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We highlight concerns regarding the approval of relugolix for patients with prostate cancer. These include the unsuitable comparator arm and primary endpoint in the HERO trial, as well as potential selection bias and the poor representativeness of the trial population. Dosing adherence to a daily tablet may also be an issue in comparison to injections at 3-mo intervals. Rigorous postmarketing trials of relugolix assessing clinically meaningful endpoints for these patients are needed.
Assuntos
Compostos de Fenilureia , Neoplasias da Próstata , Masculino , Estados Unidos , Humanos , United States Food and Drug Administration , Pirimidinonas , Neoplasias da Próstata/tratamento farmacológicoRESUMO
Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and rates of diagnosis have been fluctuating worldwide. In Western countries, HCC is driven primarily by the hepatitis C virus (HCV), alcohol use and non-alcoholic fatty liver disease (NAFLD). Hence, it is not surprising that the increased incidence of both HCV and NAFLD has been associated with a corresponding rise in rates of HCC. The introduction of antiviral medications could potentially change the landscape of HCC by reducing rates of HCV-associated HCC. In Eastern countries and Africa, HCC is driven primarily by hepatitis B virus (HBV), HCV, and to a lesser extent, aflatoxin exposure. The introduction of hepatitis B vaccines is expected to dramatically reduce hepatitis B induced liver damage and HCC. These varying etiologies of HCC result in different mutational landscapes, patient presentations and responses to treatment. This has made establishing a universal staging system difficult and several competing systems are available. Other than Sorafenib, there has also been a paucity of treatment options until the last two years, with immunotherapy and new-targeted tyrosine kinase inhibitors as potential treatment options. Management of HCC offers unique challenges during treatment, as there is often competing illness from underlying liver dysfunction and malignancy itself, both of which affects survival and treatment choice. The new era of treatment may offer additional options in this challenging field. In this review, we describe the underlying etiologies and associated mutational landscape, which drives the treatment options in this complex disease.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/genética , Hepatite B , Humanos , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/genética , Estadiamento de Neoplasias , Hepatopatia Gordurosa não Alcoólica , SorafenibeRESUMO
BACKGROUND: Men with early-onset prostate cancer are at increased risk for cancer-related mortality, yet the prevalence and spectrum of molecular alterations in this patient population is unknown. Here, we analyze comprehensive genomic profiling data to characterize the molecular drivers of early-onset prostate cancer in patients with clinically advanced and metastatic disease. METHODS: Next-generation sequencing was ordered as a part of routine clinical care for 10,189 patients with prostate cancer between 02/2013 and 03/2020 using commercially available comprehensive genomic profiling. RESULTS: Deidentified genomic data for 10,189 unique patients with prostate cancer were obtained (median age = 66 y, range = 34-90 y). 439 patients were ≤50 y (4.3%), 1928 patients were between ages of 51 and 59 y (18.9%), and 7822 patients were ≥60 y (76.8%). Of metastatic biopsy sites, lymph node, liver, and bone were the most common in all groups, accounting for 60.2% of all specimens. Overall, 97.4% of patients harbored pathologic genomic alterations. The most commonly altered genes were TP53, TMPRSS2-ERG, PTEN, AR, MYC, MLL2, RAD21, BRCA2, APC, SPOP, PIK3CA, RB1, MLL3, CDK12, ATM, and CTNNB1. Patients ≤50 y harbored significantly more TMPRSS2-ERG fusions than patients ≥60 y, while AR copy number alterations as well as SPOP and ASXL1 mutations were significantly less frequent. CONCLUSIONS: Clinically advanced and metastatic early-onset prostate cancer is a distinct clinical subgroup with characteristic genomic alterations including increased frequency of TMPRSS2-ERG fusions and fewer AR, SPOP, and ASXL1 alterations.
