The Innocenti laboratory is focused on identifying human germline genetic variants using genomic approaches that will predict clinical cancer outcomes and responses to pharmacological therapies.

 

Our current program of research aims to discover effective strategies for individualizing therapy for cancer patients. The proposed program aims to reach this goal through the identification of heritable genetic determinants of outcomes of chemotherapy, both in the laboratory and the clinic. Our lab discovers and tests the biological function of novel germline genetic variants that might serve as markers of severe toxicity and survival. Our main focus is on VEGF-pathway inhibitors. This activity integrates whole-genome strategies with more targeted gene- and pathway-based strategies. It requires multidisciplinary efforts that span from the discovery of potential genetic biomarkers to validation of their clinical utility in patients. This effort is truly collaborative.

The research program is built on a series of clinical, epidemiology and laboratory studies and is defined by three main themes.

These studies represent a framework for identifying new markers of outcome to be used for prospective clinical testing and for in vitro evaluation of molecular function, as per Theme 2. Genetic data collected from multiple tumors and multiple drugs (with shared toxicities, metabolic pathways and similar mechanisms) create a platform for testable hypothesis to individualize patient care.

Candidate-gene, pathway-based, and genome-wide association studies are ongoing and planned. Candidate genes studies include genotype-directed clinical trials in colorectal cancer patients. Pathway-based studies include sorafenib pharmacogenetic studies in renal cell carcinoma patients. Genome-wide association studies (GWAS) include a study in pancreatic cancer patients receiving gemcitabine and bevacizumab in Cancer and Leukemia Group B. Additional GWAS and interventional studies are planned and will be run at UNC, as well as in CALGB.

Angiogenesis plays a critical role in tumor development and progression, and the VEGF-pathway is centrally involved with mediating this process. Angiogenesis is a host-mediated process and we hypothesize that clinical cancer outcomes and variable responses to VEGF-pathway inhibitors may be related to common functional variation in VEGF-pathway genes.

Work in our laboratory has characterized human genetic variation in VEGF-pathway genes and identified common germline variants which associate with their expression in cell systems and lung tumor samples. Validated functional variants from this study will represent the foundation for the prospective pharmacogenetic testing of patients treated with VEGF-pathway inhibitors, as per Theme 1. The results of these studies may propose novel biomarkers for clinical investigation and will support the clinical associations of Theme 1. Furthermore, functional VEGF-pathway gene variants may act as prognostic markers for other clinical cancer outcomes and we are currently evaluating such associations.

We are studying the genetic regulation of liver gene expression because of the many important functions this organ performs. These functions include protein synthesis and detoxification, amongst many others. The fact that 75% of the 200 most widely prescribed drugs are eliminated from the body through liver metabolism means this work is of particular relevance to the field of pharmacogenetics.

By correlating the mRNA expression of genes in over 200 human livers with genetic variants, at a genome-wide level, our study provides a comprehensive assessment of the heritable component of gene expression variation in this organ. We are expanding this expression quantitative trait loci (eQTL) study to encompass the measurement of protein expression from important pharmacogenetic genes. Other ongoing analyses include the definition of genomic methylation and miRNA expression in the liver. Results from this work will provide a useful resource for UNC faculty and the scientific community as a whole, as they will be made publicly available. They will serve as the knowledge basis for any pharmacogenetic study (like those in Theme 1) to interpret associations with disposition genes, as well as for studies of heritable liver-related traits and diseases.

