Clinical trials with retinoids for breast cancer chemoprevention

Abstract

Retinoids have been studied as chemopreventive agents in clinical trials due to their established role in regulating cell growth, differentiation and apoptosis in preclinical models. Experimental evidence suggests that retinoids affect gene expression both directly, by activating and/or repressing specific genes, and indirectly, by interfering with different signal transduction pathways. Induction of apoptosis is a unique feature of fenretinide, the most widely studied retinoid in clinical trials on breast cancer chemoprevention due to its selective accumulation in breast tissue and to its favourable toxicological profile. In a phase III breast cancer prevention trial, fenretinide showed a durable trend to a reduction of second breast malignancies in premenopausal women. This pattern was associated with a favourable modulation of circulating IGF-I and its main binding protein (IGFbinding protein-3, IGFBP-3), which have been associated with breast cancer risk in premenopausal women in different prospective studies. In a subsequent biomarker study on premenopausal women who had participated in the phase III trial, high IGF-I and low IGFBP-3 baseline levels were found to predict second breast cancer risk, although the magnitude of their changes during treatment did not fulfil the requirements for suitable surrogate end-point biomarkers. In postmenopausal women, fenretinide did not reduce second breast cancer incidence, nor did it induce significant modulation of the IGF system. Similarly, fenretinide was not found to affect risk biomarkers significantly in early postmenopausal women on hormone replacement therapy, who are at increased risk of developing breast cancer. Biomarker studies of fenretinide alone or in combination with different nuclear receptor ligands are being conducted. In particular, clinical trials of fenretinide and tamoxifen have proved to be feasible, and this combination appears to be safe and well tolerated in high-risk women, especially when low-dose tamoxifen is employed. Novel retinoid X receptor-selective retinoids, or rexinoids, have been shown to suppress the development of breast cancer in several animal models with minimal toxicity, and are being intensively studied either alone or in combination with selective oestrogen receptor modulators, both in vitro and in vivo. The rexinoid, bexarotene, has recently been approved for the treatment of patients with cutaneous T-cell lymphoma, and a biomarker trial with bexarotene in women with high breast cancer risk is currently underway.

Fenretinide inhibited de novo ceramide synthesis and proinflammatory cytokines induced by Aggregatibacter actinomycetemcomitans

“…Fenretinide has been widely used in clinical trials for breast cancer chemoprevention ( 5 ) and for treatment of neuroblastoma and Ewing sarcoma ( 6 ). It has been shown that fenretinide inhibits the proliferation of many tumor cell lines (7)(8)(9)(10)(11), whereas it manifests minimal cytotoxicity to nonmalignant cells ( 7,12 ).…”

E2F1 impairs all-trans retinoic acid-induced osteogenic differentiation of osteosarcoma via promoting ubiquitination-mediated degradation of RARα

“…[9][10][11][12][13] We, along with others, also have found that ATRA induces osteoblastic differentiation of osteosarcoma cells both in vivo and in vitro. 14,15 Moreover, ATRA has been found to induce osteoblastic differentiation of mouse and rat mesenchymal stem cells and preosteoblasts.…”

The sensitivity of the Ewing's sarcoma family of tumours to fenretinide-induced cell death is increased by EWS-Fli1-dependent modulation of p38MAPK activity

“…Fenretinide is a retinamide with both chemopreventative (Zanardi et al, 2006) and chemotherapeutic properties in a range of adult malignancies (Chiesa et al, 2005;Simeone et al, 2005), and has manageable toxicity in adults (Formelli et al, 1993;Pienta et al, 1997) and children (Garaventa et al, 2003;Villablanca et al, 2006). We have reported previously that fenretinide induces cell death in the Ewing's sarcoma family of tumours (ESFT) in vitro and reduces ESFT growth in vivo (Myatt et al, 2005), suggesting it may represent a novel therapeutic strategy for the treatment of this aggressive tumour of bone and soft tissue (Burchill, 2003).…”