Metabolic starvation triggered by l-asparaginase sensitizes multiple myeloma cells to proteasome inhibitors by inducing DNA damage accumulation

Multiple Myeloma (MM) is a malignant proliferation of clonal bone marrow (BM) plasma cells (PCs) in association with monoclonal protein. Despite the dramatic improvements in MM treatment achieved in the last decade, it is still an incurable disease. A better knowledge of the biological mechanisms involved in disease occurrence and progression has led to the development of several new, innovative, drugs that significantly improved patients outcome and renewed the therapeutic approach to the disease in the last years. However, resistance develops with a 40% survival at five-years. Moreover, despite the improvement of patient riskstratification systems at diagnosis, treatment outcome is often unpredictable due to the high degree of genomic heterogeneity and genomic instability which characterize the disease. In this view, novel therapeutic strategies capable to overcome disease heterogeneity and improve patient outcome are strongly needed. A fundamental feature of all cancers is the metabolic reprogramming to promote growth, survival, proliferation, and long-term maintenance. The common feature of this altered metabolism is increased glucose uptake and fermentation of glucose to lactate, the so called \u201cWarburg Effect\u201d. Moreover, the non essential amino acid Glutamine complements glucose to meet cancer cells metabolic demands. In particular, some human tumors exhibit a high requirement for Gln for anabolic and metabolic processes, a condition that has been defined \u201cGln-addiction\u201d leading to the investigation of such Gln-dependence as therapeutic target in human cancers. Beside its role of carbon and nitrogen source for macromolecules synthesis, the metabolism of this non-essential amino acid support tumor growth by inducing essential amino acids uptake and activation of mTORC1 signaling pathways, which acts as regulator for protein translation and autophagy. Moreover, Gln maintains mitochondrial membrane potential and prevents oxidative damage driving Glutathione (GSH) and NADPH synthesis. In the recent years the importance of Gln metabolism as therapeutic target began to be explored and emerging data suggest that inhibition of glutamine metabolism with small molecules results in an energetic crisis leading to cellular death. Emerging data suggest efficacy of Gln-deprivation also in MM cells which are unable to synthesize adequate amounts of Gln and, therefore, result highly sensitive to Glntransporters blockade or glutaminase inhibition. Several approaches are reported to achieve Glu-depletion including: uptake inhibition (Gln-transporters inhibitors), metabolism targeting (Glutaminase inhibitors) or serum depletion exploiting the glutaminase-activity of L-asparaginase drug (L-ASP). L-ASP is a bacterial-derived enzyme that induces serum aminoacidic deprivation by catalyzing the hydrolysis of asparagine in aspartic acid and ammonium and glutamine in glutamic acid and ammonium. Among the above mentioned strategies to obtain Gln-deprivation, L-ASP is already available in clinic as it represents a cornerstone for acute lymphoblastic leukemia (ALL) and some aggressive lymphomas treatment. Based on these observations, we aim to explore the therapeutic relevance of Asparaginase-induced Gln depletion alone and in combination with currently usedanti-MM drugs. Moreover we will analyze biological mechanisms supporting the effectiveness of the identified therapeutic strategies

Harnessing NK Cells for Cancer Treatment

In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. NK cells are innate lymphocytes with an array of functional competences, including anti-cancer, anti-viral, and anti-graft-vs.-host disease potential. The intriguing idea of harnessing such potent innate immune system effectors for cancer treatment led to the development of clinical trials based on the adoptive therapy of NK cells or on the use of monoclonal antibodies targeting the main NK cell immune checkpoints. Indeed, checkpoint immunotherapy that targets inhibitory receptors of T cells, reversing their functional blocking, marked a breakthrough in anticancer therapy, opening new approaches for cancer immunotherapy and resulted in extensive research on immune checkpoints. However, the clinical efficacy of T cell-based immunotherapy presents a series of limitations, including the inability of T cells to recognize and kill HLA-Ineg tumor cells. For these reasons, new strategies for cancer immunotherapy are now focusing on NK cells. Blockade with NK cell checkpoint inhibitors that reverse their functional block may overcome the limitations of T cell-based immunotherapy, mainly against HLA-Ineg tumor targets. Here, we discuss recent anti-tumor approaches based on mAb-mediated blocking of immune checkpoints (either restricted to NK cells or shared with T cells), used either as a single agent or in combination with other compounds, that have demonstrated promising clinical responses in both solid tumors and hematological malignancie

High feasibility and antileukemic efficacy of fludarabine, cytarabine, and idarubicin (FLAI) induction followed by risk-oriented consolidation: A critical review of a 10-year, single-center experience in younger, non M3 AML patients