Refereed Papers/Articles

  1. Chen S, Laverdiere I, Tourancheau A, Jonker D, Couture F, Cecchin E, Villeneuve L, Harvey M, Court MH, Innocenti F, Toffoli G, Lévesque E, Guillemette C. A novel UGT1 marker associated with better tolerance against irinotecan-induced severe neutropenia in metastatic colorectal cancer patients. Clin Pharmacol Ther (submitted)
  2. Glubb MD, Pare’-Brunet  L, Jantus-Lewintre E, Jiang C, Crona D, Etheridge A, Mirza O, Zhang W, Rzyman W, Jassem J, Auman T, Hirsch RF, Owzar K, Camps C, Dzadziuszko R, Innocenti FFLT1 gene variation as a major determinant of recurrence in stage I-III non-small cell lung cancer. Ann Oncol (submitted)
  3. Crona DJ, Ramirez J, Qiao W, de Graan A-J, Ratain MJ, van Schaik RHN, Mathijssen RHJ,  Rosner GL, Innocenti F. Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study. Pharmacogenomics J (submitted)
  4. Wolpin BM, Rizzato C, Kraft P, Kooperberg C, Petersen GM, Wang Z, Arslan AA,Beane-Freeman L, Bracci PM, Buring J, Canzian F, Duell EJ, Gallinger S, Giles GG, Goodman GE, Goodman PJ, Jacobs EJ, Kamineni A, Klein AP, Kolonel LN, Kulke1 M, Li D, Malats N, Olson SH, Risch HA, Sesso HD, Visvanathan K, White E, Zheng W, Abnet CC, Albanes D, Andreotti G, Austin MA, Barfield R, Basso D, Berndt SI, Boutron-Ruault MC, Brotzman M, Büchler MW, Bueno-de-Mesquita H, Bugert P, Burdette L, Campa D, Caporaso NE, Capurso G, Chung C, Cotterchio M, Costello E, Elena J, Funel N, Gaziano Jm, Giese A,Giovannucci EL, Goggins M, Gorman MJ, Gross M, Haiman CA, Hassan M, Helzlsouer K, Henderson BE, Holly EA, Hu N, Hunter DJ, Innocenti F, Jenab M, Kaaks R, Key TJ, Khaw K, Klein EA, Kogevinas M, Krogh V, Kupcinskas J, Kurtz RC, LaCroix A, Landi MT, Landi S, Marchand LL, Mambrini A, Mannisto S, Milne RL, Nakamura Y, Oberg AL, Owzar K, Patel AV,  Peeters PH, Peters U, Pezzilli R, Piepoli A, Porta M, Real FX, Riboli E, Rothman N, Scarpa A, Shu X, Silverman DT, Soucek P, Sund M, Talar-Wojnarowska R, Taylor PR, Theodoropoulos GE, Thornquist M, Tjønneland T, Tobias GS, Trichopoulos D, Vodicka P, Wactawski-Wende J, Wentzensen N, Wu C, Yu H, Yu K, Zeleniuch-Jacquotte A, Hoover R, Hartge P, Fuchs C, Chanock S, Stolzenberg-Solomon RS, Amundadottir L. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. Nat Genet, 2014; (epub ahead of print) PubMed PMID: 25086665.
  5. Van Loon K, Owzar K, Jiang C, Kindler HL, Mulcahy MF, Niedzwiecki D, O’Reilly EM, Fuchs C, Innocenti F, Venook AP. Hydroxyvitamin D levels and survival in patients with advanced pancreatic cancer: Findings from CALGB 80303. J Nat Cancer Inst, 2014; 106 PubMed PMID: 25099612.
  6. Innocenti F, Schilsky RL, Ramírez J, Janisch L, Undevia S, House LK, Das S, Wu K, Turcich M, Marsh R, Karrison T, Maitland ML, Salgia R, Ratain MJ. A dose-finding and pharmacokinetic study to optimize the dosing of irinotecan according to the UGT1A1 genotype of cancer patients. J Clin Oncol, 2014;32:2328-34. PubMed Central PMCID: PMC4105486
  7. De Re, Valli, Caggiari L, De Zorzi M, Talamini R, Racanelli V, Andrea MD, Bonadonna A, Zagonel V, Cecchin E, Innocenti F, Toffoli G. Genetic diversity of the KIR/HLA system and outcome of patients with metastatic colorectal cancer treated with chemotherapy. PLoS One, 2014;9:e84940. PubMed Central PMCID: PMC 3908861
  8. Ramírez J, Kim TW, Liu W, Myers J, Mirkov S, Owzar K, Watson D, Mulkey F, Gamazon ER, Xia K, Stock W, Undevia S, Innocenti F, Ratain MJ. A pharmacogenetic study of aldehyde oxidase I in patients treated with XK469. Pharmacogenet Genomics, 2014;24-129-32. PubMed Central PMCID: PMC 3901533
  9. Paré-Brunet L, Glubb D, Evans E, Berenguer-Llergo T, Etheridge A, Skol A, Di Rienzo A, Duan D, Gamazon E, Innocenti F. Discovery and functional assessment of gene variants in the vascular endothelial growth factor pathway. Human Mutat, 2014;35:227-35. PubMed Central PMCID: PMC PMC 3935516
  10. Liu W, Gamazon ER, Innocenti F, Wei R, Wang L, Zhang M, Mirkov S, Ramírez J, Huang RS, Cox NJ, Ratain MJ. A genome-wide integrative study of microRNAs in human liver. BMC Genomics, 2013;14:395. PubMed Central PMCID: PMC 3710218
  11. Innocenti F, Ramírez J, Obel J, Xiong J, Mirkov S, Chiu Y, Katz DA, Carr RA, Zhang W, Das S, Adjei A, Moyer AM, Chen PX, Krivoshik A, Medina D, Gordon GB, Ratain MJ, Sahelijo L, Weinshilboum RM, Fleming GF, Bhathena A. Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751.  Pharmacogenet Genomics, 2013;374-81. PubMed Central PMCID: PMC 3858967
