RESUMO
The transformation of acute promyelocytic leukemia (APL) from the most fatal to the most curable subtype of acute myeloid leukemia (AML), with long-term survival exceeding 90%, has represented one of the most exciting successes in hematology and in oncology. APL is a paradigm for oncoprotein-targeted cure.APL is caused by a 15/17 chromosomal translocation which generates the PML-RARA fusion protein and can be cured by the chemotherapy-free approach based on the combination of two therapies targeting PML-RARA: retinoic acid (RA) and arsenic. PML-RARA is the key driver of APL and acts by deregulating transcriptional control, particularly RAR targets involved in self-renewal or myeloid differentiation, also disrupting PML nuclear bodies. PML-RARA mainly acts as a modulator of the expression of specific target genes: genes whose regulatory elements recruit PML-RARA are not uniformly repressed but also may be upregulated or remain unchanged. RA and arsenic trioxide directly target PML-RARA-mediated transcriptional deregulation and protein stability, removing the differentiation block at promyelocytic stage and inducing clinical remission of APL patients.
Assuntos
Leucemia Promielocítica Aguda , Proteínas de Fusão Oncogênica , Tretinoína , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Tretinoína/uso terapêutico , Tretinoína/farmacologia , Trióxido de Arsênio/uso terapêutico , Trióxido de Arsênio/farmacologia , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Arsenicais/uso terapêutico , Arsenicais/farmacologia , Óxidos/uso terapêutico , Óxidos/farmacologia , AnimaisRESUMO
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.
Assuntos
Antineoplásicos , Imunoconjugados , Leucemia Mieloide Aguda , Adulto , Criança , Humanos , Antineoplásicos/uso terapêutico , Terapia Combinada , Células Dendríticas/metabolismo , Toxina Diftérica/uso terapêutico , Imunoconjugados/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismoRESUMO
Citrus fruits are a natural source of ascorbic acid, and exosome-like nanovesicles obtained from these fruits contain measurable levels of ascorbic acid. We tested the ability of grapefruit-derived extracellular vesicles (EVs) to inhibit the growth of human leukemic cells and leukemic patient-derived bone marrow blasts. Transmission electron microscopy and nanoparticle tracking analysis (NTA) showed that the obtained EVs were homogeneous exosomes, defined as exosome-like plant-derived nanovesicles (ELPDNVs). The analysis of their content has shown measurable amounts of several molecules with potent antioxidant activity. ELPDNVs showed a time-dependent antiproliferative effect in both U937 and K562 leukemic cell lines, comparable with the effect of high-dosage ascorbic acid (2 mM). This result was confirmed by a clear decrease in the number of AML blasts induced by ELPDNVs, which did not affect the number of normal cells. ELPDNVs increased the ROS levels in both AML blast cells and U937 without affecting ROS storage in normal cells, and this effect was comparable to ascorbic acid (2 mM). With our study, we propose ELPDNVs from grapefruits as a combination/supporting therapy for human leukemias with the aim to improve the effectiveness of the current therapies.
Assuntos
Citrus paradisi , Exossomos , Leucemia Mieloide Aguda , Humanos , Exossomos/metabolismo , Ácido Ascórbico/farmacologia , Ácido Ascórbico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Agricultura Orgânica , Leucemia Mieloide Aguda/metabolismoRESUMO
Tumor vascularization refers to the formation of new blood vessels within a tumor and is considered one of the hallmarks of cancer. Tumor vessels supply the tumor with oxygen and nutrients, required to sustain tumor growth and progression, and provide a gateway for tumor metastasis through the blood or lymphatic vasculature. Blood vessels display an angiocrine capacity of supporting the survival and proliferation of tumor cells through the production of growth factors and cytokines. Although tumor vasculature plays an essential role in sustaining tumor growth, it represents at the same time an essential way to deliver drugs and immune cells to the tumor. However, tumor vasculature exhibits many morphological and functional abnormalities, thus resulting in the formation of hypoxic areas within tumors, believed to represent a mechanism to maintain tumor cells in an invasive state.Tumors are vascularized through a variety of modalities, mainly represented by angiogenesis, where VEGF and other members of the VEGF family play a key role. This has represented the basis for the development of anti-VEGF blocking agents and their use in cancer therapy: however, these agents failed to induce significant therapeutic effects.Much less is known about the cellular origin of vessel network in tumors. Various cell types may contribute to tumor vasculature in different tumors or in the same tumor, such as mature endothelial cells, endothelial progenitor cells (EPCs), or the same tumor cells through a process of transdifferentiation. Early studies have suggested a role for bone marrow-derived EPCs; these cells do not are true EPCs but myeloid progenitors differentiating into monocytic cells, exerting a proangiogenic effect through a paracrine mechanism. More recent studies have shown the existence of tissue-resident endothelial vascular progenitors (EVPs) present at the level of vessel endothelium and their possible involvement as cells of origin of tumor vasculature.
