Demetrio Gerace

New orally active proteasome inhibitors in multiple myeloma.

Bortezomib is the first proteasome inhibitor approved for the therapy of multiple myeloma (MM). Although Bortezomib has renovated the treatment of MM, a considerable proportion of subjects fail to respond to Bortezomib treatment and almost all patients relapse from this drug either alone or when used in combination therapies. However, the good clinical outcome of Bortezomib treatment in MM patients gave impulsion for the development of second generation proteasome inhibitors with the ambition of improving efficacy of proteasome inhibition, enhancing antitumor activity, and decreasing toxicity, as well as providing flexible dosing schedules and patient convenience. This review provides an overview of the role of oral proteasome inhibitors including Marizomib, Oprozomib, Delanzomib, chemical proteasome inhibitors, and cinnabaramides, in the therapy of MM, focusing on developments over the past five years. These emerging drugs with different mechanisms of action have exhibited promising antitumor activity in patients with relapsed/refractory MM, and they are creating chances to target multiple pathways, overcome resistance, and improve clinical outcomes, mainly for those subjects who are refractory to approved agents. Future steps in the clinical development of oral inhibitors include the optimization of the schedule and the definition of their antitumor activity in MM.

The cancer stem cell hypothesis: a guide to potential molecular targets.

Common cancer theories hold that tumor is an uncontrolled somatic cell proliferation caused by the progressive addition of random mutations in critical genes that control cell growth. Nevertheless, various contradictions related to the mutation theory have been reported previously. These events may be elucidated by the persistence of residual tumor cells, called Cancer Stem Cells (CSCs) responsible for tumorigenesis, tumor maintenance, tumor spread, and tumor relapse. Herein, we summarize the current understanding of CSCs, with a focus on the possibility to identify specific markers of CSCs, and discuss the clinical application of targeting CSCs for cancer treatment.

Novel therapeutic strategies in multiple myeloma: role of the heat shock protein inhibitors

Despite advances in understanding the molecular pathogenesis of multiple myeloma and promising new therapies, almost all patients eventually relapse with resistant disease. There is therefore a strong rationale for combining novel therapies that target intrinsic molecular pathways mediating multiple myeloma cell resistance. One such protein family is the heat shock proteins (HSP), especially the HSP90 family. Heat shock protein inhibitors have been identified as promising cancer treatments as, while they only inhibit a single biologic function, the chaperone–protein association, their effect is widespread as it results in the destruction of numerous client proteins. This article reviews the preclinical and clinical data, which support the testing of HSP90 inhibitors as cancer drugs and update the reader on the current status of the ongoing clinical trials of HSP90 inhibitors in multiple myeloma.

Anticancer Activity of Curcumin and Its Analogues: Preclinical and Clinical Studies

ABSTRACT Curcumin has been shown to have a wide variety of therapeutic effects, ranging from anti-inflammatory, chemopreventive, anti-proliferative, and anti-metastatic. This review provides an overview of the recent research conducted to overcome the problems with the bioavailability of curcumin, and of the preclinical and clinical studies that have reported success in combinatorial strategies coupling curcumin with other treatments. Research on the signaling pathways that curcumin treatment targets shows that it potently acts on major intracellular components involved in key processes such as genomic modulations, cell invasion and cell death pathways. Curcumin is a promising molecule for the prevention and treatment of cancer.

Increased serum levels of neutrophil gelatinase-associated lipocalin in patients with essential thrombocythemia and polycythemia vera

Neutrophil gelatinaase-associated lipocalin (NGAL) is a glycoprotein bound with matrix metalloproteinase-9 (MMP-9) in human neutrophils, and elevated tissue NGAL expression has been documented in different infectious and inflammatory conditions. Recent evidence suggests that NGAL expression is induced in many types of human cancer. Moreover, NGAL is required for BCR–ABL-induced tumorigenesis. The aim of the present study was to measure serum levels of NGAL in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We also evaluated NGAL levels in patients with ET and PV with and without thrombotic events, to explore a possible correlation of NGAL with platelet and leukocyte activation, and in patients with sepsis. Serum NGAL levels in the study population were significantly higher than in healthy adults and in subjects with sepsis. A correlation between NGAL and the number of white cells and neutrophils was found in patients with PV and ET. NGAL serum levels were not different depending on the presence or not of the JAK2 mutation, and a mutant allele dosage effect was not observed for NGAL levels. Patients with PV and ET with thrombosis did not have significantly higher levels of NGAL. We were unable to demonstrate a significant association between serum NGAL levels and CD11b or CD62 expression. In conclusion, our study reports evidence demonstrating that increased levels of NGAL appear to be a characteristic of patients with PV and ET.

Changes in advanced oxidation protein products, advanced glycation end products, and s-nitrosylated proteins, in patients affected by polycythemia vera and essential thrombocythemia.

