A5052775457- Lung Cancer Treatments and Mutations
- Cancer therapeutics and mechanisms
- Lymphoma Diagnosis and Treatment
- Lung Cancer Research Studies
- Colorectal Cancer Treatments and Studies
- Cancer-related gene regulation
- Genetic factors in colorectal cancer
- Neuroblastoma Research and Treatments
- PI3K/AKT/mTOR signaling in cancer
- Chronic Myeloid Leukemia Treatments
- Chronic Lymphocytic Leukemia Research
- Monoclonal and Polyclonal Antibodies Research
- Peptidase Inhibition and Analysis
- Immune Cell Function and Interaction
- Synthesis and Biological Evaluation
- Wnt/β-catenin signaling in development and cancer
- Synthesis and bioactivity of alkaloids
- RNA Research and Splicing
- Cancer Genomics and Diagnostics
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- Cancer-related molecular mechanisms research
- Neuroendocrine Tumor Research Advances
- Ubiquitin and proteasome pathways
- HER2/EGFR in Cancer Research
University of Milano-Bicocca
2010-2022
University Hospital Regensburg
2014
University of Geneva
2012
Vita-Salute San Raffaele University
2010
McGill University
2010
Anaplastic lymphoma kinase (ALK)-positive lymphomas respond to chemotherapy, but relapses, which bear a poor prognosis, occur. Crizotinib inhibits ALK in vitro and vivo was administered as monotherapy 11 ALK+ patients who were resistant/refractory cytotoxic therapy. The overall response rate 10 of (90.9%; 95% confidence interval [CI] = 58.7% 99.8%). Disease status at the latest follow-up is follows: four are complete (CR) (months >21, >30, >35, >40) under continuous crizotinib...
BCR/ABL (Breakpoint Cluster Region protein/Abelson tyrosine-protein kinase 1) domain (KD) mutations represent the most frequently described mechanism of resistance to treatment with tyrosine inhibitors (TKI) in patients chronic myeloid leukemia (CML). Mutations may impair TKI activity by directly or indirectly impairing drug binding protein. We report discovery three new mutations, L248R, T315V, and F317R identified two CML (L248R T315V) one patient Ph+ acute lymphoblastic (ALL) (F317R)....
Abstract Anaplastic lymphoma kinase ( ALK ) is a tyrosine receptor involved in both solid and hematological tumors. About 80% of ‐positive anaplastic large‐cell ALCL cases are characterized by the t(2;5)(p23;q35) translocation, encoding for aberrant fusion protein nucleophosmin NPM )‐ , whereas 5% non‐small‐cell lung cancer NSCLC patients carry inv(2)(p21;p23) rearrangement, echinoderm microtubule‐associated protein‐like 4 EML 4)‐ fusion. The /c‐ MET / ROS inhibitor crizotinib successfully...
Abstract The dual ALK/MET inhibitor crizotinib was recently approved for the treatment of metastatic and late-stage ALK+ NSCLC, is currently in clinical trial other ALK-related diseases. As predicted after tyrosine kinase inhibitors' experience, first mutations that confer resistance to have been described patients with non–small cell lung cancer (NSCLC) one patient inflammatory myofibroblastic tumor (IMT). Here, we focused our attention on anaplastic large lymphoma (ALCL), where oncogenic...
Abstract Targeted therapy changed the standard of care in ALK-dependent tumors. However, resistance remains a major challenge. Lorlatinib is third-generation ALK inhibitor that inhibits most mutants resistant to current inhibitors. In this study, we utilize lorlatinib-resistant anaplastic large cell lymphoma (ALCL), non–small lung cancer (NSCLC), and neuroblastoma lines vitro vivo investigate acquisition its underlying mechanisms. ALCL cells acquired compound mutations G1202R/G1269A...
Patients diagnosed with Anaplastic Large Cell Lymphoma (ALCL) are still treated toxic multi-agent chemotherapy and as many 25-50% of patients relapse. To understand disease pathology to uncover novel targets for therapy, Whole-Exome Sequencing (WES) Kinase (ALK)+ ALCL was performed well Gene-Set Enrichment Analysis. This revealed that the T-cell receptor (TCR) Notch pathways were most enriched in mutations. In particular, variant T349P NOTCH1, which confers a growth advantage cells it is...
CD1d-restricted invariant NKT (iNKT) cells are a subset of T lymphocytes endowed with innate effector functions that aid in the establishment adaptive and B cell immune responses. iNKT have been shown to play spontaneous protective role against experimental tumors. Yet, interplay between tumor-specific cancer surveillance/editing has never addressed. The transgenic adenocarcinoma mouse prostate (TRAMP) is realistic model oncogenesis, which cytotoxic (CTL) response undergoes full tolerance...
ALK is a tyrosine kinase receptor involved in broad range of solid and hematologic tumors. Among 70% to 80% ALK(+) anaplastic large cell lymphomas (ALCL) are caused by the aberrant oncogenic fusion protein NPM-ALK. Crizotinib was first clinically relevant inhibitor, now approved for treatment late-stage metastatic cases lung cancer. However, patients frequently develop drug resistance Crizotinib, mainly due appearance point mutations located domain. Fortunately, other inhibitors available...
Colorectal carcinomas (CRC) harbor well-defined genetic abnormalities, including aberrant activation of β-catenin (β-cat) and KRAS, but independent targeting these molecules seems to have limited therapeutic effect. In this study, we report effects combined different oncogenes in CRC. Inducible short hairpin RNA (shRNA)-mediated silencing β-cat, ITF2, or KRAS decreased proliferation by 88%, 72%, 45%, respectively, with no significant apoptosis any case. contrast, blockade β-cat ITF2...
