gdc-0449 and Neoplasms

A small subpopulation of cells within the bulk of tumors share features with somatic stem cells, in that, they are capable of self-renewal, they differentiate, and are highly resistant to conventional therapy. These cells have been referred to as cancer stem cells (CSCs). Recent reports support the central importance of a cancer stem cell-like niche that appears to help foster the generation and maintenance of CSCs. In response to signals provided by this microenvironment, CSCs express the tumorigenic characteristics that can drive tumor metastasis by the induction of epithelial-mesenchymal-transition (EMT) that in turn fosters the migration and recolonization of the cells as secondary tumors within metastatic niches. We summarize here recent advances in cancer stem cell research including the characterization of their genetic and epigenetic features, metabolic specialities, and crosstalk with aging-associated processes. Potential strategies for targeting CSCs, and their niche, by regulating CSCs plasticity, or therapeutic sensitivity is discussed. Finally, it is hoped that new strategies and related therapeutic approaches as outlined here may help prevent the formation of the metastatic niche, as well as counter tumor progression and metastatic growth.

Topics: Anilides; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Humans; Neoplasms; Neoplastic Stem Cells; Pyridines; Signal Transduction; Stem Cell Niche; Tumor Microenvironment

Hedgehog (HH) signaling pathway plays vital roles in controlling embryonic cell fate and homeostatic, and becomes dormant in mature individuals, aberrant activation of HH signaling pathway is involved in a number of human cancers. Smoothened (SMO), a vital transducer of HH signaling pathway, attracts significant attentions in HH signaling pathway-related cancer therapy. The approval of SMO antagonists vismodegib proves that SMO is a promising therapeutic target, and a number of SMO antagonists are reported since then. However, high incidence of tumor recurrence with the clinical application of vismodegib urges exploring of novel drugs with antiresistance profiles. This review provides an overview of SMO mutations reported in the literature, crystal structures of SMO, as well as reported antagonists with antiresistance profiles.

Topics: Anilides; Animals; Drug Design; Drug Discovery; Drug Resistance, Neoplasm; Hedgehog Proteins; Humans; Molecular Docking Simulation; Mutation; Neoplasms; Pyridines; Signal Transduction; Small Molecule Libraries; Smoothened Receptor

The most common cancer in both men and women is basal cell carcinoma (BCC). Although most primary and recurrent BCCs have high cure rates with standard therapies, advanced BCCs present a greater treatment challenge, especially in cosmetically and functionally sensitive areas. In patients unable to undergo surgery or radiation therapy, hedgehog inhibitors can be used neoadjuvantly to reduce tumor size, decreasing the extent and complexity of any subsequent surgery and providing either a cure or palliation. The goal of this review is to summarize the pharmacology, efficacy, and safety of systemic hedgehog inhibitors, as well as their role in daily practice as neoadjuvant therapy. Relevant English-language literature was identified and evaluated based on results from database searches of PubMed. Terms searched included, but were not limited to, "vismodegib," "Erivedge," "sonidegib," "DE225," "BCC," and "neoadjuvant treatment." Additional literature was identified from the reference lists of previously identified articles. The authors' personal experience in treating advanced BCC using hedgehog inhibitors has been incorporated into the recommendations made herein.

Topics: Anilides; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biphenyl Compounds; Combined Modality Therapy; Drug Resistance, Neoplasm; Hedgehog Proteins; Humans; Molecular Targeted Therapy; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Staging; Neoplasms; Pyridines; Signal Transduction; Standard of Care; Treatment Outcome

The hedgehog (Hh) signaling pathway is an important signaling pathway, playing a critical role in regulation of cell growth, development, metastasis and angiogenesis. Aberrant activation of this pathway has been linked to the development of several human tumor types, which makes it an attractive target for cancer treatment. Now many efforts in both industry and academia have been made to explore small molecular Hh inhibitors as anticancer agents.. This review aims to provide an overview of recent patents (2013--present) in the discovery, research and development of Hh inhibitors.. Hh signaling pathway inhibitors attract much interest for their therapeutic potential in the treatment of a variety of human cancers. In 2012, vismodegib was approved by the FDA as a smoothened inhibitor for locally advanced or metastatic basal cell carcinoma treatment, and presently, it is ongoing clinical trials for validating its use in other tumor types. It is clear that Hh inhibitors may provide a promising clinical benefit in treating tumors involving active Hh signaling pathway with a mutation-driven mechanism. However, the efficacy of Hh inhibitors on other human tumor types is still needed to further identify.

