Preclinical Assessment of Cadherin11 Antagonists for Treating Drug-Resistant Breast Cancer through Modulating Tumor Immunity and Suppression of Cancer Stem Cells

Distant metastasis and drug resistance represent the two major causes for breast cancer mortality. The majority of breast cancer patients who develop metastases also demonstrate multi-drug resistance. The presence of breast cancer stem cells (BCSCs) in these patients might be the underlying key elements for their clinical manifestations. Hence, targeting BCSCs represents an ideal goal for therapeutic development. Recently, cadherin 11 (CDH11) has been shown to be a key mediator for breast-to-bone metastasis; disrupting CDH11-mediated signaling represents an ideal target for drug development. Using bioinformatics approach, our team has identified two known small molecules (temporarily named RD-1 and RD-2) which can down-regulate CDH11 expression in different cancer cell lines including breast. In parallel, we have teamed up with an industrial partner developed who has produced a line of monoclonal anti-CDH11 antibodies with high specificity and neutralizing ability in suppressing breast cancer tumorigenesis and metastasis. Preliminarily, we have demonstrated that CDH11 level appeared to be higher in breast cancer cell lines with higher metastatic potential. In addition, mammospheres express a significantly higher level of CDH11 as compared to their parental counterparts. Our data linked the elevated CDH11 level to the higher metastatic potential and self-renewal ability. Importantly, the disruption of CDH11 signaling was accompanied with the decreased level of stemness genes. The following specific aims are proposed to achieve our objectives. Specific aim 1: Explore the role of CDH11 in the generation of BCSCs and phenotypes associated with BCSCs. Specific aim 2: Evaluation the anti-BCSC and immune modulating effects of RD-1, RD-2 and anti-CDH11 antibody Specific aim 3: Establishment of clinical association between CDH11 and breast cancer progression/recurrence. The completion of this project will provide important preclinical evidence for supporting CDH11 antagonists for treating drug-resistant breast cancer in the clinical trials and settings.