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Detecting pancreatic cancer through blood tests

Pancreatic ductal adenocarcinoma (PDAC) makes up 95% of all pancreatic cancer cases and has the lowest survival rate, and early diagnostic methods have yet to be developed. As a result, diagnosis often comes at a later stage when treatment options are limited and prognosis is poor.

Diagnosis at this stage often comes from imaging techniques followed by tissue biopsies, which are not appropriate options to use as standardised, early screening methods. New ways to diagnose PDAC at an earlier stage are needed, without the use of invasive procedures.

Liquid biopsies are becoming a more popular option to fill this demand. Taking a blood sample is minimally invasive, quick, and can tell us a lot of information about a person from their cfDNA (cell free DNA). cfDNA is released from cells and circulates in the blood, containing information about the cell they come from.

Methylation on cfDNA often appears in cancer patients, making it an effective biomarker that can be used to diagnose the presence of cancer with high accuracy and specificity about the cancer (such as location). The concept has many applications, including in the earlier diagnosis of PDAC.

The identification of these biomarkers in blood is often limited to the technology used, with DNA being damaged by the harsh chemicals that are used in the processing. The recent development of TAPS technology at the University of Oxford has helped to overcome this, using a bisulphate-free method, and making it a perfect method for PDAC biomarker identification.

DPhil students Paulina Siejka-Zielinska and Felix Jackson and Postdoctoral Researcher Jingfei Chang from Dr Chunxiao Song’s lab in collaboration with Dr Shivan Sivakumar (consultant medical oncologist) have been investigating TAPS as a method to identify PDAC biomarkers. Using blood samples from PDAC patients and healthy individuals, they are applying TAPS technology to prove that it can be used to accurately detect pancreatic cancer biomarkers in cfDNA.

Preliminary results from this study suggest that cfDNA methylation can be used for the identification of PDAC, as well as being able to accurately distinguish between pancreatic cancer and other pancreatic disorders that effect the DNA, such as pancreatitis.

If this is the case, then the results from this study will make for solid grounds for the application of TAPS in the earlier screening for pancreatic cancer.

About the Song Lab

The Song Lab combine various chemical biology and genome technologies to develop novel tools to analyse the epigenome. The lab apply these tools to two main research areas: the use of epigenetic modifications in circulating cell-free DNA from the blood for non-invasive disease diagnostics including early detection of cancer, and understanding the contribution of epigenetic heterogeneity in cancer development.

Most recently, the TAPS technology developed at the Song Lab has led to the creation of the start up Base Genomics, which has been launched to set a new gold standard in DNA methylation detection using this TAPS technology. Base Genomics will initially focus on developing a blood test for early-stage cancer and minimal residual disease. You can read more about it here.

$410 million buy out for Oxford cancer detection technology

Biotechnology company, Base Genomics, launched in June 2020 based on Oxford’s Dr Chunxiao Song’s innovative TET-assisted pyridine borane sequencing (TAPS) technology. This week, Base Genomics was bought out by Exact Sciences for $410 million.

TAPS is a new method for measuring DNA methylation, a chemical modification on cytosine bases. DNA methylation is frequently altered in cancer and these altered DNA methylation levels are preserved in the small amounts of DNA that are released into the blood from cancer cells. With its enhanced sensitivity over the standard methodology for measuring DNA methylation, TAPS has great potential as the basis for a multi-cancer blood test.

“This acquisition by Exact Sciences will enable us to accelerate the clinical and commercial development of Base Genomics and unlock a new era for early cancer detection. This is a big step forwards”

says Base Genomics co-founder and chemistry lead, Dr Yibin Liu, who co-invented the technology while a post-doc at the Ludwig Institute for Cancer Research, Oxford Branch.

Exact Sciences will continue to build on the Base Genomics team in Oxford, creating a world-leading research centre for early stage cancer detection.

“I am thrilled that the TAPS technology developed in my lab has received this level of investment. We can now proceed much more rapidly to fully leverage the power of this technology for cancer detection and patient benefit”

says Dr Chunxiao Song, Assistant Member of the Ludwig Institute for Cancer Research, Oxford Branch and Base Genomics co-founder.

Chunxiao Song’s research has received funding from the Ludwig Institute for Cancer Research, Cancer Research UK and the NIHR Oxford Biomedical Research Centre. TAPS is continuing to be developed in Chunxiao’s lab, for example it was recently adapted for long-read sequencing, to further its application to other fields of biomedical research.

The developmental origins of resistant infant leukaemia

The Roy and Milne labs are investigating the developmental origins of infant leukaemia and its influence on the biology of the disease

Understanding clonal haematopoiesis for COVID and cancer

Prof Paresh Vyas and team have been investigating how a better understanding of clonal haematopoiesis can be applied to both cancer and to care of COVID patients

Previously unknown ‘genetic vulnerability’ in breast cancer found

New Nature paper reveals discovery of a genetic vulnerability in nearly 10% of breast cancer tumours and how this can be targeted to selectively kill cancer cells.

