Research team Lewensohn/Viktorsson/Lindberg

Precision cancer medicine and precision radiotherapy in lung cancer- from molecular mechanism/biomarkers to clinical trials

Research

Our research team consists of preclinical scientists and clinical oncologists focusing on improving lung cancer treatment. In the clinical part we concentrate on further development of stereotactic radiotherapy (SBRT) for both early-stage non-small cell lung cancer (NSCLC) and advanced metastatic cases. The tolerance SBRT doses are studied with respect to critical structures in the thorax and abdomen which form the basis for expected frequencies of side effects. We are also driving prospective clinical trials using SBRT to reach tumour parts that are resistant to targeted drug therapy. Our preclinical/translational focus is on exploring biomarkers for both pharmaceutical and radiation therapy effectiveness, its enhancement, mechanisms of action relating to sensitivity and resistance as well as side effects.

Projects

  1. Development of stereotactic body radiotherapy. Our team pioneered stereotactic body radiotherapy (SBRT) radiotherapy which is precision radiotherapy that can give tumour ablative doses yet sparing normal tissue. At present our research focus is on establishing tolerance doses for organs at risk after SBRT e.g. in the thorax, adrenals and peripheral nervous system. We also run a program with consolidation of metastatic cases using SBRT after precision cancer therapy with pharmaceuticals. The work consists of retrospective analyses of real-world cases but also the build-up of prospective phase II trials for EGFR-, ALK-, KRAS- Tyrosine Kinase Inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). These will compose umbrella studies for advanced disease. The study with EGFR inhibition involves the ETOP organization and the others selected centers in Sweden, Denmark and Norway. Sampling for translational studies will be carried out both at the inclusion of patients as well as time of resistant residual disease when SBRT will be installed.
     
  2. Tumor and liquid biopsy analyses in lung cancer- translational biomarker projects. Precision cancer medicine for lung cancer i.e. targeting oncogenic drivers e.g. mutated EGFR, ALK-fusion or RAS with TKIs as well as ICI has improved patient outcome. Yet responses are heterogeneous and there is a need for biomarkers to further personalize treatment as well as to identify novel treatment targets. We focus on this in tumour and liquid biopsies e.g. plasma and pleura effusion fluids. We also run a program on biomarkers in lung cancer with Fine Needle Aspirations followed by in depth molecular analyses. Our goal is to reveal putative response biomarkers in relation to TKI or ICI alone or when combined with SBRT but also to discover resistance mechanisms which can be pharmaceutically attacked. We also have a program on tumour-derived extracellular vescicles (EVs)/exosomes isolated from LC patient plasma and pleural effusions. Here we aim for discovering non-invasive treatment response biomarkers from EVs/exosomes but also to understand the role of exosomes in tumour cell resistance as well as communication with the microenvironment. For the EV/exosome analytics we work in collaboration with researchers at the Royal Institute of technology in Stockholm and Uppsala University to set out innovative technologies for EV biomarker monitoring.
     
  3. Development of fine needle based molecular cytology for personalized cancer medicine. We are developing broad molecular profiling of tumours on minute material obtained with fine needle aspirates (FNA), both for diagnostic and treatment predictive purposes. We are directing this to lung-, breast and prostate cancer. FNA allows for analyses of mutations but also RNA and protein expression. We have recently managed to use multiplex RNA analysis (NanoString) and multiplex protein analysis (Proximity Extension Assay, PEA) for parallel molecular profiling of FNA samples from breast tumours and PEA analyses in lung cancer. In addition to benchmarking against routine clinical methods (immunohistochemistry), a tentative signature (consisting of 11 proteins) was identified that clearly separated cancer from benign tissue changes. Many immune-related proteins (e.g. chemokines) that correlate to established subtypes of breast cancer were possible to analyse. We recently showed that mol. analyses are also possible on FNA samples from lung cancers localized in the thorax. On material from tumour sites in the thorax we were able to analyse 163 proteins by PEA, e.g. levels of PD-L1 and several proteins that correlate to PD-L1 and tumour stage. Thus, our results pave the way for FNA-based molecular analysis in relation to the selection and follow-up of immunotherapy.
     
