RESUMEN
On November 14, 2022, the FDA granted accelerated approval to mirvetuximab soravtansine-gynx for treatment of adult patients with folate receptor-α (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic therapies. The VENTANA FOLR1 (FOLR-2.1) RxDx Assay was approved as a companion diagnostic device to select patients for this indication. Approval was based on Study 0417 (SORAYA, NCT04296890), a single-arm, multicenter trial. In 104 patients with measurable disease who received mirvetuximab soravtansine-gynx, the overall response rate was 31.7% [95% confidence interval (CI), 22.9-41.6] with a median duration of response of 6.9 months (95% CI, 5.6-9.7). Ocular toxicity was included as a Boxed Warning in the U.S. Prescribing Information (USPI) to alert providers of the risks of developing severe ocular toxicity including vision impairment and corneal disorders. Pneumonitis and peripheral neuropathy were additional important safety risks included as Warnings and Precautions in the USPI. This is the first approval of a targeted therapy for FRα-positive, platinum-resistant ovarian cancer and the first antibody-drug conjugate approved for ovarian cancer. This article summarizes the favorable benefit-risk assessment leading to FDA's approval of mirvetuximab soravtansine-gynx.
Asunto(s)
Inmunoconjugados , Neoplasias Ováricas , Adulto , Humanos , Femenino , Neuropatía Óptica Tóxica/tratamiento farmacológico , Resistencia a Antineoplásicos , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Inmunoconjugados/efectos adversos , Receptor 1 de FolatoRESUMEN
Drug-induced toxicity is a major public health concern that leads to patient morbidity and mortality. To address this problem, the Food and Drug Administration is working on the PredicTox initiative, a pilot research program on tyrosine kinase inhibitors, to build mechanistic and predictive models for drug-induced toxicity. This program involves integrating data acquired during preclinical studies and clinical trials within pharmaceutical company development programs that they have agreed to put in the public domain and in publicly available biological, pharmacological, and chemical databases. The integration process is accommodated by biomedical ontologies, a set of standardized vocabularies that define terms and logical relationships between them in each vocabulary. We describe a few programs that have used ontologies to address biomedical questions. The PredicTox effort is leveraging the experience gathered from these early initiatives to develop an infrastructure that allows evaluation of the hypothesis that having a mechanistic understanding underlying adverse drug reactions will improve the capacity to understand drug-induced clinical adverse drug reactions.
RESUMEN
The hepatocyte growth factor/c-MET pathway has been implicated in the pathobiology of multiple myeloma, and c-MET inhibitors induce myeloma cell apoptosis, suggesting that they could be useful clinically. We conducted a phase II study with the c-MET inhibitor tivantinib in patients with relapsed, or relapsed and refractory myeloma whose disease had progressed after one to four prior therapies. Tivantinib, 360 mg orally per dose, was administered twice daily continuously over a 4-week treatment cycle without a cap on the number of allowed cycles, barring undue toxicities or disease progression. Primary objectives were to determine the overall response rate and the toxicities of tivantinib in this patient population. Sixteen patients were enrolled in a two-stage design. Notable grade 3 and 4 hematological adverse events were limited to neutropenia in five and four patients, respectively. Nonhematological adverse events of grade 3 or higher included hypertension (in four patients); syncope, infection, and pain (two each); and fatigue, cough, and pulmonary embolism (one each). Four of 11 evaluable patients (36%) had stable disease as their best response, while the remainder showed disease progression. Overall, tivantinib as a single agent did not show promise for unselected relapsed/refractory myeloma patients. However, the ability to achieve stable disease does suggest that combination regimens incorporating targeted inhibitors in patients with c-MET pathway activation could be of interest.
