Defining the Value of a Comparative Approach to Cancer Drug Development.
Ontology highlight
ABSTRACT:
SUBMITTER: LeBlanc AK
PROVIDER: S-EPMC5111620 | biostudies-literature | 2016 May
REPOSITORIES: biostudies-literature
Publications
Defining the Value of a Comparative Approach to Cancer Drug Development.
LeBlanc Amy K AK Mazcko Christina N CN Khanna Chand C
Clinical cancer research : an official journal of the American Association for Cancer Research 20151228 9
Comparative oncology as a tool in drug development requires a deeper examination of the value of the approach and examples of where this approach can satisfy unmet needs. This review seeks to demonstrate types of drug development questions that are best answered by the comparative oncology approach. We believe common perceived risks of the comparative approach relate to uncertainty of how regulatory bodies will prioritize or react to data generated from these unique studies conducted in diseased ...[more]
Similar Datasets
Project description:ROC curve analysis is often applied to measure the diagnostic accuracy of a biomarker. The analysis results in two gains: diagnostic accuracy of the biomarker and the optimal cut-point value. There are many methods proposed in the literature to obtain the optimal cut-point value. In this study, a new approach, alternative to these methods, is proposed. The proposed approach is based on the value of the area under the ROC curve. This method defines the optimal cut-point value as the value whose sensitivity and specificity are the closest to the value of the area under the ROC curve and the absolute value of the difference between the sensitivity and specificity values is minimum. This approach is very practical. In this study, the results of the proposed method are compared with those of the standard approaches, by using simulated data with different distribution and homogeneity conditions as well as a real data. According to the simulation results, the use of the proposed method is advised for finding the true cut-point.
| S-EPMC5470053 | biostudies-literature
Project description:ImportanceValue-based care is increasingly important, with rising health care costs and advances in cancer treatment leading to greater survival for patients with cancer. Regionalization of surgical care for pancreatic cancer has been extensively studied as a strategy to improve perioperative outcomes, but investigation of long-term outcomes relative to health care costs (ie, value) is lacking.ObjectiveTo identify patient and hospital characteristics associated with improved overall survival, decreased costs, and greater value among patients with pancreatic cancer undergoing curative resection.Design, setting, and participantsThis retrospective cohort study identified 2786 patients with stages I to II pancreatic cancer who underwent pancreatic resection at 157 hospitals from January 1, 2004, through December 31, 2012. The study used the California Cancer Registry, which collects data from all California residents newly diagnosed with cancer, linked to the Office of Statewide Health Planning and Development database, which collects administrative data from all California licensed hospitals. Data were analyzed from November 11, 2017, through September 4, 2018.ExposuresPancreatic resection at high-volume and/or National Cancer Institute (NCI)-designated cancer centers.Main outcomes and measuresThe primary outcomes were overall survival, surgical hospitalization costs, and value. High value was defined as the fourth quintile or higher for survival and the second quintile or less for costs. Costs were calculated from charges using cost-charge ratios and adjusted for geographic variation and inflation. Multivariable regression models were used to determine factors associated with overall survival, costs, and high value.ResultsAmong the 2786 patients included (1394 [50.0%] male; mean [SD] age, 67.0 [10.7] years), postoperative chemotherapy (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.64-0.79; P < .001) and high-volume centers (aHR, 0.78; 95% CI, 0.61-0.99; P = .04) were associated with greater overall survival. Higher Elixhauser comorbidity index scores (estimate, 0.006; 95% CI, 0.003-0.008), complications (estimate, 0.22; 95% CI, 0.17-0.27), readmissions (estimate, 0.34; 95% CI, 0.29-0.39), and longer lengths of stay (estimate, 0.03; 95% CI, 0.03-0.04) were associated with higher costs (P < .001), whereas postoperative chemotherapy was associated with lower costs (estimate, -0.06; 95% CI, -0.11 to -0.02; P = .006). National Cancer Institute-designated and high-volume centers were not associated with costs. Although grades III and IV tumors (odds ratio [OR], 0.65; 95% CI, 0.39-0.91; P = .001), T3 category disease (OR, 0.71; 95% CI, 0.46-0.95; P = .005), complications (OR, 0.68; 95% CI, 0.49-0.86; P < .001), readmissions (OR, 0.64; 95% CI, 0.44-0.84; P < .001), and length of stay (OR, 0.82; 95% CI, 0.78-0.85; P < .001) were inversely associated with high-value care, NCI designation (OR, 1.07; 95% CI, 0.66-1.49; P = .74) and high-volume centers (OR, 1.08; 95% CI, 0.54-1.61; P = .07) were not.Conclusions and relevanceIn this study, high-value care was associated with important patient characteristics and postoperative outcomes. However, NCI-designated and high-volume centers were not associated with greater value. These data suggest that targeted measures to enhance value may be needed in these centers.
