD-1 inhibitors is variable ranging from 13%-50% but treatment costs c. US $170,000 per patient and has significant side effects. As such, there is a clear need for improved patient selection to identify responders given that non-responders risk the development of hyper-progressive disease and immune-related adverse events, and the wasted healthcare costs are significant.
There are over 2,400 clinical studies registered at clinicaltrials.gov involving PD-L1, all of which may benefit from a CTC based biomarker to assess PD-L1 status over time. ANGLE is currently validating a PD-L1 assay in its clinical laboratories which will be offered to biopharma customers for use in clinical trials.
The research has been published as a peer-reviewed publication in the journal Cancers and may be accessed via https://angleplc.com/library/publications/.
Prof Evi Lianidou, Head of the Molecular Diagnostics Laboratory focused on Liquid Biopsy (ACTC lab) at the Department of Chemistry, National and Kapodistrian University of Athens, commented:
"Whilst the prolonged survival of patients who benefit from targeted therapies is proven, in most cases resistance arises inevitably and the identification of the molecular mechanisms that lead to the progression of disease is crucial for the appropriate sequential treatment. The identification of circulating epigenetic biomarkers through DNA methylation studies is of utmost clinical importance in the liquid biopsy field and can be used for the diagnosis, prognosis and prediction of drug response".
ANGLE Founder and Chief Executive, Andrew Newland, commented:
"This study, which analysed blood samples taken from patients using the Parsortix system before and after treatment, further demonstrates the dynamic nature of NSCLC and the need for analysis of CTCs and not just ctDNA from serial liquid biopsies to provide information on disease progression and drug resistance. In addition to the clinical implications in guiding therapy decisions, this information is vital for drug companies in patient selection for clinical trials and for monitoring response to new drugs."
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Notes for editors
About ANGLE plc www.angleplc.com
ANGLE is a world leading liquid biopsy company with sample-to-answer solutions. ANGLE's proven patent protected platforms include a circulating tumor cell (CTC) harvesting technology and a downstream analysis system for cost effective, highly multiplexed analysis of nucleic acids and proteins.
ANGLE's cell separation technology is called the Parsortix® system, and it enables a liquid biopsy (a simple blood test) to be used to provide the cells of interest to the user in a format suitable for multiple types of downstream analyses. The system is based on a microfluidic device that captures cells based on a combination of their size and compressibility. The system is epitope independent and can capture all types of CTCs as well as CTC clusters in a viable form (alive). CTCs enable the complete picture of a cancer to be seen; as being an intact cell they allow DNA, RNA and protein analysis and may provide comparable analysis to a tissue biopsy. Because CTC analysis is a non-invasive process, unlike tissue biopsy, it can be repeated as often as needed. This is important because cancer develops and changes over time and there is a clear medical need for up-to-date information on the status of a patient's tumor. In addition, the live CTCs harvested by the Parsortix system can be cultured, which offers the potential for testing tumor response to drugs outside the patient.
The Parsortix technology is the subject of 26 granted patents in Europe, the United States, China, Australia, Canada, India, Japan and Mexico with three extensive families of patents are being progressed worldwide.
The Parsortix system has a CE Mark in Europe for the indicated use and, in the United States, a De Novo Submission has been made to FDA for the Parsortix® PC1 system seeking FDA clearance with Class II Classification for use with metastatic breast cancer patients. FDA clearance is seen as the global standard. ANGLE is seeking to be the first ever FDA cleared system for harvesting CTCs for subsequent analysis.
ANGLE has also completed two separate 200 subject clinical studies under a program designed to develop an ovarian cancer pelvic mass triage test, with the results showing best in class accuracy (AUC-ROC) of 95.1%. The pelvic mass triage assay has undergone further refinement and optimisation and a 200 patient clinical verification study has now completed enrolment.
ANGLE's technology for the multiplex evaluation of proteins and nucleic acids of all types is called the HyCEADTM platform and is based on a patented flow through array technology. It provides for low cost, highly multiplexed, rapid and sensitive capture of targets from a wide variety of sample types. A proprietary chemistry approach (the HyCEAD method) allows for the capture and amplification of over 100 biomarkers simultaneously in a single reaction. The HyCEAD system is extremely sensitive and is ideal for measuring gene expression and other markers directly from Parsortix harvests and was used in the ovarian cancer pelvic mass triage test to achieve best in class accuracy (AUC-ROC) of 95.1%.
ANGLE's proprietary technologies can be combined to provide automated, sample-to-answer results in both centralised laboratory and point-of-use cartridge formats.
ANGLE has established formal collaborations with world-class cancer centres and major corporates such as Abbott, Philips and QIAGEN, and works closely with leading CTC translational research customers. These Key Opinion Leaders (KOLs) are working to identify applications with medical utility (clear benefit to patients), and to secure clinical data that demonstrates that utility in patient studies. The body of evidence as to the benefits of the Parsortix system is growing rapidly from our own clinical studies in metastatic breast cancer and ovarian cancer and also from KOLs with 53 peer-reviewed publications and numerous publicly available posters, available on our website.
ANGLE has established clinical services laboratories in the UK and USA to accelerate commercialisation of the Parsortix system and act as demonstrators to support product development. The laboratories offer services to pharmaceutical and biotech customers for use of Parsortix in cancer drug trials and, once the laboratories are accredited and tests validated, will provide Laboratory Developed Tests (LDTs) for patient management.
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SOURCE: ANGLE plc