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Signal transduction--directed cancer treatments
Edward A Sausville1, Yusri Elsayed, Manish Monga
1Developmental Therapeutics Program, National Cancer Institute, Rockville, Maryland 20852, USA. sausville@nih.gov
Abstract:
The pathogenic mechanisms giving rise to cancer frequently involve altered signal transduction pathways. Therefore therapeutic agents that directly address signal transduction molecules are being explored as cancer treatments. Inhibitors of protein tyrosine and threonine kinases including STI-571, ZD-1839, OSI-774, and flavopiridol are ATP-site antagonists that have completed initial phase I and phase II evaluations. Herceptin and C225 are monoclonal antibodies also directed against signaling targets. Numerous other kinase antagonists are in clinical evaluation, including UCN-01 and PD184352. Alternative strategies to downmodulate kinase-driven signaling include 17-allyl-amino-17-demethoxygeldanamycin and rapamycin derivatives, and phospholipase-directed signaling may be modulated by alkylphospholipids. Farnesyltransferase inhibitors were originally developed as inhibitors of ras-driven signals but may have activity by affecting other or additional targets. Signal transduction will remain a fertile basis for suggesting cancer treatments of the future, the evaluation of which should include monitoring effects of the drugs on their intended target signaling molecules in preclinical and early clinical studies.
Insights
Targeting cancer
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cancer pathogenesis often involves dysregulated signal transduction pathways.
- Targeting these pathways offers a promising therapeutic strategy for cancer treatment.
Purpose of the Study:
- To review current and emerging therapeutic agents targeting signal transduction pathways in cancer.
- To highlight the role of kinase inhibitors, monoclonal antibodies, and other modulators.
Main Methods:
- Review of clinical trial data for various targeted therapies.
- Analysis of drug mechanisms targeting specific signaling molecules.
- Discussion of alternative strategies like geldanamycin and rapamycin derivatives.
Main Results:
- Several ATP-site kinase inhibitors (e.g., STI-571, ZD-1839) have advanced through early clinical trials.
- Monoclonal antibodies (e.g., Herceptin, C225) targeting signaling molecules are in use.
- Diverse agents targeting kinases, phospholipases, and farnesyltransferase are under investigation.
Conclusions:
- Signal transduction pathways are a critical focus for future cancer therapy development.
- Evaluating drug efficacy requires monitoring effects on target signaling molecules in preclinical and clinical studies.