Abstract 3132: Inhibition of the integrin αVβ3 improves the effect of bexarotene in the treatment of cutaneous T-cell lymphoma (CTCL)

Abstract

Abstract CTCL are exposed to a complex paracrine and endocrine environment that influence their progression from skin to visceral disease. One of the most common treatments for CTCL is RXR agonists or “rexinoids” such as bexarotene (BEX). The most prevalent side effect of rexinoids (~95% of patients) is the development of hypothyroidism hence these patients are prophylactically treated with thyroid hormone (TH). Paradoxically, we recently found (PMID: 25488971) that TH can activate transcriptional programs required for proliferation of CTCL. We also found that the effects of TH on CTCL are mediated through the activation of two different receptors, the classical nuclear TR and a membrane receptor integrin αVβ3. Our aim was to study how the anti-lymphoma activity of BEX is modified by the activation of TR and αVβ3 during the TH replacement therapy, and unknown topic with clinical implications. We first evaluate the cell viability of CTCL cells HuT78 and MJ treated with BEX in presence and absence of physiological levels of TH. As expected, BEX decreased the viability of CTCL cells, however in presence of TH both effects decreased by 25-60% and 20-50% on HuT78 and MJ cells. However, hypothyroidism is associated with a higher dissemination of TCL cells in syngeneic mice. Thus, to evaluate the impact of TH replacement therapy in BEX-treated mice, we implanted TCL EL-4 cells subcutaneously in C57BL/6 mice. When tumors reached ~75 mm3, mice were randomized in three groups: vehicle, bexarotene alone (BEX) and bexarotene with T4 replacement (to reach euthyroidism) (BEX-T4). Tumor growth significantly decreased in both bexarotene arms (vs. vehicle). However, in contrast to mice receiving BEX-T4, mice receiving BEX alone showed a decreased infiltration of tumor-suppressive immune cells. Specifically, these tumors had decreased NK and CD3+CD8+ cells due to BEX-induced hypothyroidism. This indicates that although TH could decrease the effect of BEX in CTCL cells, the hypothyroidism would impact in the local antitumor response. Thus determine if the inhibition of the non-canonical TH membrane receptor integrin αVβ3 would decrease the pro-survival effect of TH on CTCL treated with BEX. We found that either, αVβ3 silencing or the pharmacological inhibitor Cilengitide, not only avoided the pro-survival effect of TH but increased the anti-lymphoma activity of BEX-T4 by 15-35% in CTCL cells. To evaluate the molecular program underpinning these effects, we conducted RNA-sequencing in HuT78 cells treated with BEX-T4 in presence of siRNA for TR, αVβ3 or controls. Among the top pathways we identified genes involved in “apoptosis”, “angiogenesis” and “IL6-JAK-STAT3 signaling” as differentially expressed in si-αVβ3 vs. the others. These genes were independently validated by using Cilengitide. Our data suggest that inhibition of the non-canonical TH receptor, the integrin αVβ3, could be an effective strategy to improve BEX treatment in CTCL Citation Format: Florencia Cayrol, Victoria Revueta, Alejandra Paulazo, Mercedes Debernardi, Maria Celeste Diaz Flaque, Helena Sterle, Leandro Cerchietti, Graciela Cremaschi. Inhibition of the integrin αVβ3 improves the effect of bexarotene in the treatment of cutaneous T-cell lymphoma (CTCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3132. doi:10.1158/1538-7445.AM2017-3132