Developing bowel cancer immunotherapies that target DNA repair
Cancer types:
Bowel cancer
Project period:
–
Research institute:
University of Zurich
Award amount:
£181,252
Location:
Switzerland
Professor Alessandro Sartori aims to better explain the genetic changes underlying a condition called Lynch syndrome, which makes patients more likely to develop bowel cancer. They hope to find tools that can take advantage of this to improve immunotherapy treatment for cancer.
Hope for the future
Inherited conditions that increase a person’s risk of developing cancer account for around 10% of all cases of cancer. These cases are caused by changes, or mutations, to a person’s genes that make it more likely that a tumour will develop. Better understanding of the genes involved in these inherited conditions can lead to new ways to prevent, diagnose, or treat cancer.
Lynch syndrome is the most common cause of hereditary bowel cancer, and people with Lynch syndrome are more likely to get bowel cancer as well as certain other cancers including stomach cancer and liver cancer. Immunotherapy can sometimes treat bowel cancers caused by Lynch syndrome, but it does not work on everyone, and cancers can sometimes become resistant to this treatment.
Professor Alessandro Sartori wants to discover more about the genes involved in Lynch syndrome to identify ways to help immunotherapy work better. Moreover, he aims to go further and develop tools to use cancer immunotherapy in different types of tumours.
Meet the scientists
Ever since his undergraduate studies, Professor Sartori has been fascinated with DNA repair mechanisms and how to harness the basic biology of selective DNA repair pathways for new anti-cancer strategies. In his free time, he is a passionate swimmer, enjoys having a nice dinner with family and friends and watching all kinds of sports – especially the ZSC Lions, an ice hockey team from Zurich.
Keri Fishwick is the PhD student working on this project. Having undertaken a placement year with a focus on rare diseases, Keri was keen to further her career in research with an interest in understanding the molecular mechanisms of diseases, including cancer. Outside of the lab Keri enjoys sports, including swimming in Lake Zurich and hiking in the Swiss Alps.
The science
Lynch syndrome is caused by mutations, including a specific mutation to a gene called MLH1. This gene normally helps fix mistakes made when DNA is copied. Interestingly, we experience damage to DNA thousands of times a day, but this damage is usually repaired without issue.
In the case of Lynch syndrome, mutations in the MLH1 gene mean that this repair process does not work, and DNA can become more and more damaged. This damage makes it more likely that cancer will develop and that treatments will be unable to cure the cancer.
The protein made by MLH1 has been shown to influence cancer development through its control of two enzymes, called EXO1 and FAN1. When the MLH1 gene is mutated in cancer cells, the uncontrolled activity of EXO1 and FAN1 makes the genome (the entire set of DNA in a cell) unstable.
Professor Alessandro Sartori and his team will study how MLH1 interacts with these other proteins and discover how these proteins help cancers grow. The researchers then plan to develop molecules that block these interactions, stopping cancer in its tracks and making tumours more responsive to immunotherapy.
The funding from Worldwide Cancer Research gives us the opportunity to pursue a novel and innovative idea that builds upon a well-established correlation between DNA mismatch repair deficiency and cancer immunotherapy benefits.
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