Antitumour activity of the desmopressin analogue [V4Q5]dDAVP as a single agent and in combination with chemotherapy in aggressive V2r-expressing breast carcinoma models

GARONA J; PIFANO M; PASTRIAN MB; IANNUCCI NB; GOMEZ DE; RIPOLL GV; ALONSO DF

Congreso; 20th World Congress on Advances in Oncology and 18th International Symposium on Molecular Medicine; 2015

Metastatic breast cancer is still considered an incurable disease and remains a major therapeutic challenge. In this setting, treatment strategies have evolved in recent years, however chemotherapy remains a core component for the majority of patients. Unfortunately, there are important limitations with its use, including resistance and risk of cumulative toxicities. Desmopressin, or dDAVP, is a safe haemostatic agent with previously reported antitumour activity against aggressive breast cancer. It acts as a selective agonist for the V2 vasopressin membrane receptor (V2r) present on tumour cells and microvasculature. Experimental and clinical data revealed that perioperative dDAVP therapy can minimize spread and survival of residual breast cancer cells. In the present work, we investigated the ability of the novel peptide derivative [V4Q5]dDAVP in combination with cytotoxic therapy to impair V2r-expressing breast cancer progression. We assessed antitumour effects of [V4Q5]dDAVP plus chemotherapy using human triple-negative MDA-MB-231 breast carcinoma cells, as well as the highly metastatic and hormone-independent mouse F3II cell line. Effect on in vitro cancer cell growth was evaluated by cell proliferation and 3D cultures. In order to study the effect of intravenously administered [V4Q5]dDAVP (0.3 g/kg, thrice a week) plus paclitaxel (10 mg/kg i.p.) on tumour growth, breast cancer xenografts were generated in athymic nude mice. F3II cells were injected into syngeneic mice to evaluate the effect of [V4Q5]dDAVP plus carmustine (20 mg/kg i.p.) on spontaneous metastatic spread. During concurrent administration of cytotoxic drugs and [V4Q5]dDAVP, mammary tumour growth and aggressiveness was severely impaired compared to control and single treatment groups. In the xenograft model, sustained administration of [V4Q5]dDAVP, given alone or in combination with paclitaxel, resulted in a significant increase in survival in comparison to vehicle or paclitaxel treatment alone. In vitro, combination treatment caused a significant reduction in colony formation and multicellular tumour spheroid growth. Cooperative effects were also observed after evaluation of the carmustine-[V4Q5]dDAVP treatment regimen, where mice receiving combined therapy showed a marked reduction of skin tumour infiltration. As expected, weekly cycles of carmustine significantly reduced metastatic progression. Remarkably, the novel analogue [V4Q5]dDAVP, alone or in combination with chemotherapy, was able to completely abolish metastatic progression to lungs. Preclinical efficacy of [V4Q5]dDAVP in combination with chemotherapy supports further clinical development as a novel adjuvant combination therapy in aggressive and metastatic hormone-independent breast cancer.