10 results on '"Federico Innocenti"'
Search Results
2. Liposomal irinotecan (Onivyde): Exemplifying the benefits of nanotherapeutic drugs
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Gérard Milano, Federico Innocenti, and Hironobu Minami
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Pancreatic Neoplasms ,Cancer Research ,Clinical Trials, Phase III as Topic ,Oncology ,Antineoplastic Combined Chemotherapy Protocols ,Liposomes ,Leucovorin ,Humans ,Fluorouracil ,General Medicine ,Irinotecan ,Randomized Controlled Trials as Topic - Abstract
Irinotecan is a topoisomerase inhibitor, widely used in treatment of malignancies including pancreatic ductal adenocarcinoma (PDAC) as part of the FOLFIRINOX regimen prescribed as a first-line treatment in several countries. However, irinotecan has not been successfully introduced as a second-line treatment for pancreatic cancer and few randomized clinical studies have evaluated its added value. Efficacy of liposomal irinotecan (nal-IRI) combined with 5-fluorouracil and leucovorin (5-FU/LV) was reported in the phase III NAPOLI-1 trial in metastatic PDAC following failure of gemcitabine-based therapy. Several features of nal-IRI pharmacokinetics (PK) could result in better outcomes versus nonliposomal irinotecan. Irinotecan is a prodrug that is converted to active SN-38 by carboxylesterase enzymes and inactivated by cytochrome P450 3A4/3A5. SN-38 is inactivated by UGT1A1 enzymes. Individual variations in their expression and activity could influence enhanced localized irinotecan activity and toxicity. Liposomal irinotecan exploits the enhanced permeability and retention effect in cancer, accumulating in tumor tissues. Liposomal irinotecan also has a longer half-life and higher area under the concentration-time curve (0-∞) than nonliposomal irinotecan, as the liposomal formulation protects cargo from premature metabolism in the plasma. This results in irinotecan activation in tumor tissue, leading to enhanced cytotoxicity. Importantly, despite the longer exposure, overall toxicity for nal-IRI is no worse than nonliposomal irinotecan. Liposomal irinotecan exemplifies how liposomal encapsulation of a chemotherapeutic agent can alter its PK properties, improving clinical outcomes for patients. Liposomal irinotecan is currently under investigation in other malignancies including biliary tract cancer (amongst other gastrointestinal cancers), brain tumors, and small-cell lung cancer.
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- 2022
3. Genome‐wide association studies of survival in 1520 cancer patients treated with bevacizumab‐containing regimens
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Osvaldo Espin-Garcia, Geoffrey Liu, Kouros Owzar, Maura N Dickler, Monica M. Bertagnolli, Danyu Lin, Chen Jiang, Amy S. Etheridge, Federico Innocenti, Alan P. Venook, Heinz-Josef Lenz, Hedy L. Kindler, Mark J. Ratain, Jin Wang, Alexander B. Sibley, Wei Xu, and Julia C F Quintanilha
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Paclitaxel ,Bevacizumab ,Cetuximab ,Genome-wide association study ,Single-nucleotide polymorphism ,Article ,Carboplatin ,Neoplasms ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,medicine ,Humans ,Proportional hazards model ,business.industry ,Hazard ratio ,Cancer ,Middle Aged ,Prognosis ,medicine.disease ,Confidence interval ,Survival Rate ,Female ,Ovarian cancer ,business ,Follow-Up Studies ,Genome-Wide Association Study ,medicine.drug - Abstract
Germline variants might predict cancer progression. Bevacizumab improves overall survival (OS) in patients with advanced cancers. No biomarkers are available to identify patients that benefit from bevacizumab. A meta-analysis of genome-wide association studies (GWAS) was conducted in 1,520 patients from Phase III trials (CALGB 80303, 40503, 80405 and ICON7), where bevacizumab was randomized to treatment without bevacizumab. We aimed to identify genes and single nucleotide polymorphisms (SNPs) associated with survival independently of bevacizumab treatment or through interaction with bevacizumab. A cause-specific Cox model was used to test the SNP-OS association in both arms combined (prognostic), and the effect of SNPs-bevacizumab interaction on OS (predictive) in each study. The SNP effects across studies were combined using inverse variance. Findings were tested for replication in advanced colorectal and ovarian cancer patients from The Cancer Genome Atlas (TGCA). In the GWAS meta-analysis, patients with rs680949 in PRUNE2 experienced shorter OS compared to patients without it (P = 1.02 × 10-7 , hazard ratio [HR] = 1.57, 95% confidence interval [CI] 1.33-1.86), as well as in TCGA (P = .0219, HR = 1.58, 95% CI 1.07-2.35). In the GWAS meta-analysis, patients with rs16852804 in BARD1 experienced shorter OS compared to patients without it (P = 1.40 × 10-5 , HR = 1.51, 95% CI 1.25-1.82) as well as in TCGA (P = 1.39 × 10-4 , HR = 3.09, 95% CI 1.73-5.51). Patients with rs3795897 in AGAP1 experienced shorter OS in the bevacizumab arm compared to the nonbevacizumab arm (P = 1.43 × 10-5 ). The largest GWAS meta-analysis of bevacizumab treated patients identified PRUNE2 and BARD1 (tumor suppressor genes) as prognostic genes of colorectal and ovarian cancer, respectively, and AGAP1 as a potentially predictive gene that interacts with bevacizumab with respect to patient survival.
