84 results on '"Daniel J. Crona"'
Search Results
2. Insights and lessons learned from a prospective clinical pharmacology study in allogeneic hematopoietic stem cell transplant during the COVID‐19 pandemic
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Jing Zhu, Gauri Rao, Paul M. Armistead, Jonathan Ptachcinski, Daniel L. Weiner, Tim Wiltshire, and Daniel J. Crona
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Therapeutics. Pharmacology ,RM1-950 ,Public aspects of medicine ,RA1-1270 - Published
- 2022
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3. Evaluation of the performance of a prior tacrolimus population pharmacokinetic kidney transplant model among adult allogeneic hematopoietic stem cell transplant patients
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Jing Zhu, Olivia Campagne, Chad D. Torrice, Gabrielle Flynn, Jordan A. Miller, Tejendra Patel, Oscar Suzuki, Jonathan R. Ptachcinski, Paul M. Armistead, Tim Wiltshire, Donald E. Mager, Daniel L. Weiner, and Daniel J. Crona
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Therapeutics. Pharmacology ,RM1-950 ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Tacrolimus is a calcineurin inhibitor used to prevent acute graft versus host disease in adult patients receiving allogeneic hematopoietic stem cell transplantation (HCT). Previous population pharmacokinetic (PK) models have been developed in solid organ transplant, yet none exists for patients receiving HCT. The primary objectives of this study were to (1) use a previously published population PK model in adult patients who underwent kidney transplant and apply it to allogeneic HCT; (2) evaluate model‐predicted tacrolimus steady‐state trough concentrations and simulations in patients receiving HCT; and (3) evaluate covariates that affect tacrolimus PK in allogeneic HCT. A total of 252 adult patients receiving allogeneic HCT were included in the study. They received oral tacrolimus twice daily (0.03 mg/kg) starting 3 days prior to transplant. Data for these analyses included baseline clinical and demographic data, genotype data for single nucleotide polymorphisms in CYP3A4/5 and ABCB1, and the first tacrolimus steady‐state trough concentration. A dosing simulation strategy based on observed trough concentrations (rather than model‐based predictions) resulted in 12% more patients successfully achieving tacrolimus trough concentrations within the institutional target range (5–10 ng/ml). Stepwise covariate analyses identified HLA match and conditioning regimen (myeloablative vs. reduced intensity) as significant covariates. Ultimately, a previously published tacrolimus population PK model in kidney transplant provided a platform to help establish a model‐based dose adjustment strategy in patients receiving allogenic HCT, and identified HCT‐specific covariates to be considered for future prospective studies. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Tacrolimus is a cornerstone immunosuppressant used in patients who undergo organ transplantations. However, because of its narrow therapeutic index and wide interpatient pharmacokinetic (PK) variability, optimizing its dose is crucial to maximize efficacy and minimize tacrolimus‐induced toxicities. Prior to this study, no tacrolimus population PK models have been developed for adult patients receiving allogeneic hematopoietic stem cell transplantation (HCT). Therefore, research effort was warranted to develop a population PK model that begins to propose more precision tacrolimus dosing and begins to address both a clinical and scientific gap in this patient population. WHAT QUESTION DID THIS STUDY ADDRESS? The study addressed whether there is value in utilizing the observed tacrolimus steady‐state trough concentrations from patients receiving allogeneic HCT within the context of a pre‐existing population PK model developed for kidney transplant. The study also addressed whether there are clinically relevant covariates specific to adult patients receiving allogeneic HCT. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Inclusion of a single steady‐state tacrolimus trough concentration is beneficial to model predictions. The dosing simulation strategy based on observed tacrolimus concentration, rather than the model‐predicted concentration, resulted in more patients achieving the target range at first steady‐state collection. Future studies should evaluate HLA matching and myeloablative conditioning versus reduced intensity conditioning regimens as covariates. These data and model‐informed dose adjustments should be included in future prospective studies. This research could also serve as a template as to how to assess the utility of prior information for other disease settings. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The M2 model fitting method and D2 dosing simulation method can be applied to other clinical pharmacology studies where only a single steady‐state trough concentration is available per patient in the presence of a previously published population PK model.
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- 2021
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- View/download PDF
4. Synthesis and Evaluation of Novel 1,2,6-Thiadiazinone Kinase Inhibitors as Potent Inhibitors of Solid Tumors
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Andreas S. Kalogirou, Michael P. East, Tuomo Laitinen, Chad D. Torrice, Kaitlyn A. Maffuid, David H. Drewry, Panayiotis A. Koutentis, Gary L. Johnson, Daniel J. Crona, and Christopher R. M. Asquith
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thiadiazinone ,bladder cancer ,prostate cancer ,pancreatic cancer ,breast cancer ,chordoma ,Organic chemistry ,QD241-441 - Abstract
A focused series of substituted 4H-1,2,6-thiadiazin-4-ones was designed and synthesized to probe the anti-cancer properties of this scaffold. Insights from previous kinase inhibitor programs were used to carefully select several different substitution patterns. Compounds were tested on bladder, prostate, pancreatic, breast, chordoma, and lung cancer cell lines with an additional skin fibroblast cell line as a toxicity control. This resulted in the identification of several low single digit micro molar compounds with promising therapeutic windows, particularly for bladder and prostate cancer. A number of key structural features of the 4H-1,2,6-thiadiazin-4-one scaffold are discussed that show promising scope for future improvement.
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- 2021
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5. Utilization of a population pharmacokinetic model to improve a busulfan test‐dose strategy in allogeneic hematopoietic cell transplant recipients
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Tyler C. Dunlap, Daniel L. Weiner, Ryan M. Kemper, Miramar Kardouh, Susanna C. DeVane, Allison Symonds, J. Ryan Shaw, Paul M. Armistead, Jonathan R. Ptachcinski, and Daniel J. Crona
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Pharmacology ,Pharmacology (medical) - Published
- 2023
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6. The Pharmacogenetics of Opiates and Its Impact on Delirium in Mechanically Ventilated Adults: A Pilot Study
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C. Adrian Austin, Andy Szeto, Apoorva Gupta, Timothy Wiltshire, Daniel J. Crona, and Christine Kistler
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Pharmaceutical Science ,Research Reports - Abstract
Background: Pharmacogenetics may explain a substantial proportion of the variation seen in the efficacy and risk profile of analgesosedative drugs and the incidence of delirium in critically ill adults. Objectives: Conduct a feasibility study to demonstrate the reliability of collecting and analyzing pharmacogenetic information from critically ill patients and to assess the impact of pharmacogenetics on intensive care unit (ICU) outcomes. Methods: We prospectively enrolled subjects from the Medical ICU at the University of North Carolina (UNC). DNA was obtained via a buccal swab and evaluated using the DNA2Rx assay. We collected data on demographics, daily cumulative psychoactive medication exposure, and severity of illness. We performed daily delirium assessments via the CAM-ICU. We analyzed associations between select single nucleotide polymorphisms (SNPs) and delirium. Results: From June, 2018 through January, 2019, we screened 244 patients and enrolled 50. The median age was 62.0 years old (range: 28-82 years old), and 27 (54%) of the subjects were female. In all, 49 (98%) samples were both high quality and sufficient quantity. In secondary analyses, we found that 80% (12/15) of patients with two 2 copies of a G allele at rs4680 on COMT experienced delirium, whereas 44% (4/9) of patients with 2 copies of an A allele at this location had delirium. In all, 44% (4/9) of patients with 2 T allele copies at rs7439366 on UGT2B7 experienced delirium compared to 73% (11/15) of patients with 2 C allele copies at this location. Conclusions: We can feasibly collect genetic information from critically ill adults. We were able to efficiently collect high quality DNA of sufficient quantity to conduct pharmacogenetic analysis in this critically ill population. Although the sample size of our current study is too small to conduct robust inferential analyses, it suggests potential SNP targets for a future larger study.
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- 2022
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7. The feasibility and potential of pharmacogenetics to reduce adverse drug events in nursing home residents
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Christine E. Kistler, Charles Adrian Austin, Junjian J. Liu, Madison Cauble, Andrew Wise, Sheel M. Patel, Kimberly Ward, Tim Wiltshire, Fei Zou, Andy H. Szeto, and Daniel J. Crona
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Drug-Related Side Effects and Adverse Reactions ,Pharmacogenetics ,Feasibility Studies ,Homes for the Aged ,Humans ,Geriatrics and Gerontology ,Article ,Aged ,Nursing Homes - Published
- 2022
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8. Table S2 from Genetic Variants of VEGFA and FLT4 Are Determinants of Survival in Renal Cell Carcinoma Patients Treated with Sorafenib
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Federico Innocenti, Kari K. Alitalo, Nancy Klauber-DeMore, Yuri K. Peterson, Carol E. Peña, Eleanor Hilliard, Amy S. Etheridge, Dylan M. Glubb, Veli-Matti Leppänen, Andrew D. Skol, and Daniel J. Crona
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Bioinformatic analyses.
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- 2023
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9. Data from Genetic Variants of VEGFA and FLT4 Are Determinants of Survival in Renal Cell Carcinoma Patients Treated with Sorafenib
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Federico Innocenti, Kari K. Alitalo, Nancy Klauber-DeMore, Yuri K. Peterson, Carol E. Peña, Eleanor Hilliard, Amy S. Etheridge, Dylan M. Glubb, Veli-Matti Leppänen, Andrew D. Skol, and Daniel J. Crona
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Molecular markers of sorafenib efficacy in patients with metastatic renal cell carcinoma (mRCC) are not available. The purpose of this study was to discover genetic markers of survival in patients with mRCC treated with sorafenib. Germline variants from 56 genes were genotyped in 295 patients with mRCC. Variant-overall survival (OS) associations were tested in multivariate regression models. Mechanistic studies were conducted to validate clinical associations. VEGFA rs1885657, ITGAV rs3816375, and WWOX rs8047917 (sorafenib arm), and FLT4 rs307826 and VEGFA rs3024987 (sorafenib and placebo arms combined) were associated with shorter OS. FLT4 rs307826 increased VEGFR-3 phosphorylation, membrane trafficking, and receptor activation. VEGFA rs1885657 and rs58159269 increased transcriptional activity of the constructs containing these variants in endothelial and RCC cell lines, and VEGFA rs58159269 increased endothelial cell proliferation and tube formation. FLT4 rs307826 and VEGFA rs58159269 led to reduced sorafenib cytotoxicity. Genetic variation in VEGFA and FLT4 could affect survival in sorafenib-treated patients with mRCC. These markers should be examined in additional malignancies treated with sorafenib and in other angiogenesis inhibitors used in mRCC.Significance:Clinical and mechanistic data identify germline genetic variants in VEGFA and FLT4 as markers of survival in patients with metastatic renal cell carcinoma.
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- 2023
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10. Figure S3 from Genetic Variants of VEGFA and FLT4 Are Determinants of Survival in Renal Cell Carcinoma Patients Treated with Sorafenib
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Federico Innocenti, Kari K. Alitalo, Nancy Klauber-DeMore, Yuri K. Peterson, Carol E. Peña, Eleanor Hilliard, Amy S. Etheridge, Dylan M. Glubb, Veli-Matti Leppänen, Andrew D. Skol, and Daniel J. Crona
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Expression of WT and T494A VEGFR-3 in HUVECs (A) and replication of phosphorylation experiments testing the effect of FLT4 rs307826 (A>G, T494A) on VEGFR-3 phosphorylation (B).
