RESUMO
BACKGROUND: Salivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer, frequently associated with incurable recurrences and distant metastases (R/M). Proliferation of SDC relies on androgen receptor (AR) signalling, prompting the use of combined androgen blockade (CAB, i.e., luteinizing hormone-releasing hormone agonist and/or AR antagonists) to R/M SDC patients. However, only a subset of patients benefits from such treatments. We have shown that response to CAB is associated with steroid 5α-reductase 1 (SRD5A1) mRNA expression. SRD5A1 catalyses the intracellular conversion of testosterone into the more potent AR-agonist dihydrotestosterone. This conversion can be inhibited by dutasteride, a potent SRD5A1-inhibitor, which is currently prescribed for benign prostatic hyperplasia. We hypothesize that repurposing dutasteride to target AR signalling in SDC could enhance therapeutic response and clinical outcome in SDC patients. METHODS: This prospective, open-label, randomized controlled phase II clinical trial, is designed to investigate whether dutasteride as an adjunct drug to CAB improves response rate and clinical outcome in patients with AR-positive R/M SDC. Patients are divided in two cohorts based on their prior systemic treatments. In cohort A, CAB-naïve patients (n = 74) will be randomly assigned to either a control arm (Arm 1) receiving CAB (goserelin 10.8 mg/3m and bicalutamide 50 mg/OD) or an experimental arm (Arm 2) where dutasteride (0.5 mg/OD) is added to the CAB regimen. In cohort B, patients with disease progression after adjuvant or first-line palliative CAB therapy (max. n = 24) will receive goserelin, bicalutamide, and dutasteride to assess whether the addition of dutasteride can overcome therapy resistance. The primary endpoints are the objective response rate and duration of response. Secondary endpoints are progression-free survival, overall survival, clinical benefit rate, quality of life, and safety. Translational research will be performed to explore molecular target expression differences and their correlation with clinical outcome. DISCUSSION: The DUCT study addresses an unmet medical need by investigating the repurposing of dutasteride to enhance treatment response and improve clinical outcome for patients with R/M SDC, especially those with limited alternative treatment options, such as HER2-negative cases. By repurposing a registered low-cost drug, this trial's findings could be readily applied into clinical practice. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT05513365. Date of registration: August 24, 2022. PROTOCOL VERSION: Current protocol version 4.0, February 21, 2024.
Assuntos
Antagonistas de Androgênios , Protocolos de Quimioterapia Combinada Antineoplásica , Dutasterida , Neoplasias das Glândulas Salivares , Compostos de Tosil , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de 5-alfa Redutase/uso terapêutico , Inibidores de 5-alfa Redutase/administração & dosagem , Antagonistas de Androgênios/uso terapêutico , Antagonistas de Androgênios/administração & dosagem , Anilidas/administração & dosagem , Anilidas/uso terapêutico , Anilidas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dutasterida/uso terapêutico , Dutasterida/administração & dosagem , Nitrilas/uso terapêutico , Nitrilas/administração & dosagem , Estudos Prospectivos , Ductos Salivares/patologia , Neoplasias das Glândulas Salivares/tratamento farmacológico , Neoplasias das Glândulas Salivares/patologia , Neoplasias das Glândulas Salivares/genética , Compostos de Tosil/uso terapêutico , Compostos de Tosil/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase II como AssuntoRESUMO
AIM: To investigate the outcomes of cabozantinib in patients with unresectable hepatocellular carcinoma (uHCC), focusing on dose setting and modification. METHODS: We retrospectively analyzed 34 Japanese patients who received cabozantinib for uHCC. Trough concentrations (Ctrough) of cabozantinib were also measured weekly for 6 weeks in the 18 patients. RESULTS: Sixteen patients received ≥40 mg (high-dose group), and 18 patients received 20 mg (low-dose group). Dose escalations were performed in 27.8% of the patients in the low-dose group. Although median duration of the first dose reduction or interruption in the low-dose group was twice that in the high-dose group (28 vs. 14 days, p < 0.001), there were no significant differences in the relative dose intensity (RDI) during 6 weeks, progression free survival (PFS), and overall survival (p = 0.162, p = 0.950, p = 0.817, respectively) between the two groups. Patients who received RDI during 6 weeks ≥33.4% showed a trend toward longer median PFS (p = 0.054). Each serum aldolase value during the 6 weeks was significantly correlated with the Ctrough at any point (r = 0.500, p < 0.001). In multivariate analyses, aldolase ≥8.7 U/L within 2 weeks was significantly associated with the very early dose reduction or interruption (odds ratio 20.0, p = 0.002). CONCLUSIONS: An initial dose of 20 mg cabozantinib could be a safe option in Japanese patients. The serum aldolase value could be useful for making appropriate dose modifications of cabozantinib.