About 105 consecutive acute myeloid leukemia (AML) patients treated with the same induction-consolidation program between 2004 and 2013 were retrospectively analyzed. Median age was 47 years. The first induction course included fludarabine (Flu) and high-dose cytarabine (Ara-C) plus idarubicin (Ida), with or without gemtuzumab-ozogamicin (GO) 3 mg/m2 (FLAI-5). Patients achieving complete remission (CR) received a second course without fludarabine but with higher dose of idarubicin. Patients not achieving CR received an intensified second course. Patients not scheduled for early allogeneic bone marrow transplantation (HSCT) where planned to receive at least two courses of consolidation therapy with Ara-C. Our double induction strategy significantly differs from described fludarabine-containing regimens, as patients achieving CR receive a second course without fludarabine, to avoid excess toxicity, and Ara-C consolidation is administrated at the reduced cumulative dose of 8 g/m2 per cycle. Toxicity is a major concern in fludarabine containing induction, including the recent Medical Research Council AML15 fludarabine, cytarabine, idaraubicin and G-CSF (FLAG-Ida) arm, and, despite higher anti-leukemic efficacy, only a minority of patients is able to complete the full planned program. In this article, we show that our therapeutic program is generally well tolerated, as most patients were able to receive subsequent therapy at full dose and in a timely manner, with a 30-day mortality of 4.8%. The omission of fludarabine in the second course did not reduce efficacy, as a CR rate of 83% was achieved and 3-year disease-free survival and overall survival (OS) were 49.6% and 50.9%, respectively. Our experience shows that FLAI-5/Ara-C + Ida double induction followed by risk-oriented consolidation therapy can result in good overall outcome with acceptable toxicity. Am. J. Hematol. 91:755\u2013762, 2016. \ua9 2016 Wiley Periodicals, Inc

The new small tyrosine-kinase inhibitor ARQ531 targets acute myeloid leukemia cells by disrupting multiple tumor-addicted programs

Tyrosine kinases have been implicated in promoting tumorigenesis of several human cancers. Exploiting these vulnerabilities has been shown to be an effective anti-tumor strategy as demonstrated for example by the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, for treatment of various blood cancers. Here, we characterize a new multiple kinase inhibitor, ARQ531, and evaluate its mechanism of action in preclinical models of acute myeloid leukemia. Treatment with ARQ531, by producing global signaling pathway deregulation, resulted in impaired cell cycle progression and survival in a large panel of leukemia cell lines and patient-derived tumor cells, regardless of the specific genetic background and/or the presence of bone marrow stromal cells. RNA-seq analysis revealed that ARQ531 constrained tumor cell proliferation and survival through Bruton's tyrosine kinase and transcriptional program dysregulation, with proteasome-mediated MYB degradation and depletion of short-lived proteins that are crucial for tumor growth and survival, including ERK, MYC and MCL1. Finally, ARQ531 treatment was effective in a patient-derived leukemia mouse model with significant impairment of tumor progression and survival, at tolerated doses. These data justify the clinical development of ARQ531 as a promising targeted agent for the treatment of patients with acute myeloid leukemia

Post-Transplant Nivolumab Plus Unselected Autologous Lymphocytes in Refractory Hodgkin Lymphoma: A Feasible and Promising Salvage Therapy Associated With Expansion and Maturation of NK Cells

Immune checkpoint inhibitors (CI) have demonstrated clinical activity in Hodgkin Lymphoma (HL) patients relapsing after autologous stem cell transplantation (ASCT), although only 20% complete response (CR) rate was observed. The efficacy of CI is strictly related to the host immune competence, which is impaired in heavily pre-treated HL patients. Here, we aimed to enhance the activity of early post-ASCT CI (nivolumab) administration with the infusion of autologous lymphocytes (ALI). Twelve patients with relapse/refractory (R/R) HL (median age 28.5 years; range 18-65), underwent lymphocyte apheresis after first line chemotherapy and then proceeded to salvage therapy. Subsequently, 9 patients with progressive disease at ASCT received early post-transplant CI supported with four ALI, whereas 3 responding patients received ALI alone, as a control cohort. No severe adverse events were recorded. HL-treated patients achieved negative PET scan CR and 8 are alive and disease-free after a median follow-up of 28 months. Four patients underwent subsequent allogeneic SCT. Phenotypic analysis of circulating cells showed a faster expansion of highly differentiated NK cells in ALI plus nivolumab-treated patients as compared to control patients. Our data show anti-tumor activity with good tolerability of ALI + CI for R/R HL and suggest that this setting may accelerate NK cell development/maturation and favor the expansion of the "adaptive" NK cell compartment in patients with HCMV seropositivity, in the absence of HCMV reactivation