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- 2023
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11. Supplementary Methods and Materials from Genetic Variants of VEGFA and FLT4 Are Determinants of Survival in Renal Cell Carcinoma Patients Treated with Sorafenib
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Federico Innocenti, Kari K. Alitalo, Nancy Klauber-DeMore, Yuri K. Peterson, Carol E. Peña, Eleanor Hilliard, Amy S. Etheridge, Dylan M. Glubb, Veli-Matti Leppänen, Andrew D. Skol, and Daniel J. Crona
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SNP selection criteria, imputation and bioinformatic analyses
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- 2023
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12. Pharmacogenomic prescribing opportunities in percutaneous coronary intervention and bone marrow transplant patients
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Lindsay Ratner, Jing ‘Daisy’ Zhu, Megan N Gower, Tejendra Patel, Jordan A Miller, Amber Cipriani, George A Stouffer, Daniel J Crona, and Craig R Lee
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Pharmacology ,Male ,Middle Aged ,Drug Prescriptions ,Tacrolimus ,Clopidogrel ,Pharmacogenomic Testing ,surgical procedures, operative ,Percutaneous Coronary Intervention ,Genetics ,Molecular Medicine ,Humans ,Female ,Immunosuppressive Agents ,Platelet Aggregation Inhibitors ,Bone Marrow Transplantation ,Research Article - Abstract
Aim: To evaluate the potential impact of preemptive multigene pharmacogenomic (PGx) testing on medication prescribing in real-world clinical settings. Patients & methods: Prescription frequencies for 65 medications with actionable PGx recommendations were collected in 215 percutaneous coronary intervention (PCI) and 131 allogeneic hematopoietic cell transplant (allo-HCT) patients. A simulation projected the number of PGx-guided prescribing opportunities. Results: In PCI and allo-HCT patients, respectively, 66.5 and 90.1% were prescribed at least one medication with actionable PGx prescribing recommendations. Simulations projected 26.5 and 41.2 total PGx-guided prescribing opportunities per 100 PCI and allo-HCT patients, respectively, if multigene PGx results were available. Conclusion: A multigene PGx testing strategy offers potential to optimize medication prescribing beyond clopidogrel and tacrolimus in PCI and allo-HCT patients.
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- 2023
13. PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors
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Stefanie Denning, Andrew D. Skol, Alessandro Racioppi, Federico Innocenti, Julia C F Quintanilha, Daniel J. Crona, Jin Wang, Carol Peña, Danyu Lin, and Amy S. Etheridge
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Male ,Vascular Endothelial Growth Factor A ,Oncology ,medicine.medical_specialty ,Genome-wide association study ,Single-nucleotide polymorphism ,Significant snps ,Polymorphism, Single Nucleotide ,Risk Assessment ,Linkage Disequilibrium ,Article ,Double-Blind Method ,Predictive Value of Tests ,Internal medicine ,Genetics ,medicine ,Humans ,Genetic Testing ,Aged ,Predictive biomarker ,Pharmacology ,Predictive marker ,business.industry ,Middle Aged ,Bevacizumab ,Clinical trial ,Increased risk ,Vegf pathway ,Hypertension ,Molecular Medicine ,Female ,Phosphatidylinositol 3-Kinase ,business ,Biomarkers ,Signal Transduction - Abstract
No biomarkers are available to predict patients at risk of developing hypertension induced by VEGF-pathway inhibitors. This study aimed to identify predictive biomarkers of hypertension induced by these drugs using a discovery-replication approach. The discovery set included 140 sorafenib-treated patients (TARGET study) genotyped for 973 SNPs in 56 genes. The most statistically significant SNPs associated with grade ≥2 hypertension were tested for association with grade ≥2 hypertension in the replication set of a GWAS of 1039 bevacizumab-treated patients from four clinical trials (CALGB/Alliance). In the discovery set, rs444904 (G > A) in PIK3R5 was associated with an increased risk of sorafenib-induced hypertension (p = 0.006, OR = 3.88 95% CI 1.54–9.81). In the replication set, rs427554 (G > A) in PIK3R5 (in complete linkage disequilibrium with rs444904) was associated with an increased risk of bevacizumab-induced hypertension (p = 0.008, OR = 1.39, 95% CI 1.09–1.78). This study identified a predictive marker of drug-induced hypertension that should be evaluated for other VEGF-pathway inhibitors. ClinicalTrials.gov Identifier:NCT00073307 (TARGET).
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- 2021
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14. Tolerability of palbociclib in younger and older patients with advanced breast cancer
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Ryan Kemper, Allison M. Deal, Kelly Brunk, Taylor Dennison, Hillary M. Heiling, Aimee Faso, and Daniel J. Crona
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Oncology ,medicine.medical_specialty ,business.industry ,Kinase ,Advanced breast ,Cancer ,Palbociclib ,Neutropenia ,medicine.disease ,Tolerability ,Older patients ,Internal medicine ,medicine ,Pharmacology (medical) ,business ,Hormone - Abstract
Introduction Palbociclib is a small-molecule cyclin-dependent kinase 4/6 inhibitor used to treat hormone receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer. Patient-specific factors impacting dose reductions or discontinuations are unknown. Methods The primary objective was to evaluate the association of age (Results Among the 107 patients included, younger patients were less likely than older patients to have a palbociclib starting dose Conclusions Age (
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- 2021
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15. Response to Tyrosine Kinase Inhibitors in Real-World Patients With Chronic Myeloid Leukemia
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Andy H. Szeto, Majd Ahmad, Matthew C. Foster, Margaret R Sketch, Joshua F. Zeidner, Anqi Zhu, Tyler Bucci, Ryan Kemper, Benyam Muluneh, Daniel J. Crona, Amanda S Cass, and Allison M. Deal
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business.industry ,Dasatinib ,Myeloid leukemia ,Imatinib ,Clinical trial ,Treatment Outcome ,Nilotinib ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Imatinib Mesylate ,Cancer research ,Humans ,Medicine ,Pharmacology (medical) ,business ,Protein Kinase Inhibitors ,Tyrosine kinase ,Bosutinib ,medicine.drug - Abstract
Background: Tyrosine kinase inhibitors (TKIs) are the front-line therapy for chronic myeloid leukemia (CML), where phase 3 clinical trials have demonstrated their safety and efficacy. However, trial patients may not be representative of real-world patients (RWPs). Objective: To evaluate RWP clinical factors associated with effectiveness and safety in CML patients treated with TKIs. Methods: Patients with CML treated with at least 30 days of imatinib, dasatinib, nilotinib, or bosutinib between 2014 and 2018 were included. Patients were stratified into categories based on the number of factors that would have precluded enrollment into pivotal TKI phase 3 trials (0, 1, ≥2). End points included complete hematologic response (CHR), early molecular response (EMR), major molecular response (MMR), adverse event (AE)-induced dose decreases, treatment interruptions, and treatment discontinuations. Results: Final analyses included 174 patients. Patients with ≥2 factors had a higher risk of dose decreases (relative risk = 1.54; 95% CI = 1.02-2.34; P = 0.02) and a shorter time to dose decrease (hazard ratio = 2.43; 95% CI = 1.23-4.97; P = 0.006) compared with patients with 0 factors. Significant differences were observed in CHR at 1 month and MMR at 3 months between patients with 0 and ≥2 factors ( P = 0.03 and P = 0.04, respectively). Conclusion and Relevance: Approximately 60% of our RWPs would have been excluded from the pivotal phase 3 TKI trials. These data suggest that RWPs require more precise dosing to achieve CML clinical milestones and to mitigate AEs, but findings should be validated prospectively.
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- 2021
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16. Pharmacokinetics of perioperative FVIII in adult patients with haemophilia A: An external validation and development of an alternative population pharmacokinetic model
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Ron A. A. Mathôt, Daniel Gonzalez, Nigel S. Key, Yi Shuan Wu, Ryan J. Beechinor, Daniel J. Crona, Jing Zhu, Marjon H. Cnossen, Sheh-Li Chen, Laura H. Bukkems, Ryan Kemper, Graduate School, Pharmacy, Other Research, Amsterdam Gastroenterology Endocrinology Metabolism, and Pediatrics
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Adult ,Oncology ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Haemophilia A ,Population ,haemophilia A ,Hemorrhage ,dosing simulation ,Hemophilia A ,Article ,Hemostatics ,external validation ,Pharmacokinetics ,population pharmacokinetics ,hemic and lymphatic diseases ,Internal medicine ,Humans ,Medicine ,Dosing ,perioperative ,Prospective cohort study ,education ,Genetics (clinical) ,Retrospective Studies ,Clotting factor ,education.field_of_study ,Factor VIII ,business.industry ,Hematology ,General Medicine ,Perioperative ,medicine.disease ,Cohort ,business - Abstract
Introduction: Haemophilia A patients require perioperative clotting factor replacement to limit excessive bleeding. Weight-based dosing of Factor VIII (FVIII) does not account for inter-individual pharmacokinetic (PK) variability, and may lead to suboptimal FVIII exposure. Aim: To perform an external validation of a previously developed population PK (popPK) model of perioperative FVIII in haemophilia A patients. Methods: A retrospective chart review identified perioperative haemophilia A patients at the University of North Carolina (UNC) between April 2014 and November 2019. Patient data was used to externally validate a previously published popPK model proposed by Hazendonk. Based on these validation results, a modified popPK model was developed to characterize FVIII PK in our patients. Dosing simulations were performed using this model to compare FVIII target attainment between intermittent bolus (IB) and continuous infusion (CI) administration methods. Results: A total of 521 FVIII concentrations, drawn from 34 patients, were analysed. Validation analyses revealed that the Hazendonk model did not fully capture FVIII PK in the UNC cohort. Therefore, a modified one-compartment model, with weight and age as covariates on clearance (CL), was developed. Dosing simulations revealed that CI resulted in improved target attainment by 16%, with reduced overall FVIII usage by 58 IU/kg, compared to IB. Conclusion: External validation revealed a previously published popPK model of FVIII did not adequately characterize UNC patients, likely due to differences in patient populations. Future prospective studies are needed to evaluate our model prior to implementation into clinical practice.
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- 2021
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17. Abstract 6281: OTX-015 inhibits proliferation and migration in ARID1A-mutated bladder cancer
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Ryan M. Kemper, Manfred Meng, Jeffrey S. Damrauer, William Y. Kim, and Daniel J. Crona
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Cancer Research ,Oncology - Abstract
Background: ARID1A mutations (ARID1Amut) occur in up to 30% of metastatic bladder cancers (mBC) and have been associated with poorer response to standard treatments and shorter overall survival. We previously identified bromodomain and extraterminal (BET) protein inhibition as a potential treatment paradigm for mBC, with particular potency of BET inhibitors (BETi) in cells lines containing ARID1A inactivating mutations (ARID1Amut). BETi prevents BET protein bromodomains from interacting with acetylated histone lysine tails and promoting transcription of multiple oncogenes. Our previous data shows that treatment with the pan-BETi OTX-015 reduces ARID1B expression, and significantly reduces both gene and protein expression of RAD51/RAD51 in ARID1Amut cells compared to ARID1A wild type (ARID1AWT), suggesting impaired DNA damage repair function. Here we evaluate the phenotypic effects of BETi on proliferation and migration in preclinical models of BC. Methods: To evaluate OTX-015-induced changes to gene expression, 5637 (ARID1AWT) and HT1197 (ARID1Amut) cells were treated with 1 μM OTX-015 for 48-h. RNA was extracted and sent to Novogene for bulk RNA-seq. Differential expression was quantified using DESeq2, and gene enrichment was analyzed using GSEA. 5637 and HT1197 cells were treated with 1 or 5 μM OTX-015 for 48-h, and colony forming potential was assessed by crystal violet staining after 10 days. Cells were treated with the same treatment schema as above, and a wound-healing assay evaluated wound closure over 48-h. Differences in the percent area of wells covered with colonies and relative wound closure were assessed by FIJI v.2.9.1. Results: BET inhibition of ARID1Amut HT1197 cells lead to a significant decrease in the pathway enrichment for G2/M checkpoint (NES=-2.78, q Conclusions: These preliminary data highlight how OTX-015 potently inhibits proliferation and migration in ARID1Amut cells. These data will be confirmed in isogenic cell lines harboring inactivating ARID1A mutations, and support future mechanistic exploration (e.g., BETi-mediated cell cycle dysregulation) in ARID1Amut bladder cancer. Citation Format: Ryan M. Kemper, Manfred Meng, Jeffrey S. Damrauer, William Y. Kim, Daniel J. Crona. OTX-015 inhibits proliferation and migration in ARID1A-mutated bladder cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6281.
