Dr. Innocenti’s NIH-funded research program is currently focused on the discovery of genomic determinants of efficacy and toxicity of cancer chemotherapy, integrating clinical genomic investigation with functional evaluation of gene variation.
Federico Innocenti Lab
Professor Innocenti and his team conduct clinical and translational research aimed at the discovery of novel determinants of efficacy and safety of cancer therapy. In this framework, genomic technologies are applied to optimize treatment of cancer patients, with the ultimate goal of extending the duration of life of cancer patients and improving their quality of life.
Our research program aims to discover effective strategies for individualizing therapy for cancer patients through the identification of heritable (in the patient) and acquired (in the tumor) genetic determinants of therapeutic outcome, both in the laboratory and the clinic.
The program uses a translational model where genomics analyses are conducted in cancer patients enrolled in clinical trials of new drug therapies. The results of these analyses discover novel genetic variants, new genes, and pathways that are subsequently tested at the bench. By using model in vitro systems, the functions and underlying mechanisms of these novel molecular determinants are elucidated. 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 efficacy and safety of drug treatments.
This research activity integrates whole-genome- and 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 program is structured in three main themes:
- Theme 1: Genomic studies in patients with gastrointestinal tumors. Genomic data are obtained from patients enrolled in clinical trials of novel therapies using next-generation sequencing of DNA (tumor and germline) and RNA (tumor). Genomic profiling of the patient and the tumor will predict the outcome of patient survival and the side effects of therapy.
- Theme 2: Genome-wide regulation of gene expression. Elucidating the genetic basis of differences in gene expression in the human liver is instrumental to discover new heritable determinants of liver-mediated response to medications.
- Theme 3: Functional analysis of novel genes and their variants. The results of both Themes 1 and 2 provide a large series of new genetic variants for functional validation. The laboratory employs various cell-based assays to test the function of new genetic variants. They provide the mechanistic foundations to the novel determinants of patient outcome and safety (Theme 1) and liver gene expression (Theme 2).
Exemplary Publications from the last 5 years:
- Sharma MR, Auman JT, Patel NM, Grilley-Olson JE, Zhao X, Moschos SJ, Parker JS, Yin X, Hayward MC, Polite BN, Marangon E, Posocco B, Toffoli G, Hayes DN, Innocenti F. Exceptional Chemotherapy Response in Metastatic Colorectal Cancer Associated With Hyper-Indel-Hypermutated Cancer Genome and Comutation of POLD1 and MLH1. JCO Precis Oncol. 2017(1):1-12.
- 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
- 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 Central PMCID: PMC 5012711.
- Crona DJ, Ramirez J, Qiao W, de Graan AJ, Ratain MJ, van Schaik RH, Mathijssen RH, Rosner GL, Innocenti F. Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study. Pharmacogenomics J. 2016 Feb;16(1):54-9. PubMed Central PMCID: PMC 4729652.
- 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 Central PMCID: PMC 4494119.
- 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 Central PMCID: PMC 4105486.
- 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 3935516
- 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
Professor Innocenti’s research focuses on the discovery of effective strategies for individualizing therapy for cancer patients through the identification of heritable (in the patient) and acquired (in the tumor) genetic determinants of therapeutic outcome, both in the laboratory and the clinic.