Biologic therapy or management of cancer

Biologic  therapy or management of cancer

Over the past decade, increasing understanding of cancer biology has fostered the emerging field of 
molecular therapeutics. The basic principle of molecular therapeutics is to exploit the molecular dif­ferences 
between normal cells and cancer cells to develop targeted therapies. The ideal molecular target would be
exclusively expressed in the cancer cells, be the driving-force of the proliferation of the cancer cells, and be 
critical to their survival. A large number of molecular targets are currently being explored, both preclinically 
and in clinical trials. The major groups of targeted therapies include inhibitors of growth factor receptors, 
inhibitors of intracellular signal transduction, cell-cycle inhibitors, apoptosis-based therapies, and antiangiogenic compounds

Protein kineses have come to the forefront as attractive therapeu­tic targets with the success of ST1517 (imitanib mesylate, Gleevec) in chronic myelogenous leukemia and gastrointestinal stromal tu­mors and  
trastuzumab (Herceptin) in breast cancer, which work by targeting bcr-abl, c-kit, and HER2/neu respectively. Sequenc­ing the human genome has revealed about 500 protein kinases.
Several tyrosine kinases have been shown to have oncogenic properties­

, and many other protein kinases have been shown to be aberrantly activated in cancer cells. Therefore, protein kinases involving these aberrantly activated pathways are being ag­ gressively pursued in molecular therapeutics. Potential targets such as HER2/neu can be targeted via different strategies such as trans­ criptional downregulation, targeting of mRNA RNA inhibition, an­tisense strategies, direct inhibition of protein activity, and induction of immunity against the protein . Most of the com­pounds in development are monoclonal antibodies like trastuzumab or small-molecule kinase inhibitors like STl-571. Some of the ki­nase inhibitors in clinical development include inhibitors of EGFR. Ras, Raf, MEK. mammalian target of rapamycin (mTOR). CDK, PKC, and 3.phosphoinositide-dependent protein kinase I (PDK·I)

Development of molecularly targeted agents for clinical use has several unique challenges.Once an appropriate compound is identified and confirmed to have preclinical activity, predictive markers for activity in the preclinical setting must be defined. Expression­
.of a target may not be sufficient to predict response, since the pathway of interest may not be activated or be critical to the cancer,s although in traditional phase1 trails the goal is to identify the maximum tolerated dose the maximum dose of biologic agents may not be necessary to achieve the desired biologic effect most biologic agents are cytostatic not cytotoxic thus rational agents with either established chemotherapeutic agents that have synergy or with other biologic agents is more likely to lead to cancer cures
Strategoes Targeting HER2|neu agents
Anti-HER1|neu antibodies (trastuzumab) act by down regulation of cell surface HER2|neu expression
Tyrosine kinase inhibitors act by inhibition of HER2|neu tyrosine kinase activity
 Anti-HER2|neu peptides act by peptides based on the binding motifs of the anti-HER2|neu
Adenovirus 5 E1 A  act by repression of HER2|neu mRNA transcription
 PEA3 act by as adenovirus
HER2|neu antisense oligonucleotides act by down regulation of HER2|neu mRNA levels 
   Retinoids act by down regulation of HER2|neu mRNA and protein expression


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