New Drugs in the Treatment of Germ Cell Tumours

New Drugs in the Treatment of Germ Cell Tumours

Aude Fléchon, Jean-Pierre Droz, Jean-Yves Blay


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Amplification, specific mutations and the overexpression of KIT and KRAS (which is one signalling pathway downstream from KIT) have been reported mainly in the treatment of seminoma.45–47 RAS and KIT activate a number of signalling molecules, including PI3-kinase (PI3K). PI3K is activated by a number of proteins, such as AKT3, which is generally overexpressed in the majority of non-seminoma and seminoma.48 PTEN, which is a tumour suppressor gene, inhibits PI3K activity. Di Vizio et al.49 reported that the loss of PTEN is implicated in the progression from ITGCNU to invasive tumours. A loss or decreased expression of PTEN is reported in 56 and 86% of seminoma and non-seminoma tumours, respectively.50,51 Godard et al. have shown evidence of a constitutive activation of the RAF/MEK/ERK pathway in germ cell tumours.52 Activated ERK (part of the MAPK signalling cascade) is found with a high level of expression in germ cell tumours.50,51 The gene GRB7, which that is located to 17q12, is overexpressed in germ cell tumours.53 GRB7 protein is a small molecule that binds directly to KIT and ERBB2,54,55 and may play an important role in the regulation of the downstream signalling of these different kinases. GRB7 is implicated in cell migration.56 KIT also activates members of the STAT family of proteins.57 STAT signalling is involved in migration and proliferation of the primordial germ cells.58 High levels of activated STAT3 are observed in most non-seminomas and seminomas.50,51

New targeted agents have been developed in refractory disease. Their study is based on both knowledge of molecular biology mechanisms involved in germ cell tumours and the empirical approach of new drugs. We present the data of targeted agents published in this setting.

Suramin
Suramin, a treatment of trypanosomes, also has antitumour activity. It blocks the activity of fibroblast growth factor and platelet-derived growth factor, and inhibits angiogenesis in vitro. Motzer et al. have reported a phase II trial of continious infusion of suramin in 14 cisplatin-refractory patients with germ cell tumours and failed to demonstrate an objective response.58

Retinoids
Retinoids induce cellular differentiation and inhibit growth in many solid tumours. All-trans retinoic acid, in combination with chemotherapy, is known to induce cellular differentiation in promyelocytic leukaemia. No objective response has been observed with all-trans retinoic acid in two phase II trials including germ cell tumour patients.59,60

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