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Non-small
cell lung cancer: emerging therapies |
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| Lung cancer is a
common cancer in the Singapore, accounting for most cancer deaths.
20 years ago, non-small cell lung cancer (NSCLC) was a veritable
death sentence as the disease was not chemo-sensitive. Later,
for advanced disease, platinum-based chemotherapy showed survival
benefits over best supportive care. These drugs were the mainstays
in the last decade. However, this scenario is changing rapidly.
Better understanding of the carcinogenesis has led to discovery
of key steps that can be targeted with novel molecular targeted
therapies. These include: |
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a) Growth
factor receptors and dominant oncogenes: NSCLC
over expresses erbB-1, an oncogene that codes for epidermal
growth factor receptor (EGFR). Monoclonal antibodies (e.g.
C225) and small molecule tyrosine kinase inhibitors (e.g.
ZD1839, OSI 774) have undergone phase III trials in advanced
NSCLC and ZD1839 (IRESSA) has recently been approved as
salvage therapy after failing chemotherapy.
b) Farnesyl-transferase inhibitors (FTI):
The Ras oncogene is mutated in most NSCLC. This gene product
needs to undergo a critical step in the signalling pathway,
called ‘farrnesylation’. FTI’s block this
event and control cancer growth. These agents have been
tested alone or in combination with chemotherapy, with modest
success. This signal transduction can also be blocked with
anti-sense oligonucleotides (e.g. Isis 3521, Isis 5132),
that are also in clinical testing.
c) Cell cycle/proliferation and apoptosis:
New agents (e.g. flavopiridol) are being developed to inhibit
cyclins and cyclin-dependent kinase activity, which control
the proliferation machinery in cancerous cells.
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Apart
from discovery of these targeted therapies or smart bombs, newer,
less toxic chemotherapy agents are also being evaluated. Many
new drugs have shown good results in phase II studies in combination
with cisplatin. Further testing without cisplatin to reduce
the toxicity is currently being confirmed. These include gemcitabine,
docetaxel, vinorelbine etc. Hence the treatment of NSCLC is
not yet optimal.
The NCC Thoracic Oncology service has ongoing clinical studies
involving new drugs. Active patient participation is vital to
finding new therapeutic options. In the near future, with the
deciphering of the human genome and understanding of how each
patient responds to chemotherapy based on genotype, we hope
to ‘tailor’ chemotherapy for every patient by maximising
benefit and minimising toxicity. New trial designs are now incorporating
this pharmacogenomic strategy.
Dr Darren Lim
Registrar, Medical Oncology |
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