Dr Lyvianne Decourtye-Espiard, a cell biology researcher, brings expertise in price-clinical models of cancer, tumor pathology and drug testing to the research group.
Research
Our Need
Funding for research into rare medical conditions is hard to find, and even harder to sustain. Without stable, longterm funding, laboratories are unable to finish research objectives and translate them into better patient management.
How Will Fund Money Be Used
This $1.5m campaign will provide core funding for the Centre for Translational Research to conduct long term research into Hereditary Diffuse Gastric Cancer (HDGC). The first priority is to identify drugs that will prevent the development of cancer in affected families. Longer term objectives include identifying better ways to predict cancer risk in HDGC families and developing effective new treatments for advanced stomach cancer.
Research
Our Need
Funding for research into rare medical conditions is hard to find, and even harder to sustain. Without stable, longterm funding, laboratories are unable to finish research objectives and translate them into better patient management.
How Will Fund Money Be Used
This $1.5m campaign will provide core funding for the Centre for Translational Research to conduct long term research into Hereditary Diffuse Gastric Cancer (HDGC). The first priority is to identify drugs that will prevent the development of cancer in affected families. Longer term objectives include identifying better ways to predict cancer risk in HDGC families and developing effective new treatments for advanced stomach cancer.
Dr Lyvianne Decourtye-Espiard, a cell biology researcher, brings expertise in price-clinical models of cancer, tumor pathology and drug testing to the research group.
Every child with one parent who carries the CDH1 gene mutation has a 50% chance of inheriting it.
Every child with one parent who carries the CDH1 gene mutation has a 50% chance of inheriting it.
For The Kids | For The Future
BY PARRY GUILFORD
CDH1 Mutations Identified
The Centre for Translational Cancer Research (Te Aho Mātatu) at the University of Otago, Dunedin, New Zealand, has been studying inherited stomach cancer since 1995. That year, the laboratory formed a partnership with a large New Zealand Māori family with a multi-generational history of diffuse stomach cancer. Together, we identified the first mutations in the CDH1 gene in 1997. Following the publication of our findings in 1998, CDH1 mutations were rapidly identified in stomach cancer families around the world, with the first international clinical management guidelines on Hereditary Diffuse Gastric Cancer (HDGC) being published soon after. Since that time, the lab has been researching both the pathology of HDGC and also any vulnerabilities that might exist in CDH1-mutated cells.
Managing HDGC Cancer Risk
There are currently two options for managing cancer risk in HDGC families, endoscopic surveillance or a prophylactic total gastrectomy. Both options have considerable drawbacks. A gastrectomy results in lifelong health complications, many of which are manageable with care, but some can be severely debilitating. The alternative, annual surveillance, involves a flexible tube being pushed down the throat to allow the stomach lining to be observed, photographed and biopsied. The aim of surveillance (‘watchful waiting’) is to try and detect any emerging cancers at a stage when they can still be cured by surgery. Although surveillance generally allows CDH1 mutation carriers to delay surgery, most who choose this option will still eventually end up having a gastrectomy following the identification of an early stage cancer. Unfortunately, endoscopy is an imperfect surveillance tool and advancing cancers can be missed, leading to late diagnosis and very poor survival chances. Therefore people who choose surveillance over gastrectomy run a small, but real, risk of losing their lives to HDGC.
A New Alternative
Given this dilemma, our lab set out to identify drugs which could be used to prevent the development of advanced cancer in HDGC families. This approach, known as chemoprevention, involves identifying drugs which target vulnerabilities in the mutated cancer cells and can be used to stop the cancer developing. To achieve this goal, we first developed three novel preclinical models of HDGC- cell lines, organoids and transgenic mice- each with mutations in CDH1. Starting with the cell lines, we screened tens of thousands of drugs, including well known cancer drugs alongside novel, uncharacterised chemicals, in order to find drugs which were effective at stopping the growth of CDH1-mutant cells, but had little effect on normal cells. This led to the identification of 40-50 drugs.
Professor Parry Guilford, Director of the Centre for Translational Cancer Research (Te Aho Mātatu) at the University of Otago in Dunedin, New Zealand. Guilford’s team identified the first known cause of inherited stomach cancer in 1997-98. He stands in front of photos of some of the children his work benefits. The kids are his team’s motivation, he says.