  12. Levesque E, Belanger AS, Harvey M, Couture F, Jonker D, Innocenti F, Cecchin E, Toffoli G, Guillemette C. Refining the UGT1A haplotype associated with irinotecan-induced hematological toxicity in metastatic colorectal cancer patients treated with 5-fluorouracil/irinotecan (FOLFIRI)-based regimens. J Pharmacol Exp Ther, 2013;345:95-101. PubMed Central PMCID: PMC 3920089
  13. Cecchin E, D’Andrea M, Lonardi S, Zanusso C, Pella N, Errante D, De Mattia E, Polesel J, Innocenti F, Toffoli G. A prospective validation pharmacogenomic study in the adjuvant setting of colorectal cancer patients treated with the 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) regimenPharmacogenomics J,  2012;13:403-9. PubMed Central PMCID: PMC 3859145
  14. Glubb DM, Dholakia N, Innocenti F. Liver expression quantitative trait loci: a foundation for pharmacogenomic research. Front Genet. 2012 14;3:153. eCollection 2012. PubMed PMID: 22912647; PubMed Central PMCID: PMC 3418580.
  15. Innocenti F, Owzar K, Cox NJ, Evans P, Kubo M, Zembutsu H, Jiang C, Hollis D, Mushiroda T, Li L, Friedman P, Wang L, Glubb DM, Hurwitz HI, Giacomini KM, McLeod HL, Goldberg RM, Schlisky R, Kindler HL, Nakamura Y, Ratain MJ. A genome-wide association study of overall survival in pancreatic cancer patients treated with gemcitabine in CALGB 80303. Clin Cancer Res, 2012;18:577-84. PubMed Central PMCID: PMC 843412624
  16. Ramírez J, Wu K, Janisch L, Karrison T, House LK, Innocenti F, Cohen EE, Ratain MJ. The effect of thalidomide on the pharmacokinetics of irinotecan and metabolites in advanced solid tumor patients. Cancer Chemother Pharmacol, 2011;68:1629-32. PubMed Central PMCID: PMC 3259680
  17. Biason P, Hattinger CM, Innocenti F, Talamini R, Alberghini M, Scotlandi K, Zanusso C, Serra M, Toffoli G. Nucleotide excision repair gene variants and association with survival in osteosarcoma patients treated with neoadjuvant chemotherapy. Pharmacogenomics J, 2011;12:476-83. PubMed Central PMCID: PMC 3935514
  18. Glubb DM, Cerri E, Giese A, Zhang W, Mirza O, Thompson EE, Chen P, Das S, Jassem J, Rzyman W, Lingen MW, Salgia R, Hirsch FR, Dziadziuszko R, Ballmer-Hofer K, Innocenti F.  Novel functional germline variants in the vascular endothelial growth factor receptor 2 gene and their effect on gene expression and microvessel density in lung cancer. Clin Cancer Res, 2011;17:5257-67. PubMed Central PMCID: PMC 3156871
  19. Innocenti F, Cooper GM, Stanaway IB, E Gamazon, Smith JD, Mirkov S, Ramirez J, Liu W, Lin YS, Moloney C, Aldred SF, Trinklein ND, Schuetz EG, Nickerson DA, Thummel KE, Rieder MJ, Rettie AE, Ratain MJ, Cox NJ, Brown CD. Identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue. PLoS Genet, 2011;7:e1002078. PubMed Central PMCID: PMC 3102751
  20. O’Donnell PH, Artz AS, Undevia SD, Pai RK, del Cerro P, Horowitz S, Godley LA, Hart J, Innocenti F,  Larson RA, Odenike OM, Stock W, van Besien K.  Phase I study of dose-escalated busulfan with fludarabine and alemtuzumab as conditioning for allogeneic hematopoietic stem cell transplantation: reduced clearance at high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive disease. Leuk Lymphoma, 2010;51:2240-9.
  21. Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, Innocenti F, Mulcahy MF, O’Reilly E, Wozniak TF, Picus J, Bhargava P, Mayer RJ, Schilsky RL, Goldberg RM for the Cancer and Leukemia Group B. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: A phase III trial of the cancer and leukemia group B (CALGB 80303).  J Clin Oncol, 2010;28:3617-22. PubMed Central PMCID: PMC 2917317
  22. Toffoli G, Cecchin E, Gasparini G, D’Andrea M, Azzarello G, Basso U, Mini E, Pessa S, De Mattia E, Lo Re G, Buonadonna A, Nobili S, De Paoli P, Innocenti F. Genotype-driven phase I study of irinotecan administered in combination with 5-fluorouracil/leucovorin (FOLFIRI) in metastatic colorectal cancer patients. J Clin Oncol, 2010; 28:866-71.
  23. Innocenti F, Kroetz DL, Schuetz E, Dolan ME, Ramírez J, Relling M, Chen P, Das S, Rosner GL, Ratain MJ. Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacogenetics.  J Clin Oncol, 2009;27: 2604-14. PubMed Central PMCID: PMC 2690389
  24. Yong WP, Kim TW, Undevia SD, Innocenti F, Ratain MJ. R(+)XK469 inhibits hydroxylation of S-warfarin by CYP2C9. Eur J Cancer, 2009;45:1904-8. PubMed Central PMCID: PMC 2758059
  25. Cecchin E, Innocenti F, D’Andrea M, Corona G, De Mattia E, Biason P, Buonadonna A, De Paoli P, Toffoli G. Predictive role of the UGT1A1, UGT1A7, and UGT1A9 genetic variants and their haplotypes on the outcome of metastatic colorectal cancer patients treated with FOLFIRI. J Clin Oncol, 2009;27:2457-65.
