Vanessa Innao

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.

Monoclonal antibodies: potential new therapeutic treatment against multiple myeloma

Despite recent treatments, such as bortezomib, thalidomide, and lenalidomide, therapy of multiple myeloma (MM) is limited, and MM remains an incurable disease associated with high mortality. The outcome of patients treated with cytotoxic therapy has not been satisfactory. Therefore, new therapies are needed for relapsed MM. A new anticancer strategy is the use of monoclonal antibodies (MoAbs) that represent the best available combination of tumor cytotoxicity, environmental signal privation, and immune system redirection. Clinical results in patients with relapsed/refractory MM suggest that MoAbs are likely to operate synergistically with traditional therapies (dexamethasone), immune modulators (thalidomide, lenalidomide), and other novel therapies (bortezomib); in addition, MoAbs have shown the ability to overcome resistance to these therapies. It remains to be defined how MoAb therapy can most fruitfully be incorporated into the current therapeutic paradigms that have achieved significant survival earnings in patients with MM. This will require careful consideration of the optimal sequence of treatments and their clinical position as either short‐term induction therapy, frontline therapy in patients ineligible for ASCT, or long‐term maintenance treatment.

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.

Reduced IL-33 plasma levels in multiple myeloma patients are associated with more advanced stage of disease.

Multiple myeloma (MM) is a clonal neoplasm of the bone marrow-resident long lived plasma cells. Like normal plasma cells, MM cells depend on their interactions with bone marrow stromal cells for the survival and production of essential cytokines (Minges Wols et al, 2002). Interleukin-33 (IL-33) is an IL-1 family member that is constitutively expressed by endothelial and epithelial cells (Joshi et al, 2010) and which appears to drive T helper cell type 2 (Th2) responses in several organs (Cevikbas & Steinhoff, 2012). This study analysed the plasma levels of IL33 in 44 MM patients (19 males, 25 females; mean age 66 9 years) and in 13 patients with monoclonal gammopathy of undetermined significance (MGUS; five males, eight females; mean age 63 12 years). No patients had received any treatment for MM during the previous seven days. The study was conducted according to the principles of the Declaration of Helsinki. Informed written consent was obtained. Plasma from 63 sex-matched and age matched normal subjects (35 males, 28 females; mean age 64 11 years) were also included as controls. None of the patients or control subjects had symptoms or laboratory signs of active infections, inflammatory diseases, diabetes, obesity, neurological diseases or severe uraemia. According to the Durie–Salmon staging system, 13 patients were MM disease stage I, 13 patients were stage II, and 18 patients were disease stage III. The paraprotein class was immunoglobulin G (IgG) in 24 patients and IgA in 18 patients; two patient had non-secretory disease. 26 subjects had lytic bone disease and/or pathological fractures. Thirty patients presented an Eastern Cooperative Oncology Group (ECOG) performance status <2 while 14 patients had an ECOG >2. Median plasmocytosis of bone marrow was 47% (range 35–90%). Of the 13 MGUS subjects, the paraprotein class was IgG in 9 and IgA in 4. IL-33 protein levels were measured using the commercially available DuoSet enzyme-linked immunosorbent assay Development System kits (R&D Systems; Minneapolis, MN, USA). The detection limit was 4 0 pg/ml. Data are presented as interquartile range (IQR) and range, except age, which is presented as mean standard deviation. Differences between data series were analysed by the Mann– Whitney test; differences between categorical groups were analysed by the Pearson chi square (v) test. Correlation between two variables was evaluated with Spearman’s rho. Statistical significance was set at P < 0 05. Twenty three of 44 (52 27%) MM patients, eight of 13 (53 33%) MGUS patients and 36 of 63 (57 14%) controls showed detectable levels of IL-33; there was no statistical significant difference in detectability between the three groups (v = 0 365, P = 0 833). IL-33 levels were statistically significantly different between the MM patients (297 8 and 1491 5 pg/ml) and MGUS patients (312 775 and 1579 9 pg/ml) and those measured in controls (1375 3 and 2035 4 pg/ml) (P = 0 001 and (P = 0 03, respectively) (Fig 1). The IL-33 levels in MM patients with kidney failure (creatinine level >88 4 lmol/l) were not statistically significantly different to MM patients who did not have kidney failure (creatinine level 88 4 lmol/l) (1151,75 and 1488 1 vs. 254 175 and 1002 8 pg/ml, P = 0 322). There was no statistically significant difference in IL-33 levels between MM patients with bone lesions and those without (205 1 and 1002 8 vs. 936 55 and 1483 2 pg/ml, P = 0 096). MM patients showed a negative correlation between IL-33 level and stage (P = 0 006, correlation coefficient = 0 692), but not between IL-33 level and Hb concentration (P = 0 301, correlation coefficient = 0 298), b2 microglobulin level (P = 0 817, correlation coefficient = 0 068), and monoclonal component (P = 0 091, correlation coefficient = 0 468). The development of MM involves a series of changes in the bone marrow microenvironment, favouring the growth of the tumour and failure of local immune control. Quantitative and functional alterations in CD4 and CD8 T cells have been described in MM, and cellular immune defects in MM have been shown to negatively correlate with survival (Pratt et al, 2007). A significant impairment of T-cell function has been also described for patients with MGUS (Prabhala et al, 2006). Cytokines and their receptors play essential roles in the development, maintenance and proper functioning of the immune system. In MM, these interactions may have tumour-promoting consequences (J€ ohrer et al, 2012). IL-33 is a recent addition to the ever-growing family of cytokines. To the best of our knowledge, this is the first study to demonstrate decreased concentrations of IL-33 in patients with MM, which might contribute to the changes in the immune system found in these patients. On the other