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- 2023
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18. Evaluation of the performance of a prior tacrolimus population pharmacokinetic kidney transplant model among adult allogeneic hematopoietic stem cell transplant patients
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Gabrielle Flynn, Jonathan R. Ptachcinski, Chad Torrice, Jing Zhu, Donald E. Mager, Olivia Campagne, Jordan A Miller, Daniel Weiner, Tim Wiltshire, Daniel J. Crona, Paul M. Armistead, Tejendra Patel, and Oscar Suzuki
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,medicine.medical_treatment ,Calcineurin Inhibitors ,Population ,Administration, Oral ,Graft vs Host Disease ,Context (language use) ,RM1-950 ,Hematopoietic stem cell transplantation ,Models, Biological ,Article ,Tacrolimus ,General Biochemistry, Genetics and Molecular Biology ,law.invention ,Young Adult ,law ,Internal medicine ,Humans ,Medicine ,Computer Simulation ,Dosing ,General Pharmacology, Toxicology and Pharmaceutics ,Prospective cohort study ,education ,Aged ,education.field_of_study ,Clinical pharmacology ,Dose-Response Relationship, Drug ,business.industry ,Research ,General Neuroscience ,Hematopoietic Stem Cell Transplantation ,Articles ,General Medicine ,Middle Aged ,Kidney Transplantation ,Calcineurin ,surgical procedures, operative ,Biological Variation, Population ,Female ,Therapeutics. Pharmacology ,Public aspects of medicine ,RA1-1270 ,business - Abstract
Tacrolimus is a calcineurin inhibitor used to prevent acute graft versus host disease in adult patients receiving allogeneic hematopoietic stem cell transplantation (HCT). Previous population pharmacokinetic (PK) models have been developed in solid organ transplant, yet none exists for patients receiving HCT. The primary objectives of this study were to (1) use a previously published population PK model in adult patients who underwent kidney transplant and apply it to allogeneic HCT; (2) evaluate model‐predicted tacrolimus steady‐state trough concentrations and simulations in patients receiving HCT; and (3) evaluate covariates that affect tacrolimus PK in allogeneic HCT. A total of 252 adult patients receiving allogeneic HCT were included in the study. They received oral tacrolimus twice daily (0.03 mg/kg) starting 3 days prior to transplant. Data for these analyses included baseline clinical and demographic data, genotype data for single nucleotide polymorphisms in CYP3A4/5 and ABCB1, and the first tacrolimus steady‐state trough concentration. A dosing simulation strategy based on observed trough concentrations (rather than model‐based predictions) resulted in 12% more patients successfully achieving tacrolimus trough concentrations within the institutional target range (5–10 ng/ml). Stepwise covariate analyses identified HLA match and conditioning regimen (myeloablative vs. reduced intensity) as significant covariates. Ultimately, a previously published tacrolimus population PK model in kidney transplant provided a platform to help establish a model‐based dose adjustment strategy in patients receiving allogenic HCT, and identified HCT‐specific covariates to be considered for future prospective studies. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Tacrolimus is a cornerstone immunosuppressant used in patients who undergo organ transplantations. However, because of its narrow therapeutic index and wide interpatient pharmacokinetic (PK) variability, optimizing its dose is crucial to maximize efficacy and minimize tacrolimus‐induced toxicities. Prior to this study, no tacrolimus population PK models have been developed for adult patients receiving allogeneic hematopoietic stem cell transplantation (HCT). Therefore, research effort was warranted to develop a population PK model that begins to propose more precision tacrolimus dosing and begins to address both a clinical and scientific gap in this patient population. WHAT QUESTION DID THIS STUDY ADDRESS? The study addressed whether there is value in utilizing the observed tacrolimus steady‐state trough concentrations from patients receiving allogeneic HCT within the context of a pre‐existing population PK model developed for kidney transplant. The study also addressed whether there are clinically relevant covariates specific to adult patients receiving allogeneic HCT. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Inclusion of a single steady‐state tacrolimus trough concentration is beneficial to model predictions. The dosing simulation strategy based on observed tacrolimus concentration, rather than the model‐predicted concentration, resulted in more patients achieving the target range at first steady‐state collection. Future studies should evaluate HLA matching and myeloablative conditioning versus reduced intensity conditioning regimens as covariates. These data and model‐informed dose adjustments should be included in future prospective studies. This research could also serve as a template as to how to assess the utility of prior information for other disease settings. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The M2 model fitting method and D2 dosing simulation method can be applied to other clinical pharmacology studies where only a single steady‐state trough concentration is available per patient in the presence of a previously published population PK model.
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- 2021
- Full Text
- View/download PDF
19. KDR genetic predictor of toxicities induced by sorafenib and regorafenib
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Julia C. F. Quintanilha, Susan Geyer, Amy S. Etheridge, Alessandro Racioppi, Kelli Hammond, Daniel J. Crona, Carol E. Peña, Sawyer B. Jacobson, Federica Marmorino, Daniele Rossini, Chiara Cremolini, Hanna K. Sanoff, Ghassan K. Abou-Alfa, and Federico Innocenti
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Pharmacology ,Pyridines ,Phenylurea Compounds ,Neoplasms ,Genetics ,Molecular Medicine ,Humans ,Sorafenib ,Vascular Endothelial Growth Factor Receptor-2 ,Article - Abstract
No biomarkers are available to predict toxicities induced by VEGFR TKIs. This study aimed to identify markers of toxicities induced by these drugs using a discovery-validation approach. The discovery set included 140 sorafenib-treated cancer patients (TARGET study) genotyped for SNPs in 56 genes. The most significant SNPs associated with grade ≥2 hypertension, diarrhea, dermatologic toxicities, and composite toxicity (any one of the toxicities) were tested for association with grade ≥2 toxicity in a validation set of 201 sorafenib-treated patients (Alliance/CALGB 80802). The validated SNP was tested for association with grade ≥2 toxicity in 107 (LCCC 1029) and 82 (Italian cohort) regorafenib-treated patients. SNP-toxicity associations were evaluated using logistic regression, and a meta-analysis between the studies was performed by inverse variance. Variant rs4864950 in KDR increased the risk of grade ≥2 composite toxicity in TARGET, Alliance/CALGB 80802, and the Italian cohort (meta-analysis p=6.79×10(−4), OR=2.01, 95% CI 1.34–3.01). We identified a predictor of toxicities induced by VEGFR TKIs.
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- 2022
20. Polygenic Risk Scores for Blood Pressure to Assess the Risk of Severe Bevacizumab-Induced Hypertension in Cancer Patients (Alliance)
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Julia C.F. Quintanilha, Amy S. Etheridge, Brady J. Graynor, Nicholas B. Larson, Daniel J. Crona, Braxton D. Mitchell, and Federico Innocenti
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Pharmacology ,Bevacizumab ,Risk Factors ,Neoplasms ,Hypertension ,Humans ,Pharmacology (medical) ,Blood Pressure ,Essential Hypertension ,Genome-Wide Association Study - Abstract
Hypertension is a common bevacizumab-induced toxicity. No markers are available to predict patients at risk of developing hypertension. We hypothesized that genetic risk of essential hypertension, as measured by a blood pressure polygenic risk score (PRS), would be associated with risk of severe bevacizumab-induced hypertension. PRSs were calculated for 1,027 bevacizumab-treated patients of European descent with cancer from four clinical trials (Alliance for Clinical Trials in Oncology (Alliance) / Cancer and Leukemia Group B (CALGB) 80303, 40503, 90401, 40502) using summary systolic blood pressure (SBP) and diastolic blood pressure (DBP) genome-wide association results obtained from 757,601 individuals of European descent. The association between PRS and grade 3 bevacizumab-induced hypertension (Common Toxicity Criteria for Adverse Events version 3) in each trial was performed by multivariable logistic regression. Fixed-effect meta-analyses odds ratios (ORs) per standard deviation (SD) of the association of PRS (quantitative) and hypertension across trials were estimated by inverse-variance weighting. PRSs were additionally stratified into quintiles, with the bottom quintile as the referent group. The OR of the association between hypertension and each quintile vs. the referent group was determined by logistic regression. The most significant PRS (quantitative)-hypertension association included up to 67 single-nucleotide variants (SNPs) associated with SBP (P = 0.0077, OR per SD = 1.31, 95% confidence interval (CI), 1.07-1.60), and up to 53 SNPs associated with DBP (P = 0.0209, OR per SD = 1.27, 95% CI, 1.04-1.56). Patients in the top quintile had a higher risk of developing bevacizumab-induced hypertension compared with patients in the bottom quintile using SNPs associated with SBP (P = 4.75 × 10
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- 2022
21. Abstract B030: Combined inhibition of BET proteins and PARP promotes impaired DNA damage repair response and cell cycle dysregulation in preclinical models of bladder cancer
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Ryan M. Kemper, Manfred Meng, and Daniel J. Crona
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Cancer Research ,Oncology - Abstract
Background: Bladder cancer (BC) remains a common and deadly malignancy, with a projected 81,180 new diagnoses and 17,100 deaths in the United States in 2022. According to the MSK/TCGA Bladder Cancer dataset, mutations in DNA damage response (DDR) genes that are part of the homologous recombination (HR) pathway occurred in up to 55% of patients, representing a potential therapeutic target in BC. In previous work, we used UNC’s EpiG Diamond compound library to show that, as a class, inhibition of the methyl-lysine reader bromodomain and extra-terminal domain (BET) proteins potently abrogate BC cell line viability. Here, we evaluated mechanisms related to HR inhibition that could explain pan-BET inhibitor OTX-015’s potency in BC. Methods: 5637 and J82 BC cells were treated with 1 µM OTX-015 or 0.1% DMSO control for 48-hours, total RNA was extracted, and then bulk RNA-sequencing (RNA-seq) was performed on an Illumina NovaSeq 6000 (Novogene, Sacramento, CA). Expression data was analyzed using Geneious Prime v2022.2.1 (Biomatters, San Diego, CA). Cells were then treated with 1 μM OTX-015, 5 μM of the PARP inhibitor olaparib, or combination for gene and protein expression analysis. Gene expression changes in BRCA1, BRCA2, PALB2, and RAD51, as well as MYC as a positive control, were confirmed by RT-PCR in biological triplicates after 48-hour incubation, normalized to an SDHA housekeeper and compared to a 0.1% DMSO control. Western blotting evaluated OTX-015 and olaparib effects on BRCA1, BRCA2, c-MYC, PALB2, and RAD51 protein expression after 72-hour incubation, using a GAPDH loading control and compared to a 0.1% DMSO control. Last, cells were treated with the same treatment schema for 24-72 hours, fixed with methanol, stained with propidium iodide (25 μg/mL), and flow cytometry evaluated effects on cell cycle using a ThermoFisher Attune NxT and FlowJo v10.8.1 (BD Life Sciences, Ashland, OR). Results: Bulk RNA-seq analyses revealed significantly altered expression of HR pathway genes in 5637 and J82 cells treated with OTX-015±olaparib. In 5637 cells, OTX-015 alone significantly reduced BRCA1, BRCA2, PALB2 and RAD51 expression, (n=3; P Citation Format: Ryan M. Kemper, Manfred Meng, Daniel J. Crona. Combined inhibition of BET proteins and PARP promotes impaired DNA damage repair response and cell cycle dysregulation in preclinical models of bladder cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B030.