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- 2021
4. Pharmacogenomic‐Guided Therapy in Colorectal Cancer
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Steven M. Offer, Federico Innocenti, and Robert B. Diasio
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Drug ,Oncology ,medicine.medical_specialty ,medicine.drug_class ,Colorectal cancer ,media_common.quotation_subject ,Antineoplastic Agents ,Monoclonal antibody ,Internal medicine ,Biomarkers, Tumor ,medicine ,Adjuvant therapy ,Animals ,Humans ,Pharmacology (medical) ,media_common ,Pharmacology ,business.industry ,medicine.disease ,Drug development ,Pharmacogenetics ,Pharmacogenomics ,Biomarker (medicine) ,Colorectal Neoplasms ,business ,Companion diagnostic - Abstract
Approximately twenty drugs have been shown to be effective for the treatment of colorectal cancer (CRC). These drugs are from several classes of agents and include cytotoxic drugs, therapeutics that target cell signaling pathways at the extracellular and/or intracellular levels, and combination therapies that contain multiple targeted agents and/or cytotoxic compounds. Targeted therapeutics can include monoclonal antibodies, fusion proteins, and small molecule drugs. 5-Fluorouracil (5-FU) was first introduced into clinical use in the late 1950s and remains the foundation for most CRC treatments in both adjuvant therapy and in advanced (metastatic) treatment regimens. As with other cancers, the consideration of biomarkers has the potential to improve CRC therapy through patient stratification. The biomarkers can include germline genetic markers, tumor-specific genetic markers, immune markers, and other biomarkers that can predict antitumor efficacy or the likelihood of toxicity prior to administration of a specific drug. Consistent with the benefit of considering biomarkers in treatment, many newer targeted therapies are developed and approved simultaneously with a companion diagnostic test to determine efficacy. This review will focus on biomarkers that have demonstrated clinical utility in CRC treatment; however, it is noted that many additional biomarkers have been theorized to contribute to drug response and/or toxicity based on known biological pathways but thus far have not attained widespread use in the clinic. The importance of pre-treatment biomarker testing is expected to increase as future drug development will likely continue to focus on the concurrent development of companion diagnostics.
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- 2021
5. Cost Evaluation of Irinotecan-Related Toxicities Associated With the UGT1A1*28 Patient Genotype
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V Solfrini, E. De Mattia, Erika Cecchin, Rossana Roncato, Giuseppe Toffoli, Federico Innocenti, Angela Buonadonna, Luciana Giodini, and Marcella Montico
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Male ,0301 basic medicine ,medicine.medical_specialty ,Drug-Related Side Effects and Adverse Reactions ,Pharmacogenomic Variants ,Colorectal cancer ,Cost-Benefit Analysis ,Leucovorin ,colorectal cancer ,direct medical costs ,Irinotecan ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Genotype ,medicine ,Humans ,Pharmacology (medical) ,UGT1A1*28 ,Glucuronosyltransferase ,Italy ,cost of toxicity management ,irinotecan ,pharmacogenetics ,Retrospective Studies ,Neoplasm Staging ,Pharmacology ,business.industry ,Retrospective cohort study ,Middle Aged ,Camptothecin ,Female ,Fluorouracil ,Patient Care Management ,Topoisomerase I Inhibitors ,Colorectal Neoplasms ,Pharmacogenomic Testing ,medicine.disease ,Confidence interval ,Clinical trial ,030104 developmental biology ,030220 oncology & carcinogenesis ,Toxicity ,FOLFIRI ,business ,medicine.drug - Abstract
The adoption of a preemptive UGT1A1*28 genotyping to increase irinotecan safety in clinical practice is still limited. This is the first actual study of costs associated with the management of irinotecan-related toxicities, and their association with UGT1A1*28 genotype. A retrospective analysis of the cost of toxicity management was conducted on 243 metastatic colorectal cancer patients enrolled in a clinical trial and treated with standard of care FOLFIRI (5-fluorouracil combined with irinotecan). The mean predicted cost per patient was higher for *28/*28 (€4,886), vs. *1/*1 (€812), (regression coefficient 1.79, 95% confidence interval (CI) = 1.31-2.28; P < 0.001) and for *1/*28 (€1,119) vs. *1/*1 (regression coefficient 0.32, 95% CI = 0.04-0.60; P = 0.024). This is consistent with a different grade 4 toxicity profile among the three genotypes, and a higher frequency of costly interventions like hospitalization among patients with the *28 allele. A differential toxicity management cost by *28 genotype is herein demonstrated, representing a first step towards the demonstration of the test clinical utility.