Assuntos
Anilidas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Piridinas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Anilidas/administração & dosagem , Anilidas/uso terapêutico , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Masculino , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Feminino , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Relação Dose-Resposta a Droga , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Resultado do Tratamento , Intervalo Livre de Progressão , AdultoRESUMO
It is highly uncommon for solid tumours to metastasise to the testis. Here, we report a case of metachronous testicular metastasis from clear cell renal cell cancer (RCC) in a male patient 3 years after left radical nephrectomy. Ultrasound of the scrotum showed a 3.5 cm × 4 cm left testicular mass with normal serum tumour markers. The patient underwent left high inguinal orchidectomy, which revealed metastatic renal cell carcinoma. CT of the chest, abdomen and pelvis showed multiple liver secondaries. Cabozantinib was started for metastatic RCC, and the patient showed no evidence of disease progression in a follow-up of 1 year.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Nefrectomia , Orquiectomia , Neoplasias Testiculares , Humanos , Masculino , Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/cirurgia , Neoplasias Testiculares/patologia , Neoplasias Testiculares/cirurgia , Neoplasias Testiculares/secundário , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Pessoa de Meia-Idade , Segunda Neoplasia Primária/patologia , Anilidas/uso terapêutico , Piridinas/uso terapêuticoRESUMO
PURPOSE: Metastatic non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous disease with a poor prognosis and is treated with immunotherapy (IO)-based combinations according to the clear cell renal cell carcinoma. Tyrosine-kinase inhibitors (TKIs), such as cabozantinib and axitinib, are commonly used as the 2nd line therapy after 1st line IO combination therapy, but their efficacy as 2nd line TKI therapy for nccRCC is unknown. In this study, we performed a retrospective multicenter analysis of nccRCC patients who were previously treated with IO combination therapy and received 2nd line TKIs. METHODS: Among 254 patients enrolled in the Japanese multicenter retrospective study, 52 patients with nccRCC histology who received second-line TKIs were included in this study. Progression-free survival and overall survival (OS) from 2nd line TKIs were analyzed by log-rank test and Cox-proportional hazard model. Objective response rate (ORR) of 2nd line TKIs were analyzed. RESULTS: The 1-year PFS and OS rates were 25.0% (95% CI = 13.1-36.8) and 63.8% (95% CI, 48.0-75.9), respectively. No patients had a complete response, 11 had a partial response, and 18 had stable disease. ORR was 21.1%. IMDC poor risk and sunitinib as the 2nd line therapy were significantly associated with poor PFS. CONCLUSION: The 2nd-line TKI was effective for a small group of nccRCC patients previously treated with IO combination therapy, although this study was retrospectively analyzed with a small number of cases.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Inibidores de Proteínas Quinases , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Estudos Retrospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/secundário , Imunoterapia/métodos , Resultado do Tratamento , Adulto , Taxa de Sobrevida , Idoso de 80 Anos ou mais , Axitinibe/uso terapêutico , Anilidas , PiridinasRESUMO
Concomitant direct oral anticoagulants (DOACs) and tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (anti-VEGF TKI) have been associated with a higher risk of bleeding. Nevertheless, concomitant administration seems frequent in clinical practice in patients with cancer-associated thrombosis and appears to be safe according to the retrospective study by Boileve A. et al. But the risk of an additional pharmacokinetic interaction between anti-VEGF TKI and DOACs must be considered, in case of P-glycoprotein (P-gp) inhibition by the TKI. We describe a case report with a major bleeding event in a renal metastatic cancer patient treated with cabozantinib and rivaroxaban. This case highlights the difficult therapeutic decision in a complex patient with cancer-associated thrombosis, who refused the anticoagulant subcutaneous route. Accumulation of bleeding risk factors (genito-urinary tumor localization) was additive to several pharmacodynamic interactions (acetylsalicylic acid, venlafaxine) and a potential pharmacokinetic interaction between cabozantinib and rivaroxaban. Indeed, cabozantinib-related P-glycoprotein inhibition could have led to a supratherapeutic level of rivaroxaban, contributing partly to the bleeding event. Before combining an anti-VEGF TKI and DOACs, a multidisciplinary pretherapeutic assessment seems crucial to evaluate the patient's bleeding risk factors, pharmacodynamic interactions, and the risk of pharmacokinetic interactions mediated by P-gp.
