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Gynaecological Cancer NGR-hTNF plus Doxorubicin in Recurrent Ovarian Cancer Domenica Lorusso, 1 Paola Malaguti, 2 Giovanni Scambia, 3 Claudio Bordignon 4 and Francesco Raspagliesi 5 1. Assistant Professor, Department of Gynaecologic Oncology, National Cancer Institute, Milan; 2. Assistant Professor, Department of Gynaecologic Oncology, Catholic University of Rome; 3. Professor, Department of Gynaecologic Oncology, Catholic University of Rome; 4. Founder, MolMed SpA, Milan and Professor of Haematology, University of San Raffaele; 5. Assistant Professor, University of San Raffaele, Italy Abstract Ovarian cancer is the most lethal gynaecological cancer. Despite surgery and first-line chemotherapy, tumours recur in 60–70 % of cases and prognosis is poor. Several studies have indicated that the cytokine tumour necrosis factor (TNF) has antitumour activity when given systematically, but its high toxicity has limited its use. Peptides containing the aspargine-glycine-arginine motif (NGR peptides) selectively bind to the aminopeptidase N ligand CD13, which is overexpressed in the cells of tumour blood vessels. It has been found that the combination of an NGR peptide and human TNF (NGR-hTNF) has the ability to increase intratumoural doxorubicin distribution by altering the tumour vasculature. In this article, we describe the activity and toxicity profile of NGR-hTNF plus doxorubicin as a combination treatment for recurrent ovarian cancer. Keywords Recurrent ovarian cancer, NGR-hTNF, doxorubicin, platinum-sensitive, platinum-resistant Disclosure: Claudio Bordignon is an employee of MolMed SpA. The remaining authors have no conflicts of interest to declare. Received: 21 November 2011 Accepted: 3 January 2012 Citation: European Oncology & Haematology, 2012;8(2):107–10 Correspondence: Domenica Lorusso, Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milano, Italy. E: kettalorusso@libero.it Ovarian cancer is the most lethal gynaecological cancer. In the US, approximately 21,880 new cases were identified and 13,850 women died of the disease in 2010. 1 In the European Union, the number of newly diagnosed cases was 42,700 in 2004 and the mortality rate is 12 per 100,000 women per year. 2 The current treatment for ovarian cancer is aggressive cytoreductive surgery followed by platinum- and taxane-based chemotherapy, with an objective response rate of 65–80 %. 3 However, 60–70 % of cancers recur and patients’ prognosis and quality of life remain poor. 4 Platinum-based combinations are the standard treatment for patients whose cancer recurs more than six months after the initial therapy. 5 Combination treatment with paclitaxel and gemcitabine has been associated with better outcomes than platinum monotherapy in platinum-sensitive patients with recurrent tumours. 6 Recently, the CALYPSO trial – a multinational, randomised, Phase III study comparing pegylated liposomal doxorubicin (PLD) and carboplatin versus paclitaxel and carboplatin in patients with relapsed, platinum-sensitive ovarian cancer – reported a greater therapeutic index for the PLD plus carboplatin combination, which thus represents, for most clinicians, the preferred option in this setting. 7 The response to platinum retreatment is related to the duration of the prior response to platinum. 8,9 It has been postulated that patients with partially platinum-sensitive recurrent ovarian cancer (i.e., those with a platinum-free interval of six to 12 months before recurrence) may benefit from a strategy of artificially extending the platinum-free interval by using a non-platinum agent at first relapse, followed by platinum at subsequent relapse. 10 This strategy is supported by the results of the OVA-301 study (ClinicalTrials.gov identifier © TOUCH BRIEFINGS 2012 NCT00113607), which investigated trabectedin plus PLD in patients with relapsed, partially platinum-sensitive ovarian cancer. 11 Several clinicians accept trabectedin plus PLD combination as an alternative to platinum-based regimens in this setting. In general, platinum-resistant patients (those whose cancer recurs less than six months after the last platinum treatment) are treated with sequential, single non-platinum agents – such as paclitaxel, doxorubicin, etoposide or topotecan – rather than with combination therapy. 4 These drugs are associated with a short-lasting response in 10–25 % of patients, who have a generally dismal prognosis. 8,9 Novel treatment strategies are required to improve outcomes in women with recurrent ovarian cancer, particularly platinum-resistant disease. In this article, we look at one such option: the combination of a peptide containing the aspargine-glycine-arginine motif (NGR peptide) with human tumour necrosis factor (hTNF) plus doxorubicin. Combination of an NGR Peptide and Human Tumour Necrosis Factor (NGR-hTNF) TNF was first identified by Carswell et al. in the serum of Bacillus Calmette-Guérin-sensitised animals treated with an endotoxin that caused the release of a factor capable of inducing haemorrhagic necrosis of murine tumours. 12 TNF has been shown to have cytostatic and cytotoxic effects against a wide range of human tumour cells and human tumour xenografts in nude mice. 13,14 In addition to these properties, TNF has a broad spectrum of immunomodulatory activities, 15 such as enhancing the expression of Class I major histocompatibility antigens on human endothelial cells, dermal fibroblasts and human tumour cell line 16,17 as well as enhancing the 107