Topics: Anilides; Animals; Antineoplastic Agents; Drug Design; Hedgehog Proteins; Humans; Neoplasms; Patents as Topic; Pyridines; Signal Transduction

Vismodegib (GDC-0449, Erivedge®) is a novel small molecule antagonist of the hedgehog (Hh) pathway that binds to smoothened (SMO) and leads to inhibition of an aberrant activation of the Hh pathway. Dysregulated Hh signaling results in uncontrolled proliferation in basal cell carcinoma (BCC) and has also been found present in medulloblastoma, and many other cancers such as those of gastrointestinal tract, brain, lung, breast, and prostate. In January 2012, vismodegib became the first agent to target the Hh pathway to receive approval by the United States Food and Drug Administration (FDA) and in July 2013 approval by the European Medicines Agency (EMA) followed for the treatment of adult patients with symptomatic metastatic BCC, or locally advanced BCC inappropriate for surgery or radiotherapy. At the moment, many trials are ongoing to further investigate the role of vismodegib in other malignancies than BCC.

Topics: Anilides; Animals; Antineoplastic Agents; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Neoplasms; Pyridines; Signal Transduction

The Hedgehog (Hh) pathway is a developmental signaling pathway involved in numerous developmental processes, including determination of cell fate, patterning, proliferation, survival, and differentiation. While this pathway is silenced in most adult tissues, aberrant activation of it has been documented in a variety of malignancies. In cancers such as basal cell carcinoma (BCC), ligand-independent mechanisms lead to constitutive Hh pathway activation through mutations in components of the pathway, including patched-1 (PTCH1) or smoothened (SMO). On the contrary, numerous other solid and hematologic tumors have been shown to harbor ligand-dependent activation of the Hh pathway by autocrine or paracrine mechanisms. Given that aberrant Hh pathway signaling has been seen in a number of malignancies, this pathway has been an attractive target for drug development. While the best-characterized approach is to target the SMO receptor, other rational approaches for inhibiting the Hh pathway include inhibiting downstream components or directly binding Hh ligands. In January of 2012, vismodegib, a SMO antagonist, became the first agent to target the Hh pathway to receive approval by the United States Food and Drug Administration (FDA) after this agent showed remarkable activity in phase I and II trials for the treatment of BCC. Despite promising preclinical studies with Hh pathway inhibitors in other malignancies that have suggested a potential role for these agents, attempts to translate this potential to clinical benefit has been disappointing. Future efforts will require further careful interpretation and analysis to determine the potential determinants and predictors of efficacy. Currently, several phase I and II trials evaluating Hh inhibitors in a variety of tumor settings are underway.

Topics: Anilides; Antineoplastic Agents; Hedgehog Proteins; Humans; Molecular Targeted Therapy; Neoplasms; Pyridines; Signal Transduction