Assuntos
Células Endoteliais/patologia , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Neovascularização Patológica , Microambiente Tumoral , Humanos , Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
CD147 is a transmembrane glycoprotein with multiple functions in human healthy tissues and diseases, in particular in cancer. Overexpression of CD147 correlates with biological functions that promote tumor progression and confers resistance to chemotherapeutic drugs. In contrast to solid tumors, the role of CD147 has not been extensively studied in leukemia. Understanding whether CD147 represents a new hematologic target and whether its inhibitor AC-73 may be used in leukemia therapy may reveal an alternative treatment strategy in patients with acute myeloid leukemia (AML). We analyzed CD147 expression and function in hematopoietic progenitor cells from normal cord blood, in several leukemic cell lines and in primary leukemic blasts obtained from patients with AML. We investigated the effects of AC-73, used alone or in combination with arabinosylcytosine (Ara-C) and arsenic trioxide (ATO), on leukemic cell proliferation. We demonstrated that CD147 overexpression promotes leukemic cell proliferation. We showed that AC-73 exhibits a potent growth inhibitory activity in leukemic cells, by inhibiting the ERK/STAT3 activation pathway and activating autophagy. We demonstrated that AC-73 exerts an anti-proliferative effect additive to chemotherapy by enhancing leukemic cell sensitivity to Ara-C-induced cytotoxicity or to ATO-induced autophagy. We also reported CD147 expression in the fraction of leukemic blasts expressing CD371, a marker of leukemic stem cells. Altogether, our study indicates CD147 as a novel potential target in the treatment of AML and AC-73 as an anti-proliferative drug and an inducer of autophagy in leukemic cells to use in combination with chemotherapeutic agents.
Assuntos
Antineoplásicos/farmacologia , Autofagia , Basigina/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glicoproteínas/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Fenóis/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Trióxido de Arsênio/farmacologia , Citarabina/farmacologia , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Prognóstico , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
Vitamin C (Vit C or Ascorbate) is essential for many fundamental biochemical processes. Vit C is an essential nutrient with redox functions at normal physiologic concentrations. The main physiologic function of this vitamin is related to its capacity to act as a co-factor for a large family of enzymes, collectively known as Fe and 2-oxoglutarate-dependent dioxygenases. It also modulates epigenetic gene expression through the control of TET enzymes activity. Vit C also has several biological properties allowing to restore the deregulated epigenetic response observed in many tumors. High-dose Vit C has been investigated as a treatment for cancer patients since the 1969. Pharmacologic ascorbate acts as a pro-drug for hydrogen peroxide formation (H2O2) and, through this mechanism, kills cancer cells. To achieve high in vivo concentrations, Ascorbate must be injected by i.v. route. Initial clinical studies of Ascorbate cancer treatment have provided encouraging results, not confirmed in subsequent studies. Recent clinical studies using i.v. injection of high-dose Ascorbate have renewed the interest in the field, showing that significant anti-tumor activity. Pre-clinical studies have led to identify tumors sensitive to Ascorbate that could potentially benefit from this treatment either through an epigenetic modulator effect or through tumor killing by oxidative stress.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ácido Ascórbico/química , Proliferação de Células/efeitos dos fármacos , Metilação de DNA , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Neoplasias/metabolismoRESUMO
Circulating endothelial progenitor cells (EPCs) have been suggested as a precious source for generating functionally competent endothelial cells (ECs), candidate for various clinical applications. However, the paucity of these progenitor cells and the technical difficulties for their in vitro growth represent a main limitation to their use. In the present study we hypothesized that the paracrine effects of human umbilical vein endothelial cells (HUVECs) may improve endothelial cell generation from cord blood (CB) EPCs. In line with this hypothesis we showed that HUVEC conditioned medium (CM) or co-culture with HUVECs markedly improved the proliferation and differentiation and delayed the senescence of CB EPCs. The endothelial-promoting effect of CM seems to be related to smaller vesicles including exosomes (sEV/exo) contained in this medium and transferred to CB CD34(+) EPCs: in fact, purified preparations of sEV/exo isolated from CM mimicked the effect of CM to sustain endothelial formation. These observations provided the interesting indication that mature ECs exert a stimulatory effect on endothelial cell differentiation from CD34(+) cells.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Antígenos CD34 , Células Cultivadas , Células Endoteliais/citologia , Exossomos , Sangue Fetal/citologia , Humanos , Comunicação ParácrinaRESUMO
Studies of xenotransplantation of bone marrow and blood cells of AML patients have supported the existence of rare leukemic stem cells, able to initiate and maintain the leukemic process and bearing the typical leukemic abnormalities. LSCs possess self-renewal capacity and are responsible for the growth of the more differentiated leukemic progeny in the bone marrow and in the blood. These cells are more resistant than bulk leukemic cells to anti-leukemic drugs, thus survive to treatment and are, at a large extent, responsible for leukemia relapse. During the last two decades, considerable progresses have been made in the understanding of the peculiar cellular and molecular properties of LSCs. In this context, particularly relevant was the discovery of several membrane markers, selectively or preferentially expressed on LSCs. These membrane markers offer now unique opportunities to identify LSCs and to distinguish them from normal HSCs, to monitor the response of the various anti-leukemic treatments at the level of the LSC compartment, to identify relevant therapeutic targets. Concerning this last point, the most promising therapeutic targets are CD33 and CD123.