Assuntos
Anticoagulantes , Interações Medicamentosas , Piridinas , Rivaroxabana , Humanos , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Estudos Retrospectivos , Piridinas/efeitos adversos , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Piridinas/farmacocinética , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Rivaroxabana/farmacocinética , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Anilidas/administração & dosagem , Anilidas/efeitos adversos , Anilidas/farmacocinética , Hemorragia/induzido quimicamente , Neoplasias Renais/tratamento farmacológico , Masculino , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Trombose/induzido quimicamente , Trombose/etiologia , Neoplasias/tratamento farmacológico , Neoplasias/complicações , Administração Oral , IdosoRESUMO
The binding mechanism of molecular interaction between bicalutamide and human serum albumin (HSA) in a pH 7.4 phosphate buffer was studied using various spectroscopic techniques in combination with molecular modeling. Fluorescence data revealed that the fluorescence quenching of HSA by bicalutamide was a static quenching procedure. The binding constants and number of binding sites were evaluated at different temperatures. The thermodynamic parameters, ΔH and ΔS, were calculated to be 4.30 × 104 J·mol-1 and 245 J·mol-1·K-1, respectively, suggesting that the binding of bicalutamide to HSA was driven mainly by hydrophobic interactions and hydrogen bonds. The displacement studies indicated neither Sudlow's site I nor II but subdomain IB as the main binding site for bicalutamide on HSA. The binding distance between bicalutamide and HSA was determined to be 3.54 nm based on the Förster theory. Analysis of circular dichroism, synchronous, and 3D fluorescence spectra demonstrated that HSA conformation was slightly altered in the presence of bicalutamide.
Assuntos
Anilidas , Nitrilas , Albumina Sérica Humana , Espectrometria de Fluorescência , Termodinâmica , Compostos de Tosil , Compostos de Tosil/química , Anilidas/química , Anilidas/metabolismo , Nitrilas/química , Nitrilas/metabolismo , Humanos , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo , Dicroísmo Circular , Sítios de Ligação , Modelos Moleculares , Interações Hidrofóbicas e Hidrofílicas , Ligação de HidrogênioRESUMO
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.LIBRETTO-001 is a registrational phase I/II, single-arm, open-label study of selpercatinib in patients with RET (REarranged during Transfection)-activated cancers (ClinicalTrials.gov identifier: NCT03157128). We present long-term safety and efficacy from LIBRETTO-001 in patients with RET-mutant medullary thyroid cancer (MTC; n = 324) and RET fusion-positive thyroid cancer encompassing different histological subtypes (TC; n = 66). At the data cutoff of January 2023, the objective response rate was 82.5% among patients with cabozantinib/vandetanib-naïve MTC and 95.8% among patients with treatment-naïve TC. At a median follow-up time of 42.4 and 44.0 months in patients with cabozantinib/vandetanib-naïve and pretreated MTC, the median progression-free survival (PFS) was not reached and 41.4 months, respectively. At a median follow-up time of 24.9 and 30.4 months in patients with treatment-naïve and pretreated TC, the median PFS was not reached and 27.4 months, respectively. Three-year PFS rates were 75.2% and 87.3% among patients with cabozantinib/vandetanib-naïve MTC and treatment-naïve TC, respectively. Median PFS was similar to median duration of response for each patient group. The safety profile of selpercatinib was consistent with previous reports. With an additional follow-up of 37 months and 228 more patients from the last disclosure, selpercatinib continued to provide durable and robust responses in treatment-naïve and previously treated patients with RET-mutant MTC and RET fusion-positive TC.
Assuntos
Proteínas Proto-Oncogênicas c-ret , Pirazóis , Piridinas , Neoplasias da Glândula Tireoide , Humanos , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Idoso , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Piridinas/uso terapêutico , Piridinas/efeitos adversos , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Adulto Jovem , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Idoso de 80 Anos ou mais , Intervalo Livre de Progressão , Mutação , AnilidasRESUMO
BACKGROUND: This retrospective observational study explored the therapeutic potential of combined androgen blockade (CAB) with bicalutamide (Bic-CAB) as an initial treatment for metastatic hormone-sensitive prostate cancer (mHSPC) in Japan. METHODS: The electronic health records of 159 patients with mHSPC from three Japanese institutions who received initial treatment with Bic-CAB between 2007 and 2017 were analyzed. The time to prostate-specific antigen (PSA) progression, duration of Bic-CAB treatment, and overall survival (OS), with various definitions for PSA progression, were assessed. A multivariate Cox proportional hazards model was constructed using clinical parameters to predict time to the end of Bic-CAB treatment and OS. RESULTS: The median observation period was 46.4 months, and the median age of patients at diagnosis was 71 years. A total of 46.5% patients experienced PSA progression with a median survival duration of 29 months (according to Prostate Cancer Clinical Trials Working Group 3 criteria), and 49.1% patients achieved a PSA nadir < 0.2 ng/mL in a median time of 4.7 months. When stratified by PSA nadir and PSA change, patients at low risk for disease progression with a small PSA change due to low initial PSA had a 5-year OS of 100% and a 10-year OS of 75%. The OS during the observation period was 72.9 months. CONCLUSION: These findings highlight the potential effect of Bic-CAB in patients with mHSPC who were at low risk for disease progression. Initial treatment with Bic-CAB and adjusting treatment early based on PSA dynamics may be a reasonable treatment plan for these patients.
