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

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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.