Assuntos
Antígenos de Superfície/genética , Antígenos de Superfície/metabolismo , Antineoplásicos/farmacologia , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Animais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Células-Tronco Hematopoéticas/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Alvo Molecular , FenótipoRESUMO
High expression of the chemokine receptor 4, CXCR4, associated with a negative prognosis in acute myeloid leukemia, is related to hypoxia. Because CXCR4 expression is under the post-transcriptional control of microRNA-146a in normal and leukemic monocytic cells, we first investigated the impact of hypoxia on microRNA-146a and CXCR4 expression during monocytopoiesis and in acute monocytic leukemia. We then analyzed the effects of hypoxia on drug sensitivity of CXCR4-expressing leukemic cells. We found that microRNA-146a is a target of hypoxia-inducible factor-1α or -2α in relation to the stage of monocytopoiesis and the level of hypoxia, and demonstrated the regulation of the microRNA-146a/CXCR4 pathway by hypoxia in monocytes derived from CD34(+) cells. Thus, in myeloid leukemic cell lines, hypoxia-mediated control of the microRNA-146a/CXCR4 pathway depends only on the capacity of hypoxia-inducible factor-1α to up-regulate microRNA-146a, which in turn decreases CXCR4 expression. However, at variance with normal monocytic cells and leukemic cell lines, in acute monocytic leukemia overexpressing CXCR4, hypoxia up-modulates microRNA-146a but fails to down-modulate CXCR4 expression. We then investigated the effect of hypoxia on the response of leukemic cells to chemotherapy alone or in combination with stromal-derived factor-1α. We found that hypoxia increases stromal-derived factor-1α-induced survival of leukemic cells by decreasing their sensitivity to anti-leukemic drugs. Altogether, our results demonstrate that hypoxia-mediated regulation of microRNA-146a, which controls CXCR4 expression in monocytic cells, is lost in acute monocytic leukemia, thus contributing to maintaining CXCR4 overexpression and protecting the cells from anti-leukemic drugs in the hypoxic bone marrow microenvironment.
