The novel targeted anticancer treatments
Varshavsky N. Technion. Haifa, Israel.
Introduction. The conventional non-surgical anti-cancer treatments are mainly based on the
use of cytotoxic drugs or ionizing radiation. These treatments have a potent antitumor
activity, but also cause significant side effects, since they affect cellular targets that are
common to both cancer and normal cells. In addition, the accumulation of multiple
mutations leads to drug resistance in many cancer cells. The recent discoveries of the
molecular mechanisms of cancer development and progression made possible the
development of novel anti-cancer agents which are more specific for cancer cells molecular
targets and less toxic for normal cells.
Objective. To overview the recently developed targeted anti-cancer treatments and the
molecular mechanisms with which these treatments interfere.
Method. A review of the recent medical literature on the subject was performed using the
Medline database.
Results. Growth factors are proteins that bind to cell surface receptors and activate cell
proliferation, differentiation and survival mechanisms. Overactivation of growth factor
signaling pathways is a common reason of tumor cells abnormal proliferation. Epidermal
growth factor receptor (EGFR) is overexpressed in the majority of human cancer types. Two
EGFR targeting therapeutic strategies have shown promising clinical results in breast cancer
patients: monoclonal antibodies against the extracellular domain of EGFR that are blocking
ligand binding and receptor activation (‘Herceptin’), and small molecular inhibitors of the
receptor tyrosine kinase activity that inhibit the intracellular signal transduction (‘Iressa’,
‘Tarceva’).
Additional potential drug targets associated with abnormal control of
proliferation downstream of the EGFR, for example Ras, are under investigation.
The development of solid tumors, as well as the process of tumor metastasis, depends on the
process of tumor angiogenesis, since sprouting capillaries provide gas exchange and nutrient
supply for tumor cells. Overexpression of vascular endothelial growth factor (VEGF) by
tumor cells stimulates tumor angiogenesis. ‘Avastin’, the monoclonal antibody against
VEGF, is the first solely anti-angiogenesis therapy approved for treatment of human cancer.
Small molecular inhibitors of tyrosine kinase activity of VEGF receptors are currently under
development.
Summary. The combination of conventional chemotherapy and radiotherapy with selective
inhibitors of key cancer cells signalling increases the treatment efficiency in several types of
cancer. Increased understanding of signal transduction is now being used for development of
novel therapeutic strategies based on combination of cancer specific targets.
References
* Bianco R. et.al. Key cancer cell signal
transduction pathways as therapeutic targets.
European Journal of Cancer. 2006;42:290-294
* Melisi D. et.al. Therapeutic integration of signal
transduction targeting agents and conventional
anticancer treatments Endocrine-Related Cancer.
2004;11:51-68
* Wakeling A.E. Inhibitors of growth factors signaling.
Endocrine-Related Cancer. 2005;12: s183-s187
* Gille J. Antiangiogenic cancer therapies get their
act together: current developments and future
prospects of growth factor and growth factor receptortargeted approaches. Exp Dermatol. 2006;15(3)175-86.
Acknowledgements
I would like to thank Prof. Avraham Kuten
who offered me to participate in the course;
my supervisor Prof. Gera Neufeld for
guidance and support in my research
work; and the Israel Cancer Association
for financing my participation.
Summer School Participant
Nina Varshavsky.
Nesher
Israel
ninasya@techunix.technion.ac.il