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Biomarcadores Tumorais/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Proteínas de Fusão Oncogênica/genética , Neoplasias da Próstata/patologia , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Neoplasias da Próstata/genética , Estudos RetrospectivosRESUMO
MYC is a highly validated oncogenic transcription factor and cancer target. However, the disordered nature of this protein has made it a challenging target, with no clinical stage, direct small-molecule MYC inhibitors available. Recent work leveraging a large in silico chemical library and a rapid in vivo screen has expanded the chemotypes of direct small-molecule inhibitors (MYCi). Novel MYCi represent a class of improved MYC chemical probes that bind directly to MYC to inhibit its function and to promote its degradation by enhancing GSK3ß-mediated phosphorylation. One of these compounds, MYCi975, has shown remarkable tolerability and efficacy in vivo and is associated with a selective effect on MYC target gene expression. Additional effects of MYCi on the tumor immune microenvironment including immune cell infiltration and upregulation of PD-L1 expression provide a rationale for combining MYCi with anti-PD-1/PD-L1 therapy to enhance antitumor efficacy. Our strategy for developing MYCi demonstrates an efficient way to identify selective and well-tolerated MYC inhibitors. The new MYCi provide tools for probing MYC function and serve as starting points for the development of novel anti-MYC therapeutics.
Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Animais , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-myc/genéticaRESUMO
Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. In its active form, GTP-bound RAS is responsible for numerous critical cellular processes. Aberrant RAS activity is involved in â¼30% of all human cancers; hence, SOS1 is an attractive therapeutic target for its role in modulating RAS activation. Here, we describe a new series of benzimidazole-derived SOS1 agonists. Using structure-guided design, we discovered small molecules that increase nucleotide exchange on RAS in vitro at submicromolar concentrations, bind to SOS1 with low double-digit nanomolar affinity, rapidly enhance cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2. These compounds represent the most potent series of SOS1 agonists reported to date.
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Benzimidazóis/farmacologia , Descoberta de Drogas/normas , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína SOS1/agonistas , Proteína SOS1/metabolismo , Benzimidazóis/química , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fatores de Troca do Nucleotídeo Guanina/química , Guanosina Difosfato/metabolismo , Guanosina Trifosfato/metabolismo , Células HeLa , Humanos , Fosforilação , Conformação Proteica , Proteínas Proto-Oncogênicas p21(ras)/química , Relação Estrutura-AtividadeRESUMO
Proteins in the RAS family are important regulators of cellular signaling and, when mutated, can drive cancer pathogenesis. Despite considerable effort over the last 30 years, RAS proteins have proven to be recalcitrant therapeutic targets. One approach for modulating RAS signaling is to target proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report hit-to-lead studies on quinazoline-containing compounds that bind to SOS1 and activate nucleotide exchange on RAS. Using structure-based design, we refined the substituents attached to the quinazoline nucleus and built in additional interactions not present in the initial HTS hit. Optimized compounds activate nucleotide exchange at single-digit micromolar concentrations in vitro. In HeLa cells, these quinazolines increase the levels of RAS-GTP and cause signaling changes in the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway.
RESUMO
Deregulated RAS activity, often the result of mutation, is implicated in approximately 30% of all human cancers. Despite this statistic, no clinically successful treatment for RAS-driven tumors has yet been developed. One approach for modulating RAS activity is to target and affect the activity of proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report on structure-activity relationships (SAR) in an indole series of compounds. Using structure-based design, we systematically explored substitution patterns on the indole nucleus, the pendant amino acid moiety, and the linker unit that connects these two fragments. Best-in-class compounds activate the nucleotide exchange process at submicromolar concentrations in vitro, increase levels of active RAS-GTP in HeLa cells, and elicit signaling changes in the mitogen-activated protein kinase-extracellular regulated kinase (MAPK-ERK) pathway, resulting in a decrease in pERK1/2T202/Y204 protein levels at higher compound concentrations.
Assuntos
Desenho de Fármacos , Indóis/química , Indóis/farmacologia , Piperidinas/química , Proteína SOS1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas ras/metabolismo , Células HeLa , Humanos , Modelos Moleculares , Conformação Proteica , Proteína SOS1/química , Relação Estrutura-Atividade , Proteínas ras/químicaRESUMO
K-RAS is mutated in approximately 30% of human cancers, resulting in increased RAS signaling and tumor growth. Thus, RAS is a highly validated therapeutic target, especially in tumors of the pancreas, lung and colon. Although directly targeting RAS has proven to be challenging, it may be possible to target other proteins involved in RAS signaling, such as the guanine nucleotide exchange factor Son of Sevenless (SOS). We have previously reported on the discovery of small molecules that bind to SOS1, activate SOS-mediated nucleotide exchange on RAS, and paradoxically inhibit ERK phosphorylation (Burns et al., PNAS, 2014). Here, we describe the discovery of additional, structurally diverse small molecules that also bind to SOS1 in the same pocket and elicit similar biological effects. We tested >160,000 compounds in a fluorescence-based assay to assess their effects on SOS-mediated nucleotide exchange. X-Ray structures revealed that these small molecules bind to the CDC25 domain of SOS1. Compounds that elicited high levels of nucleotide exchange activity in vitro increased RAS-GTP levels in cells, and inhibited phospho ERK levels at higher treatment concentrations. The identification of structurally diverse SOS1 binding ligands may assist in the discovery of new molecules designed to target RAS-driven tumors.
