A5016413453- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Peptidase Inhibition and Analysis
- Epigenetics and DNA Methylation
- Cancer Genomics and Diagnostics
- Acute Myeloid Leukemia Research
- Retinoids in leukemia and cellular processes
- Virus-based gene therapy research
- Chemical Synthesis and Analysis
- CAR-T cell therapy research
- Genomics and Rare Diseases
- DNA Repair Mechanisms
- Immune Cell Function and Interaction
- Chromatin Remodeling and Cancer
- PARP inhibition in cancer therapy
- Signaling Pathways in Disease
- Protease and Inhibitor Mechanisms
- Acute Lymphoblastic Leukemia research
- Computational Drug Discovery Methods
- Cutaneous Melanoma Detection and Management
- Immune cells in cancer
- interferon and immune responses
- Lysosomal Storage Disorders Research
- Animal Genetics and Reproduction
- PI3K/AKT/mTOR signaling in cancer
European Institute of Oncology
2012-2024
Istituti di Ricovero e Cura a Carattere Scientifico
2021-2024
University of Lahore
2017
Pir Mehr Ali Shah Arid Agriculture University
2017
The San Raffaele Telethon Institute for Gene Therapy
2006
Vita-Salute San Raffaele University
2002-2005
National Cancer Institute
2002
Center for Cancer Research
2002
The function of urokinase and its receptor is essential for cell migration in pathological conditions, as shown by the analysis knockout mice phenotypes. How a protease fibrinolytic pathway can induce not understood no link between this migration-promoting G protein-coupled receptors has been described. We now show that FPRL1/LXA4R, number polypeptides endogenous lipoxin A4 (LXA4), urokinase-type plasminogen activator (uPA) it directly interacts with an activated, soluble, cleaved form uPA...
Purpose: Histone deacetylase inhibitors (HDACi) are promising anticancer drugs. Although some HDACi have entered the clinic, mechanism(s) underlying their tumor selectivity poorly understood.Experimental Design and Results: Using gene expression analysis, we define a core set of six genes commonly regulated in acute myeloid leukemia (AML) blasts cell lines. MYC, most prominently modulated, is preferentially altered leukemia. Upon treatment, c-Myc acetylated at lysine 323 its decreases,...
Deregulation of epigenetic mechanisms, including microRNA, contributes to leukemogenesis and drug resistance by interfering with cancer-specific molecular pathways. Here, we show that the balance between miR-194-5p its newly discovered target BCL2-associated transcription factor 1 (BCLAF1) regulates differentiation survival normal hematopoietic progenitors. In acute myeloid leukemias this is perturbed, locking cells into an immature, potentially 'immortal' state. Enhanced expression...
The identification of genes maintaining cancer growth is critical to our understanding tumorigenesis. We report the first in vivo genetic screen patient-derived tumors, using metastatic melanomas and targeting 236 chromatin by expression specific shRNA libraries. Our screens revealed unprecedented numerosity indispensable for tumor (∼50% tested genes) unexpected functional heterogeneity among patients (<15% common). Notably, these were not activated somatic mutations same are therefore...
Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of contribution sunitinib's numerous targets clinical response or resistance is crucial. Here, we have shown that cancer cells clinically relevant doses by enhancing stability antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition signaling sensitized in vitro was synergistic...
Synthetic lethality is an innovative framework for discovering novel anticancer drug candidates. One example the use of PARP inhibitors (PARPi) in oncology patients with BRCA mutations. Here, we exploit a new paradigm based on possibility triggering synthetic using only small organic molecules (dubbed "fully small-molecule-induced lethality"). We exploited this to target pancreatic cancer, one major unmet needs oncology. discovered dihydroquinolone pyrazoline-based molecule (35d) that...
Abstract Proteins involved in DNA double-strand break (DSB) repair localize within the promyelocytic leukemia nuclear bodies (PML-NBs), whose disruption is at root of acute (APL) pathogenesis. All- trans -retinoic acid (RA) treatment induces PML-RAR α degradation, restores PML-NB functions, and causes terminal cell differentiation APL blasts. However, precise role APL-associated oncoprotein integrity DSB response leukemogenesis tumor suppression still lacking. Primary blasts isolated from...
In BRCA2-defective cells, poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors can trigger synthetic lethality, as two independent DNA-repairing mechanisms are simultaneously impaired. Here, we have pharmacologically induced which was triggered by combining different small organic molecules. When administered with a BRCA2–Rad51 disruptor in nonmutant Olaparib showed anticancer activity comparable to that shown when alone cells. This strategy could represent an innovative approach...
