Santoni-Rugiu Group

NSCLC

Targeted therapy with tyrosine-kinase inhibitors (TKIs) has significantly improved the prognosis of NSCLC, but only for subsets of patients with specific genetic NSCLC-drivers such as mutations of Epidermal Growth Factor Receptor (EGFR) or fusions of Anaplastic Lymphoma Kinase (ALK), which are found in approx. 10% and 4% of NSCLCs. Despite very frequent and often prolonged clinical response, these patients inevitably develop variable mechanisms of resistance to TKIs. Moreover, approx. 30% of patients do not respond at all because of yet poorly understood  intrinsic resistance. Thus, we study the mechanisms of acquired and intrinsic TKI-resistance in NSCLC by comprehensive pathological/molecular profiling of patient specimens (tumor and liquid biopsies) at baseline and at disease progression, and by validation in preclinical models. Such approach may aid in designing combinatorial targeted strategies for better treatment of NSCLC patients.

MPM

MPM’s poor therapeutic response and high lethality are largely due to its insufficiently understood molecular pathogenesis, challenging diagnostics, and lack of effective predictive biomarkers and therapeutic targets. A conclusive MPM diagnosis is histological, however differentiation from other cancer types and from benign mesothelial proliferations can be difficult. Thus, we aim at characterizing more sensitive and specific diagnostic and predictive biomarkers for MPM that could open innovative therapeutic avenues for this extremely aggressive malignancy.

Predictive biomarkers for treatment of non-small cell lung cancer and resistance mechanisms

• Targeted therapy with TKIs or immunotherapy can increase survival of fractions of NSCLC patients with specific genetic NSCLC-drivers such as EGFR-mutations or ALK-fusions. Thus, chemotherapy is still widely utilized for NSCLC patients without these mutations. We have identified and characterized new biomarkers and molecular signatures for predicting chemotherapy response in both advanced and early stage NSCLC patients (Vilmar et al. ).
  
  
• We have investigated the intra-/inter-tumor heterogeneity and longitudinal variation of biomarkers for chemotherapy response (Jakobsen et al. Eur. J. Cancer 2013; Jakobsen et al. ).
  
  
• We have also implemented methods to investigate response and resistance to EGFR- and ALK-TKIs, identifying various mechanisms of acquired resistance such as secondary on-target mutations, activation of parallel/downstream by-pass pathways or phenotypic resistance mechanisms, which can change in different metastatic lesions (Rossing et al. ).
  
  
• Moreover, we have addressed the variability in extent and duration of response to clarify why certain NSCLC patients are inherently resistant to EGFR- or ALK-TKIs. We have observed that EGFR-mutations or ALK-fusions are not necessarily mutually exclusive with changes in other cancer-driver genes as anticipated, but co-mutations in multiple drivers and/or transformation to small-cell lung cancer can occur and represent mechanisms of intrinsic TKI-resistance present at baseline or very rapidly induced in surviving cells as adaptive tumor response (Jakobsen et al. ).

New diagnostic and predictive biomarkers for malignant pleural mesothelioma.

• Our group has several years of experience with MPM research, as Copenhagen University Hospital is the specialized referral center for diagnostics and treatment of MPM in Denmark and the Scandinavian center for radically intended surgery for MPM. In connection with that we have been collecting unique MPM biobank samples (MESOBANK) that are included in the Danish Cancer Biobank for research purposes and testing of new molecular markers.
  
  
• It is often difficult to distinguish MPM from nonmalignant mesothelial proliferations, as current markers still lack sensitivity and the main diagnostic criterion (deep invasion) is often not appreciable on pleural biopsies. We have tested several potential biomarkers for MPM, identifying some that could complement current diagnostic or predictive procedures (Zimling et al J. Thorac. ).
  
  
• We have also shown for the first time that MPM’s specific micro-RNA signatures, related miRNA-targets, and miRNA epigenetic changes, not only have biological and prognostic value, but can accurately distinguish MPM from nonmalignant mesothelial proliferations (Andersen et al. ). This has also allowed to study the expression and mutation status of components of the microRNA-biogenesis and the epigenetic regulation of biomarker-miRNAs in MPM (Andersen et al. Anticancer Res. 2015; Santoni-Rugiu et al. Curr. Biom. Findings 2016), and to characterize other potential markers for targeted therapy in MPM (Chapel et al. Lung Cancer 2019).

Multi-institutional collaboration within the International Mesothelioma Interest Group to update the histopathological guidelines and classification of MPM as well as assess new therapy protocols for MPM (Chapel et al. Molecular Pathways and Diagnosis in Malignant Mesothelioma: A review of the 14th International Conference of the International Mesothelioma Interest Group. Lung Cancer 127:69-75, 2019. doi: 10.1016/j.lungcan.2018.11.032; Klebe et al. Controversies in Pathology - The concept of mesothelioma in situ, with particular consideration of cytology diagnosis. Pathology, In press).

Collaboration with Niels Behrendt and Lars H. Engelholm’s groups at BRIC/Finsen on the role of the endocytic collagen receptor uPARAP in human diseases (Jürgensen et al. Immune-regulation by fibroblasts in tissue injury depends on uPARAP-mediated uptake of collectins. J. Cell Biol. 218:333-9, 2019. doi: 10.1083/jcb.201802148). This translational collaboration is currently focusing on the potential role of uPARAP as potential diagnostic marker and therapeutic target in MPM.

Collaboration with Morten Frödin’s group at BRIC on onco-kinases in mouse models for human cancers (Engelholm LH et al: CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1-Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma. Gastroenterology 153(6):1662-73, 2017. doi: 10.1053/j.gastro.2017.09.008).

Collaborative research with Oncology Phase I Unit at Rigshospitalet under the Copenhagen Prospective Personalized Oncology clinical trial program initiated in 2013 (Tuxen et al. Copenhagen Prospective Personalized Oncology (CoPPO) - Clinical utility of using molecular profiling to select patients to phase 1 trial. Clin. Cancer Res. 25:1239-47, 2019. doi: 10.1158/1078-0432.CCR-18-1780; Ahlborn et al. Application of cell-free DNA for genomic tumor profiling – A feasibility study. Oncotarget 10:1388-98, 2019. doi: 10.18632/oncotarget.26642; Bertelsen B et al. High frequency of pathogenic germline variants within homologous recombination repair in patients with advanced cancer. npj Genomic Medicine, 4(13):1-10, 2019. doi.org/10.1038/s41525-019-0087-6; Ahlborn  et al. Circulating tumor DNA as a marker of treatment response in BRAF V600E mutated non-melanoma solid tumors. Oncotarget 9:32570-9, 2018. doi: 10.18632/oncotarget.25948).