TP53 gene determines severe blood cancer development

A new study has found that the allelic appearance of the TP53 gene has great impact on development of severe types of blood cancer

Using DNA & RNA to treat cancers

Cancer research UK Oxford Centre Development Fund Awardees Ysobel Baker and Tom Brown investigate the potential of DNA and RNA molecules as precision cancer treatments

Yang Shi joins the Oxford Cancer community

Yang Shi, who joins Ludwig from Harvard University, is a world leader in the field of epigenetics, which explores how chemical modifications to chromatin—the combination of DNA and histone proteins—control the organisation and expression of the human genome. Aberrations in those processes are vital drivers of cancer and underlie many other diseases and disorders.

“Yang has an outstanding track-record of innovative research into the identity and mechanisms of action of chromatin modifiers. We are delighted that Yang is bringing his wealth of experience, international standing and collaborative spirit to lead our cancer epigenetics theme at Ludwig Oxford.”

~ Xin Lu, Director of the Ludwig Oxford Branch.

Shi is widely known for his discoveries regarding a chemical modification, methylation, made to the histone proteins. In 2004, Shi and his colleagues identified and characterised an enzyme, LSD1, that erases methyl marks from histones. Their discovery upended a 40-year-old dogma that considered such modifications irreversible, altering longstanding models of genomic regulation. Shi’s laboratory went on to identify many other histone demethylating enzymes with roles in a diverse array of biological processes. More recently, his group discovered several enzymes that methylate RNA and possibly influence the translation of gene transcripts into proteins.

Shi is applying these fundamental discoveries to the benefit of patients. His group’s work on LSD1 led to the development of LSD1-inhibitors now in clinical trials for the treatment of cancer. More recently, Shi and his colleagues demonstrated that inhibiting LSD1 might also help make otherwise non-responsive tumours susceptible to the checkpoint blockade immunotherapy. His lab is additionally studying the role and therapeutic manipulation of epigenetic modifiers in pediatric high-grade gliomas and acute myeloid leukaemia.

“Yang’s science is of the highest calibre—as rigorous and collaborative as it is original—and we are very excited to have him in the Ludwig community. I’m sure many of our researchers will benefit from his expertise, and that they will be equally generous with their own expertise and support as he explores the implications of his discoveries for cancer biology and the design of new therapies.”

~ Chi Van Dang, Scientific Director of the Ludwig Institute.

Shi obtained his PhD from New York University, completed his postdoctoral training with Thomas Shenk of Princeton University and joined the faculty of Harvard Medical School in 1991, where he was most recently C.H. Waddington Professor of Pediatrics. Shi has received many honours for his contributions to epigenetics and is a fellow of the American Association for the Advancement of Science and a member of the American Academy of Arts and Sciences.

Find out more about Yang’s research.

New start-up Base Genomics launches

 

About the technology

TET-assisted pyridine borane sequencing (TAPS) is a new method for measuring DNA methylation, a chemical modification on cytosine bases. DNA methylation has important regulatory roles in the cell but is frequently altered in cancer. These altered DNA methylation levels are preserved in DNA that is released into the blood from cancer cells and therefore DNA methylation has great potential as the basis for a multi-cancer blood test. However, a key limitation to achieving this aim, especially for detecting cancer at the earliest stages, is the low sensitivity of current DNA methylation technology.

One of the advantages of TAPS over the current standard methodology is the avoidance of the use of bisulphite, a harsh chemical that severely degrades DNA. TAPS is a mild reaction that preserves DNA integrity and is effective at very low DNA concentrations, which would increase the sensitivity of blood-based DNA methylation assays. TAPS also better retains sequence complexity, enabling simultaneous collection of DNA methylation and genetic data, and cutting sequencing costs in half. Read more about the potential of TAPS as the basis for a multi-cancer blood test here.

The company Base Genomics has been launched to set a new gold standard in DNA methylation detection using this TAPS technology.

 

“I am thrilled about the launch of Base Genomics and look forward to seeing the TAPS technology developed in my lab applied to new technologies for cancer detection and the advancement of a variety of fields of biomedical research,”

Dr Chunxiao Song, assistant member of the Ludwig Institute Oxford Branch, co-founder of Base Genomics, chemistry advisor to the company.

 

 “Genomic technologies with the power, simplicity and broad applicability of TAPS come along very infrequently,

“It has the potential to have an impact on epigenetics similar to that which Illumina’s SBS chemistry had on Next Generation Sequencing.”

