Public Funding for Phoremost Limited

A new approach to cancer therapy called 'immuno-therapy' has recently emerged that is now providing unheralded responses in certain cancer types. It is based on the concept that as tumours arise through sequential mutations in their genomes, this also creates 'foreign' antigens that can be recognised and attacked by the immune system. However, tumours also find ways to hide from immune-surveillance and a key advance has been to define, and now reverse, these mechanisms using immuno-therapies. While this is a significant step forward, unfortunately, only a few tumour types, such as melanoma and lung cancer, which possess hyper-mutated genomes (due to high levels of UV or cigarette smoke, respectively) are inherently sensitive to novel drugs that augment immune recognition. Removing the 'cloak of invisibility' is therefore not enough alone in most cancers to be effective. However, if one can find a way to accelerate or boost mutation levels in these non-sensitive cancer types, for example using a second drug that targets a DNA repair mechanism, all cancers could become hyper-responsive to immuno-therapy. To this end, we are developing small-molecule drugs that block a well validated, yet safe to inhibit, DNA repair mechanism. Genetic knock-out studies have shown that inhibiting this specific repair mechanism makes a wide range of cancer types sensitive to immuno-therapies. In this project, we will be optimising these drugs and performing key in vivo tumour response studies to facilitate their rapid progression into further clinical development with a Pharma company.

The pharmaceutical industry makes medicines designed to reverse the things that go wrong in cells and cause disease. The list of the targets that go wrong is far from complete, and we do not have the screening tools to find and then develop drugs to these targets. To cope with an increasing healthcare need, we therefore need to expand that list and to make new tools so that we can produce new medicines, more rapidly. At present, our existing screening tools can find new targets to put on the list, but they cannot tell us how to go about repairing them. PhoreMost has tried to solve this problem by directly finding new things to add to the list, at the same time as writing the instruction manual for how to mend them. Our current screening system works, but we want to make it even better, so we have deisgned a new and improved system. This new system is based on turning inhibitory or negative effects on cells into positive effects which are easier for us to identify, because only the disease cells which contain an interesting target can grow. This will make our screening process much quicker, cheaper and more efficient than it was before, allowing us tackle more diseases more quickly. In the first instance, we will use our new screening system to find new targets for cancer.

Cancer is a genetic disease caused by mutations in key genes that regulate cell-growth and survival. In recent years, new ‘targeted’ therapies that aim to functionally reverse the root genetic causes of cancer have shown success in many cancer types. However Pancreatic tumours, a particularly lethal form of cancer, has not benefited from such advances; primarily due to the difficulty in ‘drugging’ its predominant driver-gene called ‘KRAS’. PhoreMost has developed a strategy that allows us to bypass this direct drugging problem by developing first-in-class inhibitors that bind to a novel site in a separate but well established cancer clinical target (PLK1), which display a previously unappreciated combined 'synthetic lethality' with mutant KRAS. In this grant we be optimising the potency and selectivity of these compounds and then testing them for their efficacy in vivo, which if successful we will partner with a pharmaceutical company for further testing in clinical trials.