OrgTIP: A transplantable organoid-to-in vivo pipeline for targeting phospholipid metabolism to stop colorectal carcinoma

Bowel carcinoma is the 4th most common cancer in the UK, accounting for 1 out of 10 deaths from any type of cancer. While 6 out of 10 patients will respond well to current therapies, which can include surgery, radiotherapy and chemotherapy depending on the patient, 4 out of 10 patients will not respond to treatment. These non-responding patients have a very poor outlook and no current effective therapies. We therefore need to develop new therapies to treat these patients. One of the ways to do this is to: 1) look in bowel cancer cells that have the same gene signature as these poor outlook patients, 2) identify which genes are changed commonly, and 3) work out whether using drugs to turn the products of these genes on or off can stop the tumour from growing or spreading.

One family of genes that are commonly altered in many cancers, and particularly in bowel cancer, are called Phosphoinositide-modifying enzymes, which can be more easily referred to as PIP-MEs. PIP-MEs are like factory workers in an assembly chain: they each act in a sequence to modify one key part of something being built. The 'something' is a set of molecules that is essential for whether a cell lives, dies, or behaves in a certain way; the item being 'built' is a set of lipid molecules called phosphoinositides (PIPs). In bowel cancer, the PIP-MEs become uncontrolled such that they no longer work, or work when they shouldn't. The end result is that bowel cells have a PIP-ME factory that is either making too much of a particular PIP or making a PIP when it shouldn't. Targeting this PIP-ME factory may be a new way to treat bowel cancer. One major stumbling block is that this PIP-ME factory is also important for normal cells. A key question to understand is how do we treat only bowel cancer cells with drugs that target PIP-MEs and not damage healthy cells?

I aim to tackle this in this proposal. My previous research has focused on 2 complementary areas which form the basis of being able to address this question. First, I have developed new ways to map what products (which PIPs) are being mis-produced when PIP-MEs become disrupted in cancer. Second, I have developed computer-assisted ways to identify the consequence for cells of altering PIP-MEs, growing and analysing hundreds-to-thousands of 'mini-bowel' tissues in a dish in the lab. I have identified that the balance between two particular steps in the PIP-ME factory is essential to determine whether such mini-tissues undergo normal or tumour-like behaviour (e.g. grow too much or spread to where they shouldn't).

How certain PIPs are made may depend on whether the cells are normal or cancerous. Tumours may depend on ways of making certain PIPs that normal cells do not need as much of. Therefore, I propose that certain PIP-MEs can be targeted to stop tumour growth, and this will preferentially affect tumour cells (rather than normal cells).

I aim to develop the skills in this proposal to extend our studies from mini-tissues in the lab by transplanting mini-tissues back into the bowel of mice and testing whether our approaches in the dish in a lab hold true inside a living organism. This will move us a step closer towards understanding how we drug PIP-MEs in bowel cancer patients. In addition, I will work with a biotechnology industry company partner to find ways to move our approaches beyond my research lab, to provide our tools for the entire research community to develop new ways to combat cancer. My long-term goal is to identify improved ways to tackle bowel cancer by inhibiting PIP-MEs, and to provide the tools to enable other researchers to find treatments for bowel and other cancers.

Colorectal cancer is the 4th commonest cancer in the UK, and the second leading cause of cancer-related deaths (10% of all cancer-related deaths, Cancer Research UK Statistics). Put in context, a colorectal cancer-related death happens in the UK every 30 minutes (16,000/year). Colorectal cancer has become a global health issue, with over 1.8 million new cases worldwide in 2018 (American Institute for Cancer Research Statistics). Identifying new therapies for poor-prognosis colorectal cancer patients that lack effective treatments is aimed at alleviating this global burden. This project aims to understand how the metabolism of phosphoinositide lipids is altered during progression of colorectal cancer, and how they could be targeted to stop or prevent colorectal cancer. This proposal thus has strong implications for healthcare, individuals, the private sector, and the UK and global economy.

Commercial private sector beneficiaries
In the short term, direct and immediate knowledge exchange with my project partner (Essen BioScience) will occur in relation to the novel image analysis methodologies I developed, influencing this partner's commercial products in the same realm. In the longer-term, this may lead to licencing of these technologies for future commercial benefit. Secondarily, and in the longer term, one goal of this research is to understand how phosphoinositide metabolism can be targeted to stop tumour progression. Identification of such target(s) may be of substantial economic and healthcare value. Such developments would also strongly benefit the UK economy through development of new commercially available treatments.

Public healthcare services
The global health challenge of colorectal cancer is a patient-care and economic burden similarly in the UK. In the long term, research into the fundamental regulation of cancer progression may bring treatments that substantially alleviate this major cause of cancer-related death in the UK. Effective treatments that even partially blunt this health burden would have profound global impacts on health and lifespan. That this proposed work is aimed at finding new targets to treat patients, this work may indirectly decrease long-term costs to the healthcare system. This will therefore increase the effectiveness of a key UK public services, the NHS.

The wider public and policy makers
A cornerstone of this work is to engage the general public and policy makers about the importance of both my research programme and the value of medical research in general. This will occur in the short term locally in Glasgow by participation in public events designed to engage public interest in and understanding of medical research. This will occur on a wider public stage by disseminating our findings, and putting these in a lay context by writing Op-Ed pieces about our work.

UK & Global Economy
The long-term goal of this work is to help to identify new therapies to stop colorectal cancer. The development of such a therapy would be an economic driver for the commercial entity taking this to patient use. In addition, the development of treatments to stop the second leading cause of death would also likely increase lifespan, and strongly increase economic productivity worldwide.

Policy makers, government regulators, and third sector organisations
The biomedical insights gained from this fellowship may help to influence how existing clinical compounds are used in clinical trials, or in the designation of new clinical trial approaches, or healthcare policy. The technical approaches for how to identify new therapeutic targets to stop metastasis may impact charities that fund medical research (e.g. Wellcome Trust, Cancer Research UK) by supporting further research into this area, such as investing in new skills development to allow researchers to adopt our methodology.