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- 2022
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22. Insights and lessons learned from a prospective clinical pharmacology study in allogeneic hematopoietic stem cell transplant during the COVID-19 pandemic
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Daniel Weiner, Daniel J. Crona, Jonathan R. Ptachcinski, Jing Zhu, Tim Wiltshire, Paul M. Armistead, and Gauri Rao
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2019-20 coronavirus outbreak ,Clinical pharmacology ,Coronavirus disease 2019 (COVID-19) ,business.industry ,General Neuroscience ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,MEDLINE ,Hematopoietic Stem Cell Transplantation ,COVID-19 ,General Medicine ,General Biochemistry, Genetics and Molecular Biology ,law.invention ,law ,Pandemic ,Immunology ,Pharmacology, Clinical ,Commentary ,Medicine ,Humans ,Allogeneic hematopoietic stem cell transplant ,Prospective Studies ,General Pharmacology, Toxicology and Pharmaceutics ,business ,Pandemics - Published
- 2021
23. Synthesis and Evaluation of Novel 1,2,6-Thiadiazinone Kinase Inhibitors as Potent Inhibitors of Solid Tumors
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Michael P. East, Panayiotis A. Koutentis, David H. Drewry, Kaitlyn A. Maffuid, Andreas S. Kalogirou, Chad Torrice, Christopher R. M. Asquith, Tuomo Laitinen, Daniel J. Crona, and Gary L. Johnson
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Scaffold ,pancreatic cancer ,Pharmaceutical Science ,thiadiazinone ,Antineoplastic Agents ,Article ,Analytical Chemistry ,Prostate cancer ,Structure-Activity Relationship ,QD241-441 ,Breast cancer ,breast cancer ,Prostate ,Pancreatic cancer ,Neoplasms ,Drug Discovery ,medicine ,Tumor Cells, Cultured ,Humans ,Physical and Theoretical Chemistry ,Lung cancer ,chordoma ,Protein Kinase Inhibitors ,Cell Proliferation ,Bladder cancer ,Dose-Response Relationship, Drug ,Molecular Structure ,Thiadiazines ,Kinase ,Chemistry ,Organic Chemistry ,medicine.disease ,prostate cancer ,lung cancer ,medicine.anatomical_structure ,Chemistry (miscellaneous) ,Drug Design ,Cancer research ,Molecular Medicine ,bladder cancer ,Drug Screening Assays, Antitumor - Abstract
A focused series of substituted 4H-1,2,6-thiadiazin-4-ones was designed and synthesized to probe the anti-cancer properties of this scaffold. Insights from previous kinase inhibitor programs were used to carefully select several different substitution patterns. Compounds were tested on bladder, prostate, pancreatic, breast, chordoma, and lung cancer cell lines with an additional skin fibroblast cell line as a toxicity control. This resulted in the identification of several low single digit micro molar compounds with promising therapeutic windows, particularly for bladder and prostate cancer. A number of key structural features of the 4H-1,2,6-thiadiazin-4-one scaffold are discussed that show promising scope for future improvement.
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- 2021
24. Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing
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Sony Tuteja, Victoria M. Pratt, Sara L. Van Driest, D. Max Smith, J. Kevin Hicks, Benjamin Q. Duong, Nita A. Limdi, Laura B. Ramsey, Aniwaa Owusu Obeng, Josh F. Peterson, Jeffrey R. Bishop, Kristin Weitzel, Richard C. Shelton, Stuart A. Scott, Julie A. Johnson, Kathryn V. Blake, Amber L. Beitelshees, James C. Lee, Lynn G. Dressler, Todd C. Skaar, Lindsay J. Hines, Philip E. Empey, Daniel J. Crona, Ryan A. Gregg, Gillian C. Bell, Larisa H. Cavallari, and Cynthia A. Prows
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0301 basic medicine ,Genotype ,Process (engineering) ,030105 genetics & heredity ,Drug Prescriptions ,digestive system ,Clinical decision support system ,Article ,03 medical and health sciences ,Early adopter ,Humans ,Relevance (information retrieval) ,Genetic Testing ,implementation ,skin and connective tissue diseases ,Genotyping ,Genetics (clinical) ,Medical education ,CYP2D6 ,Medical record ,Stakeholder ,opioids ,Decision Support Systems, Clinical ,Pharmacogenomic Testing ,3. Good health ,Phenotype ,030104 developmental biology ,Cytochrome P-450 CYP2D6 ,Pharmacogenetics ,antidepressants ,Return of results ,Psychology - Abstract
Purpose: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers. Methods: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned. Results: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy number variation and 9 common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability. Conclusion: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.
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- 2019
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25. Targeting an EGFR Water Network with 4‐Anilinoquin(az)oline Inhibitors for Chordoma
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Graham J. Tizzard, Tuomo Laitinen, Chad Torrice, William J. Zuercher, Kaitlyn A. Maffuid, Daniel J. Crona, and Christopher R. M. Asquith
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Models, Molecular ,Lung Neoplasms ,non-small cell lung cancer (NSCLC) ,Antineoplastic Agents ,Apoptosis ,01 natural sciences ,Biochemistry ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Drug Discovery ,Chordoma ,medicine ,Humans ,Molecular Targeted Therapy ,Epidermal growth factor receptor ,General Pharmacology, Toxicology and Pharmaceutics ,Protein Kinase Inhibitors ,IC50 ,EGFR inhibitors ,Pharmacology ,Aniline Compounds ,biology ,010405 organic chemistry ,Kinase ,Chemistry ,Cellular Assay ,Organic Chemistry ,Active site ,medicine.disease ,0104 chemical sciences ,ErbB Receptors ,010404 medicinal & biomolecular chemistry ,Cell culture ,Quinazolines ,Cancer research ,biology.protein ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Protein Binding - Abstract
Quinoline- and quinazoline-based kinase inhibitors of the epidermal growth factor receptor (EGFR) have been used to target non-small cell lung cancer (NSCLC) and chordomas with varying amounts of success. We designed and prepared compounds to probe several key structural features including an interaction with Asp855 within the EGFR DGF motif and interactions with the active site water network. EGFR target engagement was then evaluated in a cellular assay, with the inhibitors then profiled in representative cellular models of NSCLC and chordomas. In addition, structure–activity relationship insight into EGFR inhibitor design with potent dimethoxyquin(az)olines identified compounds 1 [N-(3-ethynylphenyl)-6,7-dimethoxyquinolin-4-amine], 4 [N-(3-ethynylphenyl)-6,7-dimethoxyquinazolin-4-amine], and 7 [4-((3-ethynylphenyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile]. We also identified 6,7-dimethoxy-N-(4-((4-methylbenzyl)oxy)phenyl)quinolin-4-amine (compound 18), which is the most potent inhibitor (IC50=310 nm) of the UCH-2 chordoma cell line to date.
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- 2019
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26. Anti-tubercular activity of novel 4-anilinoquinolines and 4-anilinoquinazolines
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Christopher R. M. Asquith, Christoph Grundner, William J. Zuercher, Chad Torrice, Neil Fleck, and Daniel J. Crona
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Clinical Biochemistry ,Antitubercular Agents ,Pharmaceutical Science ,Microbial Sensitivity Tests ,01 natural sciences ,Biochemistry ,Article ,Mycobacterium tuberculosis ,Structure-Activity Relationship ,chemistry.chemical_compound ,Aniline ,Drug Discovery ,Quinazoline ,Potency ,Anti tubercular ,Molecular Biology ,Aniline Compounds ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Organic Chemistry ,Quinoline ,biology.organism_classification ,Combinatorial chemistry ,0104 chemical sciences ,3. Good health ,010404 medicinal & biomolecular chemistry ,chemistry ,Quinazolines ,Quinolines ,Molecular Medicine - Abstract
We screened a series of 4-anilinoquinolines and 4-anilinoquinazolines and identified novel inhibitors of Mycobacterium tuberculosis (Mtb). The focused 4-anilinoquinoline/quinazoline scaffold arrays yielded compounds with high potency and the identification of 6,7-dimethoxy-N-(4-((4-methylbenzyl)oxy)phenyl)quinolin-4-amine (34) with an MIC90 value of 0.63–1.25 µM. We also defined a series of key structural features, including the benzyloxy aniline and the 6,7-dimethoxy quinoline ring, that are important for Mtb inhibition. Importantly the compounds showed very limited toxicity and scope for further improvement by iterative medicinal chemistry.
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- 2019
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27. SGC-GAK-1: A Chemical Probe for Cyclin G Associated Kinase (GAK)
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David H. Drewry, Carrow I. Wells, James M. Bennett, Daniel J. Crona, Chad Torrice, Michael P. East, Christopher R. M. Asquith, Timothy M. Willson, Stephen J. Capuzzi, Oleg Fedorov, H. Shelton Earp, Jonathan M. Elkins, Susanne Müller, Benedict-Tilman Berger, William J. Zuercher, Debra Hunter, P.H.C. Godoi, Stefan Knapp, and Jing Wan
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Male ,Negative control ,Chemical probe ,Protein Serine-Threonine Kinases ,01 natural sciences ,Article ,Cyclin G ,RIPK2 ,03 medical and health sciences ,Drug Discovery ,Humans ,030304 developmental biology ,Cyclin ,0303 health sciences ,Chemistry ,Kinase ,HEK 293 cells ,Intracellular Signaling Peptides and Proteins ,Highly selective ,In vitro ,0104 chemical sciences ,Cell biology ,010404 medicinal & biomolecular chemistry ,HEK293 Cells ,Molecular Probes ,Molecular Medicine - Abstract
We describe SGC-GAK-1 (11), a potent, selective, and cell-active inhibitor of cyclin G-associated kinase (GAK), together with a structurally related negative control SGC-GAK-1N (14). 11 was highly selective in an in vitro kinome-wide screen, but cellular engagement assays defined RIPK2 as a collateral target. We identified 18 as a potent RIPK2 inhibitor lacking GAK activity. Together, this chemical probe set can be used to interrogate GAK cellular biology.
