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Glioblastomas and Sarcomas

Several observations provide a rationale for clinical studies with STI571 in the treatment of glioblastomas and sarcomas:

1. PDGFRa and PDGF-A chain are co-expressed in tumor cells with increasing frequency in high-grade, as compared to low-grade, tumors (Hermanson et al. 1996).

binding of STI571 (dark) to Abl kinase domain (light). Hydrogen bonds to (from left to right) M318, T315, E286, D381, I360, and H361. The inhibitor has packing interactions with Phe317, Phe382, Val256, Tyr253, Ile313, Lys271, Met290, Val299, Ala380, and Val289. c STI571 binding to Kit. Details of the binding of STI571 (dark) to Kit kinase domain (light). Hydrogen bonds to (from left to right) C673, T670, E640, I789, and H790. d STI571 binding to PDGFRb. Details of the binding of STI571 (dark) to PDGFRb kinase domain (light). Potential hydrogen bonds to (from left to right) C684, T681, E651, D844, I823, and H824

2. Amplified and oncogenic forms of the PDGFRa gene have been found in glioblastomas (Fleming et al. 1992; Kumabe et al. 1992; Clarke and Dirks 2003).

3. Expression of PDGF-B and PDGFRb are frequently observed in various soft tissue tumors and sarcomas (Smits et al. 1992), while in Ewing family sarcomas the expression of PDGF-C is strongly up regulated (Zwerner and May 2001).

4. Experimental glioblastoma can be inhibited in in vivo animal models by STI571 (Shamah et al. 1993; Strawn et al. 1994; Kilic et al. 2000), while dominant-negative PDGF-C, as well as AG1296, a PDGFR kinase antagonist, inhibited growth of Ewing sarcoma cells in vitro (Zwerner and May 2002).

As mutations causing constitutive activation of PDGFRa have recently been found in a subset of GISTs that were responsive to STI571 (Heinrich et al. 2003a,b), it cannot be excluded that the PDGFR may be mutated more frequently in tumors, including glioblastoma and sarcomas. The utility of PDGF signaling inhibitors like STI571 for the treatment of sarcoma and gli-oblastoma will only be revealed in carefully controlled clinical trials.

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