Assuntos
Antagonistas de Androgênios , Anilidas , Nitrilas , Antígeno Prostático Específico , Neoplasias da Próstata , Compostos de Tosil , Humanos , Masculino , Anilidas/uso terapêutico , Anilidas/administração & dosagem , Compostos de Tosil/uso terapêutico , Compostos de Tosil/administração & dosagem , Nitrilas/uso terapêutico , Nitrilas/administração & dosagem , Estudos Retrospectivos , Antígeno Prostático Específico/sangue , Idoso , Antagonistas de Androgênios/uso terapêutico , Antagonistas de Androgênios/administração & dosagem , Pessoa de Meia-Idade , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/mortalidade , Japão , Idoso de 80 Anos ou mais , Prognóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Progressão da Doença , População do Leste AsiáticoRESUMO
BACKGROUND: Efficacy of treatment after failure of check point inhibitors (ICI) therapy remains ill-defined in metastatic renal cell carcinoma (mRCC). OBJECTIVE: To evaluate the safety and effectiveness of cabozantinib after failure of ICI-based therapies. DESIGN, SETTING AND PARTICIPANTS: Patients with mRCC who concluded cabozantinib treatment directly after an ICI-based therapy were eligible. Data was collected retrospectively from participating sites in Germany. INTERVENTIONS: Cabozantinib was administered as a standard of care. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adverse events (AE) were reported according to CTCAE v5.0. Objective response rate according to RECIST 1.1 and Progression Free Survival (PFS) were collected from medical records. Descriptive statistics and Kaplan-Meyer-plots were utilized. RESULTS AND LIMITATIONS: About 56 eligible patients (71.4% male) with median age of 66 years and clear cell histology in 66.1% (n = 37) were analyzed. 87.5% (n = 49) had ≥ 2 previous lines. IMDC risk was intermediate or poor in 17 patients (30.4%) and missing in 66.1%. 20 patients (35.7%) started with 60 mg. 55.4% (n = 31) required dose reductions, 26.8% (n = 15) treatment delays and 1.8% (n = 1) treatment discontinuation. Partial response was reported in 10.7% (n = 6), stable and progressive disease were reported in 19.6% (n = 11) and in 12.5% (n = 7). 32 patients were not evaluable (57.1%). Median treatment duration was 6.1 months. Treatment related AE were reported in 76.8% (n = 43) and 19.6% (n = 11) had grade 3-5. Fatigue (26.8%), diarrhea (26.8%) and hand-foot-syndrome (25.0%) were the 3 most frequent AEs of any grade and causality. SAE were reported in 21.4% (n = 12), 2 were fatal. Major limitation was the retrospective data capture in our study. CONCLUSIONS: Cabozantinib followed directly after ICI-based therapy was safe and feasible. No new safety signals were reported. A lower starting dose was frequently utilized in this real-world cohort, which was associated with a favorable tolerability profile. Our data supports the use of cabozantinib after ICI treatment.
Assuntos
Anilidas , Carcinoma de Células Renais , Neoplasias Renais , Piridinas , Humanos , Anilidas/efeitos adversos , Anilidas/administração & dosagem , Anilidas/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Masculino , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Feminino , Idoso , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Estudos Retrospectivos , Pessoa de Meia-Idade , Alemanha/epidemiologia , Idoso de 80 Anos ou mais , Intervalo Livre de Progressão , Adulto , Resultado do Tratamento , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
INTRODUCTION: Real-world data are limited on treatment sequencing and outcomes after first-line (1L) immune checkpoint inhibitor (CPI)-based combination treatment of advanced renal cell carcinoma (aRCC). PATIENTS AND METHODS: In this real-world, UK-based, retrospective study (CARINA; NCT04957160), data were obtained from hospital and electronic prescribing records. Patients were aged ≥ 18 years at aRCC diagnosis and had received 1L CPI-CPI or tyrosine kinase inhibitor (TKI)-CPI combination therapy before second-line (2L) therapy including cabozantinib. We describe treatment outcomes including 1L and 2L durations of treatment (DoT) and overall survival (OS). RESULTS: Data from April 2015 to June 2022 were collected on 281 patients from nine UK centres. Median 1L DoT was 2.3 months for CPI-CPI therapy (n = 171) and 5.0 months for TKI-CPI therapy (n = 58). After 1L CPI-CPI or TKI-CPI therapy, median 2L DoT was 5.8 versus 4.2 months, respectively, for cabozantinib (n = 163), and 3.8 versus 2.4 months for other therapies (n = 118); median 2L OS was 15.2 and 15.3 months, respectively, for cabozantinib, and 14.6 and 24.2 months for other therapies. CONCLUSION: DoT for 2L treatment was numerically better for cabozantinib than for other therapies, and after 1L CPI-CPI therapy than after 1L TKI-CPI therapy. Median OS was similar for 2L cabozantinib and other 2L therapies, and median OS for 2L cabozantinib was similar after both 1L therapy types. These results demonstrate the antitumour effect of 2L therapies, including cabozantinib, after 1L CPI-based combination treatment, regardless of whether 1L CPI-CPI or TKI-CPI therapy is used.