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- 2019
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28. A real-world evaluation of radium-223 in combination with abiraterone or enzalutamide for the treatment of metastatic castration-resistant prostate cancer
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Paul A. Godley, Ethan Basch, Andy H. Szeto, Amir H. Khandani, Matthew I. Milowsky, Blaine Brower, Mary W. Dunn, Daniel J. Crona, Stephanie I. Kim, Katherine P. Morgan, Tracy L. Rose, and Young E. Whang
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Oncology ,Male ,Abiraterone Acetate ,Cancer Treatment ,Metastasis ,Prostate cancer ,chemistry.chemical_compound ,Antineoplastic Combined Chemotherapy Protocols ,Basic Cancer Research ,Clinical endpoint ,Medicine and Health Sciences ,Aged, 80 and over ,Multidisciplinary ,Prostate Cancer ,Hazard ratio ,Prostate Diseases ,Anemia ,Chemoradiotherapy ,Hematology ,Prognosis ,Survival Rate ,Prostatic Neoplasms, Castration-Resistant ,Research Design ,Benzamides ,Medicine ,Anatomy ,medicine.drug ,Radium ,Research Article ,Radium-223 ,medicine.medical_specialty ,Clinical Research Design ,Science ,Urology ,Pain ,Bone Neoplasms ,Research and Analysis Methods ,Exocrine Glands ,Signs and Symptoms ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,medicine ,Enzalutamide ,Humans ,Adverse effect ,Aged ,Retrospective Studies ,Proportional hazards model ,business.industry ,Correction ,Cancers and Neoplasms ,Biology and Life Sciences ,medicine.disease ,Log-rank test ,Genitourinary Tract Tumors ,chemistry ,Prostate Gland ,Adverse Events ,Clinical Medicine ,business ,Follow-Up Studies - Abstract
Introduction Radium-223, abiraterone, and enzalutamide have each been shown to significantly improve survival as monotherapy in patients with metastatic castration-resistant prostate cancer. However, effects of combination radium-223 plus abiraterone or enzalutamide on survival and safety remain unclear. Patients and methods This single-center retrospective cohort study used electronic health record data of patients with metastatic castration-resistant prostate cancer and bone metastases who were treated with radium-223 between April 1, 2014 and February 19, 2019. Patients who received radium-223 monotherapy were compared to patients who received a combination of radium-223 plus either abiraterone or enzalutamide. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, time to symptomatic skeletal event, symptomatic skeletal event-free survival, and incidence of drug-related adverse events. Time-to-event analyses were estimated by log rank tests using Kaplan-Meier curves. Hazard ratios and 95% confidence intervals were derived from Cox proportional hazards models. Chi-square tests evaluated difference in serious adverse events between the two arms. Results A total of 60 patients met inclusion criteria (n = 41 in the monotherapy arm, n = 19 in the combination arm). Differences in median overall survival were not observed (12.7 vs. 12.8 months; HR 1.15, 95% CI 0.59–2.23; P = 0.68), but median progression-free survival was significantly longer in the combination arm (7.6 vs. 4.9 months; HR 1.94, 95% CI 1.11–3.40; P = 0.02). Significant differences were not observed in time to first SSE (P = 0.97), SSE-free survival (P = 0.16), or in the overall incidence of serious adverse events (P = 0.45). Conclusion Combination radium-223 plus abiraterone or enzalutamide did not improve overall survival, but prolonged progression-free survival without increasing the incidence of serious adverse events in metastatic castration-resistant prostate cancer patients with bone metastases. However, these results are limited by small numbers and patient selection inherent in retrospective analysis.
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- 2021
29. Pharmacokinetics and Pharmacodynamics of Apixaban in Nephrotic Syndrome: Findings From a Phase 1a Trial
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Vimal K. Derebail, Jing Zhu, Matthew L. Crawford, Julia R. Garnier, Karlyn A. Martin, Sarah Skinner, Tejendra Patel, Anne Froment, Margaret R. Sketch, Andy H. Szeto, Sheel M. Patel, Chad D. Torrice, Stefan Tiefenbacher, Dorothy M. Adcock, Russell P. Grant, Nigel S. Key, and Daniel J. Crona
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Nephrology - Published
- 2021
30. Design and evaluation of 1,2,3-dithiazoles and fused 1,2,4-dithiazines as anti-cancer agents
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Christopher R. M. Asquith, Chad Torrice, Maria Koyioni, Kaitlyn A. Maffuid, Heemaja K. Mewada, Panayiotis A. Koutentis, Daniel J. Crona, and William A. Murphy
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Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Skin fibroblast ,01 natural sciences ,Biochemistry ,Prostate cancer ,Structure-Activity Relationship ,Breast cancer ,Prostate ,Pancreatic cancer ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Molecular Biology ,Cell Proliferation ,Bladder cancer ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Cancer ,medicine.disease ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Thiazoles ,medicine.anatomical_structure ,Lung cancer cell ,Drug Design ,Cancer research ,Molecular Medicine ,Drug Screening Assays, Antitumor - Abstract
Heteroatom rich 1,2,3-dithiazoles are relatively underexplored in medicinal chemistry. We now report screening data on a series of structurally diverse 1,2,3-dithiazoles and electronically related 1,2,4-dithiazines with the aim of identifying interesting starting points for potential future optimisation. The 1,2,3-dithiazoles, were obtained via a number of different syntheses and screened on a series of cancer cell lines. These included breast, bladder, prostate, pancreatic, chordoma and lung cancer cell lines with an additional skin fibroblast cell line as a toxicity control. Several low single digit micromolar compounds with promising therapeutic windows were identified for breast, bladder and prostate cancer. Furthermore, key structural features of 1,2,3-dithiazoles are discussed, that show encouraging scope for future refinement.
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- 2021
31. The future of research into genetics and the precision dosing of tacrolimus: what do we need to know?
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Amy L. Pasternak, Jing Zhu, and Daniel J. Crona
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Pharmacology ,medicine.medical_specialty ,Clinical pharmacology ,Biomedical Research ,business.industry ,Tacrolimus ,law.invention ,law ,Need to know ,Pharmacogenetics ,Pharmacogenomics ,Genetics ,medicine ,Molecular Medicine ,Cytochrome P-450 CYP3A ,Humans ,Dosing ,Genetic Testing ,Precision Medicine ,Intensive care medicine ,business ,Immunosuppressive Agents - Published
- 2020
32. Projected impact of pharmacogenomic testing on medications beyond antiplatelet therapy in percutaneous coronary intervention patients
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Alexis K. Williams, Tim Wiltshire, Karen E. Weck, George A. Stouffer, Craig R. Lee, Lindsay R Ratner, Daniel J. Crona, and Rachel M Black
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Male ,medicine.medical_specialty ,Ticagrelor ,medicine.medical_treatment ,Psychological intervention ,Pharmacogenomic Testing ,CYP2C19 ,030204 cardiovascular system & hematology ,030226 pharmacology & pharmacy ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Percutaneous Coronary Intervention ,Genetics ,medicine ,Humans ,cardiovascular diseases ,Intensive care medicine ,Aged ,Retrospective Studies ,Pharmacology ,business.industry ,Percutaneous coronary intervention ,Middle Aged ,Clopidogrel ,Cytochrome P-450 CYP2C19 ,Pharmacogenetics ,Pharmacogenomics ,Conventional PCI ,Cohort ,Molecular Medicine ,Female ,business ,Prasugrel Hydrochloride ,Platelet Aggregation Inhibitors ,medicine.drug ,Research Article - Abstract
Aim: CYP2C19 genotyping is used to guide antiplatelet therapy after percutaneous coronary intervention (PCI). This study evaluated the potential impact of CYP2C19 and multigene pharmacogenomics (PGx) testing on medications beyond antiplatelet therapy in a real-world cohort of PCI patients that underwent CYP2C19 testing. Methodology & results: Multiple medications with actionable PGx recommendations, including proton pump inhibitors, antidepressants and opioids, were commonly prescribed. Approximately 50% received a CYP2C19 metabolized medication beyond clopidogrel and 7% met criteria for a CYP2C19 genotype-guided intervention. A simulation analysis projected that 17.5 PGx-guided medication interventions per 100 PCI patients could have been made if multigene PGx results were available. Conclusion: This suggests that CYP2C19 and multigene PGx results could be used to optimize medication prescribing beyond antiplatelet therapy in PCI patients.
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- 2020
33. Pharmacokinetic and pharmacodynamic analyses of cocaine and its metabolites in behaviorally divergent inbred mouse strains
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Daniel J. Crona, Trey Thompson, Allison N. Schorzman, Jing Zhu, Daniel Weiner, Ryan J. Beechinor, Lisa M. Tarantino, and William C. Zamboni
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0301 basic medicine ,Male ,Future studies ,Genotype ,Population ,Brain tissue ,Pharmacology ,Biology ,Article ,03 medical and health sciences ,Behavioral Neuroscience ,chemistry.chemical_compound ,Cocaine-Related Disorders ,Mice ,0302 clinical medicine ,Pharmacokinetics ,Cocaine ,Genetics ,Animals ,Tissue Distribution ,education ,education.field_of_study ,Brain ,Norcocaine ,Mice, Inbred C57BL ,030104 developmental biology ,Neurology ,chemistry ,Pharmacodynamics ,Benzoylecgonine ,030217 neurology & neurosurgery ,Pharmacogenetics ,Locomotion - Abstract
Cocaine is a psychostimulant with a high potential for abuse and addiction. Risk for cocaine use disorder is driven, in part, by genetic factors. Animal models of addiction-relevant behaviors have proven useful for studying both genetic and non-genetic contributions to drug response. In a previous study, we examined initial locomotor sensitivity to cocaine in genetically diverse inbred mouse strains. That work highlighted the relevance of pharmacokinetics in initial locomotor response to cocaine but was limited by a single dose and two sampling points. The objective of the present study was to characterize the pharmacokinetics and pharmacodynamics of cocaine and its metabolites (norcocaine and benzoylecgonine) in 6 inbred mouse strains (I/LnJ, C57BL/6J, FVB/NJ, BTBR T+ tf/J, LG/J, LP/J) that exhibit extreme locomotor responses to cocaine. Mice were administered cocaine at one of 4 doses and concentrations of cocaine, norcocaine, and benzoylecgonine were analyzed in both plasma and brain tissue at 5 different time points. Initial locomotor sensitivity to cocaine was used as a pharmacodynamic endpoint. We developed an empirical population PK model that simultaneously characterizes cocaine, norcocaine, and benzoylecgonine in plasma and brain tissues. We observed interstrain variability occurring in the brain compartment that may contribute to pharmacodynamic differences amongst select strains. Our current work paves the way for future studies to explore strain-specific pharmacokinetic differences and identify factors other than pharmacokinetics that are responsible for the diverse behavioral response to cocaine across these inbred mouse strains.