  4. Molecular characterization of Radiotherapy and Oncogenic signaling in lung cancer- The role of Eph/Ephrin signaling cascades. Multiple growth factor receptors drive lung cancer cells and crosstalk to each other and in this way regulate response to precision cancer medicine as well as radiotherapy. Some years back we discovered a novel role for the Eph family ligand Ephrin B3 in regulating response to radiotherapy. We have continued this research line and revealed that Ephrin 3 is a ligand of multiple Eph A receptors including EphA2 and in this way control lung cancer proliferation, migration and invasion. Recently we found that Ephrin B3 and EphA signalling circuits also influence EGFR-signalling in lung cancer as well as DNA Damage and Repair (DDR) signalling in response to radiation. Our research focus is to further understand the Ephrin/Eph signalling circuits, its crosstalk with other growth factor receptors e.g. EGFR, its influence on DDR and radiotherapy sensitivity. The goal is to both target the EphrinB3/EphA interactome as well as to understand its biomarker potential in lung cancer prior and post precision cancer medicine or radiation therapy.

Group members

Rolf Lewensohn, MD/PhD/Professor (projects 1-4)
Kristina Viktorsson, PhD (projects 2-4)
Karin Lindberg, MD/PhD (project 1)
Bo Franzén, PhD, Assoc. Prof. (project 2-3)
Petra Hååg, PhD/Senior Lab Manager (projects 2-4)
Lena Kanter, MD, PhD, Pathologist (Project 2-4)
Sara Lindberg, MD, PhD-student (Project 1)
Anna Mannhag, MD, PhD-student under registration (Project 1)

Publications

Project 1

The HILUS-Trial-a Prospective Nordic Multicenter Phase 2 Study of Ultracentral Lung Tumors Treated With Stereotactic Body Radiotherapy.
Lindberg K, Grozman V, Karlsson K, Lindberg S, Lax I, Wersäll P, Persson GF, Josipovic M, Khalil AA, Moeller DS, Nyman J, Drugge N, Bergström P, Olofsson J, Rogg LV, Ramberg C, Kristiansen C, Jeppesen SS, Nielsen TB, Lödén B, Rosenbrand HO, Engelholm S, Haraldsson A, Billiet C, Lewensohn R
J Thorac Oncol 2021 Jul;16(7):1200-1210

Extending hypofractionated stereotactic body radiotherapy to tumours larger than 70cc - effects and side effects.
Grozman V, Onjukka E, Wersäll P, Lax I, Tsakonas G, Nyren S, Lewensohn R, Lindberg K
Acta Oncol 2021 Mar;60(3):305-311

Project 2

Detection of Tumor-Associated Membrane Receptors on Extracellular Vesicles from Non-Small Cell Lung Cancer Patients via Immuno-PCR.
Stiller C, Viktorsson K, Paz Gomero E, Hååg P, Arapi V, Kaminskyy VO, Kamali C, De Petris L, Ekman S, Lewensohn R, Karlström AE
Cancers (Basel) 2021 Feb;13(4):

Label-Free Surface Protein Profiling of Extracellular Vesicles by an Electrokinetic Sensor.
Cavallaro S, Horak J, Hååg P, Gupta D, Stiller C, Sahu SS, Görgens A, Gatty HK, Viktorsson K, El Andaloussi S, Lewensohn R, Karlström AE, Linnros J, Dev A
ACS Sens 2019 05;4(5):1399-1408

Exosomal RNA-profiling of pleural effusions identifies adenocarcinoma patients through elevated miR-200 and LCN2 expression.
Hydbring P, De Petris L, Zhang Y, Brandén E, Koyi H, Novak M, Kanter L, Hååg P, Hurley J, Tadigotla V, Zhu B, Skog J, Viktorsson K, Ekman S, Lewensohn R
Lung Cancer 2018 10;124():45-52