Assuntos
Anilidas , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renais , Inibidores de Checkpoint Imunológico , Neoplasias Renais , Piridinas , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Piridinas/uso terapêutico , Piridinas/administração & dosagem , Anilidas/uso terapêutico , Anilidas/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/mortalidade , Masculino , Inibidores de Checkpoint Imunológico/uso terapêutico , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resultado do Tratamento , Adulto , Idoso de 80 Anos ou mais , Reino Unido , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagemRESUMO
BACKGROUND: Genetic variants of UGT1A1, involved in glucuronidation and clearance of bilirubin, are associated with reduced bilirubin metabolization and drug-induced isolated hyperbilirubinemia. We studied the impact of the UGT1A1*28 polymorphism on drug-induced isolated hyperbilirubinemia in metastatic renal cell carcinoma patients treated with pazopanib, cabozantinib, and axitinib. METHODS: We genotyped the UGT1A1*28 TA6/TA6-TA6/TA7-TA7/TA7 polymorphism and correlated with median baseline, on-treatment and peak bilirubin levels during therapy, incidence of grade-1- or -2 (G1/2)-hyperbilirubinemia and time-to-G1-hyperbilirubinemia. RESULTS: Of the 66 patients treated with pazopanib, 29 received axitinib and 28 cabozantinib upon progression. Median baseline bilirubin was higher in TA7/TA7-carriers versus TA6/TA6+TA6/TA7-carriers at start of pazopanib (P < .0001), cabozantinib (P < .0001), and axitinib (P = .007). During pazopanib therapy, median bilirubin increased 1.4-fold in TA7/TA7+TA6/TA7-carriers but not in TA6/TA6-carriers. On cabozantinib, bilirubin increased 1.5-fold in TA7/TA7-carriers but not in TA6/TA6+TA6/TA7-carriers. Axitinib did not increase bilirubin in any genotype. Peak bilirubin in TA7/TA7- versus TA6/TA6+TA6/TA7-carriers was higher on pazopanib (P < .0001) or cabozantinib (P < .0001). With pazopanib, G1-hyperbilirubinemia occurred in 57% of TA7/TA7- and 12% of TA6/TA6+TA6/TA7-carriers (P = .0009) and G2-hyperbilirubinemia in 36% and 6% of the patients, respectively (P = .004). On cabozantinib, G1-hyperbilirubinemia occurred in 100% of TA7/TA7- and 5% of TA6/TA6+TA6/TA7-carriers (P < .0001) and G2-hyperbilirubinemia in 33% and 0% of the patients, respectively (P = .04). On axitinib, no correlation between the genotypes and G1/2-hyperbilirubinemia was observed. CONCLUSION: We validate the previously described impact of the UGT1A1*28 polymorphism on isolated bilirubin increase on pazopanib. We report for the first time that cabozantinib also interferes with UGT1A1 and causes isolated bilirubin increase.