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- 2020
34. Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients
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James M. Coghill, Tim Wiltshire, J. Ryan Shaw, Paul M. Armistead, Thomas C. Shea, Marcie L. Riches, Chad Torrice, Jordan A Miller, Mehak Aggarwal, Kamakshi V. Rao, William A. Wood, Jing Zhu, Oscar Suzuki, Tatjana Grgic, Margaret R Sketch, John L. Schmitz, Daniel J. Crona, Eric T. Weimer, Tejendra Patel, Benjamin G. Vincent, Katarzyna Jamieson, Maurice Alexander, Jonathan S. Serody, and Jonathan R. Ptachcinski
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Male ,Oncology ,medicine.medical_treatment ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,germline ,030226 pharmacology & pharmacy ,Germline ,lcsh:Chemistry ,0302 clinical medicine ,allogeneic hematopoietic stem cell transplant ,Databases, Genetic ,Odds Ratio ,Cytochrome P-450 CYP3A ,Medicine ,tacrolimus ,lcsh:QH301-705.5 ,Spectroscopy ,pharmacogenetics ,medicine.diagnostic_test ,Hematopoietic Stem Cell Transplantation ,ABCB1 ,General Medicine ,Middle Aged ,Computer Science Applications ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Female ,pharmacokinetics ,Immunosuppressive Agents ,Adult ,CYP3A4/5 ,medicine.medical_specialty ,Genotype ,chemical and pharmacologic phenomena ,Polymorphism, Single Nucleotide ,Article ,Catalysis ,Inorganic Chemistry ,Young Adult ,03 medical and health sciences ,Germline mutation ,single nucleotide polymorphism (SNP) ,Internal medicine ,pharmacodynamics ,Humans ,Transplantation, Homologous ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Physical and Theoretical Chemistry ,CYP3A5 ,Molecular Biology ,Germ-Line Mutation ,Aged ,business.industry ,Organic Chemistry ,Tacrolimus ,Logistic Models ,lcsh:Biology (General) ,lcsh:QD1-999 ,Therapeutic drug monitoring ,Pharmacodynamics ,business ,Pharmacogenetics - Abstract
Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.
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- 2020
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35. Cabozantinib-induced serum creatine kinase elevation and musculoskeletal complaints
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Sarah E. Stump, Daniel J. Crona, and Young E. Whang
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medicine.medical_specialty ,Cabozantinib ,Pyridines ,medicine.drug_class ,Urology ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Renal cell carcinoma ,medicine ,Humans ,Anilides ,Pharmacology (medical) ,Musculoskeletal Diseases ,030212 general & internal medicine ,Creatine Kinase ,Muscle Cramp ,Pharmacology ,biology ,business.industry ,Medullary thyroid cancer ,Middle Aged ,medicine.disease ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Serum creatine kinase ,Female ,Creatine kinase ,medicine.symptom ,business ,Tyrosine kinase ,Muscle cramp - Abstract
Cabozantinib is a multikinase inhibitor approved for the treatment of metastatic medullary thyroid cancer and advanced renal cell carcinoma (RCC) in patients who have received prior anti-angiogenic therapy. While associations between serum creatine kinase (CK) elevations and other tyrosine kinase inhibitors used for the treatment of solid malignancies have been previously reported, we report a case of cabozantinib-associated CK elevation that was associated with musculoskeletal complaints by an RCC patient. Nine days following initiation of cabozantinib, the patient reported muscle cramps and serum CK had increased from levels 12 months earlier that were within normal limits to a grade 1 elevation of 244 units/L. Despite a dose reduction, her CK continued to rise over the next 2 months, leading to a peak CK of 914 units/L. Due to this grade 3 elevation, cabozantinib was permanently discontinued, and her CK subsequently returned to a grade 1 elevation within one week and then to baseline within 3 weeks. The temporal relationship between drug exposure and CK increase strongly suggests causality. To the authors' knowledge, this is the first reported case of CK elevation attributed to cabozantinib, but cabozantinib-induced CK elevations could be under-reported, and providers should monitor for musculoskeletal complaints during cabozantinib therapy.
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- 2018
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36. Correction: A real-world evaluation of radium-223 in combination with abiraterone or enzalutamide for the treatment of metastatic castration-resistant prostate cancer
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Stephanie I. Kim, Andy H. Szeto, Katherine P. Morgan, Blaine Brower, Mary W. Dunn, Amir H. Khandani, Paul A. Godley, Tracy L. Rose, Ethan M. Basch, Matthew I. Milowsky, Young E Whang, and Daniel J Crona
- Subjects
Multidisciplinary ,Science ,Medicine - Published
- 2021
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37. Correction to: PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors
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Julia C. F. Quintanilha, Alessandro Racioppi, Jin Wang, Amy S. Etheridge, Stefanie Denning, Carol E. Peña, Andrew D. Skol, Daniel J. Crona, Danyu Lin, and Federico Innocenti
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Pharmacology ,Genetics ,Molecular Medicine - Published
- 2021
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38. Precision Dosing: Public Health Need, Proposed Framework, and Anticipated Impact
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Jon C. Easter, Daniel Gonzalez, Angela D. M. Kashuba, Gauri G. Rao, Stacy Cooper Bailey, Scott W. Savage, J. Robert Powell, Tim Wiltshire, J. Herbert Patterson, Craig R. Lee, Kathryn A. Morbitzer, Yanguang Cao, Daniel J. Crona, and Kim L. R. Brouwer
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medicine.medical_specialty ,Reviews ,Review ,030226 pharmacology & pharmacy ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Drug treatment ,0302 clinical medicine ,Electronic health record ,Acute care ,Humans ,Medicine ,Dosing ,Precision Medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Intensive care medicine ,Patient factors ,Dose-Response Relationship, Drug ,Drug disposition ,business.industry ,Research ,General Neuroscience ,Public health ,Environmental resource management ,General Medicine ,3. Good health ,Treatment Outcome ,030220 oncology & carcinogenesis ,Patient Care ,Public Health ,business - Abstract
“Precision dosing” focuses on the individualization of drug treatment regimens based on patient factors known to alter drug disposition and/or response. In 2015, over 8 in 10 nonfederal acute care hospitals in the United States had adopted a basic electronic health record (EHR) system,1 which will facilitate the application of precision dosing. Expanding on recent publications,2, 3 we outline the public health need, a proposed framework, and the anticipated impact for the adoption of precision dosing.
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- 2017
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39. An Initial Genetic Analysis of Gemcitabine-Induced High-Grade Neutropenia in Pancreatic Cancer Patients in CALGB 80303 (Alliance)
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Amy S. Etheridge, Yoichi Furukawa, Daniel J. Crona, Chen Jiang, Ace J. Hatch, Mark J. Ratain, Dorothy Watson, Hedy L. Kindler, Howard L. McLeod, Alexander B. Sibley, Donna Niedzwiecki, Federico Innocenti, Michiaki Kubo, Herbert Hurwitz, Stefanie Denning, Andrew B. Nixon, and Kouros Owzar
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0301 basic medicine ,Oncology ,Male ,medicine.medical_specialty ,Standard of care ,Neutropenia ,medicine.medical_treatment ,030226 pharmacology & pharmacy ,Genetic analysis ,Deoxycytidine ,Polymorphism, Single Nucleotide ,Germline ,Article ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,Pancreatic cancer ,Cytidine Deaminase ,Genetics ,Medicine ,Humans ,Prospective Studies ,General Pharmacology, Toxicology and Pharmaceutics ,Molecular Biology ,Genetics (clinical) ,Aged ,Chemotherapy ,business.industry ,Middle Aged ,medicine.disease ,Gemcitabine ,Pancreatic Neoplasms ,030104 developmental biology ,Molecular Medicine ,Administration, Intravenous ,Female ,business ,medicine.drug - Abstract
One of the standard of care regimens for advanced pancreatic cancer is gemcitabine-based chemotherapy. The efficacy of gemcitabine is limited by dose-limiting hematologic toxicities especially neutropenia. Uncovering the variability of these toxicities attributed to germline DNA variation is of great importance.CALGB 80303 was a randomized study in advanced pancreatic cancer patients treated with gemcitabine with or without bevacizumab. The study protocol included genotyping of genes of gemcitabine disposition (CDA, DCTD, SLC29A1, SLC28A1, and SLC29A2), as well as a genome-wide analysis. The clinical phenotype was time to early high-grade neutropenia event accounting for progression or death or other treatment-terminating adverse events as competing for informative events. The inference was carried out on the basis of the association between genotype and cause-specific hazard of a neutropenic event.The primary analyses were carried out on the basis of 294 genetically estimated European pancreatic cancer patients. For CDA rs2072671 (AC), AC and CC patients had a lower risk of neutropenia than AA patients (P=0.01, hazard ratio: 0.61, 95% confidence interval: 0.41-0.89). For SLC28A1 rs3825876 (GA), AA patients have a higher risk of neutropenia than GA and GG patients (P=0.02, hazard ratio: 1.51, 95% confidence interval: 1.06-2.16). CDA rs2072671 was associated with increased mRNA expression in whole blood in three studies (P=2.7e-14, 6.61e-62, and 9.70e-65). In the genome-wide analysis, variants in TGFB2 were among the top hits (lowest P=1.62e-06) but had no effect in luciferase assays.This is the first genetic analysis of gemcitabine-induced neutropenia using a competing risk model in a prospective randomized clinical study has proposed a potentially novel mechanism of the protective effect of the CDA rs2072671 variant. Further confirmation is needed.
- Published
- 2019
40. Design and evaluation of novel 4-anilinoquinolines and quinazolines EGFR inhibitors in lung cancer and chordoma
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Koshlap Km, Kaitlyn A. Maffuid, William J. Zuercher, Chad Torrice, Graham J. Tizzard, Tuomo Laitinen, Alamillo-Ferrer C, Daniel J. Crona, and Asquith Crm
- Subjects
musculoskeletal diseases ,0303 health sciences ,biology ,Chemistry ,Target engagement ,medicine.disease ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Cell culture ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,biology.protein ,Structure–activity relationship ,Chordoma ,Non small cell ,Epidermal growth factor receptor ,Lung cancer ,030304 developmental biology ,EGFR inhibitors - Abstract
Epidermal growth factor receptor (EGFR) inhibitors have been used to target non-small cell lung cancer (NSCLC) and chordomas with varying amounts of success. We have probed several key structural features including an interaction with Asp855 within the EGFR DGF motif and interactions with the active site water network. The EGFR target engagement was then evaluated in an in-cell assay. Additionally, inhibitors were profiled in representative cellular models of NSCLC and chordomas. In addition to a structure activity relationship insights for EGFR inhibtior design, we also identified a compound (18) that is the most potent inhibitor (IC50 = 310 nM) on the UCH-2 chordoma cell line to date.
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- 2019
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41. Genetic Variants of VEGFA and FLT4 Are Determinants of Survival in Renal Cell Carcinoma Patients Treated with Sorafenib
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Andrew D. Skol, Nancy Klauber-DeMore, Dylan M. Glubb, Yuri K. Peterson, Kari Alitalo, Amy S. Etheridge, Daniel J. Crona, Veli-Matti Leppänen, Carol Peña, Eleanor Hilliard, Federico Innocenti, Kari Alitalo / Principal Investigator, University of Helsinki, HUSLAB, and CAN-PRO - Translational Cancer Medicine Program
- Subjects
0301 basic medicine ,Sorafenib ,Cancer Research ,endocrine system ,Angiogenesis ,3122 Cancers ,urologic and male genital diseases ,ANGIOGENESIS ,MECHANISMS ,ACTIVATION ,03 medical and health sciences ,0302 clinical medicine ,MULTIKINASE INHIBITOR ,Renal cell carcinoma ,Medicine ,Survival rate ,ITGAV ,Tube formation ,business.industry ,Cancer ,ASSOCIATION ,medicine.disease ,CANCER ,3. Good health ,Vascular endothelial growth factor A ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,LIGAND-BINDING ,Cancer research ,GROWTH ,3111 Biomedicine ,business ,FACTOR-TARGETED THERAPY ,medicine.drug - Abstract
Molecular markers of sorafenib efficacy in patients with metastatic renal cell carcinoma (mRCC) are not available. The purpose of this study was to discover genetic markers of survival in patients with mRCC treated with sorafenib. Germline variants from 56 genes were genotyped in 295 patients with mRCC. Variant-overall survival (OS) associations were tested in multivariate regression models. Mechanistic studies were conducted to validate clinical associations. VEGFA rs1885657, ITGAV rs3816375, and WWOX rs8047917 (sorafenib arm), and FLT4 rs307826 and VEGFA rs3024987 (sorafenib and placebo arms combined) were associated with shorter OS. FLT4 rs307826 increased VEGFR-3 phosphorylation, membrane trafficking, and receptor activation. VEGFA rs1885657 and rs58159269 increased transcriptional activity of the constructs containing these variants in endothelial and RCC cell lines, and VEGFA rs58159269 increased endothelial cell proliferation and tube formation. FLT4 rs307826 and VEGFA rs58159269 led to reduced sorafenib cytotoxicity. Genetic variation in VEGFA and FLT4 could affect survival in sorafenib-treated patients with mRCC. These markers should be examined in additional malignancies treated with sorafenib and in other angiogenesis inhibitors used in mRCC. Significance: Clinical and mechanistic data identify germline genetic variants in VEGFA and FLT4 as markers of survival in patients with metastatic renal cell carcinoma.
