Cirmtuzumab Blocks Ovarian Cancer Metastasis in Preclinical Study

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Thomas Kipps, MD, PhD

The monoclonal antibody cirmtuzumab, currently in clinical trials to treat chronic lymphocytic leukemia (CLL), targets receptor tyrosine kinase-like orphan receptor 1 (ROR1) on the surface of cancerous B cells,¹and the agent may have a wider reach in the treatment of ovarian and other cancers, according to preclinical research from the University of California, San Diego School of Medicine.

ROR1 previously had been detected on other cancer cells, and the new research demonstrates that in animal models of ovarian cancer, the presence of the antibody blocks metastasis of the ROR1-expressing tumors.

ROR1 contributes to organogenesis in early embryo development and is rarely found in normal adult cells, making it an attractive anticancer target. First observed on the surface of leukemic B cells, various other malignancies have been shown to express ROR1, including ovarian, colon, lung, skin, pancreatic, testicular, bladder, uterine, prostate, and adrenal cancers.²

In normal embryonic development, ROR1 is thought to contribute to the epithelial—mesenchymal transition, which allows embryonic epithelial cells the increased motility and invasiveness required to seed developing organs. In cancer development, ROR1 is thought to regulate metastatic properties such as cell migration and invasiveness.

Thomas Kipps, MD, PhD, professor of medicine at the UCSD Moores Cancer Center and senior author on the paper published November 17, 2014 inProceedings of the National Academy of Sciences, explains the protein’s role in malignancies, “ROR1 is used by embryo cells to migrate and to develop new organs. Cancer stem cells subsequently use ROR1 for their own growth and dissemination throughout the body. They are essentially the seeds of the cancer. The more seeds a tumor has, the greater its ability to recur after therapy or metastasize.”

The researchers showed that cancer stem cells with high-grade histology expressed proportionately more ROR1 than low-grade tumors, a finding also observed for another onco-embryonic antigen named 5T4. The embryonic antigens may provide functions that help cancer cells to metastasize. Previously the group showed that in human breast adenocarcinomas, expression of ROR1 was more common among less-differentiated adenocarcinomas that lacked expression of hormone receptors and were associated with more aggressive disease.³

Similarly, ovarian cancer patients whose tumors expressed high levels of ROR1 had higher relapse rates and shorter median survival times than tumors with lower ROR1 levels. Nearly 90% of ovarian cancers are high-grade adenocarcinoma, which metastasizes early in its development, often before diagnosis. After initial treatment, ovarian cancer frequently recurs, typically within 18 months. The UCSD investigators showed that ovarian stem cells for the most part do not respond to standard chemotherapy, but ROR1 expression on the stem cells presents a potential treatment opportunity.

In transgenic mice engrafted with ovarian cancer tumors, low doses of cirmtuzumab appeared to block growth and metastasis. In the presence of the monoclonal antibody, new tumors did not appear in mice. After cirmtuzumab treatment, tumors transplanted into new mice failed to spread, suggesting that the drug effectively depleted tumors of cancer stem cells. “It seems that ROR1 may be required to keep cancer stem cells healthy,” observed Kipps.

The research demonstrates a malignant function to certain embryonic development pathways in cancer. “If we can keep cancer stem cells from replaying that growth program by targeting ROR1, then we may be able to stop cancer and prevent its recurrence. You have to go after the seeds of the cancer and kill them before they germinate into recurrent or metastatic disease,” said Kipps.

References

1. UC San Diego Health System. Novel Drug Targeting Leukemia Cells Enters Clinical Trial. http://health.ucsd.edu/news/releases/Pages/2014-09-16-clinical-trial-cll-novel-drug.aspx. Accessed November 17, 2014.
2. Zhang S, Chen L, Wang-Rodriguez J, et al. The onco-embryonic antigen ROR1 is expressed by a variety of human cancers.Am J Pathol. 2012 Dec; 181(6): 1903-1910.
3. Zhang S, Chen L, Cui B, et al. ROR1 is expressed in human breast cancer and associated with enhanced tumor-cell growth.PLoS One. 2012; 7(3): e31127.