RESUMEN
Over the last decade, the Janus kinase1/2 (JAK1/2) inhibitor ruxolitinib has emerged as a cornerstone of myelofibrosis (MF) management. Ruxolitinib improves splenomegaly and symptoms regardless of driver mutation status, and confers a survival advantage in patients with intermediate-2/high risk MF. However, cytopenias remain problematic, and evidence for a robust anti-clonal effect is lacking. Furthermore, the median duration of spleen response to ruxolitinib in clinical trials is approximately 3 years, and ruxolitinib does not appear to affect the risk of leukemic transformation. There is no therapy approved specifically for patients whose disease 'progresses' on ruxolitinib, defining which remains challenging. The recent regulatory approval of the JAK2 inihibitor fedratinib partially fulfills this unmet need, but much remains to be done. Other JAK inhibitors and a plethora of novel agents are being studied in the ruxolitinib 'failure' setting, as well as 'add-on' therapies to ruxolitinib in patients having a 'sub-optimal' response.
Asunto(s)
Inhibidores de las Cinasas Janus , Mielofibrosis Primaria , Humanos , Janus Quinasa 2 , Nitrilos , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/genética , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/uso terapéutico , Pirimidinas , EsplenomegaliaRESUMEN
Although ruxolitinib improves symptoms and splenomegaly in patients with advanced myelofibrosis, whether this agent is truly disease-modifying remains unclear. Histone deacetylase inhibitors (HDACi) downregulate JAK2 via interference with chaperone function. Pracinostat, a pan-HDACi, has modest single-agent activity in myelofibrosis. We conducted a single-institution, phase 2, investigator-initiated trial of ruxolitinib plus pracinostat (begun after 12 weeks of ruxolitinib) in 25 patients with myelofibrosis, of whom 20 received both agents. Sixteen (80%) patients had objective responses (all 'clinical improvement'). The rate of spleen response (by palpation) was 74%, and that of symptom response 80%. Most responses occurred prior to pracinostat initiation. Three patients experienced improvement in bone marrow fibrosis, and one a near-complete molecular response after two years on study treatment. All patients discontinued pracinostat and are currently off-study. Pracinostat interruptions and dose reductions were frequent, often due to worsening anemia. These findings do not support continued development of pracinostat in myelofibrosis.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mielofibrosis Primaria/tratamiento farmacológico , Anciano , Bencimidazoles/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Mielofibrosis Primaria/patología , Pronóstico , Pirazoles/administración & dosificación , Pirimidinas , Tasa de SupervivenciaRESUMEN
INTRODUCTION: The Janus kinase (JAK)1/2 inhibitor ruxolitinib provides rapid, sustained and often dramatic benefits to patients with myelofibrosis, inducing spleen shrinkage and ameliorating symptoms, and improves survival. However, the drug has little effect on the underlying bone marrow fibrosis or on mutant allele burden, and clinical resistance eventually develops. Furthermore, ruxolitinib-induced cytopenias can be challenging in everyday practice. AREAS COVERED: The developmental therapeutics landscape in MF is discussed. This includes potential partners for ruxolitinib being developed with an aim to improve cytopenias, or to enhance its disease-modifying effects. The development of other JAK inhibitors with efficacy post-ruxolitinib or other unique attributes is being pursued in earnest. Agents with novel mechanisms of action are being studied in patients whose disease responds sub-optimally to, is refractory to or progresses after ruxolitinib. EXPERT OPINION: The JAK inhibitors fedratinib, pacritinib and momelotinib are clearly active, and it is expected that one or more of these will become licensed in the future. The activin receptor ligand traps are promising as treatments for anemia. Imetelstat has shown interesting activity post-ruxolitinib, and azactidine may be a useful partner for ruxolitinib in some patients. Appropriately, multiple pre-clinical and clinical leads are being pursued in this difficult therapeutic area.