Assuntos
Anilidas , Carcinoma de Células Renais , Glucuronosiltransferase , Hiperbilirrubinemia , Indazóis , Neoplasias Renais , Piridinas , Pirimidinas , Sulfonamidas , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Glucuronosiltransferase/genética , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Hiperbilirrubinemia/induzido quimicamente , Hiperbilirrubinemia/genética , Piridinas/uso terapêutico , Piridinas/efeitos adversos , Anilidas/uso terapêutico , Anilidas/efeitos adversos , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Indazóis/uso terapêutico , Idoso , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Axitinibe/uso terapêutico , Axitinibe/efeitos adversos , Axitinibe/administração & dosagem , Bilirrubina/sangue , Genótipo , Adulto , Polimorfismo Genético , Idoso de 80 Anos ou maisRESUMO
Prostate cancer (PC) is the fifth leading cause of cancer-related deaths among men worldwide. Prostate-specific membrane antigen (PSMA), a molecular target of PC, is clinically used for the treatment and diagnosis of PC using radioligand approaches. However, no PSMA-based chemotherapies have yet been approved by the FDA. Here, we present a novel therapeutic approach using PSMA-targeted 2-deoxyglucose-dendrimer (PSMA-2DG-D) for targeted delivery of a potent tyrosine kinase inhibitor, cabozantinib (Cabo), selectively to PC cells. PSMA-2DG-D demonstrates intracellular localization in PSMA (+) PC cells through PSMA-mediated internalization. This PSMA-specific targeting translates to enhanced efficacy of Cabo compared to the free drug when conjugated to PSMA-2DG-D. Furthermore, systemically administered fluorescently labeled PSMA-2DG-D-Cy5 specifically targets PSMA (+) tumors with minimal off-target accumulation in the PC3-PIP tumor xenograft mouse model. This demonstrates that the PSMA-2DG-D platform is a promising new delivery system for potent chemotherapeutics, where systemic side effects are a significant concern.
Assuntos
Antígenos de Superfície , Dendrímeros , Desoxiglucose , Glutamato Carboxipeptidase II , Neoplasias da Próstata , Piridinas , Masculino , Humanos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Animais , Camundongos , Desoxiglucose/farmacologia , Desoxiglucose/química , Piridinas/química , Piridinas/administração & dosagem , Piridinas/farmacologia , Glutamato Carboxipeptidase II/metabolismo , Glutamato Carboxipeptidase II/antagonistas & inibidores , Dendrímeros/química , Antígenos de Superfície/metabolismo , Anilidas/farmacologia , Anilidas/administração & dosagem , Anilidas/farmacocinética , Anilidas/química , Nanomedicina/métodos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus , Sistemas de Liberação de Medicamentos/métodosRESUMO
INTRODUCTION: The existing large prospective study demonstrates the benefits of primary radiotherapy in patients with low-volume oligometastatic prostate cancer (OMPC), and there is additional evidence of the benefits of local metastasis-directed therapy (MDT) for metastatic lesions. However, there are no results from a prospective study to demonstrate the efficacy of radiotherapy for prostate and oligometastases. Therefore, the aim of the protocol is to illustrate the efficacy of radiotherapy for prostate and oligometastatic lesions in patients with low-volume de novo hormone-sensitive OMPC. METHODS AND ANALYSIS: This study involves a prospective, single-center, limited-sample, single-arm exploration of radiotherapy for prostate and oligometastatic lesions in patients diagnosed with low-volume hormone-sensitive OMPC. Eligible participants undergo thorough assessments and treatment involving endocrine therapy alongside radiation targeting metastatic lesions and the pelvic region. The primary site is treated with volumetric modulated arc therapy (VMAT), while metastatic sites are treated with either VMAT or stereotactic body radiation therapy (SBRT) depending on their location. All patients received radiation therapy for both the primary and metastatic lesions combined with endocrine therapy. Endocrine therapy with an antiandrogen (bicalutamide, for 4 weeks) androgen deprivation therapy combined with novel hormonal agents (acetate abiraterone) will be continued for 2 years. The primary objective is to evaluate progression-free survival-2 (PFS-2), while secondary endpoints include androgen deprivation therapy (ADT)-free survival, quality of life (QoL), overall survival, time to castration-resistant prostate cancer (CRPC), radiation-related complications, and endocrine therapy-related adverse events. ETHICS AND DISSEMINATION: Approval was obtained from the ethics committee of the First Affiliated Hospital of Naval Medical University (CHEC2023-220). This is a single-arm exploration pilot trial evaluating radiotherapy for prostate and oligometastatic lesions in patients with OMPC. It aims to disseminate its findings through peer-reviewed journals and relevant medical conferences, with the intention of publication and presentation at these events. TRIAL REGISTRATION NUMBERS: Clinicaltrials.gov identifier NCT06198387.
Assuntos
Metástase Neoplásica , Neoplasias da Próstata , Radiocirurgia , Humanos , Masculino , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia , Projetos Piloto , Estudos Prospectivos , Radiocirurgia/métodos , Radioterapia de Intensidade Modulada/métodos , Radioterapia de Intensidade Modulada/efeitos adversos , Qualidade de Vida , Antagonistas de Androgênios/uso terapêutico , Nitrilas/uso terapêutico , Anilidas/uso terapêutico , Anilidas/administração & dosagemRESUMO
The study presents a thorough and detailed analysis of bicalutamide's structural and conformational properties. Quantum chemical calculations were employed to explore the conformational properties of the molecule, identifying significant energy differences between conformers. Analysis revealed that hydrogen bonds stabilise the conformers, with notable variations in torsion angles. Conformers were classified into 'closed' and 'open' types based on the relative orientation of the cyclic fragments. NOE spectroscopy in different solvents (CDCl3 and DMSO-d6) was used to study the conformational preferences of the molecule. NOESY experiments provided the predominance of 'closed' conformers in non-polar solvents and a significant presence of 'open' conformers in polar solvents. The proportions of open conformers were 22.7 ± 3.7% in CDCl3 and 59.8 ± 6.2% in DMSO-d6, while closed conformers accounted for 77.3 ± 3.7% and 40.2 ± 6.2%, respectively. This comprehensive study underscores the solvent environment's impact on its structural behaviour. The findings significantly contribute to a deeper understanding of conformational dynamics, stimulating further exploration in drug development.