Asunto(s)
Mieloma Múltiple/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirrolidinonas/uso terapéutico , Quinolinas/uso terapéutico , Anciano , Supervivencia sin Enfermedad , Esquema de Medicación , Resistencia a Antineoplásicos , Fatiga/inducido químicamente , Femenino , Humanos , Hipertensión/inducido químicamente , Masculino , Persona de Mediana Edad , Mieloma Múltiple/metabolismo , Recurrencia Local de Neoplasia , Neutropenia/inducido químicamente , Dolor/inducido químicamente , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirrolidinonas/efectos adversos , Quinolinas/efectos adversos , Resultado del TratamientoRESUMEN
INTRODUCTION: A translational bioinformatics challenge exists in connecting population and individual clinical phenotypes in various formats to biological mechanisms. The Medical Dictionary for Regulatory Activities (MedDRA(®)) is the default dictionary for adverse event (AE) reporting in the US Food and Drug Administration Adverse Event Reporting System (FAERS). The ontology of adverse events (OAE) represents AEs as pathological processes occurring after drug exposures. OBJECTIVES: The aim of this work was to establish a semantic framework to link biological mechanisms to phenotypes of AEs by combining OAE with MedDRA(®) in FAERS data analysis. We investigated the AEs associated with tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) targeting tyrosine kinases. The five selected TKIs/mAbs (i.e., dasatinib, imatinib, lapatinib, cetuximab, and trastuzumab) are known to induce impaired ventricular function (non-QT) cardiotoxicity. RESULTS: Statistical analysis of FAERS data identified 1053 distinct MedDRA(®) terms significantly associated with TKIs/mAbs, where 884 did not have corresponding OAE terms. We manually annotated these terms, added them to OAE by the standard OAE development strategy, and mapped them to MedDRA(®). The data integration to provide insights into molecular mechanisms of drug-associated AEs was performed by including linkages in OAE for all related AE terms to MedDRA(®) and the existing ontologies, including the human phenotype ontology (HP), Uber anatomy ontology (UBERON), and gene ontology (GO). Sixteen AEs were shared by all five TKIs/mAbs, and each of 17 cardiotoxicity AEs was associated with at least one TKI/mAb. As an example, we analyzed "cardiac failure" using the relations established in OAE with other ontologies and demonstrated that one of the biological processes associated with cardiac failure maps to the genes associated with heart contraction. CONCLUSION: By expanding the existing OAE ontological design, our TKI use case demonstrated that the combination of OAE and MedDRA(®) provides a semantic framework to link clinical phenotypes of adverse drug events to biological mechanisms.
Asunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos , Inhibidores de Proteínas Quinasas/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Humanos , Proyectos Piloto , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Multiple myeloma (MM) is a plasma cell neoplasm that has a low apoptotic index. We investigated a new class of small molecules that target the terminal apoptosis pathway, called procaspase activating compounds (PACs), in myeloma cells. PAC agents (PAC-1 and B-PAC-1) convert executioner procaspases (procaspase 3, 6, and 7) to active caspases 3, 6, and 7, which cleave target substrates to induce cellular apoptosis cascade. We hypothesized that targeting this terminal step could overcome survival and drug-resistance signals in myeloma cells and induce programmed cell death. Myeloma cells expressed executioner caspases. Additionally, our studies demonstrated that B-PAC-1 is cytotoxic to chemotherapy-resistant or sensitive myeloma cell lines (n = 7) and primary patient cells (n = 11). Exogenous zinc abrogated B-PAC-1-induced cell demise. Apoptosis induced by B-PAC-1 treatment was similar in the presence or absence of growth-promoting cytokines such as interleukin 6 and hepatocyte growth factor. Presence or absence of antiapoptotic proteins such as BCL-2, BCL-XL, or MCL-1 did not impact B-PAC-1-mediated programmed cell death. Collectively, our data demonstrate the proapoptotic effect of B-PAC-1 in MM and suggest that activating terminal executioner procaspases 3, 6, and 7 bypasses survival and drug-resistance signals in myeloma cells. This novel strategy has the potential to become an effective antimyeloma therapy.
Asunto(s)
Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Hidrazonas/farmacología , Mieloma Múltiple/tratamiento farmacológico , Piperazinas/farmacología , Apoptosis/genética , Caspasa 3/genética , Activación Enzimática/efectos de los fármacos , Células HL-60 , Humanos , Mieloma Múltiple/enzimología , Mieloma Múltiple/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMEN
The hepatocyte growth factor (HGF)/MNNG HOS transforming gene (MET) pathway regulates cell growth, survival, and migration. MET is mutated or amplified in several malignancies. In myeloma, MET is not mutated, but patients have high plasma concentrations of HGF, high levels of MET expression, and gene copy number, which are associated with poor prognosis and advanced disease. Our previous studies demonstrated that MET is critical for myeloma cell survival and its knockdown induces apoptosis. In our current study, we tested tivantinib (ARQ 197), a small-molecule pharmacological MET inhibitor. At clinically achievable concentrations, tivantinib induced apoptosis by >50% in all 12 human myeloma cell lines tested. This biologic response was associated with down-regulation of MET signaling and inhibition of the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways, which are downstream of the HGF/MET axis. Tivantinib was equally effective in inducing apoptosis in myeloma cell lines resistant to standard chemotherapy (melphalan, dexamethasone, bortezomib, and lenalidomide) as well as in cells that were co-cultured with a protective bone marrow microenvironment or with exogenous cytokines. Tivantinib induced apoptosis in CD138+ plasma cells from patients and demonstrated efficacy in a myeloma xenograft mouse model. On the basis of these data, we initiated a clinical trial for relapsed/refractory multiple myeloma (MM). In conclusion, MET inhibitors may be an attractive target-based strategy for the treatment of MM.