- Published
- 2019
42. Genetic predictor of severe sorafenib-induced diarrhea and hand-foot syndrome (HFS)
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Alessandro Racioppi, Stefanie Denning, Amy S. Etheridge, Jin Wang, Susan Geyer, Julia C F Quintanilha, Kelli Hammond, Carol Peña, Daniel J. Crona, Federico Innocenti, Sawyer B. Jacobson, and Ghassan K. Abou-Alfa
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Sorafenib ,Cancer Research ,Diarrhea ,medicine.medical_specialty ,Oncology ,business.industry ,Internal medicine ,Medicine ,medicine.symptom ,business ,Hand-Foot Syndrome ,medicine.drug - Abstract
3030 Background: Diarrhea, HFS, and hypertension are common toxicities of sorafenib. No markers are validated to predict patients at risk of these toxicities. This study aimed to identify genetic predictors of sorafenib-induced toxicities. Methods: A two-step, discovery-validation approach was used. The discovery set included 140 renal cell carcinoma patients from the TARGET study treated with sorafenib (400 mg twice daily) and genotyped for 1040 single-nucleotide polymorphisms (SNPs) in 56 genes. The three most statistically significant SNPs associated with grade ≥2 composite toxicity (either hypertension, diarrhea, HFS, or other skin toxicities, CTCAE v.3.0) were tested for association with grade 3 composite toxicity (either hypertension, diarrhea, or HFS, CTCAE v.4.0) in a validation set of 240 hepatocellular carcinoma patients from Alliance/CALGB 80802 treated with sorafenib (400 mg twice daily) alone or with doxorubicin. Associations between SNPs and composite toxicity was performed by logistic regression, with adjusting covariates (age, gender, race, and treatment arm, the latter two covariates for the validation set only). A meta-analysis odds ratio (OR) of each SNP-grade 3 toxicity association between the discovery and validation sets was obtained by inverse variance to point toward effects specific to a type of toxicity. Results: In the discovery set, the top three SNPs associated with grade ≥2 composite toxicity were rs12366035 (C>T, minor allele frequency, MAF 0.34) in VEGFB (p 0.0007), rs4035887 (G>A, MAF 0.49) in EPAS1 (p 0.0021), and rs4864950 (T>A, MAF 0.23) in KDR (p 0.0058). These SNPs were genotyped in the validation set and only rs4864950 in KDR was replicated. No grade 4 toxicities were reported. Similar to the discovery set (OR 2.41, 95% CI 1.29-4.51), the A allele of rs4864950 increased the risk of grade 3 composite toxicity (p 0.032, OR 2.12, 95% CI 1.70-4.27) in the validation set. Grade 3 toxicity prevalence in the discovery and validation sets were 3.6% and 7.4% diarrhea, 8.6% and 12.3% HFS, 3.6% and 8.8% hypertension, respectively. The meta-analysis of the two datasets showed that the A allele of rs4864950 increased the risk of grade 3 diarrhea (p 0.045, OR 3.09, 95% CI 1.03-9.29), grade 3 HFS (p 0.012, OR 2.57, 95% CI 1.24-5.37), but not grade 3 hypertension (p 0.207, OR 0.51, 95% CI 0.18-1.45). Conclusions: We provide the first evidence of clinical validity of a marker of sorafenib-induced diarrhea and HFS. Sorafenib inhibits VEGFR2 (coded by KDR), leading to epithelial hypoxia and causing diarrhea and HFS. Variant rs4864950 might affect the function VEGFR2, which, during VEGFR2 inhibition, increases the risk of diarrhea and HFS. This SNP is common and can be genotyped in patients before receiving sorafenib for a better risk assessment. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ClinicalTrials.gov Id: NCT01015833.
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- 2021
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43. Application of a Tacrolimus Population Pharmacokinetic Model to Adult Allogeneic Hematopoietic Stem Cell Transplant Patients
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Oscar Suzuki, Gabrielle Flynn, Daniel Weiner, Tejendra Patel, Tim Wiltshire, Jordan A Miller, Paul M. Armistead, Olivia Campagne, Chad Torrice, Daniel J. Crona, Jing Zhu, Donald E. Mager, and Jonathan R. Ptachcinski
- Subjects
Transplantation ,education.field_of_study ,business.industry ,Population ,Cell Biology ,Hematology ,Tacrolimus ,Pharmacokinetics ,Immunology ,Molecular Medicine ,Immunology and Allergy ,Medicine ,Allogeneic hematopoietic stem cell transplant ,education ,business - Published
- 2021
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44. Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study
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Ron H.J. Mathijssen, R.H.N. van Schaik, Mark J. Ratain, Gary L. Rosner, Jacqueline Ramírez, Federico Innocenti, Daniel J. Crona, W. Qiao, A-J M de Graan, Medical Oncology, and Clinical Chemistry
- Subjects
0301 basic medicine ,Oncology ,Adult ,Genetic Markers ,Male ,medicine.medical_specialty ,Neutropenia ,Genotype ,Antineoplastic Agents ,Bioinformatics ,Irinotecan ,digestive system ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Neoplasms ,Genetics ,medicine ,Humans ,Aged ,Pharmacology ,Aged, 80 and over ,Univariate analysis ,business.industry ,Cancer ,Middle Aged ,medicine.disease ,Multidrug Resistance-Associated Protein 2 ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cohort ,Absolute neutrophil count ,Molecular Medicine ,Camptothecin ,Female ,business ,medicine.drug ,Cohort study - Abstract
The overall goal of this study was to provide evidence for the clinical validity of nine genetic variants in five genes previously associated with irinotecan neutropenia and pharmacokinetics. Variants associated with absolute neutrophil count (ANC) nadir and/ or irinotecan pharmacokinetics in a discovery cohort of cancer patients were genotyped in an independent replication cohort of 108 cancer patients. Patients received single-agent irinotecan every 3 weeks. For ANC nadir, we replicated UGT1A1*28, UGT1A1*93 and SLCO1B1*1b in univariate analyses. For irinotecan area under the concentration–time curve (AUC0-24), we replicated ABCC2 -24C>T; however, ABCC2 -24C>T only predicted a small fraction of the variance. For SN-38 AUC0-24 and the glucuronidation ratio, we replicated UGT1A1*28 and UGT1A1*93. In addition to UGT1A1*28, this study independently validated UGT1A1*93 and SLCO1B1*1b as new predictors of irinotecan neutropenia. Further demonstration of their clinical utility will optimize irinotecan therapy in cancer patients.
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- 2016
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45. Abstract 1743: Evaluation of the effects of combined chemical inhibition of PARP and BET proteins in preclinical models of urothelial bladder cancer
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Brian Hardy, Kaitlyn A. Maffuid, Stephen V. Frye, Chad Torrice, Lindsey I. James, Kenneth J. Pearce, William A. Murphy, Daniel J. Crona, and William Y. Kim
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Cancer Research ,Cell cycle checkpoint ,Bladder cancer ,medicine.diagnostic_test ,business.industry ,Somatic cell ,Cell cycle ,medicine.disease ,Olaparib ,Flow cytometry ,chemistry.chemical_compound ,Oncology ,chemistry ,Cancer research ,Medicine ,Viability assay ,Epigenetics ,business - Abstract
Purpose: Metastatic urothelial bladder cancer (mUC) is incurable, and options are limited after patients fail 1st and 2nd line treatments. Thus, there is an unmet need to develop novel therapeutic strategies that increase survival in mUC patients. According to data from The Cancer Genome Atlas, UC has the third highest rate of somatic mutations, and mutations in DNA damage repair (DDR) genes are common. This provides rationale for the use of PARP inhibitors in UC patients with DDR mutations. Epigenetic changes are also common in UC, so epigenetic regulator inhibitors in combination with PARP inhibitors could be a viable treatment strategy in mUC. The purpose of this study was to evaluate the effects of combined olaparib plus an epigenetic regulator inhibitor in preclinical models of UC. Methods: BRCA1-competent 5637 cells and BRCA1-mutant J82 cells were screened against 62 compounds in the UNC EpiG Diamond library to identify epigenetic regulator inhibitors that could have synergy with olaparib. Cells were treated with 5 ascending concentrations of each compound (10 nM–10 µM), and cell viability was measured by alamarBlue™. RT-qPCR and western blotting were used to evaluate the effects of birabresib (OTX-015) on MYC and BRCA1 gene and c-MYC and BRCA1 protein expression, respectively. To evaluate birabresib effects on cell cycle, flow cytometry was performed. To evaluate cell viability, cells were treated with 8 ascending concentrations of olaparib and birabresib (0.1nM–100uM), alone and in combination, and then treated with CellTitrGlo™. IC50 values were calculated using a four-parameter non-linear regression model, and synergy estimates were derived by Compusyn software. Results: The EpiG screen revealed that as a class BET inhibitors potently limited cell viability in 5637 and J82 cells. Birabresib was particularly potent (IC50 in 5637 cells=100nM and in J82 cells=330nM; n=2), and selected for further evaluation. After 24h, birabresib significantly inhibited both MYC and BRCA1 expression (P Conclusion: Birabresib represses MYC/c-MYC and BRCA1/BRCA1 expression. Olaparib plus birabresib induces cell cycle arrest, and appears to be synergistic. This provides rationale supporting additional lines of prospective inquiry to evaluate olaparib plus birabresib in UC. Citation Format: Kaitlyn A. Maffuid, Chad D. Torrice, Brian Hardy, William A. Murphy, Lindsey I. James, William Y. Kim, Stephen V. Frye, Kenneth J. Pearce, Daniel J. Crona. Evaluation of the effects of combined chemical inhibition of PARP and BET proteins in preclinical models of urothelial bladder cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1743.
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- 2020
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46. Direct oral anticoagulants in extremely obese patients: OK to use?