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- 2017
6. Implications of genome-wide association studies in cancer therapeutics
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Jai N. Patel, Federico Innocenti, and Howard L. McLeod
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Pharmacology ,Novel gene ,Disease susceptibility ,Germline mutation ,Drug response ,Cancer therapy ,Genetic variants ,Pharmacology (medical) ,Genome-wide association study ,Biology ,Bioinformatics ,Genome - Abstract
Genome wide association studies (GWAS) provide an agnostic approach to identifying potential genetic variants associated with disease susceptibility, prognosis of survival and/or predictive of drug response. Although these techniques are costly and interpretation of study results is challenging, they do allow for a more unbiased interrogation of the entire genome, resulting in the discovery of novel genes and understanding of novel biological associations. This review will focus on the implications of GWAS in cancer therapy, in particular germ-line mutations, including findings from major GWAS which have identified predictive genetic loci for clinical outcome and/or toxicity. Lessons and challenges in cancer GWAS are also discussed, including the need for functional analysis and replication, as well as future perspectives for biological and clinical utility. Given the large heterogeneity in response to cancer therapeutics, novel methods of identifying mechanisms and biology of variable drug response and ultimately treatment individualization will be indispensable.
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- 2013
7. Pharmacogenetic Testing for Uridine Diphosphate Glucuronosyltransferase 1A1 Polymorphisms: Are We There Yet?
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Mark J. Ratain, Federico Innocenti, and Minoli A. Perera
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Oncology ,Drug ,medicine.medical_specialty ,Glucuronosyltransferase ,Genotype ,Package insert ,media_common.quotation_subject ,Population ,Pharmacology ,Irinotecan ,Internal medicine ,medicine ,Humans ,Protease Inhibitors ,Pharmacology (medical) ,Medical prescription ,education ,Genetic testing ,media_common ,education.field_of_study ,Polymorphism, Genetic ,medicine.diagnostic_test ,biology ,business.industry ,Pharmacogenetics ,biology.protein ,Camptothecin ,business ,medicine.drug - Abstract
Recent changes to the labels of three prescription drugs--irinotecan, 6-mercaptopurine, and warfarin--include recommendations for pharmacogenetic testing in patients. Thus, clinicians are faced with determining the utility and practicality of pharmacogenetic testing in clinical practice. We illustrate the clinical implications that this testing may have using irinotecan, an agent approved for the treatment of metastatic colorectal cancer, as an example. A clinical association between the drug's active metabolite and toxicity has been found. By performing uridine diphosphate glucuronosyltransferase (UGT) 1A1 genetic testing, some studies have been able to predict which patients receiving irinotecan will experience the toxicity. Thus, irinotecan's package insert was revised to include a recommendation for such testing. In addition, the United States Food and Drug Administration approved a clinical test for the UGT1A1*28 allele. These events demonstrate that pharmacogenetics has entered the realm of clinical practice. However, the transition from bench to bedside of these tests has distinct challenges such as population differences, test sensitivity, and the role of other genetic and nongenetic factors that influence drug toxicity. In addition, ethical and logistic implications of pharmacogenetic testing exist.