Early Intervention is Key
95% of CDH1 mutation carriers have multiple areas of very early stage cancer in their stomachs. Most of these areas are too small to be seen by endoscopy or imaging (eg MRI). These early cancers are largely dormant, but a small proportion can, over the period of a year or more, grow and invade the underlying layers of the stomach. The goal of chemoprevention is to kill the early cancers before they have had a chance to become aggressive and invasive.
Chemoprevention Studies
The design of clinical trials for HDGC chemoprevention is complicated by the difficulty in seeing these very early cancers. As a result, initial testing of drugs will need to be done on CDH1 mutation carriers who have already decided to have a gastrectomy. Ideally, the patients would take the candidate drug for a short period before surgery, then the stomach would be examined microscopically after surgery to find any evidence of disease. As confidence grows about a drug’s effectiveness and the duration of this protective effect, the emphasis of the trials would shift to carriers who plan to keep their stomach.
We anticipate the development of chemoprevention for HDGC will be an iterative process, with constant refinement of the drugs and delivery mechanism in an effort to improve efficacy and convenience, while reducing adverse side effects. For example, our team is currently developing a direct-to-stomach drug delivery system. This system would dramatically reduce the risk of drug side effects, making treatment more likely to be well tolerated and enabling us to cast our net wider in the search for effective drugs. Similarly, the development of drug combinations has the potential to further improve efficacy with lower toxicity.
Chemoprevention
Development Timeline
1995
Genetic research begins
1998
Identification of first inherited
CDH1 mutations
HDGC pathology clarified
Cell line models of HDGC developed
2015
Genetic library screened
Drug libraries screened
Organoid models established
Candidate drugs validated
in organoid models
2022
Mouse models of HDGC characterised
___________________
Validate lead drug candidates
in mouse models
Determine drug stability and molecular effects in stomachs
2024
Develop tests to show drugs are effective against early stomach cancers
Clinical trial 1: treatment immediately
prior to gastrectomy
Clinical trial 2: treatment
~12 months prior to gastrectomy
2028
Clinical trial 3 in carriers on
prolonged surveillance
Repeat clinical trials with new
candidates, as required
See the “Research Milestones Demystified”
section below for further explanation.
After Chemoprevention
BY PARRY GUILFORD
Longer Term Research
Chemoprevention of stomach cancer is our most pressing goal, but there is much more work to be done:
- Women with a CDH1 mutation have a 40% lifetime risk of lobular breast cancer (LBC). Many of our current stomach cancer chemoprevention drug candidates are also strong candidates for the prevention of LBC, but considerably more effort will be needed in this area in the future, particularly clinical trials.
- Early stage cancers are difficult to detect by endoscopy. If we could develop fluorescent markers that bind to the early cancers it would take some of the guess work out of both surveillance and chemoprevention.
- The incidence of stomach cancer, and its age of onset, is highly variable between families and within families. This variability suggests that other genes may modify the risk of a CDH1 mutation (eg.genes involved in immune surveillance) or, alternatively, that environmental factors (eg. diet) are also at play. If we can understand these factors, we can better determine individual risk and begin to develop ways to reduce that risk.
- Our research on chemoprevention drugs also provides an important starting point for the development of new treatments for advanced stomach cancer (both advanced HDGC and the common sporadic type). Using our preclinical models and eventually clinical trials, we hope our research can reduce the mortality rates for all stomach cancers.
- Although the technology isn’t yet available, it is possible that one day chemoprevention/ surveillance and prophylactic surgery will be replaced by gene therapy. Although this is still many years away, we will be ready to apply it to CDH1 when the time comes.
After Chemoprevention
BY PARRY GUILFORD
Longer Term Research
Chemoprevention of stomach cancer is our most pressing goal, but there is much more work to be done:
- Women with a CDH1 mutation have a 40% lifetime risk of lobular breast cancer (LBC). Many of our current stomach cancer chemoprevention drug candidates are also strong candidates for the prevention of LBC, but considerably more effort will be needed in this area in the future, particularly clinical trials.
- Early stage cancers are difficult to detect by endoscopy. If we could develop fluorescent markers that bind to the early cancers it would take some of the guess work out of both surveillance and chemoprevention.