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BACKGROUND: Triple-negative breast cancer (TNBC), lacking expression of hormone and human epidermal growth factor receptor 2 receptors, is an aggressive subtype that frequently metastasizes to the brain and has no FDA-approved systemic therapies. Previous literature demonstrates mitogen-activated protein kinase kinase (MEK) pathway activation in TNBC brain metastases. Thus, we aimed to discover rational combinatorial therapies with MEK inhibition, hypothesizing that co-inhibition using clinically available brain-penetrant inhibitors would improve survival in preclinical models of TNBC brain metastases. METHODS: Using human-derived TNBC cell lines, synthetic lethal small interfering RNA kinase screens were evaluated with brain-penetrant inhibitors against MEK1/2 (selumetinib, AZD6244) or phosphatidylinositol-3 kinase (PI3K; buparlisib, BKM120). Mice bearing intracranial TNBC tumors (SUM149, MDA-MB-231Br, MDA-MB-468, or MDA-MB-436) were treated with MEK, PI3K, or platelet derived growth factor receptor (PDGFR; pazopanib) inhibitors alone or in combination. Tumors were analyzed by western blot and multiplexed kinase inhibitor beads/mass spectrometry to assess treatment effects. RESULTS: Screens identified MEK+PI3K and MEK+PDGFR inhibitors as tractable, rational combinations. Dual treatment of selumetinib with buparlisib or pazopanib was synergistic in TNBC cells in vitro. Both combinations improved survival in intracranial SUM149 and MDA-MB-231Br, but not MDA-MB-468 or MDA-MB-436. Treatments decreased mitogen-activated protein kinase (MAPK) and PI3K (Akt) signaling in sensitive (SUM149 and 231Br) but not resistant models (MDA-MB-468). Exploratory analysis of kinome reprogramming in SUM149 intracranial tumors after MEK ± PI3K inhibition demonstrates extensive kinome changes with treatment, especially in MAPK pathway members. CONCLUSIONS: Results demonstrate that rational combinations of the clinically available inhibitors selumetinib with buparlisib or pazopanib may prove to be promising therapeutic strategies for the treatment of some TNBC brain metastases. Additionally, effective combination treatments cause widespread alterations in kinase pathways, including targetable potential resistance drivers.
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Neoplasias Encefálicas/tratamiento farmacológico , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 2/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundario , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Humanos , Ratones , Fosforilación , Transducción de Señal/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: The treatment of relapsed/refractory (RR) CLL has been revolutionized by the advent of the new oral inhibitors of B-cell receptor (BCR) signaling and the pro-survival protein, B-cell lymphoma 2 (BCL2). Additionally, new and more potent monoclonal antibodies against CD20 have replaced/may replace rituximab in many settings. Areas covered: Herein, we review the entire therapeutic landscape of RR CLL, with particular attention to the new small-molecule kinase inhibitors and BH3-mimetics. We discuss preclinical data with these agents in CLL, cover available efficacy and safety information, and examine potential resistance mechanisms and possible rational combinations to circumvent them. Expert opinion: The availability of potent and selective inhibitors of BCR signaling and of the anti-apoptotic functions of BCL2 has enormously enhanced our therapeutic armamentarium, with unprecedented efficacy now observed in patients who historically had poor outcomes with chemoimmunotherapy (CIT), e.g., those with deletion 17p/11q and/or IGHV-unmutated disease. The next challenge is to optimally sequence these agents and develop rational combinations that will hopefully lead to deeper and more durable remissions than ever seen before. Indeed, long term relapse free survival, already achievable with CIT in patients with genetically favorable-risk disease, now appears to be a realistic possibility for most patients with CLL.
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Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Adulto , Agammaglobulinemia Tirosina Quinasa , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígenos CD28/antagonistas & inhibidores , Antígenos CD28/inmunología , Ensayos Clínicos como Asunto , Interacciones Farmacológicas , Humanos , Inmunoterapia/métodos , Leucemia Linfocítica Crónica de Células B/enzimología , Leucemia Linfocítica Crónica de Células B/inmunología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Recurrencia , Rituximab/administración & dosificación , Rituximab/efectos adversos , Rituximab/uso terapéutico , Resultado del TratamientoRESUMEN
The approval of venetoclax, a 'BH3-mimetic' antagonist of the BCL-2 anti-apoptotic protein, for chronic lymphocytic leukemia represents a major milestone in translational apoptosis research. Venetoclax has already received 'breakthrough' designation for acute myeloid leukemia, and is being studied in many other tumor types. However, resistance to BCL-2 inhibitor monotherapy may rapidly ensue. Several studies have shown that the other two major anti-apoptotic BCL-2 family proteins, BCL-XL and MCL-1, are the main determinants of resistance to venetoclax. This opens up possibilities for rationally combining venetoclax with other targeted agents to circumvent resistance. Here, we summarize the most promising combinations, and highlight those already in clinical trials. There is also increasing recognition that different tumors display different degrees of addiction to individual BCL-2 family proteins, and of the need to refine current 'BH3 profiling' techniques. Finally, the successful clinical development of potent and selective antagonists of BCL-XL and MCL-1 is eagerly awaited.
