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1.
Recenti Prog Med ; 115(5): 13e-16e, 2024 May.
Artigo em Italiano | MEDLINE | ID: mdl-38708541

RESUMO

Paraneoplastic leukemoid reaction (PLR) is an extremely rare condition in patients with melanoma and it is frequently associated with poor prognosis. BRAF gene mutational analysis represents the gold standard in patients with inoperable or metastatic melanoma as the possible presence of target mutations allows the use of the combination treatment with BRAF and MEK inhibitors. In this article, the case of a young woman with BRAF V600E mutated metastatic melanoma associated with PLR who received encorafenib and binimetinib is presented and discussed, with a focus on the relevant treatment response.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Benzimidazóis , Carbamatos , Melanoma , Proteínas Proto-Oncogênicas B-raf , Neoplasias Cutâneas , Sulfonamidas , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Feminino , Carbamatos/administração & dosagem , Sulfonamidas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/genética , Benzimidazóis/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/genética , Adulto , Mutação , Resultado do Tratamento
3.
Expert Opin Drug Metab Toxicol ; 20(4): 225-233, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38600865

RESUMO

INTRODUCTION: Cyclin-dependent kinase (CDK) 4/6 inhibitors are cornerstones in the treatment of Hormone Receptor (HR) positive and Human Epidermal Growth factor (HER2) negative metastatic breast cancer. Given their widespread use in the metastatic setting and emerging use in the adjuvant setting, studying drug-drug interactions (DDI) of these medications is of utmost importance. AREAS COVERED: This review provides key background information on the CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib. We discuss drug-drug interactions including those with proton pump inhibitors as well as CYP3A substrates, inhibitors, and inducers. We describe the effect of these drugs on membrane transporters and their substrates as well as those drugs that increase risk of CDK4/6 toxicities. Finally, we explore future directions for strategies to minimize drug-drug interactions. EXPERT OPINION: It is crucial to be mindful of medications that may interfere with drug absorption, such as proton pump inhibitors, as well as those that interfere with drug metabolism, such as CYP3A4 inhibitors and inducers. Additionally, special consideration should be given to populations at higher risk for polypharmacy, such as older patients with greater comorbidities. These interactions and patient characteristics should be considered when developing individual treatment plans with CDK4/6 inhibitors.


Assuntos
Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Interações Medicamentosas , Inibidores de Proteínas Quinases , Humanos , Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/farmacologia , Inibidores da Bomba de Prótons/efeitos adversos , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacologia , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacologia , Benzimidazóis/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/farmacologia , Piridinas/farmacocinética
4.
Clin Cancer Res ; 30(10): 2048-2056, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38446982

RESUMO

PURPOSE: Although fewer than 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are notable as BRAF-targeted therapy shows efficacy for some populations. The purpose of this study was to evaluate response to the combination of encorafenib with binimetinib in adults with recurrent BRAF-V600-mutated HGG. PATIENTS AND METHODS: In this phase 2, open-label, Adult Brain Tumor Consortium (ABTC) trial (NCT03973918), encorafenib and binimetinib were administered at their FDA-approved doses continuously in 28-day cycles. Eligible patients were required to have HGG or glioblastoma with a BRAF-V600E alteration that was recurrent following at least one line of therapy, including radiotherapy. RESULTS: Five patients enrolled between January 2020 and administrative termination in November 2021 (due to closure of the ABTC). Enrolled patients received treatment for 2 to 40 months; currently one patient remains on treatment. Centrally determined radiographic response rate was 60%, with one complete response and two partial responses. Methylation profiling revealed that all tumors cluster most closely with anaplastic pleomorphic xanthoastrocytoma (PXA). Transcriptional profile for MAPK-response signature was similar across all tumors at baseline and did not correlate with response in this small population. Circulating tumor DNA measured in plasma samples before treatment, during response, and upon progression showed feasibility of detection for the BRAF-V600E alteration. No new safety signal was detected. CONCLUSIONS: Encorafenib and binimetinib exhibit positive tumor responses in patients with recurrent BRAF-V600E mutant HGG in this small series, warranting therapeutic consideration. Although toxicity remains a concern for BRAF-targeted therapies, no new safety signal was observed in these patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Benzimidazóis , Neoplasias Encefálicas , Carbamatos , Glioma , Mutação , Proteínas Proto-Oncogênicas B-raf , Sulfonamidas , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Carbamatos/administração & dosagem , Carbamatos/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Feminino , Masculino , Pessoa de Meia-Idade , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Idoso , Resultado do Tratamento , Gradação de Tumores
6.
Clin Cancer Res ; 28(14): 3002-3010, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35294522