Abstract The histone demethylase LSD1 is over-expressed in hematological tumors and has emerged as a promising target for anticancer treatment, so that several inhibitors are under development testing, preclinical clinical settings. However, the complete understanding of their complex mechanism action still unreached. Here, we unraveled novel mode MC2580 DDP-38003, showing they can induce differentiation AML cells through downregulation chromatin protein GSE1. Analysis phenotypic effects...
Lysine specific demethylase-1 (LSD1) has been shown to be critical in acute myeloid leukemia (AML) pathogenesis and this led the development of LSD1 inhibitors (LSD1i) which are currently tested clinical trials. Nonetheless, preclinical studies reported that AML cells frequently exhibit intrinsic resistance inhibition, molecular basis for phenomenon is largely unknown. We explored potential involvement mammalian target rapamycin (mTOR) mediating leukemic LSD1i. Strikingly, unlike sensitive...
The RET (REarranged during Transfection) receptor tyrosine kinase is targeted by oncogenic rearrangements in thyroid and lung adenocarcinoma. Recently, a (exon 12) rearrangement with FGFR1OP [fibroblast growth factor 1 (FGFR1) oncogene partner] was identified one chronic myelomonocytic leukemia (CMML) patient. We report the molecular cloning functional characterization of novel 11)‐RET 11) gene fusion event (named FGFR1OP‐RET), mediated reciprocal translocation t(6; 10)(q27; q11), patient...
Son of Sevenless 1 (SOS1) is a dual guanine nucleotide exchange factor (GEF) that activates the small GTPases RAC and RAS. Although molecular mechanisms RAS GEF catalysis have been unveiled, how SOS1 acquires activity what physio-pathological relevance this much less understood. Here we show tyrosine phosphorylated on Y1196 by ABL. Phosphorylation controls inter-molecular interaction, required to promote nucleotides in vitro for platelet-derived growth (PDGF) activation RAC- RAC-dependent...
Combined inhibition of oxidative phosphorylation (OXPHOS) and glycolysis has been shown to activate a PP2A-dependent signaling pathway, leading tumor cell death. Here, we analyze highly selective mitochondrial complex I or III inhibitors in vitro vivo elucidate the molecular mechanisms death following OXPHOS inhibition. We show that IACS-010759 treatment (complex inhibitor) induces reactive oxygen species (ROS)-dependent dissociation CIP2A from PP2A, its destabilization degradation through...
The lysine-specific histone demethylase 1 A (LSD1) is involved in antitumor immunity; however, its role shaping CD8 + T cell (CTL) differentiation and function remains largely unexplored. Here, we show that pharmacological inhibition of LSD1 (LSD1i) CTL the context adoptive therapy (ACT) elicits phenotypic functional alterations, resulting a robust immunity preclinical models female mice. In addition, combination anti-PDL1 treatment with LSD1i-based ACT eradicates tumor leads to long-lasting...
Innate immune responses to coronavirus infections are highly cell specific. Tissue-resident macrophages, which infected by severe acute respiratory syndrome 2 (SARS-CoV-2) in patients but inconsistently vitro, exert critical conflicting effects secreting both antiviral type I interferons (IFNs) and tissue-damaging inflammatory cytokines. Steroids, the only class of host-targeting drugs approved for treatment disease 2019 (COVID-19), indiscriminately suppress responses, possibly impairing...
Neuroendocrine tumours (NETs) are highly vascularized malignancies in which angiogenesis may entail cell proliferation and survival. Among the emerging compounds with anti-vascular properties, cabozantinib (CAB) appeared promising. We analyzed anti-tumor activity of CAB against NETs utilizing vitro vivo models. For cultures we used BON-1, NCI-H727 NCI-H720 lines. Cell viability was assessed by manual count coupled quantification death, performed through FACS analysis as propidium iodide...
Abstract Tissue-resident macrophages exert critical but conflicting effects on the progression of coronavirus infections by secreting both anti-viral type I Interferons and tissue-damaging inflammatory cytokines. Steroids, only class host-targeting drugs approved for Covid19, indiscriminately suppress responses, possibly impairing viral clearance, provide limited clinical benefit. Here we set up a mouse in vitro co-culture system that reproduces macrophage response to SARS-CoV2 seen patients...