| S-EPMC6704743 | biostudies-literature
Project description:Cytochrome P450s (CYPs) represent a large class of heme-containing enzymes that catalyze the metabolism of multitudes of substrates both endogenous and exogenous. Until recently, however, CYPs have been largely overlooked in cancer drug development, acknowledged only for their role in phase I metabolism of chemotherapeutics. The first successful strategy targeting CYP enzymes in cancer therapy was the development of potent inhibitors of CYP19 (aromatase) for the treatment of breast cancer. Aromatase inhibitors ushered in a new era in hormone ablation therapy for estrogen dependent cancers, and have paved the way for similar strategies (i.e., inhibition of CYP17) that combat androgen dependent prostate cancer. Identification of CYPs involved in the inactivation of anti-cancer metabolites of vitamin D(3) and vitamin A has triggered development of agents that target these enzymes as well. The discovery of the over-expression of exogenous metabolizing CYPs, such as CYP1B1, in cancer cells has roused interest in the development of inhibitors for chemoprevention and of prodrugs designed to be activated by CYPs only in cancer cells. Finally, the expression of CYPs within tumors has been utilized in the development of bioreductive molecules that are activated by CYPs only under hypoxic conditions. This review offers the first comprehensive analysis of strategies in drug development that either inhibit or exploit CYP enzymes for the treatment of cancer.
| S-EPMC1958998 | biostudies-other
Project description:Background: Osteosarcoma is an orphan disease for which little improvement in survival has been made since the late 1980s. New drug discovery for orphan diseases is limited by the cost and time it takes to develop new drugs. Repurposing already approved FDA-drugs can help overcome this limitation. Another limitation of cancer drug discovery is the lack of preclinical models that accurately recapitulate what occurs in humans. For OS using dogs as a model can minimize this limitation as OS in canines develops spontaneously, is locally invasive and metastasizes to the lungs as it does in humans.Methods: In our present work we used high-throughput screens to identify drugs from a library of 2,286 FDA-approved drugs that demonstrated selective growth inhibition against both human and canine OS cell lines. The identified lead compound was then tested for synergy with 7 other drugs that have demonstrated activity against OS. These results were confirmed with in vitro assays and an in vivo murine model of OS.Results: We identified 13 drugs that demonstrated selective growth inhibition against both human and canine OS cell lines. Auranofin was selected for further in vitro combination drug screens. Auranofin showed synergistic effects with vorinostat and rapamycin on OS viability and apoptosis induction. Auranofin demonstrated single-agent growth inhibition in both human and canine OS xenografts, and cooperative growth inhibition was observed in combination with rapamycin or vorinostat. There was a significant decrease in Ki67-positive cells and an increase in cleaved caspase-3 levels in tumor tissues treated with a combination of auranofin and vorinostat or rapamycin.Conclusions: Auranofin, alone or in combination with rapamycin or vorinostat, may be useful new treatment strategies for OS. Future studies may evaluate the efficacy of auranofin in dogs with OS as a prelude to human clinical evaluation.