Assuntos
Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Monocítica Aguda , MicroRNAs/biossíntese , Monócitos/metabolismo , Proteínas de Neoplasias/biossíntese , RNA Neoplásico/biossíntese , Receptores CXCR4/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hipóxia Celular/efeitos dos fármacos , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Leucemia Monocítica Aguda/tratamento farmacológico , Leucemia Monocítica Aguda/metabolismo , Leucemia Monocítica Aguda/patologia , Masculino , Monócitos/patologia , Células U937RESUMO
The effect of high doses of intravenous (sodium) ascorbate (ASC) in the treatment of cancer has been controversial although there is growing evidence that ASC in high (pharmacologic) concentrations induces dose-dependent pro-apoptotic death of tumor cells, in vitro. Very few data are available on the role of ASC in the treatment of acute myeloid leukemia (AML). Ascorbate behaves as an antioxidant at low (physiologic), and as pro-oxidant at pharmacologic, concentrations, and this may account for the differences reported in different experimental settings, when human myeloid cell lines, such as HL60, were treated with ASC. Considering the myeloid origin of HL60 cells, and previous literature reports showing that some cell lines belonging to the myeloid lineage could be sensitive to the pro-apoptotic effects of high concentrations of ASC, we investigated in more details the effects of high doses (0.5 to 7 mM) of ASC in vitro, on a variety of human myeloid cell lines including the following: HL60, U937, NB4, NB4-R4 (retinoic acid [RA]-resistant), NB4/AsR (ATO-resistant) acute promyelocytic leukemia (APL)-derived cell lines, and K562 as well as on normal CD34+ progenitors derived from human cord blood. Our results indicate that all analyzed cell lines including all-trans retinoic acid (ATRA)- and arsenic trioxide (ATO)-resistant ones are highly sensitive to the cytotoxic, pro-oxidant effects of high doses of ASC, with an average 50 % lethal concentration (LC50) of 3 mM, depending on cell type, ASC concentration, and time of exposure. Conversely, high doses of ASC neither did exert significant cytotoxic effects nor impaired the differentiation potential in cord blood (CB) CD34+ normal cells. Since plasma ASC concentrations within the millimolar (mM) range can be easily and safely reached by intravenous administration, we conclude that phase I/II clinical trials using high doses of ASC should be designed for patients with advanced/refractory AML and APL.
Assuntos
Ácido Ascórbico/farmacologia , Citotoxinas/farmacologia , Células Mieloides/efeitos dos fármacos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Células HL-60 , Humanos , Peróxido de Hidrogênio/metabolismo , Células K562 , Células Mieloides/fisiologia , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Células U937RESUMO
The studies carried out during the last two decades have represented a great effort in trying to identify and define cell populations endowed with the phenotypic and functional properties of endothelial progenitors. From these studies a scenario now emerges indicating that in the blood there are very rare endothelial progenitor cells, called endothelial colony-forming cells (ECFCs) or late outgrowth endothelial cells, not originated from bone marrow, capable of generating phenotypically and functionally competent endothelial cells, capable to be incorporated in vivo into growing vessels. ECFCs are present in the circulation as well as cells resident in the vascular endothelial intima. In addition to these progenitors, there are some hematopoietic progenitor cells capable of generating a monocytic cell progeny exerting a pro-angiogenic activity in vivo, but unable to be directly incorporated into growing vessels. These cells exert a pro-angiogenic effect in vivo through a paracrine mechanism based on the secretion of growth factors and cytokines.
Assuntos
Células Endoteliais/citologia , Células-Tronco/citologia , Animais , Antígenos de Superfície/metabolismo , Diferenciação Celular , Terapia Baseada em Transplante de Células e Tecidos , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imunofenotipagem , Neovascularização Fisiológica , Transplante de Células-Tronco , Células-Tronco/metabolismoRESUMO
We investigated the role of microRNAs (miRNA) 17-5p, 20a and 106a in monocytic differentiation and maturation. In unilineage monocytic culture generated by haematopoietic progenitor cells these miRNAs are downregulated, whereas the transcription factor acute myeloid leukaemia-1 (AML1; also known as Runt-related transcription factor 1, Runx1) is upregulated at protein but not mRNA level. As miRNAs 17-5p, 20a and 106a bind the AML1 mRNA 3'UTR, their decline may unblock AML1 translation. Accordingly, transfection with miRNA 17-5p-20a-106a suppresses AML1 protein expression, leading to M-CSF receptor (M-CSFR) downregulation, enhanced blast proliferation and inhibition of monocytic differentiation and maturation. Treatment with anti-miRNA 17-5p, 20a and 106a causes opposite effects. Knockdown of AML1 or M-CSFR by short interfering RNA (siRNA) mimics the action of the miRNA 17-5p-20a-106a, confirming that these miRNAs target AML1, which promotes M-CSFR transcription. In addition, AML1 binds the miRNA 17-5p-92 and 106a-92 cluster promoters and transcriptionally inhibits the expression of miRNA 17-5p-20a-106a. These studies indicate that monocytopoiesis is controlled by a circuitry involving sequentially miRNA 17-5p-20a-106a, AML1 and M-CSFR, whereby miRNA 17-5p-20a-106a function as a master gene complex interlinked with AML1 in a mutual negative feedback loop.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Células-Tronco Hematopoéticas/citologia , MicroRNAs/fisiologia , Monócitos/citologia , Receptor de Fator Estimulador de Colônias de Macrófagos/biossíntese , Regulação para Cima , Diferenciação Celular/fisiologia , Células Cultivadas , Retroalimentação Fisiológica , Feminino , Células-Tronco Hematopoéticas/fisiologia , Humanos , Monócitos/metabolismo , Regiões Promotoras Genéticas , RNA Interferente Pequeno/metabolismoRESUMO