  26. Innocenti F, Mirkov S, Nagasubramanian R, Ramirez J, Liu W, Bleibel WK, Shukla SJ, Hennessy K, Rosner GL, Cook EH, Dolan ME, Ratain MJ.  The Werner’s syndrome 4330T>C (Cys1367Arg) gene variant does not affect the in vitro cytotoxicity of topoisomerase inhibitors and platinum compounds. Cancer Chemother Pharmacol, 2009;63:881-7. PubMed Central PMCID: PMC 2731557
  27. Hoskins JM, Rosner GL, Ratain MJ, McLeod HL, Innocenti F. Pharmacodynamic genes do not influence risk of neutropenia in cancer patients treated with moderately high dose irinotecan. Pharmacogenomics, 2009; 10:1139-46. PubMed Central PMCID: PMC 2748108
  28. Krishnaswamy S, Janamanchi V, Soulii L, Seiwert TY, Nallasura V, Loganathan S, Kanteti R, Ramnath N, Szeto L, Innocenti F, Xin Y, Nicolae DL, Ma PC, Ouyang Z, Liang J, Minna J,  Kozloff M, Natarajan V, Ferguson MK, Wang Y, Sattler M, Garcia JN, Vokes EE, Husain AN, Jagadeeswaran R, Salgia R.  Ethnic differences and functional analysis of c-met mutations in lung cancerClin Cancer Res, 2009;15:5714-23. PubMed Central PMCID: PMC 2767337
  29. Ramirez J, Mirkov S, Zhang W, Chen PX, Das S, Liu W, Ratain MJ, Innocenti F. Hepatocyte nuclear factor-1 alpha regulates UGT1A1, UGT1A9, and UGT2B7 mRNA expression in the liver.  Pharmacogenomics J, 2008; 8:152-61.
  30. Corona G, Vaccher E, Sandron S, Sartor I, Tirelli U, Innocenti F, Toffoli G.  Lopinavir-ritonavir dramatically affects the pharmacokinetics of irinotecan in HIV patients with Kaposi’s sarcoma. Clin Pharmacol Ther, 2008; 83:601-6. PubMed Central PMCID: PMC – not available
  31. Rosner GL, Panetta JC, Innocenti F, Ratain MJ.  Pharmacogenetic pathway analysis of irinotecan. Clin Pharmacol Ther, 2008; 84:393-402. PubMed Central PMCID: PMC 2759399
  32. Innocenti F, Liu W, Fackenthal D, Ramirez J, Chen P, Xin Ye, Wu X, Zhang W, Mirkov S, Das S, Cook EH, Ratain MJ. Single nucleotide polymorphism discovery and functional assessment of variation in the UDP-glucuronosyltransferase 2B7 gene. Pharmacogenet Genomics, 2008;18:683-97. PubMed Central PMCID: PMC 2680356
  33. Undevia SD, Innocenti F, Ramirez J, House L, Desai AA, Skoog LA, Singh DA, Karrison T, Kindler HL, Ratain MJ. A phase I and pharmacokinetic study of the quinoxaline antitumor agent R(+)XK469 in patients with advanced solid tumors. Eur J Cancer 2008; 44:1684-92. PubMed Central PMCID: PMC 2731567
  34. Liu W, Wu X, Zhang W, Montenegro RC, Fackenthal DL, Spitz JA, Huff LM, Innocenti F, Das S, Cook EH, Cox NJ, SE Bates, Ratain MJ. Relationship of EGFR mutations, expression, amplification, and polymorphisms to epidermal growth factor receptor inhibitors in the NCI60 cell lines. Clin Cancer Res, 2007;13:6788-95
  35. Mirkov S, Komoroski BJ, Ramírez J, Yoder Graber A, Ratain MJ, Strom SC, Innocenti F. Effects of green tea compounds on irinotecan metabolism. Drug Metab Dispos, 2007; 35:228-33
  36. Yoder Graber A, Ramírez J, Zhang W, Innocenti F, Ratain MJ. UGT1A1*28 genotype affects the in vitro glucuronidation of thyroxine in human livers. Pharmacogenet Genomics, 2007;17:619-27
  37. Ramchandani RP, Wang Y, Booth BP, Ibrahim A, Johnson J, Rahman A, Mehta M, Innocenti F, Ratain MJ, Gobburu JVS.. The role of SN-38 exposure, UGT1A1*28 polymorphisms and baseline bilirubin levels in predicting severe irinotecan toxicity. J Clin Pharmacol 2007;47:78-86
  38. Ramirez J, Liu W, Mirkov S, Desai AA, Chen P, Das S, Innocenti F, Ratain MJ.  Lack of association between common polymorphisms in UGT1A9 and gene expression and activity. Drug Metab Dispos, 2007;35:2149-53
  39. Yong WP, Desai AA, Innocenti F, Shepard D, Kobayashi K, House L, Fleming GF, Vogelzang NJ, Schilsky R, Ratain MJ. Pharmacokinetic modulation of oral etoposide by ketoconazole in patients with advanced cancer. Cancer Chemother Pharmacol, 2007;60:811-9
  40. Zhang W, Liu W, Innocenti F, Ratain MJ. Searching for tissue-specific expression pattern-linked nucleotides of UGT1A isoforms. PLoS One, 2007;2:e396
  41. Ramírez J, Komoroski BJ, Mirkov S, Yoder Graber A,  Fackenthal DL, Schuetz EG, Das S, Ratain MJ, Innocenti F, Strom SC.  Study of the genetic determinants of UGT1A1 inducibility by phenobarbital in cultured human hepatocytes.  Pharmacogenet Genomics, 2006;16:79-86
  42. Liu W, Innocenti F, Wu MH, Desai AA, Dolan ME, Cook EH, Ratain MJ.  A functional common polymorphism in a Sp1 recognition site of the epidermal growth factor receptor gene promoter.  Cancer Res, 2005;65:46-53
