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

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.

Teaching History of Pharmacy in U.S. Pharmacy Schools.

Objective. To determine how the standards for teaching pharmacy history were met by U.S. pharmacy schools, whether schools wanted to expand their commitment to pharmacy history, what pedagogical assistance, if any, was desired, and whether elective courses were offered. Methods. There were 133 school deans who were asked to identify the responsible faculty for teaching pharmacy history. A 10-question online survey instrument was designed and emailed to these faculty or the dean if no faculty were identified. Follow-up emails were sent at 2-week intervals. If they were non-responsive after three attempts, then telephone solicitation was attempted. Results. There were 100 schools (75%) that responded. Fifty-three percent were public and 47% were private; with 50% having class sizes of 100 or less, 41% with 101-250, and 9% having over 250. Eighty-six percent of respondents meet the ACPE requirement within a required course. Seventy-two percent devote only one to five hours of instruction to meet the requirement. Sixty-eight percent use no supporting literature, and among those who do, there was no common textbook. Interestingly, 21% wanted more teaching time, and 91% desired pedagogical assistance, varying from a packaged course (26%) to a syllabus with assignments and assessment banks (23%). Conclusion. Since no time or material guidelines were established to fulfill the ACPE pharmacy history educational requirements, these results provide a starting point to judge what is adequate and/or preferred. With the development of teaching guidelines and adoptable teaching materials, the pedagogical solution to this ACPE standard may become more complete and consistent.

Writing PharmD program-level, ability-based outcomes: key elements for success.

A set of PharmD program curricular outcomes form the foundation of a doctor of pharmacy (PharmD) curriculum and are critical to the development of both the structure/courses of the curriculum and the assessment plan for the program. A goal for developing these outcomes is to craft a set of clear, concise, assessable statements that accurately reflect competencies of the generalist entry-level pharmacist or graduate of the first-professional doctor of pharmacy degree. This article will provide a review of one specific type of outcome, ability-based outcomes, and present a case study of how one college revised their PharmD program-level outcomes. A discussion of key elements for the successful adoption of these outcomes is also presented.