Targeting Cancer Stem Cells with Axl inhibitors to Treat Advanced Metastatic Cancer

I den vestlige verden dør 1 av 3 personer av kreft, og 90% av disse dødsfallene skyldes sekundære eller metastaserende kreftsvulster. Behandling med kjemoterapi eller strålebehandling bekjemper ofte den primære kreftsvulsten effektivt, men samtidig utvikles gjerne metastaserende tumorer som er motstandsdyktige mot cellegift. Det er derfor et betydelig udekket medisinsk behov for å finne nye behandlingsmåter som hindrer spredning av kreft og legemiddelresistens. I dette prosjektet fokuserer BerGenBio på EMT, en grunnleggende biologisk mekanisme som driver metastaser og dannelsen av sekundære svulster. Målet med dette prosjektet har vært å utvikle nye eksperimentelle modeller for å studere metastaserende tumorer. Vi har utvikle tester for å kunne bestemme forekomsten av EMT i pasienter. Vi har også testet virkningen av BerGenBio sin ledende legemiddelkandidat BGB324, og effekten den har har på EMT alene, og i kombinasjon med etablerte kreftmedisiner. Resultater fra disse modellene har vært av avgjørende betydning for å designe den kliniske uttestingen av BGB324.

Cancer is the leading cause of death in people under the age of 65. While the detection and treatment of primary cancer has improved significantly, most fatality is caused by metastasis, and effective prognostic and therapeutic options for such disseminat ed disease remain scarce. Hence, understanding how metastatic tumor cells resist current treatments is a major health issue and a focus of drug development efforts. Likewise assessing the likely response of individual patients to available treatments is v aluable. This proposal directly addresses these needs through new knowledge discovered by BerGenBio. The project focuses on EMT, a cellular program that causes a small minority of cancer cells to acquire critical malignant traits: invasiveness, survival, chemotherapeutic resistance, and metastasis. BerGenBio have defined a powerful new approach to cancer therapy - inhibition of tumor cell EMT - to reverse drug resistance and increase the effectiveness of established cancer treatments. Using proprietary te chnologies we have identified the receptor tyrosine kinase Axl as a gatekeeper for tumor EMT. We have demonstrated that more than 40% of primary breast cancers in Norwegian patients express Axl and this expression predicts poor survival; and that Axl sign aling is required for self-renewal, invasiveness and resistance to frontline breast cancer treatments. BerGenBio has developed an original clinical hypothesis based on the insight that Axl-modulating drugs are potential treatments for advanced drug-resis tant metastatic cancers. We seek funding to develop EMT-inhibition as a novel approach to cancer treatment. Specifically: development of new experimental models for drug-resistant cancer; biomarker development for EMT profiling in disease and treatment se ttings; preclinical research to support our novel clinical hypothesis. This will be studied with our first-in-class Axl inhibitor drug candidates alone and in combination with standard cancer drugs.