  43. Innocenti F, Danesi R, Natale G, Bocci G, Del Tacca M.  5-Fluorouracil catabolism to 5-fluoro-5, 6-dihydrofluorouracil is reduced by acute liver impairment in mice.  Toxicol Appl Pharmacol 2005;203:106-13
  44. Innocenti F, Liu W, Chen P, Desai AA, Das S, Ratain MJ. Haplotypes of variants in the UDP-glucuronosyltransferase1A9 and 1A1 genes.  Pharmacogenet Genomics, 2005;15:295-301
  45. Yong WP, Ramirez J, Innocenti F, Ratain MJ. Effect of ketoconazole on glucuronidation by UDP-glucuronosyltransferase enzymes.  Clin Cancer Res, 2005;11:6699-704
  46. Desai A, Innocenti F, DeMario M, Shepard D, Ramirez J, Fleming G, Ratain MJ.  A phase I trial of pharmacokinetic modulation of carboxyamido-triazole (CAI) with ketokonazole in advanced cancer patients.  Cancer Chemother Pharmacol, 2004;54:377-84
  47. Innocenti F, Undevia SD, Ramírez J, Mani S, Schilsky RL, Vogelzang NJ, Prado M, Ratain MJ. A phase I trial of pharmacological modulation of irinotecan with cyclosporine A and phenobarbital.  Clin Pharmacol Ther, 2004;76:490-502
  48. Innocenti F, Undevia SD, Iyer L, Chen P, Das S, Kocherginsky M, Karrison T, Janisch L, Ramírez J, Rudin CM, Vokes EE, Ratain MJ.  Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan.  J Clin Oncol, 2004;22:1382-8
  49. Ramírez J, Innocenti F, Schuetz EG, Flockhart DA, Relling MV, Santucci R, Ratain MJ.  CYP2B6, CYP3A4, and CYP2C19 are responsible for the in vitro N-demethylation of meperidine in human liver microsomes.  Drug Metab Dispos, 2004;32:930-6
  50. Liu W, Innocenti F, Das S, Chen P, Cook EH, Ratain MJ.  Interethnic difference in the allelic distribution of human epidermal growth factor receptor (EGFR) intron 1 polymorphism.  Clin Cancer Res, 2003;9:1009-12
  51. Bengala C, Danesi R, Guarneri V, Pazzagli I, Donati S, Favre C, Fogli S, Biadi O, Innocenti F, Del Tacca M, Mariani M, Conte PF.  High-dose consolidation chemotherapy with idarubicin and alkylating agents following induction with gemcitabine-epirubicin-paclitaxel in metastatic breast cancer: a dose finding study.  Bone Marrow Transplant, 2003;31:275-80
  52. Sawyer MB, Innocenti F, Das S, Cheng C, Ramirez J, Pantle-Fisher FH, Wright C, Badner J, Pei D, Boyett JM, Cook EH, Ratain MJ.  A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine.  Clin Pharmacol Ther, 2003;73:566-74
  53. Toffoli G, Russo A, Innocenti F, Corona G, Tumolo S, Sartor F, Mini E, Boiocchi M.  Effect of methylenetetrahydrofolate reductase 677C®T polymorphism on toxicity and homocysteine plasma level after chronic methotrexate treatment of ovarian cancer patients.  Int J Cancer, 2003;103:294-9
  54. Innocenti F, Grimsley C, Das S, Ramírez J, Cheng C, H Kuttab-Boulos, Ratain MJ, Di Rienzo A.  Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups.  Pharmacogenetics, 2002;12:725-33
  55. Bocci G, Danesi R, Allegrini A, Innocenti F, Di Paolo A, Falcone A, Conte PF, Del Tacca M.  Severe 5-fluorouracil toxicity associated with a marked alteration of pharmacokinetics of 5-fluorouracil and its catabolite 5-fluoro-5, 6-dihydrouracil. A case report.  Eur J Clin Pharmacol, 2002;58:593-5
  56. Ramirez J, Iyer L, Journault K, Belanger P, Innocenti F, Ratain MJ, Guillemette C.  In vitro characterization of hepatic flavopiridol metabolism using human liver microsomes and recombinant UGT enzymes.  Pharm Res, 2002;19:588-94
  57. Danesi R, Innocenti F, Fogli S, Gennari A, Baldini E, Di Paolo A, Salvadori B, Bocci G, Conte PF, Del Tacca M.  Pharmacokinetics and pharmacodynamics of combination chemotherapy with paclitaxel and epirubicin in breast cancer patients.  Br J Clin Pharmacol, 2002;53:508-18
  58. Bengala C, Pazzagli I, Innocenti F, Donati S, Favre C, Menconi MC, Greco F, Danesi R, Orlandini C, Guarneri V, Del Tacca M, Conte PF.  High-dose thiotepa and melphalan with hemopoietic progenitor support following induction therapy with epirubicin-paclitaxel-containing regimens in metastatic breast cancer (MBC).  Ann Oncol, 2001; 12:69-74
  59. Innocenti F, Iyer L, Ramirez J, Green MD, Ratain MJ.  Epirubicin glucuronidation is catalyzed by human UDP-glucuronosyltransferase 2B7 (UGT2B7).  Drug Metab Dispos, 2001; 29:686-92
  60. Di Paolo A, Danesi R, Nardini D, Bocci G, Innocenti F, Fogli S, Barachini S, Marchetti A, Bevilacqua G, Del Tacca M.  Manumycin inhibits ras signal transduction pathway and induces apoptosis in COLO320-DM human colon tumor cells.  Br J Cancer, 2000;82:905-12