Since its discovery by C. Nüsslein-Volhard and E. F. Wieschaus, hedgehog (hh) signaling has come a long way. Today it is regarded as a key regulator in embryogenesis where it governs processes like cell proliferation, differentiation, and tissue patterning. Furthermore, in adults it is involved in the maintenance of stem cells, and in tissue repair and regeneration. But hh signaling has a second-much darker-face: it plays an important role in several types of human cancers where it promotes growth and enables proliferation of tumor stem cells. The etiology of medulloblastoma and basal cell carcinoma is tightly linked to aberrant hh activity, but also cancers of the prostate, the pancreas, the colon, the breasts, rhabdomyosarcoma, and leukemia, are dependent on irregular hh activity. Recent clinical studies have shown that hh signaling can be the basis of an important new class of therapeutic agents with far-reaching implications in oncology. Thus, modulation of hh signaling by means of small molecules has emerged as a valuable tool in combating these hh-dependent cancers. Cyclopamine, a unique natural product with a fascinating history, was the first identified inhibitor of hh signaling and its story is closely linked to the progress in the whole field. In this review we will trace the story of cyclopamine, give an overview on the biological modes of hh signaling both in untransformed and malignant cells, and finally present potent modulators of the hh pathway-many of them already in clinical studies. For more than 30 years now the knowledge on hh signaling has grown steadily-an end to this development is far from being conceivable.

Topics: Antineoplastic Agents; Hedgehog Proteins; Humans; Neoplasms; Signal Transduction; Veratrum Alkaloids

Hedgehog signaling is activated in a variety of solid tumors and hematologic malignancies by point mutations in hedgehog pathway members or autocrine or paracrine ligand secretion. Several hedgehog inhibitors were developed to block hedgehog pathway activity on the level of the activating receptor, Smoothened (Smo). GDC-0449 is the first systemic Smo-inhibitor entering clinical trials. It was successfully tested in a phase-I clinical trial demonstrating good pharmacodynamic (PD) and pharmacokinetic (PK) properties and showing objective response and clinical benefit in several patients with basal cell carcinoma.

Topics: Anilides; Animals; Antineoplastic Agents; Carcinoma, Basal Cell; Clinical Trials as Topic; Humans; Neoplasms; Pyridines; Receptors, G-Protein-Coupled; Smoothened Receptor

Vismodegib (GDC-0449) is a small, orally administrable molecule, belonging to the 2-arylpyridine class, which was discovered by Genentech Inc under a collaboration with Curis Inc. Vismodegib inhibits the Hedgehog (Hh) pathway, which is involved in tumorigenesis, thus providing a strong rationale for its use in the treatment of a variety of cancers. Vismodegib suppresses Hh signaling by binding to and interfering with smoothened, a membrane protein that provides positive signals to the Hh signaling pathway. Preclinical studies demonstrated the antitumor activity of vismodegib in mouse models of medulloblastoma (MB) and in xenograft models of colorectal and pancreatic cancer. Phase I clinical trials in patients with advanced basal cell carcinoma (BCC) and MB highlighted an objective response to vismodegib. Reported side effects were minor, with only one grade 4 adverse event. Vismodegib is currently undergoing phase II clinical trials for the treatment of advanced BCC, metastatic colorectal cancer, ovarian cancer, MB and other solid tumors. Because of its low toxicity and specificity for the Hh pathway, this drug has potential advantages compared with conventional chemotherapy, and may also be used in combination treatments. Clinical trials with other Hh inhibitors are also ongoing and their therapeutic potential will need to be compared with vismodegib.

Topics: Anilides; Animals; Antineoplastic Agents; Humans; Molecular Targeted Therapy; Neoplasms; Pyridines; Receptors, G-Protein-Coupled; Smoothened Receptor

It has long been known that the hedgehog signaling pathway is crucial for embryonic development, in both Drosophila and vertebrate systems. During the past few years its implication in carcinogenesis has become clear and today it is acknowledged that this pathway plays a role in the malignant transformation of multiple cell types, either owing to the mutation of some of its components or to its erratic activation. New molecular targeted therapies that inhibit the pathway have shown their unquestionable efficiency in several tumours -among which basal cell carcinoma, medulloblastoma, or pancreatic adenocarcinoma. The assessment of these inhibitors in other types of tumours is currently underway with promising results, suggesting that the Sonic hedgehog signalling pathway may become one of the therapeutic targets of the future.