RESUMO

PURPOSE: Enhanced MAPK pathway signaling and cell-cycle checkpoint dysregulation are frequent in NRAS-mutant melanoma and, as such, the regimen of the MEK inhibitor binimetinib and the selective CDK4/6 inhibitor ribociclib is a rational combination. PATIENTS AND METHODS: This is a phase Ib/II, open-label study of ribociclib + binimetinib in patients with NRAS-mutant melanoma (NCT01781572). Primary objectives were to estimate the MTD/recommended phase II dose (RP2D) of the combination (phase Ib) and to characterize combination antitumor activity at the RP2D (phase II). Tumor genomic characterization and pharmacokinetics/pharmacodynamics were also evaluated. RESULTS: Ten patients (16.4%) experienced dose-limiting toxicities in cycle 1 of phase Ib. Overall response rate in the phase II cohort (n = 41) for the selected RP2D (binimetinib 45 mg twice daily + ribociclib 200 mg once daily, 21 days on/7 days off) was 19.5% [8/41; 95% confidence interval (CI), 8.8-34.9]. The response rate was 32.5% (13/40; 95% CI, 20.1-48.0) in patients with NRAS mutation with concurrent alterations of CDKN2A, CDK4, or CCND1. Median progression-free survival was 3.7 months (95% CI, 3.5-5.6) and median overall survival was 11.3 months (95% CI, 9.3-14.2) for all patients. Common treatment-related toxicities included creatine phosphokinase elevation, rash, edema, anemia, nausea, diarrhea, and fatigue. Pharmacokinetics and safety were consistent with single-agent data, supporting a lack of drug-drug interaction. CONCLUSIONS: Ribociclib + binimetinib can be safely administered and is clinically active in patients with NRAS-mutant melanoma. Co-mutations of cell-cycle genes may define a population with greater likelihood of treatment benefit. See related commentary by Moschos, p. 2977.


Assuntos
Melanoma , Aminopiridinas/efeitos adversos , Benzimidazóis/administração & dosagem , GTP Fosfo-Hidrolases/genética , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Proteínas de Membrana/genética , Purinas
7.
Cancer Chemother Pharmacol ; 89(2): 255-265, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35066693

RESUMO

PURPOSE: Paclitaxel plus ramucirumab is a standard second-line regimen for patients with advanced gastric adenocarcinoma, but clinical benefit remains modest. One potential resistance mechanism to VEGFR2 inhibition is activation of the PDGF/PDGFR pathway, which can be blocked by the selective inhibitor crenolanib. Therefore, we performed a phase I/Ib study of crenolanib in combination with paclitaxel/ramucirumab. METHODS: Patients with metastatic esophagogastric adenocarcinoma refractory to first-line therapy received escalating doses of crenolanib [60 mg twice daily (BID) to 100 mg three times daily (TID)] in combination with paclitaxel 80 mg/m2 intravenously on days 1, 8 and 15 and ramucirumab 8 mg/kg intravenously on days 1 and 15 of a 28-day cycle. The primary objective was to determine the maximally tolerated dose (MTD) of crenolanib. Additional patients were enrolled in the dose expansion cohort to assess 6-month progression-free survival (PFS) at the MTD. RESULTS: We enrolled 19 patients in the dose escalation phase and 8 patients in the dose expansion phase at the MTD of crenolanib 100 mg BID. Common grade 3/4 treatment-emergent adverse events included leukopenia (19%), anemia (11%) and neutropenia (11%). In the 14 patients treated at the MTD, 6-month PFS was 43% [95% confidence interval (CI) 23-78%] and the objective response rate (ORR) was 42% (95% CI 15-72%). The trial was terminated early due to withdrawal of crenolanib by the sponsor. CONCLUSIONS: The addition of crenolanib to paclitaxel/ramucirumab is safe and well-tolerated at a dose level up to 100 mg BID. CLINICAL TRIAL REGISTRATION: NCT03193918. June 19, 2017.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzimidazóis/administração & dosagem , Relação Dose-Resposta a Droga , Neoplasias Esofágicas/patologia , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Piperidinas/administração & dosagem , Intervalo Livre de Progressão , Neoplasias Gástricas/patologia , Ramucirumab
8.
Hypertension ; 79(1): 261-270, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34739764