Base Genomics CTO Dr Vincent Smith.

 

About Base Genomics

Base Genomics has a team of leading scientists and clinicians, including Dr Vincent Smith, a world-leader in genomic product development and former Illumina VP; Professor Anna Schuh, Head of Molecular Diagnostics at the University of Oxford and Principal Investigator on over 30 clinical trials; Drs Chunxiao Song and Yibin Liu, co-inventors of TAPS at the Ludwig Institute for Cancer Research, Oxford; and Oliver Waterhouse, previously an Entrepreneur in Residence at Oxford Sciences Innovation and founding team member at Zinc VC.

The company has closed an oversubscribed seed funding round of $11 million USD (£9 million GBP), led by Oxford Sciences Innovation alongside investors with industry expertise in genomics and oncology. This funding will progress development of the TAPS technology, initially focusing on developing a blood test for early-stage cancer and minimal residual disease.

 

”The ability to sequence a large amount of high-quality epigenetic information from a simple blood test could unlock a new era of preventative medicine,

“In the future, individuals will not just be sequenced once to determine their largely static genetic code, but will be sequenced repeatedly over time to track dynamic epigenetic changes caused by age, lifestyle, and disease.”

Base Genomics founder and CEO Oliver Waterhouse.

 

“In order to realise the potential of liquid biopsies for clinically meaningful diagnosis and monitoring, sensitive detection and precise quantification of circulating tumour DNA is paramount,

“Current approaches are not fit for purpose to achieve this, but Base Genomics has developed a game-changing technology which has the potential to make the sensitivity of liquid biopsies a problem of the past.”

Base Genomics CMO Professor Anna Schuh

 

For more information, see the Base Genomics press release.

 

Novel sequencing techniques reveal microRNA influence on prostate cancer development

Researchers from the Nuffield Department of Surgical Sciences, Nuffield Department of Medicine and Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, have been investigating microRNA sequences and their influence on the migration and wider metastasis of prostate cancer cells around the body.

Prostate cancer is the second most fatal cancer in males, due in part to its slow growth and difficulties in early diagnosis before it spreads. Once spread, standard treatments are less effective and the disease is often incurable. Understanding mechanisms that modulate and cause the process of cancer metastasis is important in order for us to better understand how to detect, prevent and treat it.

Led by Claire Edwards, postdoctoral researcher Srinivasa Rao Rao devised a  series of transcriptomic and functional screening strategies. This novel combination of migrational and morphological analysis allowed the team to focus on the wider biological relevance of microRNA in the development of prostate cancer.

After studying the entire microRNA genome, the team focused on overexpressing microRNAs belonging to specific families, specifically, those known as miR-372 and miR-302 clusters, which emerged as interesting candidates in the regulation of prostate cancer. 16% of microRNAs screened in this novel method, were found to decrease the rate of cell migration when dysregulated. Similarly, 19% of microRNAs were found to alter the morphology and shape of cancer cells.

This publication demonstrates an application using a series of integrated screening approaches to enhance the specificity and accuracy of screens. By using a variety of screening strategies in succession, the team were able to narrow down the microRNA candidates to those more likely to be directly involved in prostate cancer progression. There are additional applications of this work through the use of these relatively stable microRNAs as diagnostics markers for the earlier detection and diagnosis of prostate cancer.

Claire Edwards, Associate Professor at the Nuffield Department of Surgical Sciences, says;

“Through our collaboration with Daniel Ebner, we have been able to develop a screen to rapidly discover those microRNAs that could reduce migration and so deduce which of them may play a role in prostate cancer metastasis.”

To read the publication in full, see here.

This research is a result of a collaboration between senior researchers Claire Edwards, Daniel Ebner and Freddie Hamdy.

Claire Edwards is an Associate Professor of Bone Oncology. Her main focuses are on obesity and adipokines in cancer-induced bone disease, metabolism and miRNA in prostate cancer bone metastases and bone marrow stromal cells in the pathogenesis of cancer-induced bone disease.

Daniel Ebner is a Principle investigator at the Nuffield Department of Medicine. He worked with the Target Discovery Institute to develop new target screening methodologies, investigate disease pathways as a means for identifying ‘drug targets’ and advance therapeutically relevant targets for drug development.

Freddie Hamdy is a Nuffield Professor of Surgery with a research focus on management of urological malignancies, in particular prostate and bladder cancer He is the Chief Investigator of many studies including the ProtecT (Prostate testing for cancer and Treatment) study of case-finding and randomised controlled trial of treatment effectiveness in prostate cancer – the largest of its kind worldwide.

This work was supported by the FP7 Marie Curie Initial Training Network PRO-NEST, Cancer Research UK, through the Cancer Research UK Oxford Centre Development Fund and through the University of Oxford Medical Research Fund.