Activation of Wnt signalling due to inability degrade β-catenin is found in >85% colorectal cancers. Approximately half colon cancers express a constitutively active KRAS protein. A significant fraction patients show both abnormalities. We previously reported that simultaneous down-regulation and was necessary induce cell death tumor growth inhibition cancer cells. Although attractive, an RNAi-based therapeutic approach still far from being employed the clinical setting. Therefore, we sought...
The regulatory microRNA miR-150 is involved in the development of hemopathies and downregulated T-lymphomas, such as anaplastic large-cell lymphoma (ALCL) tumors. ALCL defined by presence or absence translocations that activate kinase (ALK), with nucleophosmin-ALK (NPM-ALK) fusions being most common. Here, we compared samples primary NPM-ALK(+) NPM-ALK(–) to investigate role downstream NPM-ALK. Methylation MIR150 gene was substantially elevated biopsies correlated reduced expression. In cell...
ALK is involved in the onset of several tumors. Crizotinib (XalkoriTM), a potent inhibitor, represents current front-line treatment for ALK+ NSCLC and shows great clinical efficacy. However, resistant disease often develops after initial response. ASP3026 novel second-generation inhibitor with activity on crizotinib-resistant ALK-L1196M gatekeeper mutant. As resistance likely to be relevant hurdle any drug, we sought determine profile context NPM/ALK+ ALCL. We selected six ASP3026-resistant...
// Sara Redaelli 1 , Monica Ceccon Laura Antolini 2 Roberta Rigolio Alessandra Pirola Marco Peronaci Carlo Gambacorti-Passerini 1, 3 Luca Mologni University of Milano Bicocca, School Medicine, 20900 Monza, Italy Center Biostatistics for Clinical Epidemiology, San Gerardo Hospital, Hematology-Clinical Research Unit, Correspondence to: Redaelli, email: sara.redaelli@unimib.it Keywords: ALK/ALCL, synergy, TKI, targeted therapy, resistance Received: March 22, 2016 Accepted: September 13,...
Bosutinib is a recently approved ABL inhibitor. In spite of the well-documented effectiveness BCR-ABL inhibitors in treating chronic myeloid leukemia, development resistance continuous clinical challenge. Transporters that facilitate drug uptake and efflux have been proposed as one potential source to tyrosine kinase inhibitor treatment. Our aim was determine which carriers are responsible for bosutinib transport. K562S cells overexpressing transporters ABCB1, ABCG2, SLC22A1 were generated,...
Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell (ALCL) is a subtype of non-Hodgkin characterized by expression the oncogenic NPM/ALK fusion protein. When resistant or relapsed to front-line chemotherapy, ALK+ ALCL prognosis very poor. In these patients, ALK inhibitor crizotinib achieves high response rates, however 30–40% them develop further resistance monotherapy, indicating that new therapeutic approaches are needed in this population. We here investigated efficacy...
The anaplastic lymphoma kinase (ALK) is abnormally expressed and hyperactivated in a number of tumors represents an ideal therapeutic target. Despite excellent clinical responses to ALK inhibition, drug resistance still issue novel compounds that overcome drug-resistant mutants are needed. We designed, synthesized, evaluated large series azacarbazole inhibitors. Several lead endowed with submicromolar potency were identified. Compound 149 showed selective inhibition native mutant...
Ceritinib, also known as LDK-378 or Zykadia (Novartis), is a second generation inhibitor able to specifically target the anaplastic lymphoma kinase (ALK). In last five years interest for ALK small inhibitors grew rapidly, mainly because it was discovered that but significant percentage of non-small cell lung cancer (NSCLC) patients carries oncogenic fusion protein EML4-ALK, in addition about half percent large (ALCL) patients, an aggressive definitely rarer non Hodgkin's T lymphoma, and...
Targeted therapy is an effective, rational, and safe approach to solid hematological tumors treatment. Unfortunately, a significant fraction of patients treated with tyrosine kinase inhibitors (TKI) relapses mainly because gene amplification, mutations, or other bypass mechanisms. Recently growing number papers showed how, in some cases, resistance due oncogene overexpression may be associated drug addiction: cells able proliferate the presence high TKI doses become also dependent,...
Abstract Rearranged or mutated forms of the Anaplastic Lymphoma Kinase (ALK) are involved in pathogenesis various cancers, particular anaplastic large cell lymphoma (ALCL), non-small-cell lung cancer (NSCLC) and neuroblastoma. ALK-positive tumors currently treated with crizotinib (XalkoriTM, Pfizer) ceritinib (ZykadiaTM, Novartis), two oral ALK inhibitors (ALKi). Additional clinical trial. Despite high response rates, drug-resistant disease often develops patients. In order to study...
Abstract ALK is a tyrosine kinase receptor involved in broad range of solid and haematological tumors. It has been shown that about 70-80% ALK+ Anaplastic Large Cell Lymphoma (ALCL) cases, an aggressive Non Hodgkin T-cell lymphoma, are characterized by the traslocation t(2;5), originating functional, aberrant oncogenic fusion protein NPM-ALK. Crizotinib was first clinically relevant inhibitor, now approved for treatment late stage metastatic cases lung cancer. Several patients soon developed...
Abstract Most of Anaplastic Large Cell Lymphoma (ALCL) cases carry the t(2;5; p23;q35) that produces fusion protein nucleophosmin (NPM)-ALK. NPM provides an oligomerization domain causes spontaneous dimerization and ligand-independent activation ALK. NPM-ALK deregulated kinase activity drives several pathways involved in cellular proliferation survival sustains process malignant transformation. is localized both cytoplasm nucleus, but role cytoplasmic or nuclear fractions on ALCL phenotype...