ABTC-0904: targeting glioma stem cells in GBM: a phase 0/II study of hedgehog pathway inhibitor GDC-0449.

Autor: Sloan, Andrew E., Nock, Charles J., Ye, Xiaobu, Buerki, Robert, Chang, Susan, Lesser, Glenn, Norden, Andrew, Cloughesy, Timothy, Olson, Jeffrey, Kerstetter-Fogle, Amber, Rich, Jeremy, Fisher, Joy, Desideri, Serena, Takebe, Naoko, Timmer, William, Grossman, Stuart, Prados, Michael
Zdroj: Journal of Neuro-Oncology; Jan2023, Vol. 161 Issue 1, p33-43, 11p
Abstrakt: Purpose: Gliomagenesis and resistance of glioblastoma (GBM) are believed to be mediated by glioma stem cells (GSC). Evidence suggests that SHH signaling promotes GSC proliferation and self-renewal. Methods: ABTC-0904 was a two-arm, multicenter phase 0/II study of GDC-0449, an oral inhibitor of Smoothened (SMO) in patients undergoing resection for recurrent GBM. All patients (Arms I and II) had surgery and received drug post-operatively. Only patients in Arm I received drug prior to surgery. The primary objective was to determine 6-month progression free survival (PFS-6). Secondary endpoints include median PFS (mPFS) and overall survival (mOS), response rate, and toxicity. Correlative studies included bioanalysis of GDC-0449, and inhibition of SHH signaling, GSC proliferation and self-renewal. Results: Forty-one patients were enrolled. Pharmacokinetics of GDC-0449 in plasma demonstrated levels within expected therapeutic range in 75% of patients. The proportion of tumorcells producing CD133+ neurospheres, neurosphere proliferation, self-renewal, and expression of the SHh downstream signaling was significantly decreased in Arm I following GDC-0449 treatment (p < 0.005; p < 0.001 respectively) compared to Arm II (no drug pre-op). Treatment was well tolerated. There were no objective responders in either arm. Overall PFS-6 was 2.4% (95% CI 0.9–11.1%). Median PFS was 2.3 months (95% CI 1.9–2.6) and mOS was 7.8 months (95% CI 5.4–10.1). Conclusions: GDC-0449 was well tolerated, reached tumor, and inhibited CD133+ neurosphere formation, but had little clinical efficacy as a single agent in rGBM. This suggests growth and maintenance of rGBM is not solely dependent on the SHH pathway thus targeting SMO may require combined approaches. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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