  61. Bocci G, Danesi R, Di Paolo A, Innocenti F, Allegrini G, Falcone A, Melosi A, Battistoni M, Barsanti G, Conte PF, Del Tacca M.  Comparative pharmacokinetic analysis of 5-fluorouracil and its major metabolite 5-fluoro-5,6-dihydrouracil after conventional and reduced test dose in cancer patients.  Clin Cancer Res, 2000; 6:3032-7
  62. Innocenti F, Danesi R, Favre C, Nardi M, Menconi M, Di Paolo A, Bocci G, Fogli S, Barbara C, Barachini S, Casazza G, Macchia P, Del Tacca M.  Variable correlation between 6-mercaptopurine metabolites in erythrocytes and hematological toxicity: implications for drug monitoring in children with acute lymphoblastic leukemia.  Ther Drug Monitor, 2000;22:375-82
  63. Innocenti F, Stadler WM, Iyer L, Ramirez J, Vokes EE, Ratain MJ.  Metabolism of flavopiridol in cancer patients is associated with the occurrence of diarrhea.  Clin Cancer Res, 2000;6:3400-5
  64. Bocci G, Danesi R, Benelli U, Innocenti F, Di Paolo A, Fogli S, Del Tacca M. Inhibitory effect of suramin in rat models of angiogenesis in vitro and in vivo.  Cancer Chemother Pharmacol, 1999;43:205-12
  65. Fogli S, Danesi R, Innocenti F, Di Paolo A, Bocci G, Barbara C, Del Tacca M.  An improved HPLC method for therapeutic drug monitoring of daunorubicin, idarubicin, doxorubicin, epirubicin, and their 13-dihydro metabolites in human plasma.  Ther Drug Monitor, 1999;21:367-75
  66. Innocenti F, Danesi R, Bocci G, Fogli S, Di Paolo A, Del Tacca M.  Metabolism of 6-mercaptopurine in erythrocytes, liver and kidney of rats during multiple-dose regimens.  Cancer Chemother Pharmacol, 1999;43:133-40
  67. Conte PF, Baldini E, Gennari A, Michelotti A, Salvadori B, Tibaldi C, Danesi R, Innocenti F, Gentile A, Dell’Anna R, Biadi O, Mariani M, Del Tacca M.  Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: a regimen with high activity and low cardiotoxicity in advanced breast cancer.  J Clin Oncol, 1997;15:2510-7
  68. Di Paolo A, Danesi R, Innocenti F, Bocci G, Nardini D, Fogli S, Pollina L, Rossi B, Del Tacca M.  Chronic administration of suramin induces neurotoxicity in rats. J Neurol Sci, 1997;152:125-31
  69. Innocenti F, Danesi R, Di Paolo A, Loru B, Favre C, Nardi M, Bocci G, Nardini D, Macchia P, Del Tacca M.  Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine and methotrexate.  Cancer Chemother Pharmacol, 1996;37:409-14
  70. Di Paolo A, Bocci G, Innocenti F, Agen C, Nardini D, Danesi R, Del Tacca M.  Inhibitory effect of the somatostatin analogue SMS 201-995 and cytokines on the proliferation of human colon adenocarcinoma cell lines.  Pharmacol Res, 1995;32:135-9
  71. Innocenti F, Danesi R, Di Paolo A, Agen C, Nardini D, Bocci G, Del Tacca M.  Plasma and tissue disposition of paclitaxel (Taxol) after intraperitoneal administration in mice. Drug Metab Dispos, 1995;23:713-7
  72. Pinna A, Agen C, Di Paolo A, Innocenti F, Nardini D, Danesi R, Del Tacca M.  Dissociation between in vitro cytotoxicity and in vivo cardiotoxicity of two new anthracyclines: 3’-deamino-3’-(2-methoxy-4-morpholinyl) doxorubicin and 4’-deoxy-4’-iodo-doxorubicin.  J Environ Pathol Toxicol Oncol 1994;13:25-31
  1. Gillis NK, Innocenti F. Evidence required to demonstrate clinical utility of pharmacogenetic testing: the debate continues. Clin Pharmacol Ther, 2014 (submitted)
  2. Seiser EL, Innocenti F. CNV Detection Algorithms for Illumina Genotyping Microarrays, 2014 (submitted)
  3. Cooper DNJ, Brand A, Dolzan V, Fortina P, Innocenti F, Lee MTA, Macek MJ, Al-Mulla F, Prainsack B,  Squassina A, Vayena E, Vozikis A, Williams MS , Patrinos GP. Bridging genomics research between developed and developing countries: The Genomic Medicine Alliance. Personal Med, 2014 (submitted)
  4. Fortina P, Khaja N, Ali M, Hamzeh A, Nair P,  Innocenti F, Patrinos G, Kricka L. Genomics into healthcare: the 5th Pan Arab Human Genetics Conference and 2013 Golden Helix Symposium. Hum Mutat, 2014; 35 (5): 637-40. PubMed Central: PMCID: PMC4128335
  5. Patel JN, McLeod HL, Innocenti F. Implications of genome-wide association studies in cancer therapeutics. Br J Clin Pharmacol. 2013 ;76(3):370-80. Review. PubMed PMID: 23701381; PubMed Central PMCID: PMC 3769665
  6. Gillis NK, Patel JN, Innocenti F. Clinical implementation of germline cancer pharmacogenetic variants during the next-generation sequencing era. Clin Pharmacol Ther, 2013; PubMed Central PMCID: PMC 4128332
  7. Patel JN, McLeod HL, Innocenti F. Implications of genome-wide association studies in cancer therapeutics. Br J Cancer, 2013;76-370-80. PubMed Central: PMCID PMCID: PMC 3769665
  8. Glubb DM, Dholakia N, Innocenti FLiver expression quantitative trait loci: a foundation for pharmacogenomic research. Front Genet, 2012;3:153. PubMed Central: PMCID: PMC 3418580