Asunto(s)
Antineoplásicos/farmacología , Mieloma Múltiple/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirrolidinonas/farmacología , Quinolinas/farmacología , Animales , Bortezomib/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dexametasona/farmacología , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos , Humanos , Lenalidomida , Melfalán/farmacología , Ratones , Mieloma Múltiple/patología , Transducción de Señal/efectos de los fármacos , Talidomida/análogos & derivados , Talidomida/farmacología , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Multiple endocrine neoplasia type 1 (MEN1) is a syndrome characterized by tumors in multiple endocrine tissues such as the parathyroid glands, the pituitary gland, and the enteropancreatic neuroendocrine tissues. MEN1 is usually caused by mutations in the MEN1 gene that codes for the protein menin. Menin interacts with proteins that regulate transcription, DNA repair and processing, and maintenance of cytoskeletal structure. We describe the identification of FBP1 as an interacting partner of menin in a large-scale pull-down assay that also immunoprecipitated RBBP5, ASH2, and LEDGF, which are members of complex proteins associated with SET1 (COMPASS), a protein complex that methylates histone H3. This interaction was confirmed by coimmunoprecipitation and Flag-pull-down assays. Furthermore, menin localized to the FUSE site on the MYC promoter, a site that is transactivated by FBP1. This investigation therefore places menin in a pathway that regulates MYC gene expression and has important implications for the biological function of menin.
RESUMEN
Apoptosis is a cell death program that is well-orchestrated for normal tissue homeostasis and for removal of damaged, old or infected cells. It is regulated by intrinsic and extrinsic pathways. The intrinsic pathway responds to signals such as ultraviolet radiation or DNA damage and activates "executioner" caspases through a mitochondria-dependent pathway. The extrinsic pathway is activated by death signals induced, for example, by an infection that activates the immune system or receptor-mediated pathways. The extrinsic pathway signals also cascade down to executioner caspases that cleave target proteins and lead to cell death. Strict control of cellular apoptosis is important for the hematopoietic system as it has a high turnover rate. However, the apoptosis program is often deregulated in hematologic malignancies leading to the accumulation of malignant cells. Therefore, apoptosis pathways have been identified for the development of anticancer therapeutics. We review here the proteins that have been targeted for anticancer drug development in hematologic malignancies. These include BCL-2 family proteins, death ligands and receptors, inhibitor of apoptosis family proteins and caspases. Except for caspase activators, drugs that target each of these classes of proteins have advanced into clinical trials.
Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/antagonistas & inhibidores , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Neoplasias Hematológicas/genética , Humanos , Terapia Molecular DirigidaRESUMEN
BACKGROUND: MET is a receptor tyrosine kinase that is activated by the ligand HGF and this pathway promotes cell survival, migration, and motility. In accordance with its oncogenic role, MET is constitutively active, mutated, or over-expressed in many cancers. Corollary to its impact, inhibition of MET kinase activity causes reduction of the downstream signaling and demise of cells. In myeloma, a B-cell plasma malignancy, MET is neither mutated nor over-expressed, however, HGF is increased in plasma or serum obtained from myeloma patients and this was associated with poor prognosis. The small-molecule, amuvatinib, inhibits MET receptor tyrosine kinase. Based on this background, we hypothesized that targeting the HGF/MET signaling pathway is a rational approach to myeloma therapy and that myeloma cells would be sensitive to amuvatinib. METHODS: Expression of MET and HGF mRNAs in normal versus malignant plasma cells was compared during disease progression. Cell death and growth as well as MET signaling pathway were assessed in amuvatinib treated primary myeloma cells and cell lines. RESULTS: There was a progressive increase in the transcript levels of HGF (but not MET) from normal plasma cells to refractory malignant plasma cells. Amuvatinib readily inhibited MET phosphorylation in primary CD138+ cells from myeloma patients and in concordance, increased cell death. A 48-hr amuvatinib treatment in high HGF-expressing myeloma cell line, U266, resulted in growth inhibition. Levels of cytotoxicity were time-dependent; at 24, 48, and 72 h, amuvatinib (25 µM) resulted in 28%, 40%, and 55% cell death. Consistent with these data, there was an amuvatinib-mediated decrease in MET phosphorylation in the cell line. Amuvatinib at concentrations of 5, 10, or 25 µM readily inhibited HGF-dependent MET, AKT, ERK and GSK-3-beta phosphorylation. MET-mediated effects were not observed in myeloma cell line that has low MET and/or HGF expression. CONCLUSIONS: These data suggest that at the cellular level MET/HGF pathway inclines with myeloma disease progression. Amuvatinib, a small molecule MET kinase inhibitor, is effective in inducing growth inhibition and cell death in myeloma cell lines as well as primary malignant plasma cells. These cytostatic and cytotoxic effects were associated with an impact on MET/HGF pathway.