Topics: Anilides; Animals; Carcinoma, Basal Cell; Cerebellar Neoplasms; Embryonic Development; Embryonic Induction; Hedgehog Proteins; Humans; Lung Neoplasms; Medulloblastoma; Molecular Targeted Therapy; Mutation; Neoplasms; Neoplastic Stem Cells; Pancreatic Neoplasms; Patched Receptors; Patient Selection; Pyridines; Receptors, Cell Surface; Signal Transduction; Skin Neoplasms; Small Cell Lung Carcinoma

Topics: Antineoplastic Agents; Drug Discovery; Hedgehog Proteins; Humans; Neoplasms; Signal Transduction; Transcription Factors; Zinc Finger Protein GLI1

The Hedgehog (Hh) signaling pathway regulates body patterning and organ development during embryogenesis. In adults the Hh pathway is mainly quiescent, with the exception of roles in tissue maintenance and repair, and its inappropriate reactivation has been linked to several disparate human cancers. In addition to cancers with mutations in components of the Hh pathway, Hh ligand-dependent cancers have been proposed to respond to Hh in an autocrine manner. More recent findings that Hh might instead signal in a paracrine manner from the tumor to the surrounding stroma or in cancer stem cells alter our understanding of Hh mechanisms in cancer, with important implications for choice of preclinical tumor models, drug screening, patient selection and therapeutic intervention. We review here the roles of the Hh pathway in cancer, Hh pathway inhibitors (HPIs) and early clinical trial results using a novel small molecule HPI, GDC-0449.

Topics: Anilides; Animals; Antineoplastic Agents; Drug Evaluation, Preclinical; Hedgehog Proteins; Humans; Ligands; Neoplasms; Pyridines; Signal Transduction

Vismodegib is a Hedgehog pathway inhibitor approved for the treatment of advanced basal cell carcinoma. Currently, the pharmacokinetics (PK) and safety of vismodegib in patients with hepatic dysfunction are unknown and are the objective of this study.. Patients with advanced solid malignancies and hepatic impairment were enrolled into one of four cohorts: normal [bilirubin (bili) < upper limit of normal (ULN)], mild (ULN < bili ≤ 1.5 × ULN), moderate (1.5 × ULN < bili ≤ 3×ULN), and severe (3 × ULN < bili < 10 × ULN) dysfunction. Patients received oral vismodegib 150 mg daily. Plasma PK samples on days 1, 3, 5, and 8 were collected. Vismodegib therapy was continued until disease progression, intolerable toxicity, or withdrawal of consent.. Thirty-one patients were accrued: nine normal, eight mild, eight moderate, and six severe. Four patients experienced dose-limiting toxicity of hyperbilirubinemia on study: one in the moderate cohort and three in the severe cohort. Six patients died within 30 days after the last dose of vismodegib. All deaths were attributed to disease progression. Observed maximal and average steady-state concentrations and AUC of vismodegib at steady state (day 8) were similar across cohorts. Average AAG concentrations in patients with hepatic impairment were comparable to those of patients with normal hepatic function.. Hepatic impairment does not appear to impact vismodegib PK, and therefore, dose adjustment is not necessary in this special population. The study was influenced by the high number of patients with hepatocellular carcinoma with advanced cirrhosis; rendering it difficult to draw any causal relationships between vismodegib exposure and the serious adverse events.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Area Under Curve; Cohort Studies; Disease Progression; Dose-Response Relationship, Drug; Female; Humans; Liver Diseases; Male; Middle Aged; Neoplasms; Pyridines; Severity of Illness Index; Time Factors

Idiopathic pulmonary fibrosis (IPF) is associated with aberrant expression of developmental pathways, including Hedgehog (Hh). As Hh signalling contributes to multiple pro-fibrotic processes, Hh inhibition may represent a therapeutic option for IPF. However, no non-invasive biomarkers are available to monitor lung Hh activity.. We assessed gene and protein expression in IPF and control lung biopsies, mouse lung, fibroblasts stimulated in vitro with sonic hedgehog (SHh), and plasma in IPF patients versus controls, and cancer patients before and after treatment with vismodegib, a Hh inhibitor.. Lung tissue from IPF patients exhibited significantly greater expression of Hh-related genes versus controls. The gene most significantly upregulated in both IPF lung biopsies and fibroblasts stimulated in vitro with SHh was. CXCL14 is a systemic biomarker that could be used to identify IPF patients with increased Hh pathway activity and monitor the pharmacodynamic effects of Hh antagonist therapy in IPF.. Post-results, NCT00968981.

