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Targeting ROR1 identifies new treatment strategies in hematological cancers
Hanna Karvonen1, Wilhelmiina Niininen1, Astrid Murumägi2
1BioMediTech, BMT, University of Tampere, Tampere 33014, Finland.
Abstract:
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the ROR receptor family consisting of two closely related type I transmembrane proteins ROR1 and ROR2. Owing to mutations in their canonical motifs required for proper kinase activity, RORs are classified as pseudokinases lacking detectable catalytic activity. ROR1 stands out for its selective and high expression in numerous blood and solid malignancies compared with a minimal expression in healthy adult tissues, suggesting high potential for this molecule as a drug target for cancer therapy. Current understanding attributes a survival role for ROR1 in cancer cells; however, its oncogenic function is cancer-type-specific and involves various signaling pathways. High interest in ROR1-targeted therapies resulted in the development of ROR1 monoclonal antibodies such as cirmtuzumab, currently in a phase I clinical trial for chronic lymphocytic leukemia. Despite these advances in translational studies, the molecular mechanism employed by ROR1 in different cancers is not yet fully understood; therefore, more insights into the oncogenic role of ROR1 signaling are crucial in order to optimize the use of targeted drugs. Recent studies provided evidence that targeting ROR1 simultaneously with inhibition of B-cell receptor (BCR) signaling is more effective in killing ROR1-positive leukemia cells, suggesting a synergistic correlation between co-targeting ROR1 and BCR pathways. Although this synergy has been previously reported for B-cell acute lymphoblastic leukemia, the molecular mechanism appears rather different. These results provide more insights into ROR1-BCR combinatorial treatment strategies in hematological malignancies, which could benefit in tailoring more effective targeted therapies in other ROR1-positive cancers.
Insights
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a promising cancer drug target due to its high expression in malignancies. Targeting ROR1 with B-cell receptor (BCR) signaling shows synergistic effects in leukemia, suggesting new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a pseudokinase highly expressed in various cancers but minimally in healthy tissues.
- ROR1 plays a survival role in cancer cells, with its oncogenic function being cancer-type-specific and involving diverse signaling pathways.
- ROR1-targeted therapies, including monoclonal antibodies like cirmtuzumab, are under clinical investigation for hematological malignancies.
Purpose of the Study:
- To elucidate the molecular mechanisms of ROR1 signaling in different cancer types.
- To explore the potential of ROR1 as a drug target for cancer therapy.
- To investigate the synergistic effects of co-targeting ROR1 and B-cell receptor (BCR) signaling in hematological malignancies.
Main Methods:
- Analysis of ROR1 expression patterns in malignant versus healthy tissues.
- Investigation of ROR1's role in cancer cell survival and oncogenesis.
- Evaluation of ROR1-targeted therapies, including monoclonal antibodies.
- Assessment of combinatorial treatment strategies involving ROR1 and BCR signaling inhibition.
Main Results:
- ROR1 exhibits selective and high expression in numerous blood and solid tumors, indicating its potential as a therapeutic target.
- Targeting ROR1 concurrently with BCR signaling inhibition demonstrates enhanced efficacy in eliminating ROR1-positive leukemia cells.
- The molecular mechanisms underlying ROR1-BCR pathway synergy in hematological malignancies are being further elucidated.
Conclusions:
- ROR1 is a significant molecular target for developing novel cancer therapies.
- Combinatorial strategies targeting ROR1 and BCR signaling offer promising therapeutic avenues for hematological malignancies.
- Further research into ROR1's oncogenic role is crucial for optimizing targeted drug utilization across various cancers.