OBJECTIVES Oxidative stress has a clear pro tumoral effect in myeloproliferative neoplasms (MPDs). In this study, we analyzed oxidative stress in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Design and methods We analyzed serum levels of advanced oxidation protein products (AOPPs) degradation, advanced glycation end products (AGEs), and protein nitrosylation in ET and PV patients. We also evaluated neutrophil gelatinase-associated lipocalin (NGAL) levels, an acute phase protein isolated in human neutrophils, the activation status of platelets and leukocytes, and the JAK2 (V617F) mutation status. RESULTS AOPPs and s-nitrosylated proteins were significantly higher in PV and ET subjects as compared to healthy volunteers, while AGEs were higher in ET subjects with respect to controls. Moreover, in PV patients we found a correlation between s-nitrosylated proteins and Hb value. In ET patients AGEs were significantly higher in patients with thrombosis compared with those without thrombotic events. CONCLUSIONS Our results suggest that oxidative stress could play a role in the physiopathology of MPDs and in the onset of myeloproliferative associated thrombotic risk.

Decreased Plasma Levels of IL-33 Could Contribute to the Altered Function of Th2 Lymphocytes in Patients with Polycythemia Vera and Essential Thrombocythemia

To the Editor: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPNs) primarily characterized by erythrocytosis and thrombocytosis, respectively (1). In addition, quality of life is adversely affected by a spectrum of disease complications including pruritus. Interleukin-33 (IL-33) is a cytokine from the IL-1 family, which has been linked to important diseases, including asthma, rheumatoid arthritis, ulcerative colitis, metabolic, neurologic, and cardiovascular diseases. IL-33 drives cytokine production in type 2 innate lymphoid cells (ILCs), T-helper (Th)2 lymphocytes, mast cells, basophils, eosinophils, invariant natural killer T (iNKT), and natural killer (NK) cells (2). In a previous work, we found a significant decrease of IL-33 plasma levels in patients affected by multiple myeloma, with a negative correlation between levels of IL-33 and stage (3). In the present study, we analyzed the plasma levels of IL33 in patients with PV and ET. In the same subjects, we also performed analysis of the JAK2V617F mutation, and evaluated a possible relationship between interleukin levels and thrombotic complications or with pruritus. Our population consisted of 65 patients with ET (29 M, 36 F; mean age = 66 ± 9 years) and 41 patients with PV (26 M, 15 F; mean age = 68 ± 12 years). Thirty-three patients (17 ET, 16 PV) had thrombotic symptoms in the past. All patients had not received aspirin or any treatment for ET or PV over the last 7 days. The study was conducted according to the principles of the Declaration of Helsinki. Informed written consent was obtained after potential risks were explained to the subjects. Plasma levels from 63 sexand age-matched normal subjects (35 M, 28 F; mean age = 64 ± 11 years) were also included in this study as controls. None of the patients or control subjects had symptoms or laboratory signs of active infections, inflam-

Adoptive immunotherapy for hematological malignancies: Current status and new insights in chimeric antigen receptor T cells.

Hematological malignancies frequently express cancer-associated antigens that are shared with normal cells. Such tumor cells elude the host immune system because several T cells targeted against self-antigens are removed during thymic development, and those that persist are eliminated by a regulatory population of T cells. Chimeric antigen receptor-modified T cells (CAR-Ts) have emerged as a novel modality for tumor immunotherapy due to their powerful efficacy against tumor cells. These cells are created by transducing genes-coding fusion proteins of tumor antigen-recognition single-chain Fv connected to the intracellular signaling domains of T cell receptors, and are classed as first-, second- and third-generation, differing on the intracellular signaling domain number of T cell receptors. CAR-T treatment has emerged as a promising approach for patients with hematological malignancies, and there are several works reporting clinical trials of the use of CAR-modified T-cells in acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, lymphoma, and in acute myeloid leukemia by targeting different antigens. This review reports the history of adoptive immunotherapy using CAR-Ts, the CAR-T manufacturing process, and T cell therapies in development for hematological malignancies.

MiRNome expression is deregulated in the peripheral lymphoid compartment of multiple myeloma

MicroRNAs (miRNAs) are short non‐coding RNAs involved in the regulation of gene expression. Selected groups of miRNAs are differentially expressed in various types of cancers. Alterations in miRNAs gene expression have been shown in cells from the B‐cell malignancy, multiple myeloma (MM). However, although MM is a disease of plasma cells, abnormalities have been detected in the peripheral blood of the patients.

Stevens–Johnson syndrome after lenalidomide therapy for multiple myeloma: a case report and a review of treatment options

Stevens‐ Johnson syndrome (SJS) is a severe and life‐threatening condition. Although allopurinol, an antihyperuricemia drug, is the drug most commonly associated with SJS, more than 100 different causative drugs have been reported. Among hematologic drugs recently introduced into the market, drugs such as rituximab, imatinib, and bortezomib are reported. Here, we describe a patient with SJS while receiving lenalidomide in combination with prednisolone for treatment‐naïve multiple myeloma. Although SJS has been reported rarely as an adverse reaction to Lenalidomide, this drug should be considered in the etiology of SJS, and the increased number of prescriptions of Lenalidomide for the therapy of multiple myeloma has to stress the awareness of its potentially serious side‐effects. Copyright