Topics: Aged; Anilides; Animals; Antineoplastic Agents; Biomarkers; Cells, Cultured; Chemokines, CXC; Female; Gene Expression Regulation; Hedgehog Proteins; Humans; Idiopathic Pulmonary Fibrosis; Lung; Male; Mice, Inbred C57BL; Middle Aged; Neoplasms; Pyridines; Signal Transduction; Up-Regulation

Vismodegib, an orally bioavailable small-molecule Smoothened inhibitor, is approved for treatment of advanced basal cell carcinoma (BCC). We conducted a pharmacokinetic study of vismodegib in patients with advanced solid tumors to explore the effects of food on drug exposure.. In part I, patients were randomized to fasting overnight (FO), a high fat meal (HF), or a low fat meal (LF) before a single dose of vismodegib 150 mg. Plasma concentrations of vismodegib were determined by a validated liquid chromatography-tandem mass spectrometry assay. Primary endpoints were C(max) and area under the curve (AUC(0-168)). In part II, patients randomized to FO or HF in part I took vismodegib 150 mg daily after fasting; those randomized to LF took it after a meal. Primary endpoints after two weeks were C(max) and AUC(0-24).. Sixty (22 FO, 20 HF, 18 LF) and 52 (25 fasting, 27 fed) patients were evaluable for primary endpoints in parts I and II, respectively. Mean C(max) and AUC(0-168) after a single dose were higher in HF than FO patients [ratios of geometric means (90% CI) = 1.75 (1.30, 2.34) and 1.74 (1.25, 2.42), respectively]. There were no significant differences in C(max) or AUC(0-24) between fasting and fed groups after daily dosing. The frequencies of drug-related toxicities were similar in both groups.. A HF meal increases plasma exposure to a single dose of vismodegib, but there are no pharmacokinetic or safety differences between fasting and fed groups at steady-state. Vismodegib may be taken with or without food for daily dosing.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Female; Food-Drug Interactions; Humans; Male; Middle Aged; Neoplasm Staging; Neoplasms; Pyridines; Treatment Outcome

Vismodegib, a first-in-class oral hedgehog pathway inhibitor, is an effective treatment for advanced basal cell carcinoma. Based on in vitro data, a clinical drug-drug interaction (DDI) assessment of cytochrome P450 (CYP) 2C8 was necessary; vismodegib's teratogenic potential warranted a DDI study with oral contraceptives (OCs).. This single-arm, open-label study included two cohorts of patients with locally advanced or metastatic solid malignancies [Cohort 1: rosiglitazone 4 mg (selective CYP2C8 probe); Cohort 2: OC (norethindrone 1 mg/ethinyl estradiol 35 μg; CYP3A4 substrate)]. On Day 1, patients received rosiglitazone or OC. On Days 2-7, patients received vismodegib 150 mg/day. On Day 8, patients received vismodegib plus rosiglitazone or OC. The effect of vismodegib on rosiglitazone and OC pharmacokinetic parameters (primary objective) was evaluated through pharmacokinetic sampling over a 24-h period (Days 1 and 8).. The mean ± SD vismodegib steady-state plasma concentration (Day 8, N = 51) was 20.6 ± 9.72 μM (range 7.93-62.4 μM). Rosiglitazone AUC(0-inf) and C(max) were similar with concomitant vismodegib [≤8% change in geometric mean ratios (GMRs); N = 24]. Concomitant vismodegib with OC did not affect ethinyl estradiol AUC(0-inf) and C(max) (≤5% change in GMRs; N = 27); norethindrone C(max) and AUC(0-inf) GMRs were higher (12 and 23%, respectively) with concomitant vismodegib.. This DDI study in patients with cancer demonstrated that systemic exposure of rosiglitazone (a CYP2C8 substrate) or OC (ethinyl estradiol/norethindrone) is not altered with concomitant vismodegib. Overall, there appears to be a low potential for DDIs when vismodegib is co-administered with other medications.

