No abstract

Introduction: The androgen receptor (AR) is widely expressed in breast cancers and has been proposed as a therapeutic target in estrogen receptor alpha (ER) negative breast cancers that retain AR. However, controversy exists regarding the role of AR, particularly in ER + tumors. Enzalutamide, an AR inhibitor that impairs nuclear localization of AR, was used to elucidate the role of AR in preclinical models of ER positive and negative breast cancer.

A therapeutic intervention that could decrease tumor burden and increase sensitivity to chemotherapy would have a significant impact on the high morbidity rate associated with ovarian cancer. MicroRNAs (miRNAs) have emerged as potential therapeutic candidates due to their ability to down regulate multiple targets involved in tumor progression and chemoresistance. MiR-200c is down regulated in ovarian cancer cell lines and stage III ovarian tumors, and low miR-200c correlates with poor prognosis. MiR-200c increases sensitivity to taxanes in vitro, by targeting TUBB3, a tubulin known to mediate chemoresistance. Indeed, we find that patients with tumors with low TUBB3 had significantly prolonged survival (average survival 52.73 ± 4.08 months) compared to those with high TUBB3 (average survival 42.56 ±3.19 months). MiR-200c also targets TrkB, a mediator of resistance to anoikis. We demonstrate that restoration of miR-200c to ovarian cancer cells results in increased anoikis sensitivity and reduced adherence to biological substrates in vitro. Since both chemo- and anoikis-resistance are critical steps in the progression of ovarian cancer, we sought to determine how restoration of miR-200c affects tumor burden and chemosensitivity in an in vivo preclinical model of ovarian cancer. Restoration of miR-200c in an intraperitoneal xenograft model of human ovarian cancer, results in decreased tumor formation and tumor burden. Furthermore, even in established tumors, restoration of miR-200c, alone or in combination with paclitaxel, results in significantly decreased tumor burden. Our study suggests that restoration of miR-200c immediately prior to cytotoxic chemotherapy may allow for a better response or lower effective dose.

Immunotherapies targeting the PD-1/PD-L1 axis are now a mainstay in the clinical management of multiple cancer types, however, many tumors still fail to respond. CCL2 is highly expressed in various cancer types and has been shown to be associated with poor prognosis. Inhibition or blockade of the CCL2/CCR2 signaling axis has thus been an area of interest for cancer therapy. Here we show across multiple murine tumor and metastasis models that CCR2 antagonism in combination with anti-PD-1 therapy leads to sensitization and enhanced tumor response over anti-PD-1 monotherapy. We show that enhanced treatment response correlates with enhanced CD8+ T cell recruitment and activation and a concomitant decrease in CD4+ regulatory T cell. These results provide strong preclinical rationale for further clinical exploration of combining CCR2 antagonism with PD-1/PD-L1-directed immunotherapies across multiple tumor types especially given the availability of small molecule CCR2 inhibitors and antibodies.