Recent results indicate that the reduction of ß-adrenergic signaling impairs angiogenesis under ischemic conditions. Because angiogenesis may occur in the absence of ischemia, it remains to be determined whether and how ß-adrenergic signaling regulates angiogenesis, which develops under normoxic conditions. The effect of ß-adrenergic ligands on angiogenesis was investigated using 3-dimensional cultures of mouse aortic rings embedded in collagen type I, in which luminized microvessels develop in response to vascular endothelial growth factor (VEGF). Under normoxic conditions, both isoproterenol, a ß-adrenergic receptor (ß-AR) agonist, and forskolin, an adenylate cyclase activator, were unable to influence aortic microvessel sprouting. On the contrary, treatment with propranolol, a ß-AR antagonist, caused an approximately 70% increase in VEGF-mediated microvessel sprouting. This effect was abolished in rings from both double ß-AR and ß1-AR knockout mice, but not in rings from ß2-AR knockout mice. Significant increases in microvessel sprouting were also observed when mouse aortic rings from C57BL/6 mice were treated with the ß1-AR-selective antagonists metoprolol and bisoprolol or with the ß2-AR-selective antagonist ICI 118,551. Conversely, carvedilol, a nonselective ß-AR antagonist, was unable to affect aortic sprouting. These findings suggest that some ß-blockers display proangiogenic activity through a mechanism that is independent of their ability to antagonize catecholamine action. The present results also identify a new function for ß-AR signaling as a facilitator for VEGF-mediated angiogenesis and have implications for understanding the mechanisms that regulate angiogenic responses under normoxic conditions.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Aorta Torácica/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Agonistas Adrenérgicos beta/farmacologia , Animais , Aorta Torácica/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Receptores Adrenérgicos beta 2/genética , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Anaplastic Lymphoma Kinase (ALK) is a potent oncogenic driver of lung adenocarcinoma (LUAD). ALK is constitutively activated by gene fusion events between the ALK and other gene fusion partners in about 2-3% of LUADs, characterized by few other gene alterations. ALK-fusions are a druggable target through potent pharmacological inhibitors of tyrosine kinase activity. Thus, several ALK-TKIs (Tyrosine Kinase Inhibitors) of first-, second- and third-generation have been developed that improved the outcomes of ALK-rearranged LUADs when used as first- or second-line agents. However, resistance mechanisms greatly limit the durability of the therapeutic effects elicited by these TKIs. The molecular mechanisms responsible for these resistance mechanisms have been in part elucidated, but overcoming acquired resistance to ALK-derived therapy remains a great challenge. Some new therapeutic strategies under investigation aim to induce long-term remission in ALK-fusion positive LUADs.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/genéticaRESUMO
Multiple myeloma (MM) is a disorder of the monoclonal plasma cells and is the second most common hematologic malignancy. MM initiation and progression are dependent upon complex genomic abnormalities. The current pathogenic model of MM includes two types of primary events, represented by chromosome translocations or chromosome number alterations resulting in hyperdiploidy. These primary molecular events are observed both in MM and in monoclonal gammopathy, its premalignant precursor. Subsequent genetic events allow the progression of monoclonal gammopathy to MM and, together with primary events, contribute to the genetic complexity and heterogeneity of MM. Newer therapies have considerably improved patient outcomes; however, MM remains an incurable disease and most patients experience multiple relapses. The dramatic progresses achieved in the analysis of the heterogeneous molecular features of different MM patients allowed a comprehensive molecular classification of MM and the definition of an individualized prognostic model to predict an individual MM patient's response to different therapeutic options. Despite these progresses, prognostic models fail to identify a significant proportion of patients destined to early relapse. Treatment strategies are increasingly. Based on disease biology, trials are enriched for high-risk MMs, whose careful definition and categorization requires DNA sequencing studies.
RESUMO
The treatment outcomes of patients with chronic lymphocytic leukemia (CLL) have considerably improved with the introduction of targeted therapies based on Bruton kinase inhibitors (BTKIs), venetoclax, and anti-CD20 monoclonal antibodies. However, despite these consistent improvements, patients who become resistant to these agents have poor outcomes and need new and more efficacious therapeutic strategies. Among these new treatments, a potentially curative approach consists of the use of chimeric antigen receptor T (CAR-T) cell therapy, which achieved remarkable success in various B-cell malignancies, including B-cell Non-Hodgkin Lymphomas (NHLs) and B-acute lymphoblastic Leukemia (ALL). However, although CAR-T cells were initially used for the treatment of CLL, their efficacy in CLL patients was lower than in other B-cell malignancies. This review analyses possible mechanisms of these failures, highlighting some recent developments that could offer the perspective of the incorporation of CAR-T cells in treatment protocols for relapsed/refractory CLL patients.