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Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Resistencia a Antineoplásicos , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Sulfonamidas/farmacología , Animales , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Biomimética , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Ensayos Clínicos como Asunto , Descubrimiento de Drogas , Resistencia a Antineoplásicos/genética , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Fragmentos de Péptidos/farmacología , Fragmentos de Péptidos/uso terapéutico , Proteínas Proto-Oncogénicas/farmacología , Proteínas Proto-Oncogénicas/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/química , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Sulfonamidas/uso terapéutico , Proteína bcl-X/antagonistas & inhibidores , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMEN
INTRODUCTION: The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) mainly comprise polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF, primary or post-PV/ET). Therapy in PV and ET focuses on minimizing thrombosis and bleeding risk, while in MF, prolongation of survival is an important goal. Different cytoreductive agents are employed in high risk PV and ET, while the JAK inhibtior ruxolitinib is the cornerstone of therapy in MF. Histone deacetylase inhibitors (HDACi) are pleiotropic agents with diverse epigenetic and non-epigenetic actions, selectively in transformed cells. A number of HDACi have been or are being investigated in MPN. Areas covered: The mechanisms of action of HDACI in neoplastic cells are summarized, and the preclinical rationale and data supporting their development in MPN specifically examined, particularly their synergism with JAK inhibitors. Major findings of clinical trials of HDACi, both alone and in combination with ruxolitinib, in MPN are then discussed, with particular attention to their toxicities and disease-modifying effects. Expert opinion: HDACi are clearly active in MPN, and there is good preclinical rationale for this. Their combination with ruxolitinib in MF is promising, but the long-term tolerability of these agents is an important concern. Further development in PV or ET appears unlikely.
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Diseño de Fármacos , Inhibidores de Histona Desacetilasas/uso terapéutico , Trastornos Mieloproliferativos/tratamiento farmacológico , Animales , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Quinasas Janus/antagonistas & inhibidores , Trastornos Mieloproliferativos/patología , Nitrilos , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/patología , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/patología , Pirazoles/administración & dosificación , Pirazoles/farmacología , Pirazoles/uso terapéutico , Pirimidinas , Sobrevida , Trombocitemia Esencial/tratamiento farmacológico , Trombocitemia Esencial/patologíaRESUMEN
Despite modest improvements in survival over the last several decades, the treatment of AML continues to present a formidable challenge. Most patients are elderly, and these individuals, as well as those with secondary, therapy-related, or relapsed/refractory AML, are particularly difficult to treat, owing to both aggressive disease biology and the high toxicity of current chemotherapeutic regimens. It has become increasingly apparent in recent years that coordinated interruption of cooperative survival signaling pathways in malignant cells is necessary for optimal therapeutic results. The modest efficacy of monotherapy with both cytotoxic and targeted agents in AML testifies to this. As the complex biology of AML continues to be elucidated, many "synthetic lethal" strategies involving rational combinations of targeted agents have been developed. Unfortunately, relatively few of these have been tested clinically, although there is growing interest in this area. In this article, the preclinical and, where available, clinical data on some of the most promising rational combinations of targeted agents in AML are summarized. While new molecules should continue to be combined with conventional genotoxic drugs of proven efficacy, there is perhaps a need to rethink traditional philosophies of clinical trial development and regulatory approval with a focus on mechanism-based, synergistic strategies.
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Antineoplásicos/uso terapéutico , Bencimidazoles/clasificación , Flavonoides/clasificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Producción de Medicamentos sin Interés Comercial , Piperidinas/clasificación , Pteridinas/clasificación , Animales , Bencimidazoles/uso terapéutico , Descubrimiento de Drogas/tendencias , Epigénesis Genética/efectos de los fármacos , Flavonoides/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pteridinas/uso terapéutico , Terminología como AsuntoRESUMEN
Initially regarded as "epigenetic modifiers" acting predominantly through chromatin remodeling via histone acetylation, HDACIs, alternatively referred to as lysine deacetylase or simply deacetylase inhibitors, have since been recognized to exert multiple cytotoxic actions in cancer cells, often through acetylation of non-histone proteins. Some well-recognized mechanisms of HDACI lethality include, in addition to relaxation of DNA and de-repression of gene transcription, interference with chaperone protein function, free radical generation, induction of DNA damage, up-regulation of endogenous inhibitors of cell cycle progression, e.g., p21, and promotion of apoptosis. Intriguingly, this class of agents is relatively selective for transformed cells, at least in pre-clinical studies. In recent years, additional mechanisms of action of these agents have been uncovered. For example, HDACIs interfere with multiple DNA repair processes, as well as disrupt cell cycle checkpoints, critical to the maintenance of genomic integrity in the face of diverse genotoxic insults. Despite their pre-clinical potential, the clinical use of HDACIs remains restricted to certain subsets of T-cell lymphoma. Currently, it appears likely that the ultimate role of these agents will lie in rational combinations, only a few of which have been pursued in the clinic to date. This review focuses on relatively recently identified mechanisms of action of HDACIs, with particular emphasis on those that relate to the DNA damage response (DDR), and discusses synergistic strategies combining HDACIs with several novel targeted agents that disrupt the DDR or antagonize anti-apoptotic proteins that could have implications for the future use of HDACIs in patients with cancer.