| S-EPMC5868798 | biostudies-literature
Project description:ObjectiveThis study reports the use of exploratory factor analysis to describe essential skills and knowledge for an important segment of the domestic public health workforce-Centers for Disease Control and Prevention (CDC) project officers-using an evidence-based approach to competency development and validation.DesignA multicomponent survey was conducted. Exploratory factor analysis was used to examine the underlying domains and relationships between competency domains and key behaviors. The Cronbach α coefficient determined the reliability of the overall scale and identified factors.Setting and participantsAll domestic (US state, tribe, local, and territorial) grantees who received funding from the CDC during fiscal year 2011 to implement nonresearch prevention or intervention programs were invited to participate in a Web-based questionnaire.Main outcome measure(s)A total of 34 key behaviors representing knowledge, skills, and abilities, grouped in 7 domains-communication, grant administration and management, public health applied science and knowledge, program planning and development, program management, program monitoring and improvement, and organizational consultation-were examined.ResultsThere were 795 responses (58% response rate). A total of 6 factors were identified with loadings of 0.40 or more for all 34 behavioral items. The Cronbach α coefficient was 0.95 overall and ranged between 0.73 and 0.91 for the factors.ConclusionsThis study provides empirical evidence for the construct validity of 6 competencies and 34 key behaviors important for CDC project officers and serves as an important first step to evidence-driven workforce development efforts in public health.
| S-EPMC5614504 | biostudies-literature
Project description:The traditional Chinese medicine (TCM) bupleurum-ginger-licorice formula presents significant anti-cancer effects, but its active ingredients and inhibitory mechanism remain unclear. In this work, the core effective ingredient quercetin and its signal transducer and activator of transcription 3 (Stat3) receptor both were identified by network pharmacology. Quercetin is a low-toxicity, non-carcinogenic flavonoid with antioxidant, anti-inflammatory and anticancer activities, which is widely distributed in edible plants. Stat3 can bind to specific DNA response elements and serves as a transcription factor to promote the translation of some invasion/migration-related target genes, considered as a potential anticancer target. Here, molecular docking and molecular dynamics (MD) simulation both were used to explore molecular recognition of quercetin with Stat3. The results show that quercetin impairs DNA transcription efficiency by hindering Stat3 dimerization, partially destroying DNA conformation. Specifically, when the ligand occupies the SH2 cavity of the enzyme, spatial rejection is not conductive to phosphokinase binding. It indirectly prevents the phosphorylation of Y705 and the formation of Stat3 dimer. When the inhibitor binds to the DT1005 position, it obviously shortens the distance between DNA and DBD, enhances their binding capacity, and thereby reduces the degree of freedom required for transcription. This work not only provides the binding modes between Stat3 and quercetin, but also contributes to the optimization and design of such anti-cancer inhibitors.
| S-EPMC11341021 | biostudies-literature
Project description:PurposeThis study presents the validation of an index that defines and measures a patient-centered approach to quality survivorship care.MethodsWe conducted a national survey of 1,278 survivors of breast, prostate, and colorectal cancers to identify their priorities for cancer survivorship care. We identified 42 items that were "very important or absolutely essential" to study participants. We then conducted exploratory and confirmatory factor analyses (EFA/CFA) to develop and validate the Patient-Centered Survivorship Care Index (PC-SCI).ResultsA seven-factor structure was identified based on EFA on a randomly split half sample and then validated by CFA based on the other half sample. The seven factors include: (1) information and support in survivorship (7 items), (2) having a medical home (10 items) (3) patient engagement in care (3 items), (4) care coordination (5 items), (5) insurance navigation (3 items), (6) care transitions from oncologist to primary care (3 items), and (7) prevention and wellness services (5 items). All factors have excellent composite reliabilities (Cronbach's alpha 0.84-0.94, Coefficient of Omega: 0.81-0.94).ConclusionsProviding quality post-treatment care is critical for the long-term health and well-being of survivors. The PC-SCI defines a patient-centered approach to survivorship care to complement clinical practice guidelines. The PC-SCI has acceptable composite reliability, providing the field with a valid instrument of patient-centered survivorship care. The PC-SCI provides cancer centers with a means to guide, measure and monitor the development of their survivorship care to align with patient priorities of care.Trial registrationClinicalTrials.gov ID: NCT02362750 , 13 February 2015.