Assuntos
Sistema de Sinalização das MAP Quinases , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína SOS1/metabolismo , Células HeLa , Humanos , Proteínas Proto-Oncogênicas p21(ras)/química , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína SOS1/química , Proteína SOS1/genéticaRESUMO
Oncogenic mutation of RAS results in aberrant cellular signaling and is responsible for more than 30% of all human tumors. Therefore, pharmacologic modulation of RAS has attracted great interest as a therapeutic strategy. Our laboratory has recently discovered small molecules that activate Son of Sevenless (SOS)-catalyzed nucleotide exchange on RAS and inhibit downstream signaling. Here, we describe how pharmacologically targeting SOS1 induced biphasic modulation of RAS-GTP and ERK phosphorylation levels, which we observed in a variety of cell lines expressing different RAS-mutant isoforms. We show that compound treatment caused an increase in phosphorylation at ERK consensus motifs on SOS1 that was not observed with the expression of a non-phosphorylatable S1178A SOS1 mutant or after pretreatment with an ERK inhibitor. Phosphorylation at S1178 on SOS1 is known to inhibit the association between SOS1 and GRB2 and disrupt SOS1 membrane localization. Consistent with this, we show that wild-type SOS1 and GRB2 dissociated in a time-dependent fashion in response to compound treatment, and conversely, this interaction was enhanced with the expression of an S1178A SOS1 mutant. Furthermore, in cells expressing either S1178A SOS1 or a constitutively membrane-bound CAAX box tagged SOS1 mutant, we observed elevated RAS-GTP levels over time in response to compound, as compared with the biphasic changes in RAS-GTP exhibited in cells expressing wild-type SOS1. These results suggest that small molecule targeting of SOS1 can elicit a biphasic modulation of RAS-GTP and phospho-ERK levels through negative feedback on SOS1 that regulates the interaction between SOS1 and GRB2. Mol Cancer Ther; 17(5); 1051-60. ©2018 AACR.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Retroalimentação Fisiológica/efeitos dos fármacos , Proteína SOS1/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Proteínas ras/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Estrutura Molecular , Mutação de Sentido Incorreto , Fosforilação/efeitos dos fármacos , Ligação Proteica , Proteína SOS1/genética , Bibliotecas de Moléculas Pequenas/química , Proteínas ras/genéticaRESUMO
INTRODUCTION: Since 2010 multiple targeted therapies and immunotherapies have been approved for the treatment of advanced melanoma. Pembrolizumab, a humanized monoclonal antibody directed against programed death receptor 1 has shown significant activity in advanced melanoma resulting in its approval first as post-ipilimumab and subsequently as frontline treatment. AREAS COVERED: This article reviews the approved agents for the treatment of advanced melanoma with a focus on the preclinical and clinical evidence for the use of pembrolizumab in this setting. Primary emphasis is given to the clinical development of pembrolizumab, including phase I-III trials. Finally, we explore the role of pembrolizumab in combination with other therapies and ongoing investigations into its effectiveness in expanded patient populations. EXPERT OPINION: Pembrolizumab provides durable responses and represents a major advancement in the treatment options for patients with advanced melanoma. Early studies of pembrolizumab in combination with other therapeutic agents have generated significant interest and further investigations including advanced clinical trials are warranted to evaluate safety and potential improved outcomes. Pembrolizumab and other immune checkpoint inhibitors are likely to play an expanded role in the treatment of advanced melanoma and other solid tumors over the next decade.