  9. Soo RA, Yong WP, Innocenti F. Systemic therapies for pancreatic cancer – the role of pharmacogenetics. Curr Drug Targets, 2012;13:811-28. PubMed Central: PMCID: PMC 3795429
  10. Crona D, Innocenti F. Can knowledge of germline markers of toxicity optimize dosing and efficacy of cancer therapy? Biomark Med, 2012;6:349-62. PubMed Central: PMCID: PMC 3704209
  11. Dupuis R, Yuen A, Innocenti F. The influence of UGT polymorphisms as biomarkers in solid organ transplantation. Clin Chim Acta, 2012;413:1318-25. PubMed Central: PMCID: PMC 3795433
  12. Mitropoulos K, Innocenti F, van Schaik RH, Lezhava A, Tzimas G, Kollia P, Macek M, Fortina P, Patrinos GP. Institutional profile: Golden Helix Institute of Biomedical Research: interdisciplinary research and educational activities in pharmacogenomics and personalized medicine. Pharmacogenomics, 2012;13:387-92. PubMed Central: PMCID PMC 3858958
  13. Peng Soh TI, Peng Yong W, Innocenti F.  Recent progress and clinical importance of pharmacogenetics in cancer therapy. Clin Chem Lab Med 2011; 49:1621-32. PubMed Central: PMCID PMC 3858908
  14. Patrinos GP, Innocenti F, Cox N, Fortina P. Genetic Analysis in Translational Medicine: The 2010 Golden Helix Symposium. Hum Mutat, 2011; 32:698. PubMed Central: PMCID PMC 3795430
  15. Innocenti F, Cox NJ, Dolan ME. The use of genomic information to optimize cancer chemotherapy. Semin Oncol, 2011; 38:186-95. PubMed Central: PMCID PMC 3076508
  16. Glubb DM, Innocenti F. Mechanisms of genetic regulation in gene expression: examples from drug metabolizing enzyme and transporter genes. Wiley Interdiscip Rev Syst Biol Med, 2010;3:299-313.
  17. Patrinos PG, Innocenti F. Conference scene. Pharmacogenomics: paving the path to personalized medicine. Golden Helix Symposium. Athens, Greece, 15-17 October 2009. Pharmacogenomics, 2010; 11:141-6.
  18. Ramirez J, Ratain MJ, Innocenti F.  Uridine 5′-diphospho-glucuronosyltransferase (UGT) genetic polymorphisms and response to cancer chemotherapy.  Future Oncol, 2010; 6:563-85. PubMed Central: PMCID PMC 3102300
  19. Wong A, Soo R, Yong W-P, Innocenti F. Clinical pharmacology and pharmacogenetics of gemcitabine. Drug Metab Rev, 2009; 41:77-88.
  20. Perera M, Innocenti F, Ratain MJ. Are we there yet? UGT1A1 and pharmacogenetic testing. Pharmacotherapy, 2008; 28:755-68. PubMed Central: PMCID PMC – not available
  21. Perera MA, Innocenti F, Ratain MJ. Pharmacogenetic testing for uridine diphosphate glucuronosyltransferase 1A1 polymorphisms: are we there yet? Pharmacotherapy. 2008; 28(6):755-68. PubMed Central: PMCID PMC – not available
  22. Yong W-P, Innocenti F. Translation of pharmacogenetic knowledge into cancer therapeutics. Clin Adv Hematol Oncol, 2007;5:698-706
  23. Innocenti F.  Challenges in the development and use of pharmacogenomic markers in oncology. J Support Oncol, 2007;5:15-6
  24. Kim TW, Innocenti F. Insights, challenges and future directions in irinogenetics. Ther Drug Monitor, 2007;29:265-70
  25. Cerri E, Falcone A, Innocenti F.  Cancer pharmacogenomics: germ line DNA, tumor DNA, or both? Curr Pharmacogenomics, 2007;5:87-101
  26. Innocenti F, Ratain MJ.  Pharmacogenetics of irinotecan: clinical perspectives on the utility of genotyping. Pharmacogenomics, 2006;7:1211-21
  27. Yong W-P, Innocenti F, Ratain MJ.  The role of pharmacogenetics in cancer therapeutics. Br J Clin Pharmacol, 2006;62:35-46
  28. Innocenti F, Ratain MJ.  “Irinogenetics” and UGT1A1: from genotypes to haplotypes. Clin Pharmacol Ther, 2004;75:495-500
  29. Desai AA, Innocenti F, Ratain MJ.  Pharmacogenomics:  road to anticancer therapeutics nirvana?  Oncogene Rev, 2003;22:6621-8
  30. Innocenti F, Ratain MJ.  Irinotecan treatment in cancer patients with UGT1A1 polymorphisms.  Oncology, 2003; 17:52-5
  31. Desai AA, Innocenti F, Ratain MJ.  UGT pharmacogenomics:  Implications for cancer risk and cancer therapeutics.  Pharmacogenetics, 2003; 13:517-23
  32. Nagasubramanian R, Innocenti F, Ratain MJ.  Pharmacogenetics in cancer treatment.  Ann Rev Med, 2003;54:437-52
  33. Innocenti F, Ratain MJ.  Update on pharmacogenetics in cancer chemotherapy.  Eur J Cancer, 2002;38:639-44
  34. Innocenti F, Iyer L, Ratain MJ.  Pharmacogenetics of anti-cancer agents: lessons from amonafide and irinotecan.  Drug Metab Dispos, 2001;29:596-600
  35. Innocenti F, Iyer L, Ratain MJ.  Pharmacogenetics: a tool for individualizing antineoplastic therapy. Clin Pharmacokin, 2000;39:315-25

