DL: Pipeline for individually tailoring new treatments in hematological cancers (PINpOINT)

The blood cancers that were examined in the project (mainly AML, CLL and multiple myeloma) have many treatment options but frequently the treatment does not offer a cure. The primary objective of the PINpOINT-project was to develop and validate methods to test effects of libraries of available cancer drugs on primary patient samples ex vivo. We also examined the effect of combining drugs using these methods. We used these data to describe synergy of drugs and model the data to be able to predict optimal drug combinations with good treatment effect, and validated some of these drugs and drug combinations in animal models. Furthermore, using these data, in addition to other types of heterogenous data (such as sequencing data and flow cytometry data), we designed a diagnostic pipeline where the output of results can be used to support clinical treatment decisions. This project has resulted in several publications (as well as multiple manuscripts that are still in preparation or that are in various stages of the publication process) where (i) large datasets have been made publicly accessible for reuse by other researchers; (ii) comprehensive bioinformatics pipelines were described for designing and executing large-scale drug screens; (iii) novel statistical tools have been presented to model, predict and analyze drug response data. Finally, several manuscripts have been published that describe new strategies for more accurate stratification of patients into risk groups, and that report early-response biomarkers that predict treatment outcome with high statistical significance. The methods developed are now being used as clincial decision support to stratify patients into clinical trials.

Følgende effekter kan listes: 1. For forskningsfeltet: -Det er utviklet nye og forbedrede metoder for å undersøke sensitivitet for kreftlegemidler i pasientprøver fra pasienter med blodkreft (funksjonell presisjonsmedisin) og til å forutsi behandlingsrespons, spesielt for kombinasjoner av medikamenter. - Vi har levert standardiserte, detaljerte protokoller for funksjonell presisjonsmedisin for blodkreft som vil hjelpe feltet med å harmonisere metoder og gjøre data mer sammenlignbare mellom ulike sentre. – Vi har utviklet Phenopop, en metode for å kartlegge utvikling av undergrupper av kreftceller som er sensitive eller motstandsdyktibe mot ulike medikamenter. 2. Av potensiell relevans i klinikken: - Utvikling av nye beslutningsverktøy som kan brukes i klinikken i fremtiden for å bestemme behandling for pasienter med akutt myelogen leukemi og kronisk lymfatisk leukemi. Disse metodene er bredt anvendelige på andre hematologiske sykdommer for å bestemme behandling og forutsi behandlingsresultater og brukes nå i kliniske studier. 3. Utvikling av kompetanse: - Flere doktorgradsstudenter, enten ansatt på prosjektet eller tilgrensende prosjekter har hatt nytte av miljøet rundt PINpOINT prosjektet. En rekke postdoktorer har bygd kompetanse og og vi har utviklet kunnskap om hvordan man kan bruke screening for legemiddelsensitivitet i funksjonelle presisjonsmedisinske tilnærminger.

Hematological cancers are well suited to leverage the power of digital analysis to tailor drug therapy. Here, we will implement cancer drug sensitivity screening (CDSS) using a large panel of FDA approved and developmental drugs. Guided by predictive statistical models we aim to identify tailored treatments for individual patients in hematological cancer. Our pipeline involves database integration and network modeling of cancer cell signaling, ultimately supporting clinical decisions on individualized treatments. This unique pipeline incorporates modeling the patient's own tumor cells with top drug candidates in in-vitro and ex-vivo systems, in addition to in-vivo systems (patient derived mouse and zebrafish xenografts). The knowledge gained from this integration of computational analysis and cancer drug discovery will be channeled into an iterative learning cycle of systems medicine, to deliver new modalities to combat hematological cancer in individual patients. The successful implementation of this project will capitalize on the recent advances in cancer-precision medicine by translating the massive silos of -omics data currently being generated into actionable therapy in the clinic. It will bring together a network of multi-disciplinary groups of clinicians, molecular cell biologists, chemists, bioinformaticians, statisticians and systems-biologists at the national level. In addition it will network into the National Centre for Digital Life through our collaborations, prominent systems biology groups at FIMM, and Universites of Cambridge, Copenhagen, Heidelberg and Minnesota. The proposed project provides an ideal platform for innovation and commercialization that fits the call for proposals. It incorporates alliances with Big Pharma companies, harnessing the potential of this pipeline in their discovery programs and a Norwegian bioinformatics SME will have the opportunity to collaborate and analyze key proof-of-concept data for their software solutions.