CYP17 blockade by abiraterone acetate is safe and has significant antitumor activity in CRPC. These data confirm that CRPC commonly remains dependent on ligand-activated AR signaling.

Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/ Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. The synthesis, biological activity, and further profiling of these compounds are described. This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer.

A B S T R A C T PurposeTo study the toxicity and pharmacokinetic-pharmacodynamic profile of 17-allylamino, 17-demethoxygeldanamycin (17-AAG) and to recommend a dose for phase II trials. Patients and MethodsThis was a phase I study examining a once-weekly dosing schedule of 17-AAG. Thirty patients with advanced malignancies were treated. ResultsThe highest dose level reached was 450 mg/m 2 /week. The dose-limiting toxicities (DLTs) encountered were grade 3 diarrhea in three patients (one at 320 mg/m 2 /week and two at 450 mg/m 2 /week) and grade 3 to 4 hepatotoxicity (AST/ALT) in one patient at 450 mg/m 2 /week. Two of nine DLTs were at the highest dose level. Two patients with metastatic melanoma had stable disease and were treated for 15 and 41 months, respectively. The dose versus area under the curve-relationship for 17-AAG was linear (r 2 ϭ .71) over the dose range 10 to 450 mg/m 2 /week, with peak plasma concentrations of 8,998 g/L (standard deviation, 2,881) at the highest dose level. After the demonstration of pharmacodynamic changes in peripheral blood leukocytes, pre-and 24 hours post-treatment, tumor biopsies were performed and demonstrated target inhibition (c-RAF-1 inhibition in four of six patients, CDK4 depletion in eight of nine patients and HSP70 induction in eight of nine patients) at the dose levels 320 and 450 mg/m 2 /week. It was not possible to reproducibly demonstrate these changes in biopsies taken 5 days after treatment. ConclusionIt has been possible to demonstrate that 17-AAG exhibits a tolerable toxicity profile with therapeutic plasma concentrations and target inhibition for 24 hours after treatment and some indications of clinical activity at the dose level 450 mg/m 2 /week. We recommend this dose for phase II clinical trials.