RESUMO

Majority of patients with hypertension and chronic kidney disease (CKD) undergoing renal denervation (RDN) are maintained on antihypertensive medication. However, RDN may impair compensatory responses to hypotension induced by blood loss. Therefore, continuation of antihypertensive medications in denervated patients may exacerbate hypotensive episodes. This study examined whether antihypertensive medication compromised hemodynamic responses to blood loss in normotensive (control) sheep and in sheep with hypertensive CKD at 30 months after RDN (control-RDN, CKD-RDN) or sham (control-intact, CKD-intact) procedure. CKD-RDN sheep had lower basal blood pressure (BP; ≈9 mm Hg) and higher basal renal blood flow (≈38%) than CKD-intact. Candesartan lowered BP and increased renal blood flow in all groups. 10% loss of blood volume alone caused a modest fall in BP (≈6-8 mm Hg) in all groups but did not affect the recovery of BP. 10% loss of blood volume in the presence of candesartan prolonged the time at trough BP by 9 minutes and attenuated the fall in renal blood flow in the CKD-RDN group compared with CKD-intact. Candesartan in combination with RDN prolonged trough BP and attenuated renal hemodynamic responses to blood loss. To minimize the risk of hypotension-mediated organ damage, patients with RDN maintained on antihypertensive medications may require closer monitoring when undergoing surgery or experiencing traumatic blood loss.


Assuntos
Antagonistas de Receptores de Angiotensina/administração & dosagem , Benzimidazóis/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Hemorragia/fisiopatologia , Rim/inervação , Simpatectomia/métodos , Tetrazóis/administração & dosagem , Antagonistas de Receptores de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Hemodinâmica/fisiologia , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/fisiopatologia , Ovinos
9.
Cancer Chemother Pharmacol ; 89(1): 31-40, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34655298

RESUMO

BACKGROUND: Osteosarcoma is a prevalent type of bone tumor in children and adolescents, with limited treatment and poor prognosis. Abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), is approved for the treatment of advanced breast cancer as single agent therapy and is currently under investigation in clinical trials for the treatment of several solid tumors. METHODS: The efficacy of abemaciclib was determined using osteosarcoma cellular assays and xenograft mouse model. The combination studies were performed based on the Chou-Talalay method. Immunoblotting analysis was performed to determine the underlying mechanisms of abemaciclib in osteosarcoma cell lines. RESULTS: Abemaciclib potently inhibits growth, anchorage-independent colony formation and survival of a panel of osteosarcoma cell lines, with IC50 range from 90 nM to >20 µM. In addition, the combination of abemaciclib and doxorubicin is synergistic and antagonistic in abemaciclib-sensitive (IC50 <1 µM) and abemaciclib-resistant (IC50 >1 µM), respectively. Abemaciclib inhibits tumor formation and growth in a dose-dependent manner without causing significant drug toxicity in mice. The combination of abemaciclib and doxorubicin results in much greater efficacy than doxorubicin alone in inhibiting tumor growth throughout the whole treatment duration. Abemaciclib acts on osteosarcoma via suppressing CDK4/6-Cyclin D-Rb pathway. CONCLUSIONS: Our pre-clinical evidence provides a rationale of initializing clinical trial of investigating the efficacy of abemaciclib in combination with doxorubicin in osteosarcoma patients. Our work also highlights the therapeutic value of CDK4/6 inhibition in osteosarcoma with proper function of Rb.


Assuntos
Aminopiridinas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzimidazóis/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Aminopiridinas/administração & dosagem , Animais , Benzimidazóis/administração & dosagem , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclina D/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Doxorrubicina/administração & dosagem , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos SCID , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Proteína do Retinoblastoma/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Invest New Drugs ; 40(1): 115-123, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34515877

RESUMO

PURPOSE: Targeting the vascular endothelial growth factor (VEGF) pathway improves progression free survival in multiple advanced malignancies but durable responses are uncommon. Inhibition of the VEGF pathway at multiple levels of signal transduction may improve clinical outcomes. Preclinical data with cediranib, an inhibitor of all 3 VEGF receptors, in combination with selumetinib, an inhibitor of MEK 1/2, demonstrated improved tumor control experimentally. This phase I trial was designed to test the two agents in combination to evaluate the tolerability, safety and assess disease response. METHODS: Patients with advanced solid malignancies were enrolled into this phase I trial. Cediranib and selumetinib were dosed using a toxicity-adaptive isotonic design for the dose escalation/de-escalation of each agent. Both cediranib and selumetinib were administered daily and continuously. Cycles were 28 days in length. RESULTS: Eighteen patients were enrolled. At all dose levels, dose limiting toxicities (DLT) were observed, which limited dose escalation and further evaluation. The maximum tolerated dose of cediranib and selumetinib in combination could not be determined. The best response of stable disease was observed in eight patients. CONCLUSIONS: Cediranib and selumetinib in combination on a continuous schedule was not tolerable, with patients experiencing cardiovascular and other DLTs. Intermittent schedules may be needed to establish a safe and tolerable combination of cediranib and selumetinib.