Topics: Aged; Anilides; Antineoplastic Agents; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Cohort Studies; Contraceptives, Oral, Combined; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Drug Interactions; Ethinyl Estradiol; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Norethindrone; Pyridines; Rosiglitazone; Thiazolidinediones

In a phase I trial for patients with refractory solid tumors, hedgehog pathway inhibitor vismodegib (GDC-0449) showed little decline in plasma concentrations over 7 days after a single oral dose and nonlinearity with respect to dose and time after single and multiple dosing. We studied the role of GDC-0449 binding to plasma protein alpha-1-acid glycoprotein (AAG) to better understand these unusual pharmacokinetics.. Sixty-eight patients received GDC-0449 at 150 (n = 41), 270 (n = 23), or 540 (n = 4) mg/d, with pharmacokinetic (PK) sampling at multiple time points. Total and unbound (dialyzed) GDC-0449 plasma concentrations were assessed by liquid chromatography/tandem mass spectrometry, binding kinetics by surface plasmon resonance-based microsensor, and AAG levels by ELISA.. A linear relationship between total GDC-0449 and AAG plasma concentrations was observed across dose groups (R(2) = 0.73). In several patients, GDC-0449 levels varied with fluctuations in AAG levels over time. Steady-state, unbound GDC-0449 levels were less than 1% of total, independent of dose or total plasma concentration. In vitro, GDC-0449 binds AAG strongly and reversibly (K(D) = 13 μmol/L) and human serum albumin less strongly (K(D) = 120 μmol/L). Simulations from a derived mechanistic PK model suggest that GDC-0449 pharmacokinetics are mediated by AAG binding, solubility-limited absorption, and slow metabolic elimination.. GDC-0449 levels strongly correlated with AAG levels, showing parallel fluctuations of AAG and total drug over time and consistently low, unbound drug levels, different from previously reported AAG-binding drugs. This PK profile is due to high-affinity, reversible binding to AAG and binding to albumin, in addition to solubility-limited absorption and slow metabolic elimination properties.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Binding, Competitive; Biological Availability; Chromatography, Liquid; Dose-Response Relationship, Drug; Female; Hedgehog Proteins; Humans; Male; Metabolic Clearance Rate; Middle Aged; Neoplasm Metastasis; Neoplasms; Orosomucoid; Protein Binding; Pyridines; Serum Albumin; Signal Transduction; Tandem Mass Spectrometry; Time Factors; Treatment Outcome

The hedgehog (Hh) signaling pathway, a key regulator of cell growth and differentiation during development is implicated in pathogenesis of certain cancers. Vismodegib (GDC-0449) is a small-molecule inhibitor of smoothened, a key component of Hh signaling. This phase I trial assessed GDC-0449 treatment in patients with solid tumors refractory to current therapies or for which no standard therapy existed.. Sixty-eight patients received GDC-0449 at 150 mg/d (n = 41), 270 mg/d (n = 23), or 540 mg/d (n = 4). Adverse events, tumor responses, pharmacokinetics, and pharmacodynamic down-modulation of GLI1 expression in noninvolved skin were assessed.. Thirty-three of 68 patients had advanced basal cell carcinoma (BCC), 8 had pancreatic cancer, 1 had medulloblastoma; 17 other types of cancer were also represented. GDC-0449 was generally well-tolerated. Six patients (8.8%) experienced 7 grade 4 events (hyponatremia, fatigue, pyelonephritis, presyncope, resectable pancreatic adenocarcinoma, and paranoia with hyperglycemia), and 27.9% of patients experienced a grade 3 event [most commonly hyponatremia (10.3%), abdominal pain (7.4%), and fatigue (5.9%)]. No maximum tolerated dose was reached. The recommended phase II dose was 150 mg/d, based on achievement of maximal plasma concentration and pharmacodynamic response at this dose. Tumor responses were observed in 20 patients (19 with BCC and 1 unconfirmed response in medulloblastoma), 14 patients had stable disease as best response, and 28 had progressive disease. Evidence of GLI1 down-modulation was observed in noninvolved skin.. GDC-0449 has an acceptable safety profile and encouraging anti-tumor activity in advanced BCC and medulloblastoma. Further study in these and other cancer types is warranted.

