Tankyrase inhibition in cancer immune therapy

Tankyrase inhibition in cancer immune therapy Cancer therapy is undergoing rapid advances. Immune checkpoint inhibitors are considered a major breakthrough in the field and have shown a significant survival benefit for patients with melanoma and other tumors. It is predicted that within the next 10 years, the immune-oncology market could be worth USD 45 billion (374 billion NOK). Despite this progress, a substantial number of patients fail to respond to PD-1 pathway blockade or develop resistance. It is therefore expected that the next breakthroughs in the field will be based on combining checkpoint inhibitors with other reagents such as chemotherapy, drugs or therapeutic antibodies. In this project we explore the effect of combining the proprietary tankyrase inhibitor G007-LK with anti PD-1 immune modulators in isogenic preclinical proof of concept melanoma models. Treatment with G007-LK and the immunotherapeutic agent aPD-1, using a syngeneic model mouse model (B16-F10) mouse melanoma, together results in induced immune activation and reduced tumor growth. The ongoing work consists mainly of describing the mechanisms of action behind the combined treatment effect. We have also tested the effect of tankyrase inhibition against a panel of human melanoma cell lines. The samples are tested using RNA sequencing and have been analyzed using Bioinformatics. A paper describing our biological findings is currently being revised. On top we have also optimized the lead-stage tankyrase inhibitor to obtain higher target specificity, potency, and uptake/stability in animal models. The upcoming clinical candidate is named OM-0153 and an article describing its development is in progress. We are currently writing the patent for clinical candidate.

Som et resultat av prosjektarbeidet har vi kunnet påvise en synergistisk effekt av kombinasjonsbehandling med WNT/tankyrasehemmer og immunterapi (PD1-immunsjekkpunkthemmer). I en innsendt artikkel beskriver vi hvordan tankyrasehemmeren motvirket immunterapiresistens i melanoma. I tillegg har vi strukturelt videreutviklet tankyrasehemmeren til en nært opptil klinisk kandidat som vi nå ønsker å bruke i kliniske forsøk. Tilsammen utgjør disse funnene et fundament for ny behandling av ikke bare melanoma men også andre kreftformer, eksempelvis tarmkreft. I prosjektperioden inngikk vi en partnerskapsavtale med det kjemisk-medisinske selskapet Mercachem fra Nederland. Tett sammen med kommersialiseringsaktøren Inven2 arbeider Mercachem med den hensikt å tiltrekke privat kapital for opprettelse av et selskap eller inngå en lisensavtale med basis i produktet som patenteres. Interessen er stor og vi har store forhåpninger til positiv utvikling i 2019 og årene som kommer.

Cancer therapy is undergoing rapid advances. Immune checkpoint inhibitors are considered a major breakthrough in the field. Blockade of either the PD-1 receptor or its ligand PD-L1 has improved overall survival in patients with melanoma. Nevertheless, a substantial number of patients fail to respond to PD-1 pathway blockade. In this project we will explore the effect of combining proprietary pathway inhibitors with anti PD-1 immune modulators in an isogenic, immune-competent mouse melanoma model.