E!113882 GLYCex: A novel therapeutic strategy to fight glycolytic cancers

The overall aim is to develop a new targeted therapy against glycolytic cancers for personalized medicine. The goal of this Eurostars project was to advance our lead compound into a drug candidate to be used in stratified patient groups carrying glycolytic cancers, and to achieve pharmacological proof-of-concept (POC) in animals. Arctic Pharma aimed to develop a drug candidate and license it to a large pharmaceutical company after completion of clinical phase IIa. Xentech was to perform research studies with developed patient-derived xenografts, and patent and out-license the development of a companion diagnostic predictive of the efficacy of Artic Pharma's drug. During the project we continued the modifications of the most potent compounds and testing of those in PDX cell lines. Over 120 new compounds were designed, synthesised and tested. The development of PDX models from biopsies was started for preparation for the pharmacokinetics/ pharmacodynamics (PK/PD) and preclinical evaluation of drug candidate (prioritized lead) in PDX models. Unfortunately, none of the +120 compounds met the criteria for continued development. During the porject we learnt that the metabolism of glycolytic cancers is more complex than we first had envisioned. To be able to develop a targeted therapy, we have learn that we need to better understand the mechanisms of how glycolytic cells generate energy.

During the project we learnt that it was more challenging than anticipated to identify molecular tumour signatures or biomarkers that would predict response to potential therapy for glycolytic cancers. We learnt that the metabolism of cancer cells seem to have a high level of plasticity. It appears that energy for glycolytic cancers is not only generated through glycolysis but will switch to oxidative phosphorylation. As we also still need a more potent compound than the original lead compound, we were still not able to obtain results that allowed comparison of molecular signatures across different tumour types. For the continuation of the project we need a more potent compound and a clear molecular signature for the development of a diagnostic tool for patient selection.

The overall aim of the consortium is to develop a new targeted therapy against glycolytic cancers, including a tool for patient selection. The goal of this Eurostars project is to advance our lead compound into a drug candidate included a tool for patient selection, and to achieve pharmacological proof-of-concept (POC) in animals. Arctic Pharma will develop a drug candidate and license it to a large pharmaceutical company after completion of clinical phase IIa. A license agreement yielding initial upfront payments followed by milestone payments and royalties from global sales revenue is envisioned. XenTech we will perform contract research studies with developed patient-derived xenografts, and we will patent and out-license the development of a companion diagnostic predictive of the efficacy of Artic Pharma’s drug. Cancer remains a major threat to life, with estimated 18.1 million new cases and 9.6 million deaths in 2018. Current systemic therapies for glycolytic cancers are limited and have severe side effects, emphasizing the substantial unmet need. Treatments based on molecular tumour characteristics, i.e. precision medicine, might provide a remedy. Adopting this concept will provide an effective targeted therapy with few side effects paired with a diagnostic tool for patient selection.