WHAT IS TRANSLATIONAL CANCER RESEARCH?

“Translational cancer research bridges the gap between laboratory-based science and treatment in the clinic. We now have sufficient knowledge in the fields of cancer biology, molecular biology, and immunology to make a significant impact on the treatment and management of cancer.”
From the University of Otago, Centre for Translational Cancer Research, Dunedin NZ

HDGC RESEARCH UPDATES FROM OTAGO

HDGC Research Update: Two new papers from Otago: November, 2019

Parry Guilford, November 4, 2019

“Bougen-Zhukov et al presents data that shows that CDH1 mutant cells are more sensitive to a class of drugs called allosteric AKT inhibitors. We showed this both in cell lines and in our new stomach organoids. The stomach organoids are a big step up in complexity, and also in how closely they resemble HDGC. We are therefore really pleased to have them established in the lab now. Allosteric AKT inhibitors are highly specific drugs that target a protein called AKT. Some of these inhibitors are FDA approved. We can therefore progress this class of drugs towards human clinical trials without first having to demonstrate drug safety.

We are now setting up a drug testing pipeline for about another 25 drugs which have shown promise in cell line experiments and will now be tested in the stomach organoids, followed by further triage in a mouse model of HDGC we have developed. Each of these 25 drugs is either FDA approved or at least has been through phase 1 safeety testing. The goal is to whittle down the list to 3-4 drugs to take to a chemoprevention study in CDH1 mutation carriers within the next 2-5 years.

Beetham et al is largely the work of a recent PhD student in the lab, Henry Beetham. Henry screened over 100,000 compounds to find novel chemicals that killed CDH1 mutant cells. About 80 compounds were identified, with these compounds falling into 12 similar groups. Our lab is now trying to identify the targets of these chemicals. We expect the targets will align with those we are already working on (eg AKT), but there may be new ones we haven’t yet identified. They may also give us new, more effective chemical leads to inhibit our targets of interest. Because none of these compounds have been tested in humans, they are further down our drug development pipeline, but they are likely to be of great value one day as we gradually improve the HDGC chemoprevention compounds.”

Allosteric AKT inhibitors target synthetic lethal vulnerabilities in E-cadnerin-deficient cells (2019)
Nicola Bougen-Zhukov, Yasmin Nouri, Tanis Godwin, Megan Taylor, Christopher Hakkaart, Andrew Single, Tom Brew, Elizabeth Permina, Augustine Chen, Michael A. Black and Parry Guilford

A high-throughput screen to identify novel synthetic lethal compounds for the treatment of E-cadherin-deficient cells (August 2019)
Henry Beetham, Augustine Chen, Bryony J. Telford, Andrew Single, Kate E. Jarman, Kurt Lackovic, Andreas Luxenburger & Parry Guilford

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Hot Off The Press: July 31, 2018

Parry Guilford, August 1, 2018
“The key point of the paper is that we have identified major differences between cells with and without a CDH1 mutation. We saw these differences using two distinct approaches- the analysis of cell lines and also whole stomach tumours. Many of these differences represent vulnerabilities in the E-cadherin mutant cells which have the potential to be targeted with drugs. This paper enables us to start transitioning our work towards the testing of drugs that target specific cellular characteristics.”

E-cadherin-deficient cells have synthetic lethal vulnerabilities in plasma membrane organization, dynamics and function (July 2018)
Tanis D. Godwin, S. Thomas Kelly, Tom P. Brew, Nicola M. Bougen-Zhukov, Andrew B. Single, Augustine Chen, Cassie E. Stylianou, Lawrence D. Harris, Sophie K. Currie, Bryony J. Telford, Henry G. Beetham, Gary B. Evans, Michael A. Black, Parry J. Guilford

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HDGC Research Update: June 23, 2018

Dr. Parry Guilford

We are aiming to develop or identify drugs which can be used to eliminate early cancers in the stomachs of CDH1 mutation carriers. We believe that such drugs could be used to reduce or eliminate the risk of gastric cancer in HDGC families.

We know that CDH1 mutations change how cells and tissues behave, leading in time to cancer development. However, normal human cells are in a state of delicate balance, so any mutation can also be expected to have additional consequences that weaken a cell’s capacity to survive. If we can find these vulnerabilities, we have a way to target those cells with drugs in a very specific way.

We have approached this problem for CDH1 in two ways. Firstly, working with a pair of normal cell lines that are identical except for the presence/absence of CDH1 mutations, we have used a genetic approach to identify weaknesses in the CDH1-mutant cells. What we observed was numerous weaknesses in various cellular processes, probably all stemming from a degree of disorganisation in the cell membrane in the mutant cells. This knowledge has enabled us to focus our efforts on these processes. Secondly, using the same cell line pair, we have tested thousands of different drugs to see which ones hurt the mutated cells, but have little or no effect on the normal cells. By overlapping these two approaches, we have been left with a list of candidate drugs that hit the mutant cell’s vulnerabilities. We are ever-expanding this list of candidate drugs and working on combinations that are synergistic together. By identifying synergistic combinations, it is possible to dramatically reduce the dose of drug used (and hence the risk of side-effects) without comprising the therapeutic benefit. Moreover, by understanding the vulnerable cellular processes we want to target, we are able to rationally build these combinations and continue to add in new, related alternatives.

A second line of research is on the development of new, improved models to test our drugs on. Because eventual clinical trials will be long in duration, we want to have maximum confidence in our drugs before moving to that stage. Accordingly, we have put a lot of effort into developing more complex pre-clinical models. Our strategy is to take promising drugs stepwise through these additional models. Our three new models are: (i) stomach cancer cells with and without CDH1, (ii) normal mouse organoids with and without CDH1 (organoids are small clusters of cells that resemble an organ, eg. a stomach, but can be grown in the lab); and (iii) a mouse that has CDH1 mutations in its stomach cells; some of these cells should develop into early stage cancers, mimicking the early stage T1a cancers we see in mutation carriers. We are still validating this mouse, but it is looking very promising, and we are confident it will be an excellent model.

Use this link if unable to view photo of organoid at end of page.

Together, these two pipelines give us an enduring, rational way to develop drugs for HDGC. With the current progress, we would hope to be starting our first human trials within five years.

The overall goal is to eliminate the breast cancer risk and remove the need for CDH1 mutation carriers to undergo a prophylactic total gastrectomy.

A TASTE OF PROMISING HDGC RESEARCH IN OTAGO

Targeting CDH1 deficient cells using synthetic lethal drugs

PhD candidate Henry Beetham assessing CDH1 expression in gastric cancer cells

Unraveling tumour suppression
E-cadherin belongs to a class of proteins called tumour suppressors. They provide normal cells with brakes to protect against cells growing out of control and becoming cancers. Mutation of the gene that encodes E-cadherin (CDH1) is frequently seen in tumours. This leads to tumours with increased ability to survive and invade other tissues.

Finding vulnerabilities in tumour cells

We propose that the loss of E-cadherin creates vulnerabilities in the tumour cells that could be targeted with drugs. In this project we are systematically searching for proteins which, if inactivated, will not affect cells with normal levels of E-cadherin but will lead to the death of cancerous cells lacking E-cadherin. This is known as a synthetic lethal relationship.<–more–>