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

Det overordnede målet er å utvikle ny og målrettet terapi mot glykolytiske kreftformer som kan benyttes i persontilpasset behandling. Målet med dette Eurostars-prosjektet var å videreføre vårt kjemiske stoff til en legemiddelkandidat som inkluderer et verktøy for pasientvalg, og å oppnå farmakologisk "proof-of-concept (POC)" i dyr. Arctic Pharma har jobbet mot utvikling av en legemiddelkandidat for så å kunne lisensiere den til et stort farmasøytisk selskap etter fullført klinisk fase IIa. Xentech hadde som mål å utføre forskningsstudier med pasient-avledede xenografter, og patentere og lisensiere en diagnostisk prediktiv effekt av legemiddelkandidaten til Arctic Pharma. Gjennom prosjektet har vi fortsatt arbeidet med modifikasjoner av de mest potente kjemiske stoffene og testing i PDX cellelinjer. Over 120 nye kjemiske stoffer ble designet, syntetisert og testet. Utviklingen av PDX-modeller fra biopsier ble started som forberedelse til farmakokinetikk / farmakodynamikk (PK / PD) og preklinisk evaluering av legemiddelkandidat (prioritert kjemisk stoff) i PDX-modeller. Dessverre møtte ingen av de +120 stoffene kriteriene for videre utvikling. Gjennom prosjektet har vi lært at metabolismen i glykolytiske kreftformer er mer kompleks enn det vi hadde forestilt oss. For å kunne utvikle en målrettet terapi, har vi lært at vi må bedre forstå mekanismene for hvordan glykolytiske kreftceller tar opp energi.

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.