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Aberrant activation of the small GTPase Ras by oncogenic mutation or constitutively active upstream receptor tyrosine kinases results in the deregulation of cellular signals governing growth and survival in â¼30% of all human cancers. However, the discovery of potent inhibitors of Ras has been difficult to achieve. Here, we report the identification of small molecules that bind to a unique pocket on the Ras:Son of Sevenless (SOS):Ras complex, increase the rate of SOS-catalyzed nucleotide exchange in vitro, and modulate Ras signaling pathways in cells. X-ray crystallography of Ras:SOS:Ras in complex with these molecules reveals that the compounds bind in a hydrophobic pocket in the CDC25 domain of SOS adjacent to the Switch II region of Ras. The structure-activity relationships exhibited by these compounds can be rationalized on the basis of multiple X-ray cocrystal structures. Mutational analyses confirmed the functional relevance of this binding site and showed it to be essential for compound activity. These molecules increase Ras-GTP levels and disrupt MAPK and PI3K signaling in cells at low micromolar concentrations. These small molecules represent tools to study the acute activation of Ras and highlight a pocket on SOS that may be exploited to modulate Ras signaling.
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Indóis/metabolismo , Modelos Moleculares , Complexos Multiproteicos/metabolismo , Piperidinas/metabolismo , Conformação Proteica , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteína SOS1/metabolismo , Cromatografia Líquida , Cromatografia em Camada Fina , Cristalografia por Raios X , Polarização de Fluorescência , Células HeLa , Humanos , Ligantes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Complexos Multiproteicos/química , Proteínas Proto-Oncogênicas p21(ras)/química , Proteína SOS1/químicaRESUMO
The mouse fracture model is ideal for research into the pathways of healing because of the availability of genetic and transgenic mice and the ability to create cell-specific genetic mutations. While biomechanical tests and histology are available to assess callus integrity and tissue differentiation, respectively, micro-computed tomography (µCT) analysis has increasingly been utilized in fracture studies because it is non-destructive and provides descriptions of the structural and compositional properties of the callus. However, the dynamic changes of µCT properties that occur during healing are not well defined. Thus, the purpose of this study was to determine which µCT properties change with the progression of fracture repair and converge to values similar to unfractured bone in the mouse femur fracture model. A unilateral femur fracture was performed in C57BL/6 mice and intramedullary fixation performed. Fractured and un-fractured contralateral specimens were harvested from groups of mice between 2 and 12 weeks post-fracture. Parameters describing callus based on µCT were obtained, including polar moment of inertia (J), bending moment of inertia (I), total volume (TV), tissue mineral density (TMD), total bone volume fraction (BV/TV), and volumetric bone mineral density (vBMD). For comparison, plain radiographs were used to measure the callus diameter (D) and area (A); and biomechanical properties were evaluated using either three-point bending or torsion. The µCT parameters J, I, TV, and TMD converged toward their respective values of the un-fractured femurs over time, although significant differences existed between the two sides at every time point evaluated (p<0.05). Radiograph measurement D changed with repair progression in similar manner to TV. In contrast, BV/TV and BMD increased and decreased over time with statistical differences between callus and un-fractured bone occurring sporadically. Similarly, none of the biomechanical properties were found to distinguish consistently between the fractured and un-fractured femur. Micro-CT parameters assessing callus structure and size (J, I, and TV) were more sensitive to changes in callus over time post-fracture than those assessing callus substance (TMD, BV/TV, and BMD). Sample size estimates based on these results indicate that utilization of µCT requires fewer animals than biomechanics and thus is more practical for evaluating the healing femur in the mouse fracture model.
Assuntos
Fraturas do Fêmur/diagnóstico por imagem , Consolidação da Fratura , Animais , Fenômenos Biomecânicos , Densidade Óssea , Calo Ósseo/diagnóstico por imagem , Calo Ósseo/fisiopatologia , Feminino , Fraturas do Fêmur/fisiopatologia , Fraturas do Fêmur/cirurgia , Fixação Intramedular de Fraturas , Consolidação da Fratura/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Estresse Mecânico , Torção Mecânica , Microtomografia por Raio-XRESUMO
A new heterometallic iodoplumbate was synthesized solvothermally. The complex, [Co(phen)3][Pb3Cu6I16].C2H5OH, contains a novel Pb3Cu6I16 net made up of linked Pb3I11 and Cu6I11 clusters. The clusters form a BN-type layer, where the Pb3I11 and Cu6I11 clusters take the place of B and N. The layers, which are separated by [Co(phen)3]2+ cations, contain cavities in which ethanol molecules are located.