Inflammatory and Anti-Inflammatory Equilibrium, Proliferative and Antiproliferative Balance: The Role of Cytokines in Multiple Myeloma

Multiple myeloma (MM) is typically exemplified by a desynchronized cytokine system with increased levels of inflammatory cytokines. We focused on the contrast between inflammatory and anti-inflammatory systems by assessing the role of cytokines and their influence on MM. The aim of this review is to summarize the available information to date concerning this equilibrium to provide an overview of the research exploring the roles of serum cytokines in MM. However, the association between MM and inflammatory cytokines appears to be inadequate, and other functions, such as pro-proliferative or antiproliferative effects, can assume the role of cytokines in the genesis and progression of MM. It is possible that inflammation, when guided by cancer-specific Th1 cells, may inhibit tumour onset and progression. In a Th1 microenvironment, proinflammatory cytokines (e.g., IL-6 and IL-1) may contribute to tumour eradication by attracting leucocytes from the circulation and by increasing CD4 + T cell activity. Hence, caution should be used when considering therapies that target factors with pro- or anti-inflammatory activity. Drugs that may reduce the tumour-suppressive Th1-driven inflammatory immune response should be avoided. A better understanding of the relationship between inflammation and myeloma will ensure more effective therapeutic interventions.

Corneal Structural Changes in Nonneoplastic and Neoplastic Monoclonal Gammopathies

PURPOSE To investigate corneal confocal microscopic changes in nonneoplastic and neoplastic monoclonal gammopathies. METHODS Three groups of subjects were considered: group 1, twenty normal subjects; group 2, fifteen patients with monoclonal gammopathy of undetermined significance (MGUS); group 3, eight patients with smoldering multiple myeloma and eight patients with untreated multiple myeloma. After hematologic diagnosis, patients underwent ophthalmologic exam and in vivo confocal microscopic study. The statistical analysis was performed using ANOVA and Student-Newman-Keuls tests and receiver operating characteristic (ROC) curve analysis. RESULTS Epithelial cells of gammopathic patients showed significantly higher reflectivity than controls, demonstrated by optical density (P < 0.001). Subbasal nerve density, branching, and beading were significantly altered in gammopathic patients (P = 0.01, P = 0.02, P = 0.02, respectively). The number of keratocytes was significantly reduced in neoplastic patients (P < 0.001 versus both normal and MGUS) in the anterior, medium, and posterior stroma. The ROC curve analysis showed good sensitivity and specificity for this parameter. Group 2 and 3 keratocytes showed higher nuclear and cytoplasmatic reflectivity in the medium and posterior stroma. Endothelial cells were not affected. CONCLUSIONS Patients with neoplastic gammopathies showed peculiar alterations of the keratocyte number, which appeared significantly reduced. A follow-up with corneal confocal microscopy of patients with MGUS is suggested as a useful tool to identify peripheral tissue alterations linked to possible neoplastic disease development.

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.

Immunoproteasome-selective and non-selective inhibitors: A promising approach for the treatment of multiple myeloma

Abstract The ubiquitin‐proteasome system (UPS) is the major non‐lysosomal proteolytic system for the degradation of abnormal or damaged proteins no longer required. The proteasome is involved in degradation of numerous proteins which regulate the cell cycle, indicating a role in controlling cell proliferation and maintaining cell survival. Defects in the UPS can lead to anarchic cell proliferation and to tumor development. For these reasons UPS inhibition has become a significant new strategy for drug development in cancer treatment. In addition to the constitutive proteasome, which is expressed in all cells and tissues, higher organisms such as vertebrates possess two immune‐type proteasomes, the thymoproteasome and the immunoproteasome. The thymoproteasome is specifically expressed by thymic cortical epithelial cells and has a role in positive selection of CD8 + T cells, whereas the immunoproteasome is predominantly expressed in monocytes and lymphocytes and is responsible for the generation of antigenic peptides for cell‐mediated immunity. Recent studies demonstrated that the immunoproteasome has a preservative role during oxidative stress and is up‐regulated in a number of pathological disorders including cancer, inflammatory and autoimmune diseases. As a consequence, immunoproteasome‐selective inhibitors are currently the focus of anticancer drug design. At present, the commercially available proteasome inhibitors bortezomib and carfilzomib which have been validated in multiple myeloma and other model systems, appear to target both the constitutive and immunoproteasomes, indiscriminately. This lack of specificity may, in part, explain some of the side effects of these agents, such as peripheral neuropathy and gastrointestinal effects, which may be due to targeting of the constitutive proteasome in these tissues. In contrast, by selectively inhibiting the immunoproteasome, it may be possible to maintain the antimyeloma and antilymphoma efficacy while reducing these toxicities, thereby increasing the therapeutic index. This review article will be focused on the discussion of the most promising immunoproteasome specific inhibitors which have been developed in recent years. Particular attention will be devoted to the description of their mechanism of action, their structure‐activity relationship, and their potential application in therapy.

Vaccination strategies in lymphoproliferative disorders: Failures and successes

Anti-tumor vaccines in lymphoproliferative disorders hold out the prospect of effective tumor therapies with minimal side effects. The addition of immunotherapy to old and new chemotherapy regimens has improved both response rates and disease-free survival, leading in many cases to an extended overall survival. Ideally, an antigen that is used for vaccination would be specifically expressed in the tumor; it must have an important, causal part in the multifactorial process that leads to cancer, and it must be expressed stably even after it is attacked by the immune system. Immunotherapies, which aim to activate the immune system to kill cancer cells, include strategies to increase the frequency or potency of antitumor T cells, to overcome suppressive factors in the tumor microenvironment, and to reduce T-cell suppression systemically. In this review, we focus on the results of clinical trials of vaccination in lymphoma, and discuss potential strategies to enhance the efficacy of immunotherapy in the future.