RESUMO
The study of monoclonal serum proteins has led to the generation of two major theories: one proposing that individuals who had monoclonal proteins without any symptoms or evidence of end-organ damage have a benign condition, the other one suggesting that some individuals with asymptomatic monoclonal proteins may progress to multiple myeloma and thus are affected by a monoclonal gammopathy of undetermined significance (MGUS). Longitudinal studies of subjects with MGUS have supported the second theory. Subsequent studies have characterized and defined the existence of another precursor of multiple myeloma, smoldering multiple myeloma (SMM), intermediate between MGUS and multiple myeloma. Primary molecular events, chromosome translocations, and chromosome number alterations resulting in hyperploidy, required for multiple myeloma development, are already observed in myeloma precursors. MGUS and SMM are heterogeneous conditions with the presence of tumors with distinct pathogenic phenotypes and clinical outcomes. The identification of MGUS and SMM patients with a molecularly defined high risk of progression to MM offers the unique opportunity of early intervention with a therapeutic approach on a low tumor burden.
RESUMO
Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell lymphoid neoplasia and, in some instances, improved disease outcomes. Thus, six FDA-approved commercial CAR-T cell products that target antigens preferentially expressed on malignant B-cells or plasma cells have been introduced in the therapy of B-cell lymphomas, B-ALLs, and multiple myeloma. These therapeutic successes have triggered the application of CAR-T cell therapy to other hematologic tumors, including T-cell malignancies. However, the success of CAR-T cell therapies in T-cell neoplasms was considerably more limited due to the existence of some limiting factors, such as: 1) the sharing of mutual antigens between normal T-cells and CAR-T cells and malignant cells, determining fratricide events and severe T-cell aplasia; 2) the contamination of CAR-T cells used for CAR transduction with malignant T-cells. Allogeneic CAR-T products can avoid tumor contamination but raise other problems related to immunological incompatibility. In spite of these limitations, there has been significant progress in CD7- and CD5-targeted CAR-T cell therapy of T-cell malignancies in the last few years.
RESUMO
Treatment of refractory and relapsed (R/R) B acute lymphoblastic leukemia (B-ALL) is an unmet medical need in both children and adults. Studies carried out in the last two decades have shown that autologous T cells engineered to express a chimeric antigen receptor (CAR-T) represent an effective technique for treating these patients. Antigens expressed on B-cells, such as CD19, CD20, and CD22, represent targets suitable for treating patients with R/R B-ALL. CD19 CAR-T cells induce a high rate (80-90%) of complete remissions in both pediatric and adult R/R B-ALL patients. However, despite this impressive rate of responses, about half of responding patients relapse within 1-2 years after CAR-T cell therapy. Allo-HSCT after CAR-T cell therapy might consolidate the therapeutic efficacy of CAR-T and increase long-term outcomes; however, not all the studies that have adopted allo-HSCT as a consolidative treatment strategy have shown a benefit deriving from transplantation. For B-ALL patients who relapse early after allo-HSCT or those with insufficient T-cell numbers for an autologous approach, using T cells from the original stem cell donor offers the opportunity for the successful generation of CAR-T cells and for an effective therapeutic approach. Finally, recent studies have introduced allogeneic CAR-T cells generated from healthy donors or unmatched, which are opportunely manipulated with gene editing to reduce the risk of immunological incompatibility, with promising therapeutic effects.
RESUMO
Follicular lymphoma is the second most diagnosed lymphoma in Western Europe. Significant advancements have considerably improved the survival of FL patients. However, 10-20% of these patients are refractory to standard treatments, and most of them will relapse. The treatment of follicular lymphoma patients with multiply relapsed or refractory disease represents an area of high-unmet needing new treatments with stronger efficacy. Chimeric antigen receptor (CAR)-T cell therapy targeting B-cell antigens, such as CD19 or CD20, is emerging as an efficacious treatment for R/R follicular lymphoma patients, particularly for those with early relapse and refractory to alkylating agents and to anti-CD20 monoclonal antibodies, resulting in a high rate of durable responses in a high proportion of patients.