| S-EPMC8684610 | biostudies-literature
Project description:The role of comparative oncology in translational research is receiving increasing attention from drug developers and the greater biomedical research community. Pet dogs with spontaneous cancer are important and underutilized translational models, owing to dogs' large size and relative outbreeding, combined with their high incidence of certain tumor histotypes with significant biological, genetic, and histological similarities to their human tumor counterparts. Dogs with spontaneous tumors naturally develop therapy resistance and spontaneous metastasis, all in the context of an intact immune system. These fundamental features of cancer biology are often lacking in induced or genetically engineered preclinical tumor models and likely contribute to their poor predictive value and the associated overall high failure rate in oncology drug development. Thus, the conduct of clinical trials in pet dogs with naturally occurring cancer represents a viable surrogate and valuable intermediary step that should be increasingly incorporated into the cancer drug discovery and development pipeline. The development of molecular-targeted therapies has resulted in an expanded role of the pathologist in human oncology trials, and similarly the expertise of veterinary pathologists will be increasingly valuable to all phases of comparative oncology trial design and conduct. In this review, we provide a framework of clinical, ethical, and pathology-focused considerations for the increasing integration of translational research investigations in dogs with spontaneous cancer as a means to accelerate clinical cancer discovery and drug development.
| S-EPMC6927823 | biostudies-literature
Project description:Danio rerio (zebrafish) are a powerful experimental model for genetic and developmental studies. Adaptation of zebrafish to study seizures was initially established using the common convulsant agent pentylenetetrazole (PTZ). Larval PTZ-exposed zebrafish exhibit clear behavioral convulsions and abnormal electrographic activity, reminiscent of interictal and ictal epileptiform discharge. By using this model, our laboratory developed simple locomotion-based and electrophysiological assays to monitor and quantify seizures in larval zebrafish. Zebrafish also offer multiple advantages for rapid genetic manipulation and high-throughput phenotype-based drug screening. Combining these seizure assays with genetically modified zebrafish that represent Dravet syndrome, a rare genetic epilepsy, ultimately contributed to a phenotype-based screen of over 3500 drugs. Several drugs identified in these zebrafish screens are currently in clinical or compassionate-use trials. The emergence of this 'aquarium-to-bedside' approach suggests that broader efforts to adapt and improve upon this zebrafish-centric strategy can drive a variety of exciting new discoveries.
| S-EPMC8277967 | biostudies-literature
Project description:ObjectivesIn recent years, discussions on the importance and scope of therapeutic value of new medicines have intensified, stimulated by the increase of prices and number of medicines entering the market. This study aims to perform a scoping review identifying factors contributing to the definition of the therapeutic value of medicines.DesignScoping review.Data sourcesWe searched the MEDLINE, CINAHL, Embase, Business Source Premier, EconLit, Regional Business News, Cochrane, Web of Science, Scope and Pool databases through December 2020 in English, German, French, Italian and Spanish.Eligibility criteriaStudies that included determinants for the definition of therapeutic value of medicines were included.Data extraction and synthesisData were extracted using the mentioned data sources. Two reviewers independently screened and analysed the articles. Data were analysed from April 2021 to May 2022.ResultsOf the 1883 studies screened, 51 were selected and the identified factors contributing to the definition of therapeutic value of medicines were classified in three categories: patient perspective, public health perspective and socioeconomic perspective. More than three-quarters of the included studies were published after 2014, with the majority of the studies focusing on either cancer disorders (14 of 51, 27.5%) or rare diseases (11 of 51, 21.6%). Frequently mentioned determinants for value were quality of life, therapeutic alternatives and side effects (all patient perspective), prevalence/incidence and clinical endpoints (all public health perspective), and costs (socioeconomic perspective).ConclusionsMultiple determinants have been developed to define the therapeutic value of medicines, most of them focusing on cancer disorders and rare diseases. Considering the relevance of value of medicines to guide patients and physicians in decision-making as well as policymakers in resource allocation decisions, a development of evidence-based factors for the definition of therapeutic value of medicines is needed across all therapeutic areas.
| S-EPMC10748878 | biostudies-literature