Asunto(s)
Mieloma Múltiple/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirimidinas/farmacología , Anciano , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/enzimología , Mieloma Múltiple/patología , Piperazinas , Transducción de Señal/efectos de los fármacos , TioureaRESUMEN
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder associated mainly with tumors of multiple endocrine organs. Mutations in the MEN1 gene that encodes for the menin protein are the predominant cause for hereditary MEN1 syndrome. Though menin is a tumor suppressor, its molecular mechanism of action has not been defined. Here, we report that menin interacts with AKT1 in vitro and in vivo. Menin downregulates the level of active AKT and its kinase activity. Through interaction with AKT1, menin suppresses both AKT1-induced proliferation and antiapoptosis in nonendocrine and endocrine cells. Confocal microscopy analysis revealed that menin regulates AKT1 in part by reducing the translocation of AKT1 from the cytoplasm to the plasma membrane during growth factor stimulation. Our findings may be generalizable to other cancers, insofar as we found that loss of menin expression was also associated with AKT activation in a mouse model of pancreatic islet adenoma. Together, our results suggest menin as an important novel negative regulator of AKT kinase activity.
Asunto(s)
Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Animales , Procesos de Crecimiento Celular , Membrana Celular/enzimología , Membrana Celular/metabolismo , Activación Enzimática , Células HEK293 , Humanos , Ratones , Microscopía Confocal , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas/deficiencia , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , TransfecciónRESUMEN
Addition of glucose to yeast cells increases their growth rate and results in a massive restructuring of their transcriptional output. We have used microarray analysis in conjunction with conditional mutations to obtain a systems view of the signaling network responsible for glucose-induced transcriptional changes. We found that several well-studied signaling pathways-such as Snf1 and Rgt-are responsible for specialized but limited responses to glucose. However, 90% of the glucose-induced changes can be recapitulated by the activation of protein kinase A (PKA) or by the induction of PKB (Sch9). Blocking signaling through Sch9 does not interfere with the glucose response, whereas blocking signaling through PKA does. We conclude that both Sch9 and PKA regulate a massive, nutrient-responsive transcriptional program promoting growth, but that they do so in response to different nutritional inputs. Moreover, activating PKA completely recapitulates the transcriptional growth program in the absence of any increase in growth or metabolism, demonstrating that activation of the growth program results solely from the cell's perception of its nutritional status.
Asunto(s)
Regulación Fúngica de la Expresión Génica , Glucosa/fisiología , Transducción de Señal , Transcripción Genética , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Perfilación de la Expresión Génica , Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , LevadurasRESUMEN
Yeast cells sense the amount and quality of external nutrients through multiple interconnected signaling networks, which allow them to adjust their metabolism, transcriptional profile and developmental program to adapt readily and appropriately to changing nutritional states. We present our current understanding of the nutritional sensing networks yeast cells rely on for perceiving the nutritional landscape, with particular emphasis on those sensitive to carbon and nitrogen sources. We describe the means by which these networks inform the cell's decision among the different developmental programs available to them-growth, quiescence, filamentous development, or meiosis/sporulation. We conclude that the highly interconnected signaling networks provide the cell with a highly nuanced view of the environment and that the cell can interpret that information through a sophisticated calculus to achieve optimum responses to any nutritional condition.
Asunto(s)
Saccharomyces/metabolismo , Aminoácidos/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas de Unión al ADN , Genes Fúngicos , Glucosa/metabolismo , Redes y Vías Metabólicas , Modelos Biológicos , Nitrógeno/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Represoras/metabolismo , Saccharomyces/citología , Saccharomyces/genética , Saccharomyces/crecimiento & desarrollo , Proteínas de Saccharomyces cerevisiae/metabolismo , Transducción de Señal , Estrés Fisiológico , Transactivadores/metabolismo , Factores de Transcripción , Transcripción Genética , Proteínas ras/metabolismoRESUMEN
Autophagy is a highly conserved, degradative process in eukaryotic cells. The rapamycin-sensitive Tor kinase complex 1 (TORC1) has a major role in regulating induction of autophagy; however, the regulatory mechanisms are not fully understood. Here, we find that the protein kinase A (PKA) and Sch9 signaling pathways regulate autophagy cooperatively in yeast. Autophagy is induced in cells when PKA and Sch9 are simultaneously inactivated. Mutant alleles of these kinases bearing a mutation that confers sensitivity to the ATP-analogue inhibitor C3-1'-naphthyl-methyl PP1 revealed that autophagy was induced independently of effects on Tor kinase. The PKA-Sch9-mediated autophagy depends on the autophagy-related 1 kinase complex, which is also essential for TORC1-regulated autophagy, the transcription factors Msn2/4, and the Rim15 kinase. The present results suggest that autophagy is controlled by the signals from at least three partly separate nutrient-sensing pathways that include PKA, Sch9, and TORC1.