Multicenter Observational Retrospective Study on Febrile Events in Patients with Acute Myeloid Leukemia Treated with Cpx-351 in "Real-Life": The SEIFEM Experience

: In the present study, we aimed to evaluate the absolute risk of infection in the real-life setting of AML patients treated with CPX-351. The study included all patients with AML from 30 Italian hematology centers of the SEIFEM group who received CPX-351 from July 2018 to June 2021. There were 200 patients included. Overall, 336 CPX-351 courses were counted: all 200 patients received the first induction cycle, 18 patients (5%) received a second CPX-351 induction, while 86 patients (26%) proceeded with the first CPX-351 consolidation cycle, and 32 patients (10%) received a second CPX-351 consolidation. A total of 249 febrile events were recorded: 193 during the first or second induction, and 56 after the first or second consolidation. After the diagnostic work-up, 92 events (37%) were classified as febrile neutropenia of unknown origin (FUO), 118 (47%) were classifiable as microbiologically documented infections, and 39 (17%) were classifiable as clinically documented infections. The overall 30-day mortality rate was 14% (28/200). The attributable mortality-infection rate was 6% (15/249). A lack of response to the CPX-351 treatment was the only factor significantly associated with mortality in the multivariate analysis [p-value: 0.004, OR 0.05, 95% CI 0.01-0.39]. Our study confirms the good safety profile of CPX-351 in a real-life setting, with an incidence of infectious complications comparable to that of the pivotal studies; despite prolonged neutropenia, the incidence of fungal infections was low, as was infection-related mortality

Intesive fludarabine-high dose cytarabine-idarubicin combination as induction therapy with risk-adapted consolidation may improve treatment efficacy in younger Acute Myeloid Leukemia (AML) patients: Rationales, evidences and future perspectives

Acute Myeloid Leukemia (AML) is the commonest form of leukemia in the adults, with an incidence of 3-4 cases per 100,000 people/year. After the first description of the effective cytarabine + antracycline (3+7) induction regimen, in the last 3 decades, no effective targeted drug has been included in the standard treatment of AML. Many efforts of modifying 3+7 adding a third drug or increasing the dose of anthracycline, cytarabine or both did not lead to substantial improvements, mainly due to increased toxicity. Many in vitro and in vivo evidences suggested that fludarabine may increase efficacy of cytarabine through a synergistic effect. Considering the continuous improvements in supportive care and management of infectious complications the feasibility of more intensive induction strategies have increased and a renewed interest in fludarabine-containing induction strategies arose. The recent MRC AML 15 trial has shown that a fludarabine-containing induction, FLAG-Ida, resulted superior to conventional 3+7 in terms of complete remission rates, relapse incidence and survival, although only a minority of patients could complete the whole planned consolidation program due to an excessive hematological toxicity. Our group recently published a 10-year experience with a fludarabine-containing induction that slightly differed from the MRC one and resulted in good efficacy and higher feasibility. In this commentary we review the major evidences supporting the employ of a fludarabine-containing induction in AML, and discuss the future perspectives

Genetics and Inflammation in Endometriosis: Improving Knowledge for Development of New Pharmacological Strategies

According to a rich body of literature, immune cell dysfunctions, both locally and systemically, and an inflammatory environment characterize all forms of endometriosis. Alterations in transcripts and proteins involved in the recruitment of immune cells, in the interaction between cytokines and their receptors, cellular adhesion and apoptosis have been demonstrated in endometriotic lesions. The objective of this narrative review is to provide an overview of the components and mechanisms at the intersection between inflammation and genetics that may constitute vanguard therapeutic approaches in endometriosis. The GWAS technology and pathway-based analysis highlighted the role of the MAPK and the WNT/β-catenin cascades in the pathogenesis of endometriosis. These signaling pathways have been suggested to interfere with the disease establishment via several mechanisms, including apoptosis, migration and angiogenesis. Extracellular vesicle-associated molecules may be not only interesting to explain some aspects of endometriosis progression, but they may also serve as therapeutic regimens per se. Immune/inflammatory dysfunctions have always represented attractive therapeutic targets in endometriosis. These would be even more interesting if genetic evidence supported the involvement of functional pathways at the basis of these alterations. Targeting these dysfunctions through next-generation inhibitors can constitute a therapeutic alternative for endometriosis