Advances in chemotherapy and endocrine therapy have reduced breast cancer mortality, but 20% of patients still relapse and ultimately succumb to this disease. One model accounting for this position is that there exists cancer stem cells (CSCs), which are relatively resistant to chemotherapy, have self-renewal capacity, can repopulate the tumor, and can spread to distant sites. If so, therapies that also target CSCs may improve treatment outcomes and patient survival.
Studies have identified characteristics that distinguish CSCs from other cancer cells. Breast CSCs have phenotypic features that distinguish them from other neoplastic cells. For example the receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed in many cancers, but not by normal post-partum tissues. Breast cancers with high-levels of ROR1 cells tend to be poorly differentiated and to express markers associated with epithelial-to-mesenchymal transition (EMT). In line with a role for ROR1 in tumor cell survival metastasis, high-level expression of ROR1 is associated with relatively short post-treatment disease-free or overall survival of patients with triple-negative breast cancer. However, the targeting of ROR1 in breast CSCs which constitute a subpopulation of cancer cells that are relatively resistant to conventional chemotherapy and have self-renewing capacities needs further investigation.
Researchers at UC San Diego have interrogated transcriptome data of primary-breast-cancer specimens collected from patients before and after chemotherapy. The effect of chemotherapy on breast cancer patient-derived xenografts (PDX) was examined in immune-deficient mice and assessed whether ROR1+ breast-cancer cells have activated Rho-GTPases, Hippo-YAP, or BMI1, and/or features of breast CSCs. Humanized anti-ROR1 antibody, cirmtuzumab, could inhibit activation of Rho-GTPases and repress expression of genes targeted by Hippo-YAP or BMI1. In addition it was found that cirmtuzumab could enhance the sensitivity of ROR1+ tumor cells to treatment with paclitaxel, in vitro.
The results indicate that cirmtuzumab is a potential therapeutic for the treatment of a patient with chemotherapy resistant tumors in conjunction with the mitotic inhibitor, paclitaxel.
The combination of cirmtuzumab and paclitaxel was more effective in eradicating breast-cancer PDX than either agent alone, indicating that cirmtuzumab may improve the treatment outcome of patients with advanced breast cancer.
The work has been conducted in cancer cell lines and in patient-derived xenografts (PDX) in immune-deficient mice.
A provisional patent has been submitted and the technology is available for licensing.
ROR1, Rho-GTPase signaling, YAP/TAZ, BMI1, Breast Cancer Stem Cells, Paclitaxel Treatment, Combination therapy