IntroductionChronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the United States, with approximately 15 000 new cases and approximately 4500 deaths per year. 1 CLL is characterized by a B1 monoclonal lymphocyte immunophenotype with expression of the surface antigens CD19, CD5, CD20, CD23, and dim surface immunoglobulin G. The cell of origin of CLL is uncertain, but a gene expression pattern most similar to a mature memory B cell has been hypothesized. 2 In addition, CLL cells display disrupted apoptosis that is caused by both primary tumor features and codependent stromal elements. 3 Although many patients are asymptomatic at diagnosis, CLL is a progressive disease that in most patients eventually will require treatment. Once they become symptomatic, patients have a relatively short overall survival, ranging from 18 months to 6 years, with a 22.5% 10-year survival expectation. 4 Common treatments for CLL include alkylating chemotherapeutic drugs (such as chlorambucil and cyclophosphamide), purine analogs (such as fludarabine), and rituximab (used in combination with fludarabine, fludarabine and cyclophosphamide, or pentostatin and cyclophosphamide). Newer studies with either single-agent bendamustine or alemtuzumab have been shown to have improved response and progression-free survival over alkylator-based therapy. However, no current treatment option results in curative therapy, and all patients eventually relapse. This provides strong justification for developing additional types of therapies for CLL. Of particular interest are therapies that target signal transduction pathways essential to CLL cell survival mechanisms that are known to be aberrantly activated.One such pathway is the phosphoinositide 3-kinase (PI3K) pathway. The PI3K pathway is acknowledged as a key component of cell survival in many cancers, including CLL. It is activated by receptors, or the small guanosine triphosphatase Ras, and is made up of various classes of PI3K isoforms. 5 There are 3 classes of PI3K isoforms; however, only the class I isoforms phosphorylate inositol lipids to form second messenger phosphoinositides. Specifically, class I PI3K enzymes convert PtdIns(3,4)P 2 into PtdIns(3,4,5)P 3 , in the cell membrane that recruit, via binding to the amino-terminal pleckstrin homology domain, downstream signaling proteins such as Tec kinases, phosphatidylinositol-dependent kinase, Akt, integrin-linked kinase, and Rac guanine exchange factor. Class I isoforms are made up of 2 subsets (IA and IB). Class IA encompasses p110␣, p110␤, and p110␦ (catalytic domains), bound by p85, p50, or p55 (regulatory domains). Class IB is made up solely of the p110␥ (catalytic domain) bound by the regulatory domain p101. The p110␣ and p110␤ isoforms are ubiquitously expressed, and knock-out mice for both are embryonic lethal. 6 It is thought that this widespread functionality of PI3K signaling is at An Inside Blood analysis of this article appears at the front of this issue.The publication costs of this article were defrayed ...

Sorafenib is reasonably well-tolerated therapy with clinical and biologic antitumor activity in metastatic PTC.

Antifungal agents exert their activity through a variety of mechanisms, some of which are poorly understood. We examined changes in the gene expression profile of Candida albicans following exposure to representatives of the four currently available classes of antifungal agents used in the treatment of systemic fungal infections. Ketoconazole exposure increased expression of genes involved in lipid, fatty acid, and sterol metabolism, including NCP1, MCR1, CYB5, ERG2, ERG3, ERG10, ERG25, ERG251, and that encoding the azole target, ERG11. Ketoconazole also increased expression of several genes associated with azole resistance, including CDR1, CDR2, IFD4, DDR48, and RTA3. Amphotericin B produced changes in the expression of genes involved in small-molecule transport (ENA21), and in cell stress (YHB1, CTA1, AOX1, and SOD2). Also observed was decreased expression of genes involved in ergosterol biosynthesis, including ERG3 and ERG11. Caspofungin produced changes in expression of genes encoding cell wall maintenance proteins, including the ␤-1,3-glucan synthase subunit GSL22, as well as PHR1, ECM21, ECM33, and FEN12. Flucytosine increased the expression of proteins involved in purine and pyrimidine biosynthesis, including YNK1, FUR1, and that encoding its target, CDC21. Real-time reverse transcription-PCR was used to confirm microarray results. Genes responding similarly to two or more drugs were also identified. These data shed new light on the effects of these classes of antifungal agents on C. albicans.Candida albicans is the most common human fungal pathogen and is the fourth leading cause of bloodstream infections in the United States (6,14,24). Currently only four antifungal drug classes are available for the management of systemic infections due to Candida species. Recently we examined changes in the genome-wide expression profile of Saccharomyces cerevisiae in response to representatives of the polyene, pyrimidine, azole, and echinocandin antifungal agents in an effort to identify class-specific and mechanism-independent changes in gene expression (1). In the present study, we extend this analysis to the pathogenic fungus C. albicans. By using the same representative drugs and similar growth conditions as in our previous study, we are able to show similarities and differences in the responses to these antifungal agents between S. cerevisiae and C. albicans. Gene expression profiling experiments revealed drug-specific responses consistent with their mechanisms of action, responses indicative of other pathways that may be affected by these agents, and responses that reflect known and potential mechanisms of resistance to these antifungal drugs. MATERIALS AND METHODSAntifungal agents. Ketoconazole (KTZ) and flucytosine (5-FC) were obtained from Sigma (St. Louis, MO). Amphotericin B (AMB) was obtained from ICN Biomedicals (Aurora, OH). The commercially available preparation of caspofungin (CPF) acetate for injection (Cancidas) was used. Stock solutions of various concentrations were made in dimethyl sulfoxide (DMS...

A B S T R A C T PurposeMutations in the RET proto-oncogene and vascular endothelial growth factor receptor (VEGFR) activity are critical in the pathogenesis of medullary thyroid cancer (MTC). Sorafenib, a multikinase inhibitor targeting Ret and VEGFR, showed antitumor activity in preclinical studies of MTC. Patients and MethodsIn this phase II trial of sorafenib in patients with advanced MTC, the primary end point was objective response. Secondary end points included toxicity assessment and response correlation with tumor markers, functional imaging, and RET mutations. Using a two-stage design, 16 or 25 patients were to be enrolled onto arms A (hereditary) and B (sporadic). Patients received sorafenib 400 mg orally twice daily. ResultsOf 16 patients treated in arm B, one achieved partial response (PR; 6.3%; 95% CI, 0.2% to 30.2%), 14 had stable disease (SD; 87.5%; 95% CI, 61.7% to 99.5%), and one was nonevaluable. In a post hoc analysis of 10 arm B patients with progressive disease (PD) before study, one patient had PR of 21ϩ months, four patients had SD Ն 15 months, four patients had SD Յ 6 months, and one patient had clinical PD. Median progression-free survival was 17.9 months. Arm A was prematurely terminated because of slow accrual. Common adverse events (AEs) included diarrhea, hand-foot-skin reaction, rash, and hypertension. Although serious AEs were rare, one death was seen. Tumor markers decreased in the majority of patients, and RET mutations were detected in 10 of 12 sporadic MTCs analyzed. ConclusionSorafenib is reasonably well tolerated, with suggestion of clinical benefit for patients with sporadic MTC. Caution should be taken because of the rare but fatal toxicity potentially associated with sorafenib.