Pancreatic cancer tumours grow and spread by hijacking a hormone that normally helps regulate blood pressure. This matters because pancreatic cancer is notoriously difficult to treat. The best available therapies extend life by only a few months, and survival rates have not improved in decades. The problem is that the hormone adrenomedullin acts through two different receptors—one controls blood pressure, the other drives cancer growth. Existing drugs cannot tell them apart, so blocking the cancer-related receptor would also dangerously disrupt blood pressure control. The team has developed new compounds that selectively block only the adrenomedullin-2 receptor, the one involved in cancer. In model systems, this blockade reduces tumour growth and spread while leaving the blood-pressure receptor untouched. If these compounds succeed in further development and clinical trials, they could lead to a treatment that slows pancreatic cancer progression without the side effects that come from interfering with the hormone’s normal functions. That would give patients more time and better quality of life than current options allow.
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Pancreatic cancer is the 10th most common cancer, but in the next 15 years, it will become the second highest cause of cancer-related death. Unlike almost all other cancers, the prognosis has not changed in the last 30 years. After diagnosis, outcomes are very poor, with 1-year and 5-year survival rates of <25% and <5% respectively. The best current therapies offer only a few months of increased life expectancy, and patients’ quality of life is poor despite palliative treatments. There is clearly a pressing need for better treatments for pancreatic cancer. In 2015 a team from the University of Sheffield led by Professor Tim Skerry, with Peakdale Molecular and Sandexis Medicinal Chemistry was awarded Seeding Drug Discovery funding. They received just under £3M to develop selective antagonists of the adrenomedullin-2 receptor. Adrenomedullin is a hormone involved in cancer growth and spread, which also has important roles in the control of blood pressure. Adrenomedullin acts through two different receptors one of which mostly regulates blood pressure. The other has important roles in cancer biology. The team have shown that in model systems, blockade of the receptor reduces tumour growth and spread. They have developed novel lead compounds to block the adrenomedullin-2 receptor and inhibit its important roles in cancer, while keeping its normal functions.In 2017 a further award of up to £2M was made to the team of Skerry, Richards and Harrity to support further medicinal chemistry and compound development with a view to nominating by mid 2019, a candidate drug for regulatory approvals prior to clinical trials.
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