We recently had the opportunity to interview Professor Andrew Beggs , a renowned expert in the field of bowel cancer research. Our discussion covered various aspects of his work, from treatment resistance in bowel cancer to the transformative impact of long-read sequencing technologies. Here are the key insights from our conversation.
What are the primary mechanisms behind treatment resistance in bowel cancer?
Prof. Beggs:
Treatment resistance in bowel cancer primarily depends on the type of cancer. There are two broad types: hypermutant bowel cancers driven by mismatch repair gene mutations or DNA polymerase mutations, and chromosomally unstable bowel cancers.
For hypermutant bowel cancers, they are very sensitive to checkpoint blockade therapies. However, when these tumors metastasize to the liver, they become much harder to treat because the liver metastases change the immune surveillance, making checkpoint blockade less effective. Moreover, these tumors or regions are not homogeneously hypermutant; and when the hypermutant parts are eradicated with immunotherapy, the non-hypermutant parts often remain and cause relapse.
Chromosomally unstable bowel cancers, which make up about 60% of cases, show variable responses to treatments. Precision medicine is required to better target therapy for these patients as some tumors are intrinsically resistant from the start, and others develop resistance over time.
For example, tumors lacking ligands for EGFR signaling, such as amphiregulin (AREG) and epiregulin (EREG), do not respond well to anti-EGFR therapies and may develop resistance during treatment. Monitoring circulating tumor DNA (ctDNA) in plasma can help detect these resistance mutations and adapt treatments accordingly.
How do you envision overcoming treatment resistance with current or emerging therapies?
Prof. Beggs:
Overcoming treatment resistance will likely involve a combination of strategies. Genomics-driven approaches are crucial, as demonstrated by the National Lung Matrix study in the UK, where ctDNA sequencing of 600-700 patients revealed resistance mutations in plasma during treatment. This approach allows us to treat cancer like a chronic disease by selecting subsequent therapies based on the evolving resistance profile.
We also use CRISPR-Cas9 screening to identify genetic targets in resistant cancer cells.
For example, in a subtype of bowel cancer known as BRAF MSS (it has a BRAF mutation and is microsatellite stable), which is aggressive and affects young people, we discovered that targeting the cell cycle could be effective. This finding has led to a phase one trial. The combination of multiomics profiling, basic science, and precision medicine will help us overcome resistance.
How has long-read sequencing transformed your research approach?
Prof. Beggs:
Long-read sequencing, such as that provided by Oxford Nanopore, has significantly enhanced our research capabilities. The technology allows for better mapping, especially in regions of the genome that are difficult to sequence with short reads due to repetitive sequences or high GC content. This has enabled us to detect complex insertions and deletions (indels) and single nucleotide variants that were previously missed.
Moreover, long-read sequencing provides native detection of methylation and hydroxy methylation, which is crucial for subclassifying tumor types and understanding the epigenetic landscape. This capability is transformative for both cancer and rare disease research.
For example, methylation profiling is now being used to subclassify brain tumors in the UK, moving away from less effective methylation arrays to long-read sequencing for rapid diagnosis.
What recent technological advancements will significantly impact your research in the next five years?
Prof. Beggs:
There are two main areas where I see significant advancements impacting our research:
Firstly, improvements in long-read sequencing technology and the integration of AI and machine learning in genomics.
Long-read sequencing technologies, particularly those from Oxford Nanopore, are becoming more accurate and affordable. The miniaturization of sequencing devices will make this technology accessible to more researchers and clinicians.
The second major advancement will come from AI and machine learning. These technologies will automate many tasks currently performed manually by clinical scientists, such as variant prioritization and annotation. AI will help predict the pathogenicity of missense mutations and integrate genetic data with clinical records, driving forward precision medicine. Companies like Geneyx are leading the way in developing these AI-driven solutions.
What are the next big steps for your research team in terms of technology and methodology to further your research and treatment development?
Prof. Beggs:
Our research team is focusing on the use of circulating free DNA (cfDNA) to advance our studies. cfDNA analysis is a non-invasive method that allows us to monitor tumor dynamics and detect resistance mutations in real-time. We are also speeding up our IT infrastructure, using platforms like Geneyx that provide rapid analysis, delivering results in as little as five minutes.
Additionally, we are exploring multiomics profiling to better understand the genetic and epigenetic changes in cancers. This integrated approach will help us develop more targeted and effective treatments.
What do you see as the biggest hurdles for biotechnology companies in bringing precision medicine to clinical practice?
Prof. Beggs:
The biggest hurdles for biotechnology companies include cost, software accreditation, and education.
Precision medicine technologies can be expensive, and making them affordable for widespread clinical use is a significant challenge. Additionally, the software used for genomic analysis must be accredited to ensure accuracy and reliability, which can be a complex and time-consuming process.
Education is also critical. Clinicians need ongoing training to stay updated with the latest advancements in precision medicine. National training programs and continuing professional development (CPD) courses are essential to equip healthcare providers with the knowledge and skills to implement these technologies effectively.
Professor Andrew Beggs’ insights highlight the transformative potential of genomic data integration in clinical practice. Advances in long-read sequencing, AI, and multi-omics profiling are paving the way for more precise and effective treatments for bowel cancer and other diseases. However, addressing challenges related to cost, software accreditation, and education will be crucial for realizing the full potential of precision medicine.
Abbreviations:
- EGFR: (Epidermal Growth Factor Receptor)
- AREG: Amphiregulin
- EREG: Epiregulin
- CtDNA: circulating tumor DNA
- BRAF: B-Rapidly Accelerated Fibrosarcoma
- MSS: Microsatellite Stable.
- GC: Guanine-Cytosine content
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