Topics: Abdominal Pain; Adult; Aged; Aged, 80 and over; Anilides; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Fatigue; Female; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Humans; Hyponatremia; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Neoplasms; Pyridines; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Transcription Factors; Treatment Outcome; Zinc Finger Protein GLI1

This study was designed to evaluate whether less frequent dosing [three times per week (TIW) or once weekly (QW)] of 150 mg vismodegib following a loading dose [150 mg once daily (QD) for 11 days] would result in similar safety, tolerability, and steady-state levels of total and unbound vismodegib as continuous QD dosing.. Sixty-seven patients with advanced solid tumors were stratified by baseline plasma alpha 1-acid glycoprotein (AAG) levels and randomized to one of three vismodegib 150 mg regimens: QD (n = 23), TIW (n = 22), or QW (n = 22) for up to 42 days after an 11-day loading phase (150 mg QD). Total and unbound (dialyzed) plasma vismodegib concentrations were determined by LC-MS/MS.. The most frequently reported adverse events were consistent with those in prior monotherapy trials, with similar incidence and severity regardless of dosing schedule. After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose. Mean total and unbound vismodegib steady-state concentrations were lower after TIW and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug. Mechanism-based PK model simulations accurately and prospectively predicted the PK results.. Vismodegib 150 mg TIW or QW failed to achieve unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a QD loading dose period. The 150 mg QD regimen is appropriate for vismodegib based on its clinical activity, tolerability, and favorable unbound concentrations.

Topics: Anilides; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hedgehog Proteins; Humans; Male; Neoplasms; Pyridines

Scientists working in translational oncology regularly conduct multigroup studies of mice with serially measured tumors. Longitudinal data collected can feature mid-study dropouts and complex nonlinear temporal response patterns. Parametric statistical models such as ones assuming exponential growth are useful for summarizing tumor volume over ranges for which the growth model holds, with the advantage that the model's parameter estimates can be used to summarize between-group differences in tumor volume growth with statistical measures of uncertainty. However, these same assumed growth models are too rigid to recapitulate patterns observed in many experiments, which in turn diminishes the effectiveness of their parameter estimates as summary statistics. To address this problem, we generalized such models by adopting a nonparametric approach in which group-level response trends for logarithmically scaled tumor volume are estimated as regression splines in a generalized additive mixed model. We also describe a novel summary statistic for group level splines over user-defined, experimentally relevant time ranges. This statistic reduces to the log-linear growth rate for data well described by exponential growth and also has a sampling distribution across groups that is well approximated by a multivariate Gaussian, thus facilitating downstream analysis. Real-data examples show that this nonparametric approach not only enhances fidelity in describing nonlinear growth scenarios but also improves statistical power to detect interregimen differences when compared with the simple exponential model so that it generalizes the linear mixed effects paradigm for analysis of log-linear growth to nonlinear scenarios in a useful way. SIGNIFICANCE: This work generalizes the statistical linear mixed modeling paradigm for summarizing longitudinally measured preclinical tumor volume studies to encompass studies with nonlinear and nonmonotonic group response patterns in a statistically rigorous manner.