- The incidence of stomach cancer, and its age of onset, is highly variable between families and within families. This variability suggests that other genes may modify the risk of a CDH1 mutation (eg.genes involved in immune surveillance) or, alternatively, that environmental factors (eg. diet) are also at play. If we can understand these factors, we can better determine individual risk and begin to develop ways to reduce that risk.
- Our research on chemoprevention drugs also provides an important starting point for the development of new treatments for advanced stomach cancer (both advanced HDGC and the common sporadic type). Using our preclinical models and eventually clinical trials, we hope our research can reduce the mortality rates for all stomach cancers.
- Although the technology isn’t yet available, it is possible that one day chemoprevention/ surveillance and prophylactic surgery will be replaced by gene therapy. Although this is still many years away, we will be ready to apply it to CDH1 when the time comes.
Parry’s Promise
Learning you have the CDH1 gene mutation is difficult news to receive. Knowing you may pass the gene mutation on if you choose to have children is even more difficult for younger, newly diagnosed patients. For parents whose fears are confirmed, knowing their children inherited the gene mutation and likely face life without a stomach, can be emotionally devastating. Parry Guilford understands this and it drives the research he and his team pursue.
Research Milestones Demystified
HDGC pathology clarified
A better understanding of how HDGC cancers begin and grow.
Cell line models of HDGC developed
Human cells that resemble HDGC cancers need to be grown in the lab in order to test drugs. Cell lines grow quickly and are suitable for high throughput drug testing. We established breast and stomach cell lines with and without CDH1 mutations.
Genetic library screened
Each individual gene in the human genome was inactivated and its effect on the survival of the cell line models determined. This taught us about vulnerabilities in CDH1-mutant cells which had the potential to be targeted with drugs.
Drug libraries screened
Drug libraries are large collections of individual drugs, often grouped according to their chemical type or cellular target. We tested several different libraries in our cell line models, looking for drugs that were particularly damaging to the cells with CDH1 mutations.
Organoid models established
Cell lines are great for high throughput drug screens, but more complex models are required for deeper drug characterization. Our organoids are 3D clusters of cells that closely resemble stomach tissue. We have organoids with and without CDH1 mutations which we use to test candidate drugs identified in the drug screens.
Mouse models of HDGC characterized/validate lead drug candidates in mouse models
We have developed a mouse model of HDGC which we are using for the final testing of drugs prior to clinical trials.
Determine drug stability and molecular effects in stomachs
Our lead drug candidates were not originally developed for the treatment of early stage stomach cancer, so we need to ensure they are reaching the stomach OK and having the expected effect on their cellular targets.
Develop tests to show drugs are effective against early stomach cancers
Because we usually can’t see the early stage cancers, we need to develop an indirect way to be confident the drugs have reached sufficient concentrations in the stomach to kill these cancers.
Clinical trials
Because we can’t see all the early cancers, it will be necessary to develop a staged approach to the clinical trials to build our confidence that the drugs are working as expected. For example, out first trial will be with CDH1 carriers who have decided to have a gastrectomy but are happy to take a candidate drug prior to surgery. We will then be able to examine their stomachs to make sure the drugs have been effective.
The research conducted in Otago, has an international reach, helping families worldwide. HDGC research is all about international collaboration. Research groups from around the world regularly get together to discuss progress and plan new studies. The Otago team have been taking the lead on the development of drugs for the chemoprevention of stomach and breast cancer. However, this too is a big international effort. The Otago researchers are working closely with teams at Columbia University and the University of Pennsylvania to develop model systems for drug testing, and promising drugs will be passed on to the NIH in Bethesda for clinical trials.
Researchers and patient advocates throughout the world come together every four years to share research findings, update international clinical guidelines for care of Hereditary Diffuse Gastric Cancer families, and identify needs for future research. Wanaka, New Zealand, 2019.
© 2023 Save Our Stomachs
Disclaimer | Privacy
Site Map
The DLH Foundation supports the Charter of Save Our Stomachs with time and financial investments. The grassroots economic support we can provide here has a significant and meaningful impact on the futures of our CDH1 community. As a parent, you can imagine how difficult it is for us knowing we passed this gene on to our children, and we’re doing everything we can to save their stomachs and avoid a cancer diagnosis. We need and ask for your help to fund our initiative.
Our thanks to the DLH Foundation and Allison Gritton | Gritton Design for bringing this site to life.