Targeting PDGF receptors in cancer--rationales and proof of concept clinical trials

The platelet-derived growth factors (PDGF) are a pleotrophic family of peptide growth factors that signal through cell surface, tyrosine kinase receptors (PDGFR) and stimulate various cellular functions including growth, proliferation, and differentiation. To date, PDGF expression has been demonstrated in a number of different solid tumors, from glioblastomas to prostate carcinomas. In these various tumor types, the biologic role of PDGF signaling can vary from autocrine stimulation of cancer cell growth to subtler paracrine interactions involving adjacent stroma and vasculature. The tyrosine kinase inhibitor imatinib mesylate (formerly STI571, Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) blocks activity of the Bcr-Abl oncoprotein and the cell surface tyrosine kinase receptor c-Kit, and as such was recently approved for several indications in the treatment on chronic myeloid leukemia and gastrointestinal stromal tumors. In both of these examples the target protein was identified by an oncogenic, activating mutation. Imatinib mesylate is also a potent inhibitor of PDGFR kinase and is currently being evaluated for the treatment of chronic myelomonocytic leukemia and glioblastoma multiforme, based upon evidence in these diseases of activating mutations in PDGFR. However, the PDGF pathway may represent a therapeutic target in other solid tumors in which it is not part of the oncogenic transformation. In order to investigate the potential biologic implications of inhibiting PDGFR in these tumor types, clinical trials that investigate both established clinical endpoints of response and benefit, as well as surrogate endpoints that describe the biologic significance of PDGF inhibition in vivo are needed.

Medienart:

Artikel

Erscheinungsjahr:

2003

Erschienen:

2003

Enthalten in:

Zur Gesamtaufnahme - volume:532

Enthalten in:

Advances in experimental medicine and biology - 532(2003) vom: 07., Seite 141-51

Sprache:

Englisch

Beteiligte Personen:

George, Daniel [VerfasserIn]

Themen:

8A1O1M485B
Benzamides
EC 2.7.10.1
Enzyme Inhibitors
Imatinib Mesylate
Journal Article
Ligands
Piperazines
Platelet-Derived Growth Factor
Protein-Tyrosine Kinases
Pyrimidines
Receptors, Platelet-Derived Growth Factor
Review

Anmerkungen:

Date Completed 03.02.2004

Date Revised 22.06.2019

published: Print

Citation Status MEDLINE

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM126628580