Precision medicine of colorectal cancer
Objectives: (i) develop a platform for tumor organoid culturing and ex vivo drug sensitivity testing to model cancer treatment in a personalized manner; and (ii) identify new treatment options as well as biomarkers and mechanisms of treatment response and resistance by integrated pharmacogenomics analyses.
Background: Almost 900,000 patients die from colorectal cancer every year, and the main cause of death is metastasis to the liver. Overall survival among patients with metastatic colorectal cancer has increased to almost 3 years with currently available therapies. Recent advances hold promise to further improve treatment efficacy by biologically-based patient stratification, but the number of available drugs is low compared to other major cancer types. Each “actionable” molecular marker is found in only 1-5% of the cancers, and the overall clinical benefit is modest (with the notable exception of long-lasting responses to immune checkpoint inhibitors in MSI cancers) (Sveen, Kopetz and Lothe, Nat Rev Clin Oncol 2020). Drug sensitivity testing offers a complimentary approach to personalized treatment.
Immune check point inhibition in microsatellite unstable CRC: we discovered that the microsatellite instability hypermutation phenotype is present in a subgroup of sporadic CRC and that it is a marker of good prognosis (Lothe et al., Cancer Research 1993; cited > 800 times). We also found that MSI is present in subgroups of other solid tumors (Peltomaki et al., Cancer Research 1993; cited > 600 times). MSI was in 2017 approved by FDA as the first pan-cancer biomarker, predicting benefit from immune checkpoint blockade in metastatic cancers. Despite the strong effect of this therapy on clinical care, only half of the MSI positive metastatic cancers respond. We have identified a resistance mechanism and negative predictive marker (Sveen et al., Genome Med, 2017).
Outcomes: preclinical resources and underlying research. We have established large preclinical pharmacogenomics data resources including (i) >100 conventional colorectal cancer cell lines screened for sensitivity to ~500 drugs and analyzed for gene expression and mutations; and (ii) a living biobank of >300 tumor organoids of liver metastases (>1 metastatic lesion from 65% of 150 patients), all screened for sensitivity to 40-73 selected drugs and analyzed for gene expression and mutations.
We developed CMScaller, a computational tool to translate the consensus molecular subtypes to pre-clinical models, and used our cell line resource to identify the specific drug vulnerabilities of each subtype (Sveen et al. Clin Cancer Res 2018, Eide et al. Sci Rep 2017, Berg et al., Mol Cancer 2017). We published the first large study of inter-metastatic heterogeneity of drug sensitivities in tumor organoids of colorectal cancer, and showed that organoids can model development of chemoresistance in a personalized manner (Bruun et al., Clin Cancer Res 2020 and Kryeziu et al., J Transl Med 2021). We have used this personalized treatment approach to successfully guide the rechallenge with chemotherapy in a patient who had exhausted all treatment options (in Norwegian). Ongoing analyses of the complete living biobank confirm that organoids are good personal cancer models also on the molecular level, and we develop models to predict new drug vulnerabilities based on histopathological and molecular subtypes. We have shown a biological rationale for repurposing of PARP-inhibitors to colorectal cancers with wild-type TP53 activity (Smeby et al., EBioMed 2020), and clinical translation is pursued in the EVIDENT trial.
Outcomes: functional oncology trial
Using our living biobank as a reference for personalized treatment nominations, we are currently conducting a functional oncology trial of metastatic colorectal cancer. EVIDENT (ex vivo drug sensitivity testing; ClinicalTrials.gov Identifier: NCT05725200) is a prospective intervention study of tumor organoid-guided treatment in the context of tumor heterogeneity. The trial combines standard precision cancer medicine approaches and analyses of “actionable” biomarkers with drug sensitivity testing of both chemotherapies and experimental cancer drugs. The trial evaluates the potential to translate tumor organoids from research tools to treatment decision tools.