Other Publications

  1. Glubb DM, Innocenti F. Architecture of pharmacogenomic associations: structures with functional foundations or castles made of sand? Pharmacogenomics, 2013;14:1-4. PubMed Central: PMCID: PMC 23252941
  2. Innocenti F. Moving away from candidate genes: a ‘genome-wise’ discovery of gemcitabine myelotoxicity. Pharmacogenomics, 2012;13:1113-4. PubMed Central: PMCID PMC 4131678
  3. Innocenti F. One SNP for both cancer risk and survival in colorectal cancer: two for the price of one? Pharmacogenomics, 2012;13:1114. PubMed Central: PMCID PMC 4128334
  4. Ratain MJ, Innocenti F. Individualizing dosing of irinotecan. Clin Cancer Res, 2010;16:371-2. PubMed Central: PMCID PMC – not available
  5. Innocenti F, Schilsky LR. Translating the cancer genome into clinically useful tools and strategies. Dis Model Mech, 2009; 2:426-9. PubMed Central: PMCID PMC – not available
  6. Toffoli G, Innocenti F. MTHFR and ALL risk: a challenge. Leuk Lymphoma, 2006; 47:1203-4
  7. Innocenti F, Vokes EE, Ratain MJ.  Irinogenetics: what is the right “star”?  J Clin Oncol, 2006; 24:1-4
  1. Liu W, Innocenti F, Ratain MJ.  Linkage Disequilibrium Across the UGT1A Locus Should not be Ignored in Association Studies of Cancer Susceptibility.  Correspondence re: Wang Y, et al.  UDP-glucuronosyltransferase 1A7 genetic polymorphisms are associated with hepatocellular carcinoma in Japanese patients with hepatitis C virus infection.  Clin Cancer Res, 2004; 10:2441-6.  Clin Cancer Res, 2005;11:1348-9
  2. Innocenti F, Ratain MJ.  Correspondence re:  Raida M. et al., Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5′-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)-related toxicity compared with controls, published on Clin Cancer Res, 2001;7:2832–9.  Clin Cancer Res, 2002;8:1314-6
  1. Innocenti F. Pharmacogenetics and individualized therapy. Clin Pharmacol Ther, 2012;92:682
  2. Innocenti F. Polypharmacology in drug discovery. Clin Pharmacol Ther, 2012;92:279-80

 

 

 

Innocenti Lab

 

Daniel Crona, Pharm.D., Ph.D.

(919) 966-4343 crona@email.unc.edu

Daniel Crona, Pharm.D., Ph.D., joined the UNC Eshelman School of Pharmacy in 2015 as an assistant professor after completing the UNC/Duke/Hamner Institute collaborative postdoctoral fellowship in clinical pharmacology, under the tutelage of Federico Innocenti, M.D., Ph.D., and Howard McLeod, Pharm.D. Crona received his B.S. from the University of Colorado-Denver in 2006 ...

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