Assuntos
Anilidas , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Conformação Molecular , Nitrilas , Solventes , Compostos de Tosil , Anilidas/química , Compostos de Tosil/química , Solventes/química , Nitrilas/química , Espectroscopia de Ressonância Magnética/métodos , Teoria Quântica , Modelos Moleculares , SoluçõesAssuntos
Anilidas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Piridinas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/terapia , Piridinas/uso terapêutico , Anilidas/uso terapêutico , Antineoplásicos/uso terapêuticoRESUMO
ABSTRACT: Targeted immunotherapy became the most advanced approach for cancer treatment. Programmed death-1 (PD-1) expressed on activated T cells can reverse immune suppression and cause T-cell activation. Nivolumab, a PD-1 immune checkpoint inhibitor antibody that is a fully human immunoglobulin G4, blocks PD-1 and promotes antitumor immunity. Cabozantinib (tyrosine kinase inhibitor) inhibits the tyrosine kinase activity of vascular endothelial growth factor receptors 1, 2, and 3. As a result of enhancing immune response in normal tissues, immune-related adverse events can occur. Thyroid dysfunction is a common form of immune-related adverse event and seen on 18 F-FDG PET/CT scans post therapy.
Assuntos
Anilidas , Carcinoma de Células Renais , Fluordesoxiglucose F18 , Imunoterapia , Neoplasias Renais , Nivolumabe , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Piridinas , Humanos , Nivolumabe/efeitos adversos , Anilidas/efeitos adversos , Piridinas/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/diagnóstico por imagem , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/diagnóstico por imagem , Imunoterapia/efeitos adversos , Masculino , Doenças da Glândula Tireoide/diagnóstico por imagem , Doenças da Glândula Tireoide/induzido quimicamente , Pessoa de Meia-IdadeRESUMO
We designed and synthesized an N-ortho-nitrobenzylated benzanilide-based amino acid having a cis-amide structure that facilitates cyclization of peptides containing it. Photo-induced removal of the nitrobenzyl group from this residue in the resulting cyclized peptides dramatically alters their conformation and passive membrane permeability via complete cis-amide to trans-amide conversion.
Assuntos
Aminoácidos , Permeabilidade da Membrana Celular , Peptídeos Cíclicos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Aminoácidos/química , Anilidas/química , Nitrobenzenos/química , Ciclização , Conformação ProteicaRESUMO
BACKGROUND: The selection of appropriate second-line therapy for liver cancer after first-line treatment failure poses a significant clinical challenge due to the lack of direct comparative studies and standard treatment protocols. A network meta-analysis (NMA) provides a robust method to systematically evaluate the clinical outcomes and adverse effects of various second-line treatments for hepatocellular carcinoma (HCC). METHODS: We systematically searched PubMed, Embase, Web of Science and the Cochrane Library to identify phase III/IV randomized controlled trials (RCTs) published up to March 11, 2024. The outcomes extracted were median overall survival (OS), median progression-free survival (PFS), time to disease progression (TTP), disease control rate (DCR), objective response rate (ORR), and adverse reactions. This study was registered in the Prospective Register of Systematic Reviews (CRD42023427843) to ensure transparency, novelty, and reliability. RESULTS: We included 16 RCTs involving 7,005 patients and 10 second-line treatments. For advanced HCC patients, regorafenib (HR = 0.62, 95%CI: 0.53-0.73) and cabozantinib (HR = 0.74, 95%CI: 0.63-0.85) provided the best OS benefits compared to placebo. Cabozantinib (HR = 0.42, 95%CI: 0.32-0.55) and regorafenib (HR = 0.46, 95% CI: 0.31-0.68) also offered the most significant PFS benefits. For TTP, apatinib (HR = 0.43, 95% CI: 0.33-0.57), ramucirumab (HR = 0.44, 95% CI: 0.34-0.57), and regorafenib (HR = 0.44, 95% CI: 0.38-0.51) showed significant benefits over placebo. Regarding ORR, ramucirumab (OR = 9.90, 95% CI: 3.40-42.98) and S-1 (OR = 8.68, 95% CI: 1.4-154.68) showed the most significant increases over placebo. Apatinib (OR = 3.88, 95% CI: 2.48-6.10) and cabozantinib (OR = 3.53, 95% CI: 2.54-4.90) provided the best DCR benefits compared to placebo. Tivantinib showed the most significant advantages in terms of three different safety outcome measures. CONCLUSIONS: Our findings suggest that, in terms of overall efficacy and safety, regorafenib and cabozantinib are the optimal second-line treatment options for patients with advanced HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Metanálise em Rede , Piridinas , Ensaios Clínicos Controlados Aleatórios como Assunto , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/mortalidade , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/mortalidade , Piridinas/uso terapêutico , Piridinas/efeitos adversos , Anilidas/uso terapêutico , Anilidas/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Ramucirumab , Resultado do Tratamento , Intervalo Livre de Progressão , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
