Blay_edit2.qxp 23/10/08 09:42 Page 89
New Drugs in the Treatment of Germ Cell Tumours
treated, half of whom obtained an objective response. This combination Suramin
was considered to be feasible and had acceptable toxicities. The main Suramin, a treatment of trypanosomes, also has antitumour activity. It blocks
toxicities were haematological: grade 3/4 leucocytopenia in 15% of the the activity of fibroblast growth factor and platelet-derived growth factor,
patients, anaemia in 7% and thrombocytopenia in 49%. 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
New drugs such as paclitaxel, oxaliplatin and gemcitabine are active germ cell tumours and failed to demonstrate an objective response.
58
when used as single agents or in combination in heavily pre-treated
patients. The response rates and numbers of long-term responders Retinoids
obtained with the association of paclitaxel, ifosfamide and cisplatin in Retinoids induce cellular differentiation and inhibit growth in many solid
good-risk patients receiving first-line salvage therapy are encouraging. tumours. All-trans retinoic acid, in combination with chemotherapy, is
However, there are too few of these patients to perform a phase III trial known to induce cellular differentiation in promyelocytic leukaemia. No
comparing VeIP with TIP regimens. The efficacy of paclitaxel and objective response has been observed with all-trans retinoic acid in two
oxaliplatin in combination with the BEP regimen is being evaluated as phase II trials including germ cell tumour patients.
59,60
first-line treatment in poor-risk groups.
Thalidomide
New Targets Thalidomide has antiangiogenic properties and cytotoxic activity. Fifteen
Intratubular germ-cell neoplasia unclassified (IGCNU) is the precursor patients with disease progression after two cisplatin-based chemotherapy
of invasive testicular germ cell tumour.
37
Patients with IGCNU develop courses have received thalidomide at doses escalated from 100 to a
invasive lesions within five years of diagnosis.
38
Activating mutations of maximum of 600mg daily.
61
No patient has achieved either complete or
KIT
39
and gain of material from 12p are warranted to the development partial response. However, five of the 15 patients had decreased serum
of invasive tumour from IGCNU.
40
All post-pubertal germ cell tumours are tumour marker levels, with a median response duration of three months.
characterised genetically by having one or more copies of isochromosome
12p or excess 12p genetic material.
41
Skotheim et al. have identified an Arsenic Trioxide
amplified region at 12p11.2–12.1 in which several genes of interest Arsenic trioxide has demonstrated activity in acute promyelocytic leukaemia.
(SOX5, JAW1 and K-RAS) are located.
42
OCT3/4, NANOG and SOX2 are In the Southwest Oncology Group (SWOG), 20 heavily pre-treated germ cell
transcription factors that are implicated in embryonic development.
43
tumour patients received arsenic trioxide at a dose of 0.25mg/kg/day
OCT3/4 and NANOG are mainly expressed in IGCNU and seminoma tumour administered intravenously over one to two hours on days one to five; the
specimens. The SOX2 protein is not expressed in germ cell tumours and treatment was repeated every 28 days.
62
There were no complete or partial
human embryonic germ cells; instead, SOX17 is overexpressed in precursor responses. The median progression-free survival was one month and the
of germ cell tumours and seminoma.
44
Germ cell tumours show median overall survival was two months. Severe toxicities were reported.
predominantly wild-type p53.
4
KIT (c-KIT Stem Cell Factor Receptor)
Amplification, specific mutations and the overexpression of KIT and KRAS KIT is a 145kDa transmembrane glycoprotein, a member of the type III
(which is one signalling pathway downstream from KIT) have been reported receptor tyrosine kinase family. Somatic mutations of the KIT gene have
mainly in the treatment of seminoma.
45–47
RAS and KIT activate a number of been reported in mast cell diseases and gastrointestinal stromal tumours. KIT
signalling molecules, including PI3-kinase (PI3K). PI3K is activated by a is necessary for the migration and survival of primordial germ cells and is
number of proteins, such as AKT3, which is generally overexpressed in the expressed in intratubular neoplastic germ cells and seminomas.
63
Mutations
majority of non-seminoma and seminoma.
48
PTEN, which is a tumour of c-Kit in seminoma have been observed in exon 17 and, less frequently, in
suppressor gene, inhibits PI3K activity. Di Vizio et al.
49
reported that the loss exon 11.
64
In a retrospective study, Looijenga et al. have found a mutation
of PTEN is implicated in the progression from ITGCNU to invasive tumours. of c-KIT on codon 816 in three of 224 (1.3%) unilateral and in 57 of 61
A loss or decreased expression of PTEN is reported in 56 and 86% of (93%) proven bilateral germ cell tumours.
39
Bierman et al. have confirmed
seminoma and non-seminoma tumours, respectively.
50,51
Godard et al. have the risk of bilateral germ cell tumour when a somatic c-KIT mutation of
shown evidence of a constitutive activation of the RAF/MEK/ERK pathway in codon 816 is present in the tumour.
65
Unfortunately, these results have not
germ cell tumours.
52
Activated ERK (part of the MAPK signalling cascade) is been confirmed in recent publications.
66
Coffey et al. analysed the
found with a high level of expression in germ cell tumours.
50,51
The gene percentage of activating mutations of c-KIT in exons 11 and 17 in a series of
GRB7, which that is located to 17q12, is overexpressed in germ cell 220 germ cell tumours. Mutations were observed in all seminomas. In germ
tumours.
53
GRB7 protein is a small molecule that binds directly to KIT and cell tumours, one activating mutation was found in exon 11 in a patient with
ERBB2,
54,55
and may play an important role in the regulation of the unilateral disease, and eight in exon 17. One patient of 32 with bilateral
downstream signalling of these different kinases. GRB7 is implicated in cell germ cell tumours had an activating KIT mutation in exon 17 (3.1%).
66
migration.
56
KIT also activates members of the STAT family of proteins.
57
STAT signalling is involved in migration and proliferation of the primordial The most important retrospective analysis of KIT expression in germ cell
germ cells.
58
High levels of activated STAT3 are observed in most tumours was published by Nikolaou.
67
Thirty-eight of 49 patients (77.5%)
non-seminomas and seminomas.
50,51
with pure seminoma had positive staining for KIT. Scarce data are available
in refractory germ cell tumours. In a series of 22 cisplatin-refractory germ
New targeted agents have been developed in refractory disease. Their cell tumours, only tissues from pure seminoma or with a seminoma
study is based on both knowledge of molecular biology mechanisms component were positively stained for KIT.
68
Madani et al.
69
performed an
involved in germ cell tumours and the empirical approach of new drugs. immunohistochemical analysis of KIT expression in 23 tissue samples
We present the data of targeted agents published in this setting. obtained from the most recently available metastatic site in
EUROPEAN ONCOLOGY 89
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99