Topics: Anilides; Animals; Antineoplastic Agents, Alkylating; Bias; Decision Making; Disease Models, Animal; Female; Genes, Tumor Suppressor; Glioblastoma; Heterografts; Humans; Medical Oncology; Mice; Mice, Nude; Models, Statistical; Neoplasm Transplantation; Neoplasms; Normal Distribution; Patched-1 Receptor; Piperazines; Pyridines; Random Allocation; Statistics, Nonparametric; Temozolomide; Translational Research, Biomedical; Tumor Burden

A series of novel hedgehog signaling pathway inhibitors have been designed by structural modification based on the former reported scaffold of 4-(2-pyrimidinylamino)benzamide. The SAR for this series was described and many derivatives showed potent inhibitory activity. Among these compounds, compounds 12af and 12bf were identified to have high potency and optimal PK profiles. Although both of compounds 12af and 12bf did not show strong antitumor efficacy in LS-174T nude mice model, they were promising candidates as Hh signaling inhibitors due to great potency against Hh signaling pathway and outstanding PK properties, deserving further evaluation in other Hh signaling operative tumor models.

Topics: Administration, Oral; Amination; Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Hedgehog Proteins; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Pyridines; Signal Transduction; Structure-Activity Relationship

The hedgehog (Hh) signaling pathway is a key regulator during embryonic development, while in adults, it has limited functions such as stem cell maintenance and tissue repair. The aberrant activity of the Hh signaling in adults has been linked to numerous human cancers. Inhibition of Hh signaling therefore represents a promising approach toward novel anticancer therapies. The Smoothened (Smo) receptor mediates Hh signaling. Here we report a new series of Smo antagonists which were obtained by a scaffold hopping strategy. Compounds from this new scaffold demonstrated decent inhibition of Hh pathway signaling. The new scaffold can serve as a starting point for further optimization.

Topics: Antineoplastic Agents; Cell Proliferation; Hedgehog Proteins; Humans; Neoplasms; Receptors, G-Protein-Coupled; Signal Transduction; Smoothened Receptor

Aberrant Hedgehog (Hh) pathway signaling has been suggested to play a role in the development of multiple solid tumors and hematologic malignancies. GDC-0449 is a novel first-in-human, first-in-class smoothened (SMO) inhibitor, which has completed its phase I evaluation and achieved proof of concept in tumors with Hh pathway mutations.

Topics: Anilides; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Humans; Metabolic Clearance Rate; Neoplasm Metastasis; Neoplasms; Orosomucoid; Protein Binding; Pyridines; Signal Transduction; Transcription Factors; Treatment Outcome; Zinc Finger Protein GLI1

CHI's 17th International Tri-Conference on Molecular Medicine, held in San Francisco, included topics covering new developments in the field of medicinal chemistry. This conference report highlights selected presentations on fragment-based drug discovery, quantum mechanical energy decomposition for the analysis of SARs, medicinal chemistry strategies and the role of imaging in drug discovery. Investigational drugs discussed include MLN-4924 (Millennium Pharmaceuticals Inc), GDC-0449 (Chugai Pharmaceutical Co Ltd/Curis Inc/F Hoffmann-La Roche Ltd/Genentech Inc/NCI), RDEA-119 (Ardea Biosciences Inc/Bayer HealthCare AG) and tafamidis (Fx-1006A; FoldRx Pharmaceuticals Inc).

Topics: Alzheimer Disease; Amyloidosis; Anilides; Animals; Benzoxazoles; Chemistry, Pharmaceutical; Drug Discovery; Drug-Related Side Effects and Adverse Reactions; Enzyme Inhibitors; HSP90 Heat-Shock Proteins; Humans; Macrocyclic Compounds; Neoplasms; Pharmacokinetics; Positron-Emission Tomography; Pyridines; Quantum Theory; Receptors, Immunologic; Receptors, Prostaglandin; Structure-Activity Relationship

Topics: Anilides; Antineoplastic Agents; Benzimidazoles; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Neoplasms; Patched Receptors; Pyridines; Receptors, Cell Surface; Signal Transduction; Skin Neoplasms

Topics: Anilides; Animals; Antineoplastic Agents; Clinical Trials as Topic; Drosophila melanogaster; Drug Industry; Hedgehog Proteins; Humans; Ligands; Neoplasms; Neoplastic Stem Cells; Pyridines; Signal Transduction