Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a protein found on the surface of cells. It functions as a receptor, receiving signals from the external environment of the cell. These signals influence various actions and processes occurring inside the cell, helping to guide cellular behavior. ROR1 is encoded by the ROR1 gene in humans.
The Role of ROR1 in Normal Development
ROR1 plays a specific role during human embryonic development. It is highly expressed in early embryonic stages, where it contributes to processes such as skeletal, cardiorespiratory, and neurological development. ROR1 helps guide cell migration and differentiation, which are essential for the proper formation of various tissues and organs. After this period of rapid development, ROR1 expression typically decreases significantly. Consequently, ROR1 is generally absent or found at very low levels on most healthy adult tissues.
Re-emergence in Cancer
Certain types of cancer cells aberrantly begin to express ROR1 on their surface, a process known as re-expression. This re-emergence of ROR1 provides cancer cells with advantages for survival, proliferation, and metastasis. ROR1 achieves this by activating specific internal signaling pathways, including PI3K/AKT, MAPK, NF-κB, STAT3, and Hippo. These pathways contribute to anti-apoptotic effects, allowing cancer cells to evade programmed cell death, and also promote uncontrolled cell growth and division.
The presence of ROR1 on cancer cells also facilitates their ability to spread. It promotes epithelial-mesenchymal transition (EMT), a process that allows cancer cells to become more migratory and invasive, thereby enhancing metastasis. ROR1 expression is observed in various malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), and solid tumors such as triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). In many of these cancers, high ROR1 expression correlates with more aggressive disease and poorer patient outcomes.
ROR1 as a Therapeutic Target
ROR1’s distinct expression pattern makes it a target for cancer therapies. It is present on cancer cells but largely absent or at very low levels in most healthy adult tissues. This differential expression provides a therapeutic window, allowing for the development of treatments that can specifically target cancer cells. By targeting ROR1, these treatments aim to minimize damage to healthy tissues, reducing side effects often associated with conventional cancer treatments. This selective approach enhances the precision of cancer therapy.
Medical Treatments Targeting ROR1
Several therapeutic approaches are being developed to target ROR1-expressing cancers. These strategies aim to selectively eliminate cancer cells while sparing healthy tissues, leveraging ROR1’s unique expression pattern. Many of these treatments are currently in clinical trials to evaluate their safety and effectiveness in human patients.
Antibody-Drug Conjugates (ADCs)
ADCs combine a monoclonal antibody that specifically binds to ROR1 on the cancer cell surface with a potent chemotherapy drug. Once the antibody binds, the ADC is internalized by the cancer cell, releasing the chemotherapy payload directly inside to kill the cell. For example, zilovertamab vedotin (MK-2140) links an anti-ROR1 antibody to monomethyl auristatin E (MMAE), a microtubule-targeting agent.
CAR-T Cell Therapy
This immunotherapy involves genetically engineering a patient’s T-cells to express a Chimeric Antigen Receptor (CAR) that specifically recognizes ROR1. After modification and multiplication in the lab, these ROR1-specific CAR-T cells are infused back into the patient. Once in the body, they identify and destroy cancer cells displaying the ROR1 antigen. Clinical trials are exploring ROR1 CAR-T cell therapy for various cancers, including CLL, MCL, ALL, and certain solid tumors.
Monoclonal Antibodies
These laboratory-made antibodies bind directly to ROR1 on cancer cells. By binding, they can either block ROR1’s function, inhibiting signaling pathways that support cancer cell growth and survival, or “flag” the cancer cell for destruction by the patient’s immune system. For instance, zilovertamab (cirmtuzumab or UC-961) is a humanized ROR1 monoclonal antibody that has shown safety and some efficacy in early clinical trials for ROR1-associated malignancies.