Maya Kardouh
Enhanced tyrosine kinase-like orphan receptor (ROR1) expression in cancer stem cells has been linked to many cancers, such as breast, lung, melanoma, leukemia, and ovarian cancers. While ROR1 is expressed during the fetal and embryonic stages, its expression is normally downregulated in the adult cells. The association with the increased ROR1 expression and malignancies could be attributed to the protein’s role in promoting cancer stem cell proliferation, survival, and metastasis (Karvonen et al, 2019).
Moreover, the high expression of ROR1 has been linked with breast cancer chemoresistance and relapse. Efforts to target the ROR1 receptor have emerged with anti-ROR1 antibodies, such as cirmtuzumab, to prevent its activation. Prior research on the mouse model has shown that in combination with the chemotherapeutic paclitaxel, cirmtuzumab treatment eradicates breast cancer stem cells and weakens their persistence more effectively than when treated with each alone (Zhang et al, 2019). To translate this effect into the context of human breast cancer, Oncternal Therapeutics, a company for developing cancer treatments, initiated its ongoing open-label clinical trial for cirmtuzumab. This trial is currently investigating whether the administration of cirmtuzumab with paclitaxel is safe and efficacious in treating advanced, unresectable and metastatic breast cancer (Shatsky et al, 2020). As of today, the trial is in phase 1b and actively recruiting patients for the study.
Further, cirmtuzumab clinical trials showed efficacy in other cancers, such as chronic lymphocytic leukemia (CLL). Phase I for an Oncternal Therapeutics CLL clinical trial provided evidence for cirmtuzumab’s efficacy and safety in inhibiting the ability of cancer stem cells to self-renew and give rise to different cell types, and potentially eradicating CLL in humans (Choi et al, 2018). Currently in its phase II, an ongoing open-label Oncternal Therapeutics clinical trial aims to determine if cirmtuzumab with venetoclax would better eliminate residual cancer stem cells in CLL patients than when treated with venetoclax alone for 1 year. Venetoclax is one of the effective drugs prescribed to CLL patients to target their cancer cells, however, about 30% of venetoclax treated patients still show cancer remnants after 1 year of their treatment, which increases their chances of relapse. This trial aims to evaluate if the combination of venetoclax with cirmtuzumab lowers CLL patients’ risk of cancer progression more effectively (Heyman et al, 2020). This trial is also actively recruiting patients to be enrolled in the study.
Evidenced by the different clinical trials for cirmtuzumab, this antibody holds great promise for a safe and effective treatment for not only eradicating cancer but preventing its relapse, which has been a huge hurdle when treating resistant cancer. Additionally, cirmtuzumab may be an effective treatment for multiple malignancies since many are associated with elevated ROR1 expression. Nevertheless, more and sufficient evidence is needed for such conclusions to be drawn, of which the field is getting closer to.
References:
Choi MY, Widhopf GF 2nd, Ghia EM, Kidwell RL, Hasan MK, Yu J, Rassenti LZ, Chen L, Chen Y, Pittman E, Pu M, Messer K, Prussak CE, Castro JE, Jamieson C, Kipps TJ. Phase I Trial: Cirmtuzumab Inhibits ROR1 Signaling and Stemness Signatures in Patients with Chronic Lymphocytic Leukemia. Cell Stem Cell. 2018 Jun 1;22(6):951-959.e3. doi: 10.1016/j.stem.2018.05.018. PMID: 29859176; PMCID: PMC7001723.
Heyman, B., Choi, M. Y., Ghia, E. M., Widhopf II, G. F., Pu, M., Pittman, E., . . . Kipps, T. J. (2020). Cirmtuzumab consolidation for treatment of patients with DETECTABLE cll on Venetoclax. Blood, 136(Supplement 1), 13-13. doi:10.1182/blood-2020-134711
Karvonen, H., Barker, H., Kaleva, L., Niininen, W., & Ungureanu, D. (2019). Molecular Mechanisms Associated with ROR1-Mediated Drug Resistance: Crosstalk with Hippo-YAP/TAZ and BMI-1 Pathways. Cells, 8(8), 812. https://doi.org/10.3390/cells8080812
Shatsky, R. A., Schwab, R. B., Helsten, T. L., Pittman, E. I., Chen, R., Breitmeyer, J. B., . . . Parker, B. A. (2020). Abstract p3-10-18: Phase 1b trial of cirmtuzumab and paclitaxel for locally advanced, unresectable and metastatic breast cancer. Poster Session Abstracts. doi:10.1158/1538-7445.sabcs19-p3-10-18
Zhang, S., Zhang, H., Ghia, E. M., Huang, J., Wu, L., Zhang, J., Lam, S., Lei, Y., He, J., Cui, B., Widhopf, G. F., 2nd, Yu, J., Schwab, R., Messer, K., Jiang, W., Parker, B. A., Carson, D. A., & Kipps, T. J. (2019). Inhibition of chemotherapy resistant breast cancer stem cells by a ROR1 specific antibody. Proceedings of the National Academy of Sciences of the United States of America, 116(4), 1370–1377. https://doi.org/10.1073/pnas.1816262116
Picture from the Oncternal Therapeutics website: https://oncternal.com/pipeline/cirmtuzumab
Moreover, the high expression of ROR1 has been linked with breast cancer chemoresistance and relapse. Efforts to target the ROR1 receptor have emerged with anti-ROR1 antibodies, such as cirmtuzumab, to prevent its activation. Prior research on the mouse model has shown that in combination with the chemotherapeutic paclitaxel, cirmtuzumab treatment eradicates breast cancer stem cells and weakens their persistence more effectively than when treated with each alone (Zhang et al, 2019). To translate this effect into the context of human breast cancer, Oncternal Therapeutics, a company for developing cancer treatments, initiated its ongoing open-label clinical trial for cirmtuzumab. This trial is currently investigating whether the administration of cirmtuzumab with paclitaxel is safe and efficacious in treating advanced, unresectable and metastatic breast cancer (Shatsky et al, 2020). As of today, the trial is in phase 1b and actively recruiting patients for the study.
