Showing papers by "Germana Castelli published in 2023"
TL;DR: A number of drugs targeting CD123 have been developed and evaluated at clinical level: interleukin-3 conjugated with diphtheria toxin; naked neutralizing anti-CD123 antibodies; drug-antibody conjugates; bispecific antibodies targeting both CD123 and CD3; and chimeric antigen receptor (CAR) T cells engineered to target CD123 as discussed by the authors .
Abstract: In spite of consistent progress at the level of basic research and of clinical treatment, acute myeloid leukemia (AML) still represents an unmet clinical need for adult and pediatric patients. To improve the outcomes of these patients, it is necessary to identify new therapeutic targets. IL3RA (CD123, alpha subunit of the interleukin 3 receptor) is a cell membrane protein overexpressed in several hematologic malignancies, including AML blastic plasmocytoid dendritic cell neoplasms (BPDCN). Given the higher expression of CD123 on leukemic cells compared to normal hematopoietic cells and its low/absent expression on normal hematopoietic stem cells, it appears as a suitable and attractive target for therapy. Various drugs targeting CD123 have been developed and evaluated at clinical level: interleukin-3 conjugated with diphtheria toxin; naked neutralizing anti-CD123 antibodies; drug–antibody conjugates; bispecific antibodies targeting both CD123 and CD3; and chimeric antigen receptor (CAR) T cells engineered to target CD123. Some of these agents have shown promising results at the clinical level, including tagraxofusp (CD123 conjugated with diphtheria toxin) for the treatment of BPDCN and IMGN632 (anti-CD123 drug-conjugate), and flotetuzumab (bispecific anti-CD123 and anti-CD3 monoclonal antibody) for the treatment of AML. However, the therapeutic efficacy of CD123-targeting treatments is still unsatisfactory and must be improved through new therapeutic strategies and combined treatments with other antileukemic drugs.
2 citations
TL;DR: In this article , the consistent heterogeneity observed for CCA may result from the convergence of various key elements mainly represented by risk factors, heterogeneity of the associated molecular abnormalities at genetic and epigenetic levels and by different potential cells of origin.
Abstract: Cholangiocarcinomas (CCAs) are a group of heterogeneous epithelial malignancies that can originate at the level of any location of the biliary tree. These tumors are relatively rare but associated with a high rate of mortality. CCAs are morphologically and molecularly heterogeneous and for their location can be distinguished as intracellular and extracellular, subdivided into perihilar and distal. Recent epidemiological, molecular, and cellular studies have supported that the consistent heterogeneity observed for CCAs may result from the convergence of various key elements mainly represented by risk factors, heterogeneity of the associated molecular abnormalities at genetic and epigenetic levels and by different potential cells of origin. These studies have consistently contributed to better defining the pathogenesis of CCAs and to identify in some instances new therapeutic targets. Although the therapeutic progress were still limited, these observations suggest that a better understanding of the molecular mechanisms underlying CCA in the future will help to develop more efficacious treatment strategies.
1 citations
TL;DR: In this paper , the development of molecular analysis techniques has led to the definition of the molecular alterations observed in esophageal cancer, consistently differing from those observed in EAC.
Abstract: Esophageal cancer is among the most common tumors in the world and is associated with poor outcomes, with a 5-year survival rate of about 10–20%. Two main histological subtypes are observed: esophageal squamous cell carcinoma (ESCC), more frequent among Asian populations, and esophageal adenocarcinoma (EAC), the predominant type in Western populations. The development of molecular analysis techniques has led to the definition of the molecular alterations observed in ESCC, consistently differing from those observed in EAC. The genetic alterations observed are complex and heterogeneous and involve gene mutations, gene deletions and gene amplifications. However, despite the consistent progress in the definition of the molecular basis of ESCC, precision oncology for these patients is still virtually absent. The recent identification of molecular subtypes of ESCC with clinical relevance may foster the development of new therapeutic strategies. It is estimated that about 40% of the genetic alterations observed in ESCC are actionable. Furthermore, the recent introduction of solid tumor immunotherapy with immune checkpoint inhibitors (ICIs) showed that a minority of ESCC patients are responsive, and the administration of ICIs, in combination with standard chemotherapy, significantly improves overall survival over chemotherapy in ESCC patients with advanced disease.
TL;DR: In this article , the authors investigated the role played by TP53 mutations in the pathogenesis of these myeloid disorders and in the mechanisms of drug resistance, and proposed new immune and non-immune strategies to improve survival and increase the number of TP53-mutated MDS/AML patients in remission.
Abstract: TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) form a distinct and heterogeneous group of myeloid malignancies associated with poor outcomes. Studies carried out in the last years have in part elucidated the complex role played by TP53 mutations in the pathogenesis of these myeloid disorders and in the mechanisms of drug resistance. A consistent number of studies has shown that some molecular parameters, such as the presence of a single or multiple TP53 mutations, the presence of concomitant TP53 deletions, the association with co-occurring mutations, the clonal size of TP53 mutations, the involvement of a single (monoallelic) or of both TP53 alleles (biallelic) and the cytogenetic architecture of concomitant chromosome abnormalities are major determinants of outcomes of patients. The limited response of these patients to standard treatments, including induction chemotherapy, hypomethylating agents and venetoclax-based therapies and the discovery of an immune dysregulation have induced a shift to new emerging therapies, some of which being associated with promising efficacy. The main aim of these novel immune and nonimmune strategies consists in improving survival and in increasing the number of TP53-mutated MDS/AML patients in remission amenable to allogeneic stem cell transplantation.
TL;DR: In this article , the authors provide an updated analysis of studies of genetic characterization of CCA at the level of gene mutation profiling, copy number alterations and gene expression, with definition of molecular subgroups and identification of some molecular biomarkers and therapeutic targets.
Abstract: ABSTRACT Introduction Cholangiocarcinomas (CCAs) are a heterogenous group of epithelial malignancies originating at any level of the biliary tree and are subdivided according to their location into intrahepatic (iCCA) and extrahepatic (eCCA). Areas covered This review provides an updated analysis of studies of genetic characterization of CCA at the level of gene mutation profiling, copy number alterations and gene expression, with definition of molecular subgroups and identification of some molecular biomarkers and therapeutic targets. Expert opinion With the development of genetic sequencing, several driver mutations have been identified and targeted as novel therapeutic approaches, including FGFR2, IDH1, BRAF, NTRK, HER2, ROS, and RET. Furthermore, identification of the cellular and molecular structure of the tumor microenvironment has contributed to the development of novel therapies, such as tumor immunotherapy. Combination therapies of chemotherapy plus targeted molecules or immunotherapy are under evaluation and offer the unique opportunity to improve the outcomes of CCA patients with advanced disease.
TL;DR: In this paper , the authors proposed an additional stratification aiming to improve the therapeutic response of the different subgroups of mutated nucleophosmin 1 (NPM1-mut) patients.
Abstract: The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. AML with mutated nucleophosmin 1 (NPM1-mut) is the largest of the genetically defined groups, involving about 30% of adult AMLs and is currently recognized as a distinct entity in the actual AML classifications. NPM1-mut AML usually occurs in de novo AML and is associated predominantly with a normal karyotype and relatively favorable prognosis. However, NPM1-mut AMLs are genetically, transcriptionally, and phenotypically heterogeneous. Furthermore, NPM1-mut is a clinically heterogenous group. Recent studies have in part clarified the consistent heterogeneities of these AMLs and have strongly supported the need for an additional stratification aiming to improve the therapeutic response of the different subgroups of NPM1-mut AML patients.