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Renal Cell Carcinoma
Targeted Therapy in Advanced Renal Cell Carcinoma
a report by
Cora N Sternberg
Chief, Department of Medical Oncology, San Camillo and Forlanini Hospitals, and Professor, Oncology School, University of Rome
Renal cell carcinoma (RCC) comprises approximately 3% of adult (Nexavar
®
, Bayer) and sunitinib (Sutent
®
, Pfizer) – and the mammalian
malignancies
1
and is the most common neoplasm arising from the target of rapamycin (mTOR) inhibitor temsirolimus (Torisel
®
, Wyeth),
kidney. RCC is a highly heterogeneous disease, with the most frequent which was approved by the FDA for metastastic RCC in May 2007 and
form being clear-cell RCC.
2
Early detection of RCC and surgical is currently undergoing review by the EMEA.
management can cure 60–70% of patients with localised disease.
1
Advances in non-invasive diagnostic imaging procedures have Rationale for Targeted Therapy
increased the rate of early detection;
3
however, approximately one- In recent years, advances in genetics and molecular markers have led to
third of the patients with RCC still present with metastatic disease and a better understanding of the biology of RCC. Specifically, the discovery
up to 50% relapse following initial surgical resection.
4
The poor of the von Hippel–Lindau (VHL) tumour-suppressor gene and the
prognosis for metastatic disease is due to a high degree of resistance hypoxia-inducing factor (HIF) pathway in clear-cell RCC has provided a
to chemotherapy.
5
Until recently, immunotherapy with interferon (IFN) valuable substrate for the application of targeted therapy.
7,8
and interleukin-2 (IL-2) were the only effective treatments for
metastatic disease. However, response rates with these therapeutic Mutations and loss of function of the VHL tumour-suppressor gene
options are at best still only 15%, and the consensus is that cytokine lead to an increased concentration of HIF-1, which in turn lead to the
therapy is of limited benefit for the majority of patients.
6
This induction of hundreds of genes and proteins that affect many
highlights the urgent need for more effective treatments for patients signalling pathways. These signalling pathways, in part, assist the cell
with advanced RCC. to respond to hypoxia and stimulate angiogenesis.
7
Advances in the understanding of the biology and genetics of RCC In RCC, expression of vascular endothelial growth factor (VEGF), 74
have led to the development of novel targeted approaches for the kDa serine/threonine kinase (Raf), platelet-derived growth factor
treatment of metastatic RCC. These targeted therapies promise (PDGF) and its receptor (PDGFR) are increased and appear to be
improvements in progression-free survival, better response rates and integral to tumour proliferation and angiogenesis of clear-cell RCC.
9
improved overall survival (OS) in selected populations. Coupled with Thus, RCC is specifically suited for targeting with inhibitors of one or
greater knowledge of prognostic factors, these new targeted agents more of these kinase pathways.
may have improved the poor outcome rates that have been unchanged
for decades. In cancer cells, signal transduction is a complex process that involves
receptors and receptor TKs (RTKs) that in turn trigger cytoplasmic
This review focuses on three new therapeutic options that target signal kinases. Several cellular signalling pathways may work independently,
transduction for use in metastatic RCC, which have been approved by in parallel and/or through interconnections to promote cancer
the US Food and Drug Administration (FDA) and the European development, growth and survival. Clear-cell RCC has been associated
Medicines Agency (EMEA). The three new therapeutic options are two with VEGF, PDGF and phosphatidylinositol-3-kinase (PI3K)/AKT/
multitargeted tyrosine kinase (TK) inhibitor agents – sorafenib mTOR/S6/HIF pathways.
10
Multitargeted Agents
Cora N Sternberg is Chief of the Department of Medical
Considering that many biological pathways are implicated in tumour
Oncology at San Camillo and Forlanini Hospitals in Rome,
and Professor in the Oncology School of Specialisation at proliferation, antitumour activity should theoretically be increased by
the University of Rome. She is also Adjunct Professor of
using multitargeted agents.
Medicine, Urology and Urological Oncology in the
Department of Medicine at Tufts University School of
Medicine and Lahey Clinic, both in Boston. Professor Sunitinib
Sternberg is an Executive Board Member of the European
Sunitinib is an orally bioavailable, small-molecule, multitargeted RTK
Organisation for Research and Treatment of Cancer
(EORTC) and a Faculty Member of the Educational Committee of the European Society of
inhibitor. Sunitinib targets VEGFR-2, PDGFR-µ, CD117 protein (c-KIT)
Medical Oncology (CRSMO), where she is the Co-ordinator of Genito-urinary–Oncology
and FMS-like tyrosine kinase (Flt-3) receptors, all multiple-signalling
Education 2006–2008. Her primary interests include clinical and translational research,
molecular mechanisms of risk and progression of tumours and developmental therapeutics in
pathways, resulting in a dual-action antiproliferative and
solid tumours. Professor Sternberg has published two books, more than 155 articles in peer- antiangiogenic effect.
reviewed journals and 60 book chapters, and has given more than 360 invited lectures. She is
a strong advocate of education and the rights of patients.
The antineoplastic agent has shown antitumour activity by inhibiting
RTKs expressed by endothelial or stromal cells (pericytes) that
40 © TOUCH BRIEFINGS 2007
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