Oncological molecular medicine

Laboratory activities

This laboratory is actively involved in new diagnostic strategies, mainly focused on massive parallel sequencing, devoted to a more detailed characterization of neoplastic diseases for the best therapeutic choice.

In particular, the Team is involved in two main fields:

the use of liquid biopsy for real-time discovery of the genetic alterations developing during tumor progression and responsible of resistance to drug treatment.

Many studies have established that the genomic landscape of tumors and metastases dynamically evolve over time in response to selective pressure of therapies that can suppress or promote the growth of different cellular clones. The assessment of these genetic changes is a very challenge since the difficulty to obtain tissue at progression.

Liquid biopsy is a new strategy to evaluate biomarkers directly from body fluids such as plasma or urine instead of solid tissue as from the traditional biopsy. The liquid biopsy may be the optimal source both of circulating tumor DNA and circulating cancer cells for molecular tests predictive of response to tailored treatments, selected on the basis of specific genetic alterations. Indeed, traditional biopsies and surgical procedures are invasive, with potential clinical complications, and cannot be performed when clinical conditions have worsened or when a tumor is inaccessible. In addition, molecular test performed on liquid biopsy may allow early to catch additional alterations, predictive of resistance, that could be potential target for further specific drugs and may address toward other treatment options.

In addition, the liquid biopsy allows a more accurate follow-up of the neoplastic patient as it can be repeated many times allowing to monitor the neoplastic disease over time. An early detection of the mutation/s involved in the resistance mechanism may be important in further selecting patients for specific treatments and contributes to better knowledge of genetic landscape during progressive disease.

At present, the liquid biopsy is approved for clinical practice only for patients with NSCLC, but there is a great interest in liquid biopsy as a diagnostic tool in other forms of neoplastic disease.

The assessment of molecular mechanisms involved in the acquisition of resistance requires complex multi-gene tests, mainly based on massive parallel sequencing (MPS). Our team has worked for many years in the field of liquid biopsy and deep sequencing through Massive Parallel Sequencing. Our research activity is currently dedicated to assessing the usefulness of liquid biopsy in monitoring patients with malignancies who at progression could benefit to new therapeutic strategies.

The assessment of BRCA mutations in uncommon types of neoplastic disease.

Tumor suppressor genes BRCA1 and BRCA2 were first linked to the breast and ovarian cancer susceptibility. In addition, BRCA1 mutation carriers may be at high risk for the development of other types of cancer including prostate, colon, rectal and pancreatic cancer as well as stomach cancer. Mutations in BRCA2 predispose not just to breast, ovarian and prostate cancer, but are also associated with malignant cutaneous and ocular melanoma, pancreatic, gall bladder, bile duct and stomach cancer.

Due to reduced DNA repair capacity, BRCA-mutated cancers are also more responsive to

the distinct types of treatment such as platinum-based compounds and PARP inhibitors, which induce accumulation of DNA DSBs. However, acquired resistance to these treatments represents a recent interesting field of research studies. Our Team is involved in the assessment of incidence of BRCA somatic mutations in pancreatic and prostate carcinomas and their clinical role in the progression free survival and overal survival.

Image modified from here.

References

Buttitta F, Felicioni L, Lorito AD, Cortellini A, Irtelli L, Brocco D, Marino PD, Traisci D, D'Ostilio N, Paolo AD, Malorgio F, Assalone P, Felice SD, Fabbri F, Cianci G, Tursi M, Marchetti A Early prediction of resistance to tyrosine kinase inhibitors by plasma monitoring of EGFR mutations in NSCLC: a new algorithm for patient selection and personalized treatment. Oncotarget. 2020 Mar 17;11(11):982-991. doi: 10.18632/oncotarget.27517. eCollection 2020 Mar 17.

Marchetti A, Palma JF, Felicioni L, De Pas TM, Chiari R, Del Grammastro M, Filice G, Ludovini V, Brandes AA, Chella A, Malorgio F, Guglielmi F, De Tursi M, Santoro A, Crinò L, Buttitta F. Early Prediction of Response to Tyrosine Kinase Inhibitors by Quantification of EGFR Mutations in Plasma of NSCLC Patients. J Thorac Oncol. 2015 Oct;10(10):1437-43. doi: 10.1097/JTO.0000000000000643.

Marchetti A, Del Grammastro M, Felicioni L, Malatesta S, Filice G, Centi I, De Pas T, Santoro A, Chella A, Brandes AA, Venturino P, Cuccurullo F, Crinò L, Buttitta F. Assessment of EGFR mutations in circulating tumor cell preparations from NSCLC patients by next generation sequencing: toward a real-time liquid biopsy for treatment. PLoS One. 2014 Aug 19;9(8):e103883. doi: 10.1371/journal.pone.0103883.

Buttitta F, Felicioni L, Del Grammastro M, Filice G, Di Lorito A, Malatesta S, Viola P, Centi I, D'Antuono T, Zappacosta R, Rosini S, Cuccurullo F, Marchetti A. Effective assessment of EGFR mutation status in bronchoalveolar lavage and pleural fluids by next-generation sequencing. Clin Cancer Res. 2013 Feb 1;19(3):691-8. doi: 10.1158/1078-0432.CCR-12- 1958.

Cazzoli R, Buttitta F, Di Nicola M, Malatesta S, Marchetti A, Rom WN, Pass HI. microRNAs derived from circulating exosomes as noninvasive biomarkers for screening and diagnosing lung cancer. J Thorac Oncol. 2013 Sep;8(9):1156-62. doi: 10.1097/JTO.0b013e318299ac32.

Marchetti A, Del Grammastro M, Filice G, Felicioni L, Rossi G, Graziano P, Sartori G, Leone A, Malatesta S, Iacono M, Guetti L, Viola P, Mucilli F, Cuccurullo F, Buttitta F. Complex mutations & subpopulations of deletions at exon 19 of EGFR in NSCLC revealed by next generation sequencing: potential clinical implications. PLoS One. 2012;7(7):e42164. doi: 10.1371/journal.pone.0042164

BRCA1/2 Molecular Assay for Ovarian Cancer Patients: A Survey through Italian Departments of Oncology and Molecular and Genomic Diagnostic Laboratories. Capoluongo E, La Verde N, Barberis M, Bella MA, Buttitta F, Carrera P, Colombo N, Cortesi L, Gion M, Guarneri V, Lorusso D, Marchetti A, Marchetti P, Normanno N, Pasini B, Pensabene M, Pignata S, Radice P, Ricevuto E, Sapino A, Tagliaferri P, Tassone P, Trevisiol C, Truini M, Varesco L, Russo A, Gori S.Diagnostics (Basel). 2019 Oct 9;9(4):146. doi: 10.3390/diagnostics9040146.PMID: 31600986

Recommendations for the implementation of BRCA testing in ovarian cancer patients and their relatives. Gori S, Barberis M, Bella MA, Buttitta F, Capoluongo E, Carrera P, Colombo N, Cortesi L, Genuardi M, Gion M, Guarneri V, Incorvaia L, La Verde N, Lorusso D, Marchetti A, Marchetti P, Normanno N, Pasini B, Pensabene M, Pignata S, Radice P, Ricevuto E, Sapino A, Tagliaferri P, Tassone P, Trevisiol C, Truini M, Varesco L, Russo A; AIOM-SIGU-SIBIOC-SIAPEC-IAP Working Group.Crit Rev Oncol Hematol. 2019 Aug;140:67-72. doi: 10.1016/j.critrevonc.2019.05.012. Epub 2019 May 25.PMID: 31176273

Group Leader