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Karlyn Martin, Daniel J. Crona, and Stephan Moll
- Subjects
medicine.medical_specialty ,business.industry ,MEDLINE ,Hematology ,030204 cardiovascular system & hematology ,030226 pharmacology & pharmacy ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Internal medicine ,Commentaries ,medicine ,Commentary ,business - Published
- 2018
47. Recurrent venous thromboembolism in primary membranous nephropathy despite direct Xa inhibitor therapy
- Author
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Micah J. Mooberry, Daniel J. Crona, Vimal K. Derebail, Monica L. Reynolds, and Patrick H. Nachman
- Subjects
Male ,medicine.medical_specialty ,medicine.drug_mechanism_of_action ,Pyridones ,Factor Xa Inhibitor ,Population ,030232 urology & nephrology ,030204 cardiovascular system & hematology ,Gastroenterology ,Glomerulonephritis, Membranous ,Article ,03 medical and health sciences ,0302 clinical medicine ,Membranous nephropathy ,Recurrence ,Internal medicine ,medicine ,Humans ,Hypoalbuminemia ,cardiovascular diseases ,Risk factor ,education ,Serum Albumin ,education.field_of_study ,business.industry ,Warfarin ,Venous Thromboembolism ,Middle Aged ,medicine.disease ,Fondaparinux ,Nephrology ,Pyrazoles ,Apixaban ,business ,Nephrotic syndrome ,medicine.drug ,Factor Xa Inhibitors - Abstract
Clinically apparent venous thromboembolism (VTE) occurs in approximately 7% of patients with membranous nephropathy. Hypoalbuminemia at diagnosis is an independent risk factor for VTE, and risk increases significantly as albumin falls. Optimal prophylactic and treatment anticoagulation regimens in the nephrotic syndrome remain unproven but novel oral anti-coagulants have become attractive therapeutic options. We describe a patient diagnosed with anti-phospholipase A2 receptor antibody positive membranous nephropathy and recurrent VTE while on therapeutic dosing of apixaban. A direct factor Xa inhibitor, apixaban has been shown to be non-inferior to warfarin for the treatment of VTE in the general population. However, because it is highly protein-bound, apixaban may have altered pharmacokinetics and pharmacodynamics in patients with nephrotic syndrome and hypoalbuminemia. This case report highlights the need for further studies of direct oral anticoagulants to fully assess their effectiveness in this high-risk population.
- Published
- 2018
48. Genetic Variants of
- Author
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Daniel J, Crona, Andrew D, Skol, Veli-Matti, Leppänen, Dylan M, Glubb, Amy S, Etheridge, Eleanor, Hilliard, Carol E, Peña, Yuri K, Peterson, Nancy, Klauber-DeMore, Kari K, Alitalo, and Federico, Innocenti
- Subjects
Adult ,Male ,Vascular Endothelial Growth Factor A ,endocrine system ,Antineoplastic Agents ,Apoptosis ,urologic and male genital diseases ,Article ,Young Adult ,Double-Blind Method ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Humans ,neoplasms ,Carcinoma, Renal Cell ,Aged ,Cell Proliferation ,Aged, 80 and over ,Middle Aged ,Sorafenib ,Prognosis ,Vascular Endothelial Growth Factor Receptor-3 ,digestive system diseases ,female genital diseases and pregnancy complications ,Kidney Neoplasms ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Mutation ,Female ,Follow-Up Studies - Abstract
Molecular markers of sorafenib efficacy in metastatic renal cell carcinoma (mRCC) patients are not available. The purpose of this study was to discover genetic markers of survival in mRCC patients treated with sorafenib. Germline variants from 56 genes were genotyped in 295 mRCC patients. Variant-overall survival (OS) associations were tested in multivariate regression models. Mechanistic studies were conducted to validate clinical associations. VEGFA rs1885657, ITGAV rs3816375, and WWOX rs8047917 (sorafenib arm), and FLT4 rs307826 and VEGFA rs3024987 (sorafenib and placebo arms combined) were associated with shorter OS. FLT4 rs307826 increased VEGFR-3 phosphorylation, membrane trafficking and receptor activation. VEGFA rs1885657 and rs58159269 increased transcriptional activity of the constructs containing these variants in endothelial and RCC cell lines, and VEGFA rs58159269 increased endothelial cell proliferation and tube formation. FLT4 rs307826 and VEGFA rs58159269 led to reduced sorafenib cytotoxicity. Genetic variation in VEGFA and FLT4 could affect survival in sorafenib-treated mRCC patients. These markers should be examined in additional malignancies treated with sorafenib, and in other angiogenesis inhibitors used in mRCC.
- Published
- 2018
49. Statin use and survival in patients with metastatic castrationresistant prostate cancer treated with abiraterone or enzalutamide after docetaxel failure: The international retrospective observational STABEN study
- Author
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Michele Battaglia, Gaetano Facchini, Aurelius Omlin, Jacob A Gordon, Kim N. Chi, Sabrina Rossetti, Gaetano Buonocore, Daniel Khalaf, Dario Ribera, Christian Kollmannsberger, Gregory R. Pond, Davide Bosso, Tanya B. Dorff, Mira Sofie Witek, Giuseppe Lucarelli, Cyrus Cherhroudi, Michael E. Cox, Jennifer A. Locke, Silke Gillessen, Carlo Buonerba, Sabino De Placido, Bernhard J. Eigl, Daniel J. Crona, Guru Sonpavde, Sandro Pignata, Salvatore Artale, Giuseppe Di Lorenzo, Matthew I. Milowsky, Pietro De Placido, Gordon, J. A., Buonerba, C., Pond, G., Crona, D., Gillessen, S., Lucarelli, G., Rossetti, S., Dorff, T., Artale, S., Locke, J. A., Bosso, D., Milowsky, M. I., Witek, M. S., Battaglia, M., Pignata, S., Cherhroudi, C., Cox, M. E., De Placido, P., Ribera, D., Omlin, A., Buonocore, G., Chi, K., Kollmannsberger, C., Khalaf, D., Facchini, G., Sonpavde, G., De Placido, S., Eigl, B. J., and Di Lorenzo, G.
- Subjects
0301 basic medicine ,medicine.medical_specialty ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Enzalutamide ,Medicine ,In patient ,Abiraterone ,Manchester Cancer Research Centre ,business.industry ,ResearchInstitutes_Networks_Beacons/mcrc ,General surgery ,Statins ,Cancer ,Retrospective cohort study ,medicine.disease ,030104 developmental biology ,Oncology ,chemistry ,Docetaxel ,030220 oncology & carcinogenesis ,Observational study ,business ,medicine.drug ,Research Paper - Abstract
// Jacob A. Gordon 1, * , Carlo Buonerba 2, 3, * , Gregory Pond 4 , Daniel Crona 5 , Silke Gillessen 6 , Giuseppe Lucarelli 7 , Sabrina Rossetti 8 , Tanya Dorff 9 , Salvatore Artale 10 , Jennifer A. Locke 1 , Davide Bosso 2 , Matthew Ivan Milowsky 5 , Mira Sofie Witek 6 , Michele Battaglia 7 , Sandro Pignata 11 , Cyrus Cherhroudi 12 , Michael E. Cox 1 , Pietro De Placido 2 , Dario Ribera 2 , Aurelius Omlin 6 , Gaetano Buonocore 13 , Kim Chi 14 , Christian Kollmannsberger 14 , Daniel Khalaf 14 , Gaetano Facchini 8 , Guru Sonpavde 15 , Sabino De Placido 2 , Bernhard J. Eigl 14, # and Giuseppe Di Lorenzo 2, # 1 Vancouver Prostate Center, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada 2 Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy 3 Istituto Zooprofilattico Sperimentale del Mezzogiorno, Portici, Italy 4 McMaster University, Hamilton, Ontario, Canada 5 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA 6 Department of Medical Oncology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland 7 Department of Emergency and Organ Transplantation, Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy 8 S.S.D Oncologia Clinica Sperimentale Uro-Andrologica, Dipartimento Corp-S Assistenziale dei Percorsi Oncologici Uro-Genitale, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, Naples, Italy 9 University of Southern California Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, California, USA 10 Oncology Department, Ospedale di Gallarate ASST Valle Olona, Gallarate, Italy 11 Division of Medical Oncology, Department of Uro-Gynecologi cal Oncology, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, Naples, Italy 12 Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada 13 Hospital Directorate, Azienda Ospedaliera Universitaria Federico II of Naples, Naples, Italy 14 BC Cancer, Vancouver, British Columbia, Canada 15 Genitourinary Oncology Section, Dana Farber Cancer Institute, Boston, Massachusetts, USA * These two authors equally contributed to this work # These two authors share equal senior authorship Correspondence to: Giuseppe Di Lorenzo, email: dilorengiuseppe@gmail.com Keywords: prostate cancer; abiraterone; enzalutamide; statins Received: February 01, 2018 Accepted: February 27, 2018, 2018 Published: April 13, 2018 ABSTRACT Background: Statins may potentiate the effects of anti-hormonal agents for metastatic castration-resistant prostate cancer (mCRPC) through further disruption of essential steroidogenic processes. We investigated the effects of statin use on clinical outcomes in patients with mCRPC receiving abiraterone or enzalutamide. Materials and methods: This was a retrospective multicenter study including patients that received abiraterone or enzalutamide for mCRPC. The effect of concurrent statin use on outcomes was evaluated. The associations of statins with early (≤12 weeks) prostate-specific antigen (PSA) declines (> 30%), cancer-specific survival and overall survival (OS) were evaluated after controlling for known prognostic factors. Results: Five hundred and ninety-eight patients treated with second-line abiraterone or enzalutamide after docetaxel for mCRPC were included. A total of 199 men (33.3%) received statins during abiraterone/enzalutamide treatment. Median OS was 20.8 months (95% CI = 18.3–23.2) for patients who received statins, versus 12.9 months (95% CI = 11.4–14.6) for patients who did not receive statins ( P 30% PSA decline within the first 12 weeks of treatment (OR = 1.63; 95% CI = 1.03–2.60; P = 0.039). Conclusions: In this retrospective cohort, statin use was significantly associated with both prolonged OS and cancer-specific survival and increased early > 30% PSA declines. Prospective validation is warranted.
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- 2018
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50. Androgen Receptor-Dependent and -Independent Mechanisms Involved in Prostate Cancer Therapy Resistance
- Author
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Young E. Whang and Daniel J. Crona
- Subjects
0301 basic medicine ,Cancer Research ,medicine.drug_class ,Review ,resistance mechanisms ,Pharmacology ,urologic and male genital diseases ,Neuroendocrine differentiation ,lcsh:RC254-282 ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Glucocorticoid receptor ,androgen receptor ,abiraterone ,Medicine ,Enzalutamide ,castration-resistant prostate cancer ,Seviteronel ,enzalutamide ,business.industry ,Apalutamide ,Androgen ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Androgen receptor ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,progression ,business - Abstract
Despite the initial efficacy of androgen deprivation in prostate cancer, virtually all patients progress to castration-resistant prostate cancer (CRPC). Androgen receptor (AR) signaling is critically required for CRPC. A new generation of medications targeting AR, such as abiraterone and enzalutamide, has improved survival of metastatic CRPC (mCRPC) patients. However, a significant proportion of patients presents with primary resistance to these agents, and in the remainder, secondary resistance will invariably develop, which makes mCRPC the lethal form of the disease. Mechanisms underlying progression to mCRPC and treatment resistance are extremely complex. AR-dependent resistance mechanisms include AR amplification, AR point mutations, expression of constitutively active AR splice variants, and altered intratumoral androgen biosynthesis. AR-independent resistance mechanisms include glucocorticoid receptor activation, immune-mediated resistance, and neuroendocrine differentiation. The development of novel agents, such as seviteronel, apalutamide, and EPI-001/EPI-506, as well as the identification and validation of novel predictive biomarkers of resistance, may lead to improved therapeutics for mCRPC patients.
- Published
- 2017
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