Repurposing hemostatic drug desmopressin in AVPR2-expressing triple-negative breast cancer: Target expression analysis and preclinical antineoplastic effects on tumor growth and metastatic progression.

Juan Garona Center of Translational Medicine, El Cruce “Néstor Kirchner” Hospital, Florencio Varela, Argentina info_outline Juan Garona, Jesus Del Santo Anampa Mesias, Shuwen Lin, Luisina María Solernó, Candela Llavona, Maria florencia Gottardo, Giselle Ripoll, Marina Pifano, Daniel Fernando Alonso

Authors Juan Garona Center of Translational Medicine, El Cruce “Néstor Kirchner” Hospital, Florencio Varela, Argentina info_outline Juan Garona, Jesus Del Santo Anampa Mesias, Shuwen Lin, Luisina María Solernó, Candela Llavona, Maria florencia Gottardo, Giselle Ripoll, Marina Pifano, Daniel Fernando Alonso Organizations Center of Translational Medicine, El Cruce “Néstor Kirchner” Hospital, Florencio Varela, Argentina, Montefiore Einstein Comprehensive Cancer Center/Albert Einstein College of Medicine, Bronx, NY, Center for Molecular and Translational Oncology (COMTra), Science and Technology Department, National University of Quilmes, Bernal, Argentina, Provincial Institute for Cancer Prevention and Treatment (IPC), Buenos Aires, Argentina Abstract Disclosures Research Funding No funding sources reported Background: Desmopressin (dDAVP) is a hemostatic drug that acts as an agonist of the arginine vasopressin receptor 2 (AVPR2) that is present in vascular and malignant cells. Preclinical data show that dDAVP triggers cytostatic mechanisms, blocking angiogenesis and reducing metastases by limiting the survival of circulating tumor cells. Triple-negative breast cancer (TNBC) is associated with poor prognosis due to limited response to therapy and frequent early metastatic recurrence. Considering the unsatisfied clinical need for novel therapeutic options in TNBC, we evaluated the antitumoral activity of dDAVP on experimental models of TNBC, alone or in addition to chemotherapy. We also assessed the expression and clinical impact of AVPR2 in breast cancer samples. Methods: Human and murine TNBC cell lines were used for in vitro experiments. Target expression was assessed by qPCR and immunohistochemistry (IHC), in experimental or clinical tumors (NCT01606072). Effects of dDAVP were evaluated by proliferation, clonogenic, 3D growth and chemotaxis assays, qPCR arrays, and confocal microscopy. Local and distant tumor progression were assessed in vivo in nude or BALB/c mice. TIMER2.0 and UCSC Xena platforms (BRCA TCGA /n = 1260) were used for bioinformatic studies. Results: dDAVP significantly reduced growth and chemotaxis of AVPR2-expressing TNBC cells. Cytostatic effects of dDAVP were associated with altered actin cytoskeleton dynamics and differential expression of angiogenesis and metastasis-related genes. Cooperative effects were observed in vitro and in vivo after combining dDAVP with taxane or alkylating therapy. Tumor-bearing mice were treated with intravenous injections of dDAVP (0.3 µg/kg, thrice weekly) in combination with weekly cycles of paclitaxel (10 mg/kg i.p.) or carmustine (25 mg/kg i.p.). Combination regimens resulted in greater survival and tumor growth and metastasis inhibition. Bioinformatic analysis of the TCGA database showed that AVPR2 had a positive prognostic impact on overall survival in breast cancer patients, especially in the basal-like molecular subtype. AVPR2 also correlated with different immune cell infiltrates such as NK and dendritic cells, and CD4+ and CD8+ T cells. Moreover, AVPR2 expression was detected by IHC in 6/18 breast cancer clinical samples using a small cohort of surgical specimens. Conclusions: AVPR2 expression is associated with improved outcomes in patients with TNBC. Agonist activation of AVPR2 using dDAVP leads to cancer cell growth inhibition in TNBC cell lines and mouse models. We propose dDAVP as a potential novel therapeutic option for treating TNBC either as monotherapy or in combination with chemotherapy. The therapeutic impact of its addition to immune checkpoint inhibitors remains to be explored.

Clinical