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- 2008
8. The role of pharmacogenetics in cancer therapeutics
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Wei Peng Yong, Federico Innocenti, and Mark J. Ratain
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Pharmacology ,Polymorphism, Genetic ,Cancer ,Antineoplastic Agents ,Original Articles ,Biology ,Bioinformatics ,medicine.disease ,Enzymes ,ErbB Receptors ,Clinical Practice ,Germline mutation ,Therapeutic index ,Pharmacogenetics ,Drug Design ,Neoplasms ,Drug response ,medicine ,Humans ,Drug Interactions ,Pharmacology (medical) ,Germ-Line Mutation ,Forecasting - Abstract
The variability in treatment responses and narrow therapeutic index of anticancer drugs are some of the key challenges oncologists face. The knowledge of pharmacogenetics can potentially aid in the discovery, development and ultimately individualization of anticancer drugs. The identification of genetic variations that predict for drug response is the first step towards the translation of pharmacogenetics into clinical practice. This review provides an update on the results of studies assessing the effects of germline polymorphisms and somatic mutations on therapeutic outcomes and highlights the potential applications and future challenges in pharmacogenetic research pertaining to cancer therapeutics.
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- 2006
9. Pharmacokinetics and pharmacodynamics of combination chemotherapy with paclitaxel and epirubicin in breast cancer patients
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Federico Innocenti, Guido Bocci, Editta Baldini, Stefano Fogli, Pierfranco Conte, Mario Del Tacca, Romano Danesi, Antonello Di Paolo, Alessandra Gennari, and Barbara Salvadori
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Pharmacology ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Combination chemotherapy ,medicine.disease ,chemistry.chemical_compound ,Breast cancer ,Pharmacokinetics ,Paclitaxel ,chemistry ,Pharmacodynamics ,medicine ,Pharmacology (medical) ,Doxorubicin ,business ,medicine.drug ,Epirubicin - Abstract
) model.Finally, the influence of paclitaxel and Cremophor EL on epirubicin metabolism bywhole blood was examined.Results An increase in epirubicinol plasma concentrations occurred after the start ofthe paclitaxel infusion, resulting in a significant increase in the area under the plasmaconcentration-time curve (AUC) of epirubicinol (+0.5
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- 2002
10. Discovery and functional assessment of gene variants in the vascular endothelial growth factor pathway
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Patrick Evans, Laia Paré-Brunet, Anna Di Rienzo, Dylan M. Glubb, Eric R. Gamazon, Amy S. Etheridge, Shiwei Duan, Federico Innocenti, Andrew D. Skol, and Antoni Berenguer-Llergo
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Vascular Endothelial Growth Factor A ,Angiogenesis ,Population ,Quantitative Trait Loci ,Black People ,Gene Expression ,Neovascularization, Physiologic ,Nigeria ,Genome-wide association study ,Quantitative trait locus ,Biology ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Article ,Cell Line, Tumor ,Genetics ,Humans ,International HapMap Project ,education ,Genetics (clinical) ,Neovascularization ,Genetic association ,education.field_of_study ,Neovascularization, Pathologic ,Computational Biology ,Genetic Variation ,Angiogènesi ,Pharmacogenetics ,Expression quantitative trait loci ,Multivariate Analysis ,Farmacogenètica ,Allelic heterogeneity ,Genome-Wide Association Study - Abstract
Angiogenesis is a host-mediated mechanism in disease pathophysiology. The vascular endothelial growth factor (VEGF) pathway is a major determinant of angiogenesis, and a comprehensive annotation of the functional variation in this pathway is essential to understand the genetic basis of angiogenesis-related diseases. We assessed the allelic heterogeneity of gene expression, population specificity of cis expression quantitative trait loci (eQTLs), and eQTL function in luciferase assays in CEU and Yoruba people of Ibadan, Nigeria (YRI) HapMap lymphoblastoid cell lines in 23 resequenced genes. Among 356 cis-eQTLs, 155 and 174 were unique to CEU and YRI, respectively, and 27 were shared between CEU and YRI. Two cis-eQTLs provided mechanistic evidence for two genome-wide association study findings. Five eQTLs were tested for function in luciferase assays and the effect of two KRAS variants was concordant with the eQTL effect. Two eQTLs found in each of PRKCE, PIK3C2A, and MAP2K6 could predict 44%, 37%, and 45% of the variance in gene expression, respectively. This is the first analysis focusing on the pattern of functional genetic variation of the VEGF pathway genes in CEU and YRI populations and providing mechanistic evidence for genetic association studies of diseases for which angiogenesis plays a pathophysiologic role. (C) 2013 Wiley Periodicals, Inc.
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