Project 3

Multiplex immune protein profiling of fine-needle aspirates from patients with non-small-cell lung cancer reveals signatures associated with PD-L1 expression and tumor stage.
Franzén B, Viktorsson K, Kamali C, Darai-Ramqvist E, Grozman V, Arapi V, Hååg P, Kaminskyy VO, Hydbring P, Kanter L, Nyrén S, Ekman S, De Petris L, Lewensohn R
Mol Oncol 2021 Mar;():

Protein profiling of fine-needle aspirates reveals subtype-associated immune signatures and involvement of chemokines in breast cancer.
Franzén B, Alexeyenko A, Kamali-Moghaddam M, Hatschek T, Kanter L, Ramqvist T, Kierkegaard J, Masucci G, Auer G, Landegren U, Lewensohn R
Mol Oncol 2019 02;13(2):376-391

A fine-needle aspiration-based protein signature discriminates benign from malignant breast lesions.
Franzén B, Kamali-Moghaddam M, Alexeyenko A, Hatschek T, Becker S, Wik L, Kierkegaard J, Eriksson A, Muppani NR, Auer G, Landegren U, Lewensohn R
Mol Oncol 2018 09;12(9):1415-1428

Project 4

EPHA2 Interacts with DNA-PKcs in Cell Nucleus and Controls Ionizing Radiation Responses in Non-Small Cell Lung Cancer Cells.
Kaminskyy VO, Hååg P, Novak M, Végvári Á, Arapi V, Lewensohn R, Viktorsson K
Cancers (Basel) 2021 Feb;13(5):

Ephrin B3 interacts with multiple EphA receptors and drives migration and invasion in non-small cell lung cancer.
Efazat G, Novak M, Kaminskyy VO, De Petris L, Kanter L, Juntti T, Bergman P, Zhivotovsky B, Lewensohn R, Hååg P, Viktorsson K
Oncotarget 2016 Sep;7(37):60332-60347

Phosphoproteomic profiling of NSCLC cells reveals that ephrin B3 regulates pro-survival signaling through Akt1-mediated phosphorylation of the EphA2 receptor.
Ståhl S, Branca RM, Efazat G, Ruzzene M, Zhivotovsky B, Lewensohn R, Viktorsson K, Lehtiö J
J Proteome Res 2011 May;10(5):2566-78

Inhibition of Ephrin B3-mediated survival signaling contributes to increased cell death response of non-small cell lung carcinoma cells after combined treatment with ionizing radiation and PKC 412.
Ståhl S, Kaminskyy VO, Efazat G, Hyrslova Vaculova A, Rodriguez-Nieto S, Moshfegh A, Lewensohn R, Viktorsson K, Zhivotovsky B
Cell Death Dis 2013 Jan;4():e454

Collaborators:

Our SBRT studies are driven with collaborators from the Nordic SBRT group and is further described on:

https://nordicsbrt.wordpress.com.

Our collaborators on innovative technologies for EV analytics are: Associate Prof. Apurba Dev, Uppsala University and Royal Inst. of Technology (KTH), Prof. Jan Linnros, Prof. Amelie Eriksson-Karlström, and Prof. Afshin Ahmadian, all KTH and Dr Kristina Fogel, RISE Research Institute of Sweden AB.

Funding bodies:

Our studies are conducted with the generous support from: Karolinska Institutet, Swedish Cancer Society (Cancerfonden), Stockholm Cancer Society (Radiumhemmets forskningsfonder), The Erling Persson Family Foundation (Familjen Erling Perssons stiftelse), The Sjöberg Foundation (Sjöberg Stiftelsen), Swedish Society of Medicine (Svenska Läkaresällskapet) and Stockholm County Council (SLL/Region Stockholm)