Assuntos
Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Quinazolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
11.
Cancer Rep (Hoboken) ; 5(1): e1402, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33939324

RESUMO

BACKGROUND: Various cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have demonstrated promising anti-tumor effects. The Japanese Ministry of Health, Labour and Welfare has issued a warning about interstitial lung diseases as an adverse effect of CDK4/6 inhibitors. However, a large-scale evaluation of potential complications has not been conducted to date, and the occurrence of these adverse effects is unclear. AIM: The aim of this study was to evaluate the clinical incidence of interstitial lung disease caused by two CDK4/6 inhibitors, abemaciclib and palbociclib, and assess the relationship between each drug and interstitial lung disease. METHODS AND RESULTS: We evaluated the relationship between the CDK4/6 inhibitors (abemaciclib and palbociclib) and interstitial lung disease in clinical practice using data from the Japanese Adverse Drug Event Report (JADER) database and FDA Adverse Event Reporting System (FAERS) to detect adverse event signals with reported odds ratios (RORs). Furthermore, we performed an adverse event-time analysis for each drug using data from the JADER database to examine the time of onset of the adverse events. The analysis of the reports in the JADER database showed that the lower limit of the 95% confidence interval (CI) of ROR for abemaciclib was >1 regardless of age, and a signal was detected. Interstitial lung disease associated with abemaciclib and palbociclib use has been reported, with an average onset period from treatment initiation [median (25th-75th quartile)] of 65.1 [56.0 days (25.3-98.3 days)] and 53.1 days [38.0 days (10.8-76.0 days)], respectively. The analysis of the reports in the FAERS showed that the lower limit of the 95% CI of the ROR for the two drugs was >1, and a signal was detected. CONCLUSION: Treatment with abemaciclib and palbociclib is associated with a potential complication of interstitial lung disease, regardless of age.


Assuntos
Aminopiridinas/efeitos adversos , Benzimidazóis/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Adulto , Idoso , Aminopiridinas/administração & dosagem , Benzimidazóis/administração & dosagem , Bases de Dados Factuais , Feminino , Humanos , Incidência , Japão , Doenças Pulmonares Intersticiais/epidemiologia , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Estudos Retrospectivos
12.
Future Oncol ; 18(7): 781-791, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34918546

RESUMO

BRAFV600 oncogenic driver mutations occur in 1-2% of non-small-cell lung cancers (NSCLCs) and have been shown to be a clinically relevant target. Preclinical/clinical evidence support the efficacy and safety of BRAF and MEK inhibitor combinations in patients with NSCLC with these mutations. We describe the design of PHAROS, an ongoing, open-label, single-arm, phase II trial evaluating the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib in patients with metastatic BRAFV600-mutant NSCLC, as first- or second-line treatment. The primary end point is objective response rate, based on independent radiologic review (per RECIST v1.1); secondary objectives evaluated additional efficacy end points and safety. Results from PHAROS will describe the antitumor activity/safety of encorafenib plus binimetinib in patients with metastatic BRAFV600-mutant NSCLC.


Plain language summary Some people with non-small-cell lung cancer (NSCLC) have changes in a gene called BRAF (known as 'gene mutations'). One common BRAF mutation is called 'V600'. Combinations of medicines that block proteins encoded by mutant BRAF and another gene called MEK can shrink tumors and slow their progression. We describe the design of PHAROS, a clinical trial investigating encorafenib (mutant BRAF inhibitor) combined with binimetinib (MEK inhibitor) in people with BRAFV600-mutant NSCLC that had spread to other parts of the body ('metastatic disease'). People are monitored for side effects and to see if their tumor shrunk. PHAROS includes people treated with encorafenib plus binimetinib as their first treatment for metastatic disease, and people whose cancer progressed after previous anticancer therapy. Clinical trial registration: Clinicaltrials.gov (NCT03915951) and EudraCT (2019-000417-37).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Idoso , Benzimidazóis/administração & dosagem , Carbamatos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Sulfonamidas/administração & dosagem
13.
Cancer Chemother Pharmacol ; 89(1): 49-58, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34669023