Further, cirmtuzumab clinical trials showed efficacy in other cancers, such as chronic lymphocytic leukemia (CLL). Phase I for an Oncternal Therapeutics CLL clinical trial provided evidence for cirmtuzumab’s efficacy and safety in inhibiting the ability of cancer stem cells to self-renew and give rise to different cell types, and potentially eradicating CLL in humans (Choi et al, 2018). Currently in its phase II, an ongoing open-label Oncternal Therapeutics clinical trial aims to determine if cirmtuzumab with venetoclax would better eliminate residual cancer stem cells in CLL patients than when treated with venetoclax alone for 1 year. Venetoclax is one of the effective drugs prescribed to CLL patients to target their cancer cells, however, about 30% of venetoclax treated patients still show cancer remnants after 1 year of their treatment, which increases their chances of relapse. This trial aims to evaluate if the combination of venetoclax with cirmtuzumab lowers CLL patients’ risk of cancer progression more effectively (Heyman et al, 2020). This trial is also actively recruiting patients to be enrolled in the study.
Evidenced by the different clinical trials for cirmtuzumab, this antibody holds great promise for a safe and effective treatment for not only eradicating cancer but preventing its relapse, which has been a huge hurdle when treating resistant cancer. Additionally, cirmtuzumab may be an effective treatment for multiple malignancies since many are associated with elevated ROR1 expression. Nevertheless, more and sufficient evidence is needed for such conclusions to be drawn, of which the field is getting closer to.
References:
Choi MY, Widhopf GF 2nd, Ghia EM, Kidwell RL, Hasan MK, Yu J, Rassenti LZ, Chen L, Chen Y, Pittman E, Pu M, Messer K, Prussak CE, Castro JE, Jamieson C, Kipps TJ. Phase I Trial: Cirmtuzumab Inhibits ROR1 Signaling and Stemness Signatures in Patients with Chronic Lymphocytic Leukemia. Cell Stem Cell. 2018 Jun 1;22(6):951-959.e3. doi: 10.1016/j.stem.2018.05.018. PMID: 29859176; PMCID: PMC7001723.
Heyman, B., Choi, M. Y., Ghia, E. M., Widhopf II, G. F., Pu, M., Pittman, E., . . . Kipps, T. J. (2020). Cirmtuzumab consolidation for treatment of patients with DETECTABLE cll on Venetoclax. Blood, 136(Supplement 1), 13-13. doi:10.1182/blood-2020-134711
Karvonen, H., Barker, H., Kaleva, L., Niininen, W., & Ungureanu, D. (2019). Molecular Mechanisms Associated with ROR1-Mediated Drug Resistance: Crosstalk with Hippo-YAP/TAZ and BMI-1 Pathways. Cells, 8(8), 812. https://doi.org/10.3390/cells8080812
Shatsky, R. A., Schwab, R. B., Helsten, T. L., Pittman, E. I., Chen, R., Breitmeyer, J. B., . . . Parker, B. A. (2020). Abstract p3-10-18: Phase 1b trial of cirmtuzumab and paclitaxel for locally advanced, unresectable and metastatic breast cancer. Poster Session Abstracts. doi:10.1158/1538-7445.sabcs19-p3-10-18
Zhang, S., Zhang, H., Ghia, E. M., Huang, J., Wu, L., Zhang, J., Lam, S., Lei, Y., He, J., Cui, B., Widhopf, G. F., 2nd, Yu, J., Schwab, R., Messer, K., Jiang, W., Parker, B. A., Carson, D. A., & Kipps, T. J. (2019). Inhibition of chemotherapy resistant breast cancer stem cells by a ROR1 specific antibody. Proceedings of the National Academy of Sciences of the United States of America, 116(4), 1370–1377. https://doi.org/10.1073/pnas.1816262116
Picture from the Oncternal Therapeutics website: https://oncternal.com/pipeline/cirmtuzumab
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