James Lorens
The Tumor Plasticity Group.
About the research group
Professor Lorens did his PhD in Molecular Biology at the University of Bergen in 1992 and completed his postdoc at Stanford University Medical Center in 1996, working in cancer biology and immunology. He founded the Tumor Plasticity Group at the University in Bergen in 2004, as well as the company BerGenBio ASA in 2007, and was Chief Scientific Officer at BerGenBio in Bergen, Norway and Oxford, UK, and previously Director of Oncology Research and Development, Rigel Pharmaceuticals Inc, South San Francisco, CA USA. Currently, he is a professor at the Department of Biomedicine, University of Bergen, as well as PI at CCBIO.
For the last 25 years, Lorens has studied molecular mechanisms regulating tumor progression and developed novel targeting agents to facilitate clinical translation both in the academic and biotech settings. He applied functional genetic approaches to delineate new mechanisms that regulate tumor angiogenesis, apoptosis, and epithelial-to-mesenchymal transition (EMT), metastasis, and acquired drug resistance.
Brief group presentation and history
In 1999, Lorens cloned the AXL receptor tyrosine kinase as part of a functional genetic screening effort and oversaw the development of the first selective small-molecule Axl kinase inhibitor (bemcentinib). The Tumor Plasticity Group was established in 2004, and using a novel retroviral RNA interference system, the group discovered a central role for Axl in tumor plasticity, metastasis, and drug resistance, and subsequently showed that Axl regulates both tumor intrinsic and immune cell functions that affect cancer treatment outcomes. Lorens founded BerGenBio ASA in 2007 to facilitate clinical translation of these results. In 2013, bemcentinib was the first Axl kinase inhibitor to enter clinical trials and has subsequently been studied in 14 phase I/II studies spanning both myeloid leukemia and solid tumors, and COVID-19. His group has also contributed anti-Axl antibodies that formed the basis for clinical targeting agents in three more clinical trials. They have further studied the role of Axl in viral infection, fibrosis, and neurodegenerative diseases, where Axl-expressing immune cells serve key roles in disease progression. Lorens has active research programs to study Axl in cancer immunotherapy resistance and multiomic analysis of tumor biopsy samples from a melanoma clinical trial (NCT02872259).
Research focus of the group
The Tumor Plasticity Group focuses on how the altered tumor microenvironment drives tumor plasticity, metastases, and acquired resistance to cancer treatments. The confounding reality for cancer treatment is the astonishing heterogeneity of tumors. The breakdown of normal tissue architecture by a growing tumor exposes cancer cells to numerous biophysical and metabolic challenges, such as oxygen and nutritional deprivation and an altered microenvironment. These conflate to drive tumor cell phenotypic plasticity related to EMT that increases metastases and confers resistance to cancer treatments, including immunotherapy. The Axl receptor is a key determinant of tumor cell phenotypic plasticity and important clinical cancer target and biomarker.
Subprojects
Axl in acquired resistance to cancer therapy.
Translational, clinical, and societal importance
The Lorens group has contributed to the clinical translation of Axl targeting agents that have been used in 17 clinical trials; Axl small molecule kinase inhibitor (bemcentinib, BerGenBio ASA); and Axl antibodies developed in the Lorens laboratory: anti-Axl monoclonal antibody (tilvestamab, BerGenBio ASA); anti-Axl ADC (ADCT-601, ADC Therapeutics).
Future perspectives from 2024
The Tumor Plasticity Group is continuing to apply high-dimensional multiomic analysis of patient samples to derive predictive biomarkers for immunotherapy response. In particular, they are following up with a deep biomarker profiling for patients who participated in their combination immunotherapy trial.
Results from the CoE period 2013-2024
Most important results
- Association of AXL and PD-L1 expression with clinical outcomes in patients with advanced renal cell carcinoma (Terry et al., Clin Can Res 2021) and NSCLC (Rayford et al., submitted) treated with anti-PD-1.
- AXL targeting abrogates autophagic flux and induces immunogenic cell death in drug resistant lung cancer cells (Lie et al., J Thorac Onc 2020).
- AXL targeting enhances lymphocyte-mediated cytotoxicity of lung cancer cells (Terry et al., Can Immunol Res 2019).
- AXL inhibition improves immunotherapy by targeting tumor infiltrating suppressive DC cells (Davidsen, Grøndal et al., in revision).
- AXL inhibition promotes cytosolic DNA sensor cGAS activity and sensitizes poorly immunogenic low TMB tumors to chemo-immunotherapy (Dhakal et al., submitted).
- AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells (Li et al., Cell Rep Med 2022).
Most important papers
- Holland SJ et al. Multiple roles for the receptor tyrosine kinase Axl in tumor formation. Cancer Res 2005. PMID: 16230391.
- Gjerdrum C et al. Axl is an essential epithelial-tomesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc Natl Acad Sci U S A 2010. PMID: 20080645.
- Pelissier Vatter, FA et al. AXL is a driver of stemness in normal mammary gland and breast cancer. iScience 2020. PMID: 33103086.
- Lotsberg ML et al. AXL Targeting Abrogates Autophagic Flux and Induces Immunogenic Cell Death in Drug-Resistant Cancer Cells. J Thorac Oncol 2020. PMID: 32018052.
- Haaland GS et al. Association of Warfarin Use with Lower Overall Cancer Incidence Among Patients Older Than 50 Years. JAMA Intern Med 2017. PMID: 29114736.
- Ludwig KF et al. Small-Molecule Inhibition of Axl Targets Tumor Immune Suppression and Enhances Chemotherapy in Pancreatic Cancer. Cancer Res 2018. PMID: 29180468.
- Terry S et al. AXL targeting overcomes human lung cancer cell resistance to NK and CTL-mediated cytotoxicity. Cancer Immunol Res 2019. PMID: 31488404.
CCBIO significance
Lorens commends CCBIO’s ability to bring together a diversity of PIs and international faculty that enabled productive clinical translation of the research results of the involved groups. Further, he finds that the stellar CCBIO scientific environment promoted the training and career development of a new generation of cancer researchers, ensuring the continued impact of the center’s scientific principles and results.