Sepsis-related brain injury (SRBI) refers to brain dysfunction and structural damage caused by sepsis, which is characterized by inflammation, oxidative stress, and destruction of the blood-brain barrier. Pioglitazone is a PPAR-γ agonist in which PPAR-γ acts as an inflammatory modulator, determining the relationship between PPAR-γ and SRBI and inflammatory state is critical for the disease. This study aimed to construct a drug-target-disease network for SRBI and Pioglitazone based on network pharmacology, and to investigate the therapeutic effect and potential mechanism of Pioglitazone in SRBI induced by lipopolysaccharide (LPS) in rats through transcriptomics. To establish a rat Model of SRBI by intraperitoneal injection of LPS (10 mg/kg): SD rats were divided into Control, Model (LPS), Pioglitazone, (LPS + Pioglitazone) and GW9662 group (LPS+GW9662). The effects and potential mechanisms of Pioglitazone in the treatment of SRBI were studied using biochemical indexes, pathological changes and transcriptome-sequencing (RNA-seq). RNA-seq results showed 620 DEGs between the Model and the Pioglitazone groups. Enrichment analysis involved multiple inflammatory response processes and chemokine receptor binding functions. TLR4 and CXCL10 in the Toll signaling pathway may play an important role in SRBI as important targets. Pioglitazone may ameliorate SRBI through the PPAR-γ/TLR4/CXCL10 pathway.
Assuntos
Lipopolissacarídeos , PPAR gama , Pioglitazona , Ratos Sprague-Dawley , Sepse , Transcriptoma , Pioglitazona/farmacologia , Animais , Ratos , PPAR gama/metabolismo , PPAR gama/genética , Masculino , Transcriptoma/efeitos dos fármacos , Sepse/tratamento farmacológico , Sepse/genética , Sepse/complicações , Sepse/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Modelos Animais de Doenças , Transdução de Sinais/efeitos dos fármacos , Anilidas/farmacologia , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/metabolismo , Lesões Encefálicas/genética , Lesões Encefálicas/etiologia , Perfilação da Expressão Gênica , Encefalopatia Associada a Sepse/tratamento farmacológico , Encefalopatia Associada a Sepse/genética , Encefalopatia Associada a Sepse/metabolismoRESUMO
PURPOSE: Tenosynovial giant cell tumor (TGCT) is a locally aggressive neoplasm caused by dysregulation of the colony-stimulating factor 1 (CSF1) gene and overexpression of the CSF1 ligand. Surgery is the standard of care for most patients, but there are limited treatment options for patients with TGCT not amenable to surgery. This study evaluates vimseltinib, an investigational, oral, switch-control tyrosine kinase inhibitor designed to selectively and potently inhibit the CSF1 receptor. PATIENTS AND METHODS: This first-in-human, multicenter, open-label phase I/II study of vimseltinib in patients with malignant solid tumors (N = 37) or TGCT not amenable to surgery (N = 32) followed a pharmacologically guided 3 + 3 study design (NCT03069469). The primary objectives were to assess safety and tolerability, determine the recommended phase II dose, and characterize the pharmacokinetics; exploratory objectives included pharmacodynamics and efficacy. RESULTS: Vimseltinib was well tolerated; the majority of non-laboratory treatment-emergent adverse events were of grade 1/2 severity. There was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. The recommended phase II dose was determined to be 30 mg twice weekly (no loading dose), and vimseltinib plasma exposure increased with the dose. In patients with TGCT, the median treatment duration was 25.1 months (range, 0.7-46.9), and the objective response rate as assessed by independent radiological review using RECIST version 1.1 was 72%. CONCLUSIONS: Vimseltinib demonstrated long-term tolerability, manageable safety, dose-dependent exposure, and robust antitumor activity in patients with TGCT not amenable to surgery.