The Innocenti laboratory is devoted to the study of human pharmacology and genetics, with the aim of improving the efficacy of drug treatments for cancer patients.

 

Our research program aims to discover effective strategies for individualizing therapy for cancer patients through the identification of heritable and acquired genetic determinants of therapeutic outcome, both in the laboratory and the clinic.

The program uses a translational model where genetics and genomics analyses are conducted in cancer patients enrolled in clinical trials of new drug therapies. The results of such analyses identify novel genetic variants, new genes, and pathways that are subsequently tested at the bench, using model in vitro systems, for their function and underlying mechanism of action. In this framework, the clinical effects are linked to and explained by the biological function of novel genetic variants. The end result is the discovery and clinical validation of novel genetic determinants of severe toxicity and response to therapy.

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 and involves the contribution of oncologists, pharmacologists, biologists, statisticians, bioinformaticians, and geneticists.

The research program is defined by three main themes.

Genetic data collected from clinical trials that span a variety of tumor types and include patients treated with multiple drugs (with shared toxicities, metabolic pathways, and similar mechanisms of action) create a platform for testable hypotheses to individualize patient care. These studies represent a framework for identifying new markers of outcome (safety and efficacy) to be used for prospective clinical testing and for in vitro evaluation of molecular function, as per Theme 3.

Candidate-gene, pathway-based, genome-wide studies are ongoing and planned. They interrogate both the germline heritable genome as well as the somatic, tumor-specific genome. Candidate gene studies also include prospective, genotype-directed clinical trials where dose is assigned based upon the genetic makeup of the patient.

The liver is a metabolically active tissue that is critical to core biological processes related to the maintenance of homeostasis and health, including detoxification of xenobiotics. Therefore, in pharmacogenomics, identifying genetic variation impacting hepatic gene expression is important for understanding the genetic basis of drug response. We have built a resource of knowledge by performing a meta-analysis of 1180 human hepatic samples with mRNA gene expression and genomic DNA variation. This is the most comprehensive assessment of the heritable component of gene expression variation in the liver.  We are expanding this expression quantitative trait loci (eQTL) study to encompass the measurement of protein expression from important pharmacogenetics genes, the evaluation of sex-biased differences in the regulation of gene expression, and the association of hepatic eQTL with blood metabolite levels. RNA-seq analysis of over 200 human livers has been also performed. 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 drug disposition genes, as well as for studies of liver-related traits and diseases.

Establishing statistical associations between genetic variation and outcome measured in patients usually does not provide evidence of causation and more mechanistic validation is needed. Validating the function of novel genes and their variants represents the foundation of the clinical validity of findings. The comprehensive nature of the interrogation in both Theme 1 and Theme 2 results in a large series of candidate genetic variants for functional validation testing using model experimental systems, including cytotoxicity assays, luciferase assays, electrophoretic mobility shift assays (EMSA), chromatin immunoprecipitation (ChIP), gene editing with CRISPR, gene knockdown with siRNA, cDNA overexpression, epigenome editing, and others. Through our extensive network of collaborators, we are able to integrate these assays with additional experimental models, such as assays for investigating the mechanisms of angiogenesis and experiments utilizing zebrafish as an in vivo model.

Exemplary Publications from the last 5 years:

  1. Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O’Neil BH, Atkins JN, Berry S, Polite BN, O’Reilly EM, Goldberg RM, Hochster HS, Schilsky RL, Bertagnolli MM, El-Khoueiry AB, Watson P, Benson AB 3rd, Mulkerin DL, Mayer RJ, Blanke C. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2017 Jun 20;317(23):2392-2401. PubMed PMID: 28632865; PubMed Central PMCID: PMC5545896.
  2. Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu; Cancer Genome Atlas Research Network. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell. 2017 Jun 15;169(7):1327-1341.e23. PubMed PMID: 28622513.
  3. Innocenti F. Bringing a genomic perspective to the safety of drug treatment in oncology. F1000Res. 2017 Mar 29;6. pii: F1000 Faculty Rev-385. Review. PubMed PMID: 28408974; PubMed Central PMCID: PMC5373416.
  4. Toffoli G, Sharma MR, Marangon E, Posocco B, Gray E, Mai Q, Buonadonna A, Polite BN, Miolo G, Tabaro G, Innocenti F. Genotype-Guided Dosing Study of FOLFIRI plus Bevacizumab in Patients with Metastatic Colorectal Cancer. Clin Cancer Res. 2017 Feb 15;23(4):918-924. PubMed PMID: 27507617.
  5. Zhou K, Yee SW, Seiser EL, van Leeuwen N, Tavendale R, Bennett AJ, Groves CJ, Coleman RL, van der Heijden AA, Beulens JW, de Keyser CE, Zaharenko L, Rotroff DM, Out M, Jablonski KA, Chen L, Javorský M, Židzik J, Levin AM, Williams LK, Dujic T, Semiz S, Kubo M, Chien HC, Maeda S, Witte JS, Wu L, Tkáč I, Kooy A, van Schaik RHN, Stehouwer CDA, Logie L; MetGen Investigators; DPP Investigators; ACCORD Investigators, Sutherland C, Klovins J, Pirags V, Hofman A, Stricker BH, Motsinger-Reif AA, Wagner MJ, Innocenti F, ‘t Hart LM, Holman RR, McCarthy MI, Hedderson MM, Palmer CNA, Florez JC, Giacomini KM, Pearson ER. Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin. Nat Genet. 2016 Sep;48(9):1055-1059. PubMed PMID: 27500523; PubMed Central PMCID: PMC5007158.
  6. Niedzwiecki D, Frankel WL, Venook AP, Ye X, Friedman PN, Goldberg RM, Mayer RJ, Colacchio TA, Mulligan JM, Davison TS, O’Brien E, Kerr P, Johnston PG, Kennedy RD, Harkin DP, Schilsky RL, Bertagnolli MM, Warren RS, Innocenti F. Association Between Results of a Gene Expression Signature Assay and Recurrence-Free Interval in Patients With Stage II Colon Cancer in Cancer and Leukemia Group B 9581 (Alliance). J Clin Oncol. 2016 Sep 1;34(25):3047-53. PubMed PMID: 27432924; PubMed Central PMCID: PMC5012711.
  7. Dickler MN, Barry WT, Cirrincione CT, Ellis MJ, Moynahan ME, Innocenti F, Hurria A, Rugo HS, Lake DE, Hahn O, Schneider BP, Tripathy D, Carey LA, Winer EP, Hudis CA. Phase III Trial Evaluating Letrozole As First-Line Endocrine Therapy With or Without Bevacizumab for the Treatment of Postmenopausal Women With Hormone Receptor-Positive Advanced-Stage Breast Cancer: CALGB 40503 (Alliance). J Clin Oncol. 2016 Aug 1;34(22):2602-9. PubMed PMID: 27138575; PubMed Central PMCID: PMC5012690.
  8. Glubb DM, Paré-Brunet L, Jantus-Lewintre E, Jiang C, Crona D, Etheridge AS, Mirza O, Zhang W, Seiser EL, Rzyman W, Jassem J, Auman T, Hirsch FR, Owzar K, Camps C, Dziadziuszko R, Innocenti F. Functional FLT1 Genetic Variation is a Prognostic Factor for Recurrence in Stage I-III Non-Small-Cell Lung Cancer. J Thorac Oncol. 2015 Jul;10(7):1067-75. PubMed PMID: 26134224; PubMed Central PMCID: PMC4494119.
  9. Innocenti F. DPYD variants to predict 5-FU toxicity: the ultimate proof. J Natl Cancer Inst. 2014 Nov 7;106(12). pii: dju351. PubMed PMID: 25381394.
  10. Van Loon K, Owzar K, Jiang C, Kindler HL, Mulcahy MF, Niedzwiecki D, O’Reilly EM, Fuchs C, Innocenti F, Venook AP; Alliance for Clinical Trials in Oncology. 25-Hydroxyvitamin D levels and survival in advanced pancreatic cancer: findings from CALGB 80303 (Alliance). J Natl Cancer Inst. 2014 Aug 6;106(8). pii: dju185. PubMed PMID: 25099612; PubMed Central PMCID: PMC4155431.
  11. 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. Dose-finding and pharmacokinetic study to optimize the dosing of irinotecan according to the UGT1A1 genotype of patients with cancer. J Clin Oncol. 2014 Aug 1;32(22):2328-34. PubMed PMID: 24958824; PubMed Central PMCID: PMC4105486.
  12. Paré-Brunet L, Glubb D, Evans P, Berenguer-Llergo A, Etheridge AS, Skol AD, Di Rienzo A, Duan S, Gamazon ER, Innocenti F. Discovery and functional assessment of gene variants in the vascular endothelial growth factor pathway. Hum Mutat. 2014 Feb;35(2):227-35. PubMed PMID: 24186849; PubMed Central PMCID: PMC3935516.
  13. Innocenti F, Owzar K, Cox NL, Evans P, Kubo M, Zembutsu H, Jiang C, Hollis D, Mushiroda T, Li L, Friedman P, Wang L, Glubb D, Hurwitz H, Giacomini KM, McLeod HL, Goldberg RM, Schilsky RL, 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 Jan 15;18(2):577-84. PubMed PMID: 22142827; PubMed Central PMCID: PMC3412624.

Dr. Innocenti’s CV

Amy Etheridge – Research Specialist/Lab Manager
aetheridge@unc.edu

Stefanie Denning – Research Associate
scdenning@unc.edu

Kelli Hammond – Soc/Clin Research Assistant
hammondk@email.unc.edu

Alessandro Racioppi – Research Intern

Sarah Mills – Research Intern