Una propuesta de tendencias en estudios sobre creatividad

PROGRAM HIGHLIGHTS

This project will address currently unmet clinical needs in the management of hematological malignancies. New biomarkers for the upfront identification of patients with aggressive disease, refractory and/or relapsing and new treatments tailored to target can- cer-driving lesions are mandatory. Although a variety of genetic and epigenetic lesions as well as microenvironmental features have been mechanistically implicated in the pathogenesis and progression of hematological malignancies, the pathogenesis of chemo-re- fractoriness remains unclear. Major improvements in sequencing technologies could provide the opportunity to discover genomic alterations and therapeutic targets accounting for chemo-refractoriness and early relapse. This project will also define preclinical models mainly for PTCLs that reliably predict the clinical activity of novel compounds specifically targeting the key genetic lesions identified. The potential role of genes/proteins as diagnostic tools and novel biomarkers with prognostic and predictive value will be assessed. Our research project has the clear goal of a rapid translation in the clinical setting by: i) improving the early identification of chemo-refractory/relapsing patients and patients requiring auto- or allo-SCT as first line treatment with novel biomarkers; ii) designing phase 1/2 clinical studies aimed at exploring the clinical activity of rationale combinations of targeted drugs that have been previously tested in in-vitro models.

PROGRAM MEMBERSHIP

The goals of this project will be achieved by integrating the complementary and synergistic skills and facilities of members (clinicians, researchers and data managers) of the Hematology Unit. The clinical staff (Prof Paolo Corradini, Dr. Anna Dodero, Dr. Vittorio Montefusco, Dr. Lucia Farina, Dr. Francesco Spina) has been working in

the field of hematological malignancies and stem cell transplantation for many years and will be instrumental in designing clinical studies and selecting patients for biological analysis. All clinical information necessary to correlate the biological results with outcome will be collected by or data managers (Dr. Debora Degli Innocenti, Dr. Anisa Bermema). Well-characterized bio-repositories of biospecimens (blood,

plasma, biopsies) from patients enrolled in several clinical trials are available to the research team as a biobanking system, which is ongoing within the Unit and coordinated by Dr. Cristiana Carniti. The biobank

will provide a sufficient number of samples for analysis and validation of results. The expertise for the use of new sequencing technologies is increasing in our Unit. Specifically Dr. Silvia Gimondi of the Hematology

Branch has recently attended the Ion PGM teaching course at Life Technologies laboratories, Darmstadt, Germany to learn the use of this technology and complement her existing bioinformatic skills. Other members of the team include researchers (Dr. Antonio Vendramin, Dr. Alessandra Cavanè, Dr. Sara Rizzitano) with different but synergistic

expertise that have been selected according to their proven well- defined scientific and technical skills.

SELECTED RECENT PUBLICATIONS Perrone G., Farina L., Corradini P.: Current state of art for

transplantation paradigms in peripheral T-cell lymphomas. Expert Rev Hematol 2013; 6(4): 465-474

Larocca A., Montefusco V., Bringhen S., Rossi D., Crippa C., Mina R., Galli M., Marcatti M., La Verde G., Giuliani N., Magarotto V., Guglielmelli T., Rota-Scalabrini D., Omedé P., Santagostino A., Baldi I., Carella A.M., Boccadoro M., Corradini P., Palumbo A.: Pomalidomide, cyclophosphamide, and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open-label study. Blood 2013; 122(16): 2799-2806

Gay F., Magarotto V., Crippa C., Pescosta N., Guglielmelli T., Cavallo F., Pezzatti S., Ferrari S., Liberati A.M., Oliva S., Patriarca F., Offidani M., Omedé P., Montefusco V., Petrucci M.T., Giuliani N., Passera R., Pietrantuono G., Boccadoro M., Corradini P., Palumbo A.: Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood 2013; 122(8): 1376-1383

Montefusco V., Spina F., Patriarca F., Offidani M., Bruno B., Montanari M., Mussetti A., Sperotto A., Scortechini I., Dodero A., Fanin R., Valagussa P., Corradini P.: Bortezomib plus dexamethasone followed by escalating donor lymphocyte infusions for patients with multiple myeloma relapsing or progressing after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19(3): 424-428

ASSOCIATED CLINICAL TRIALS

INT 118/13 - Protocol COEB071X2103: An open-label, single- arm, Phase Ib/II study of AEB071 (a protein kinase C inhibitor) and everolimus (mTOR inhibitor) in patients with CD79-mutant or ABC subtype diffuse large B-cell lymphoma

INT 134/13 - Protocol CC-122-DLBCL-001: A PHASE 1B, MULTI- CENTER, OPEN-LABEL STUDY OF NOVEL COMBINATIONS OF CC-122, CC-223, CC-292, AND RITUXIMAB IN DIFFUSE LARGE B-CELL LYMPHOMA

INT 31/13 – IST-CAR-561: A MULTICENTER, OPEN LABEL STUDY OF WEEKLY CARFILZOMIB, CYCLOPHOSPHAMIDE AND DEXAMETHASONE (wCCyd) IN NEWLY DIAGNOSED MULTIPLE MYELOMA (MM) PATIENTS

INT 19/13: Studio dei meccanismi molecolari di chemio-resistenza nei  linfomi a cellule T periferiche (PTCL) mediante sequenziamento massivo del genoma

INT 86/13: Identificazione delle cause genetiche responsabili di una forma famigliare di mieloma

INT 149/13: Studio retrospettivo osservazionale sul monitoraggio dei livelli sierici di TARC e i risultati PET dei pazienti con linfoma di Hodgkin sottoposti a trapianto allogenico di cellule staminali emopoietiche GRANTS

AIRC IG 2013 Prof Paolo Corradini UNDERSTANDING THE BIOLOGICAL BASIS OF CHEMOREFRACTORINESS IN PERIPHERAL T-CELL LYMPHOMA TO DEVELOP NOVEL TREATMENTS

MFAG Mariotti Identifying new molecular pathways and predictor biomarkers of GVHD after allogeneic-HSCT

FP7 PEOPLE 2010 RG Role and Modulation of Jak and STAT signaling in Graft Rejection and Graft versus

KEYWORDS

Hematological malignancies; Drug response and/or resistance; Targeted therapy; Next Generation Sequencing