A drug that blocks the enzyme lysyl oxidase (LOX) is being developed for a first-in-human clinical trial in patients with advanced pancreatic cancer. This matters because pancreatic ductal adenocarcinoma (PDAC) is a disease with no effective cure. The enzyme LOX helps tumours grow and spread by stiffening the surrounding tissue and preparing distant sites for metastasis. High LOX levels in patients correlate with worse survival, yet no drug that targets this enzyme has ever reached clinical trials. If this research succeeds, the team will have produced the first orally bioavailable LOX inhibitor to enter a Phase I dose-escalation study. A safe, well-tolerated drug could eventually become part of a treatment regimen for pancreatic cancer, and potentially for colorectal cancer as well, where LOX also plays a role. The project also includes late-stage lead optimisation, GLP toxicity testing in two species, and GMP manufacturing—steps that move a fundamental discovery about tumour biology directly toward a tangible clinical option for patients who currently have none.
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The enzyme lysyl oxidase (LOX) regulates cross-linking of structural proteins in the extracellular matrix. LOX also plays an essential role in stimulating the growth of tumours and in the metastatic spread of cancer through the body. Its expression is increased in hypoxic cancers and is correlated with tumour metastasis and decreased patient survival. Tumour-secreted LOX plays a critical role in the growth of pancreatic ductal adenocarcinoma (PDAC) and other cancers such as colorectal cancer. There is also evidence that LOX conditions and maintains a pre-metastatic niche at future sites of metastatic spread, in a range of tumour types. With Wellcome Trust and Cancer Research UK funding, we have developed 2 series of LOX inhibitors that are currently in lead optimisation. We have demonstrated in vivo efficacy with inhibitors from both series, in PDAC allografts and colon tumour xenograft models. We aim to develop our LOX inhibitors for the treatment of advanced pancreatic cancer, a disease for which there is no effective cure. There are currently no clinical trials nor approved LOX inhibitors. We will develop first-in-class orally bioavailable, small molecule drugs that inhibit LOX activity for the treatment of pancreatic cancers in the first instance. These inhibitors are likely to be useful in other indications such as colorectal carcinoma. We propose to conduct a Phase I clinical trial with one of our inhibitors. The project involves late stage lead optimisation of our LOX inhibitors leading to the nomination of lead and backup preclinical candidates. The preclinical development programme will include: (1) non-good laboratory practice (non-GLP) toxicity studies by a CRO on two inhibitors in one rodent and one non rodent species; (2) good laboratory practice (GLP) toxicity studies by a CRO of one inhibitor selected from previous two (see (1) above). Key activities in the preclinical stage will also involve non-good manufacturing practice (non-GMP) manufacture of the lead and backup, GMP manufacture of lead compound and formulation development. The safety and maximum tolerated dose (MTD) of the candidate drug will then be assessed in a Phase I dose escalation clinical study.
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