RESUMO

PURPOSE: Veliparib (V), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, potentiates effects of alkylating agents and topoisomerase inhibitors in preclinical tumor models. We conducted a phase I trial of V with iv cyclophosphamide (C) and V plus iv doxorubicin (A) and C. METHODS: Objectives were to establish the maximum tolerated dose (MTD) of the combinations, characterize V pharmacokinetics (PK) in the presence and absence of C, measure PAR in peripheral blood mononuclear cells (PBMCs) and γH2AX in circulating tumor cells (CTCs). In Group 1, dose escalations of V from 10 to 50 mg every 12 h Days 1-4 plus C 450 to 750 mg/m2 Day 3 in 21-day cycles were evaluated. In Group 2, V doses ranged from 50 to 150 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 in 21-day cycles. In Group 3, patients received AC Day 1 plus V Days 1-7, and in Group 4, AC Day 1 plus V Days 1-14 was given in 21-day cycles to evaluate effects on γH2AX foci. RESULTS: Eighty patients were enrolled. MTD was not reached for V and C. MTD for V and AC was V 100 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 every 21 days. V PK appears to be dose-dependent and has no effect on the PK of C. Overall, neutropenia and anemia were the most common adverse events. Objective response in V and AC treated groups was 22% (11/49). Overall clinical benefit rate was 31% (25/80). PAR decreased in PBMCs. Percentage of γH2AX-positive CTCs increased after treatment with V and AC. CONCLUSION: V and AC can be safely combined. Activity was observed in patients with metastatic breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/farmacocinética , Ciclofosfamida/farmacocinética , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/sangue , Doxorrubicina/administração & dosagem , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Poli Adenosina Difosfato Ribose/sangue , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
14.
Biomolecules ; 11(12)2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-34944506

RESUMO

Renin-angiotensin systems produce angiotensin II (Ang II) and angiotensin 1-7 (Ang 1-7), which are able to induce opposite effects on circulation. This study in vivo assessed the effects induced by Ang II or Ang 1-7 on rat pial microcirculation during hypoperfusion-reperfusion, clarifying the mechanisms causing the imbalance between Ang II and Ang 1-7. The fluorescence microscopy was used to quantify the microvascular parameters. Hypoperfusion and reperfusion caused vasoconstriction, disruption of blood-brain barrier, reduction of capillary perfusion and an increase in reactive oxygen species production. Rats treated with Ang II showed exacerbated microvascular damage with stronger vasoconstriction compared to hypoperfused rats, a further increase in leakage, higher decrease in capillary perfusion and marker oxidative stress. Candesartan cilexetil (specific Ang II type 1 receptor (AT1R) antagonist) administration prior to Ang II prevented the effects induced by Ang II, blunting the hypoperfusion-reperfusion injury. Ang 1-7 or ACE2 activator administration, preserved the pial microcirculation from hypoperfusion-reperfusion damage. These effects of Ang 1-7 were blunted by a Mas (Mas oncogene-encoded protein) receptor antagonist, while Ang II type 2 receptor antagonists did not affect Ang 1-7-induced changes. In conclusion, Ang II and Ang 1-7 triggered different mechanisms through AT1R or MAS receptors able to affect cerebral microvascular injury.


Assuntos
Angiotensina II/administração & dosagem , Angiotensina I/administração & dosagem , Benzimidazóis/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Pia-Máter/irrigação sanguínea , Traumatismo por Reperfusão/metabolismo , Tetrazóis/administração & dosagem , Angiotensina I/efeitos adversos , Angiotensina II/efeitos adversos , Animais , Benzimidazóis/farmacologia , Compostos de Bifenilo/farmacologia , Feminino , Masculino , Microcirculação/efeitos dos fármacos , Microscopia de Fluorescência , Fragmentos de Peptídeos/efeitos adversos , Pia-Máter/efeitos dos fármacos , Pia-Máter/metabolismo , Proto-Oncogene Mas/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Tetrazóis/farmacologia
15.
Ann Surg ; 274(4): 613-620, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34506316

RESUMO

OBJECTIVE: To investigate the optimal timing of direct acting antiviral (DAA) administration in patients with hepatitis C-associated hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). SUMMARY OF BACKGROUND DATA: In patients with hepatitis C (HCV) associated HCC undergoing LT, the optimal timing of direct-acting antivirals (DAA) administration to achieve sustained virologic response (SVR) and improved oncologic outcomes remains a topic of much debate. METHODS: The United States HCC LT Consortium (2015-2019) was reviewed for patients with primary HCV-associated HCC who underwent LT and received DAA therapy at 20 institutions. Primary outcomes were SVR and HCC recurrence-free survival (RFS). RESULTS: Of 857 patients, 725 were within Milan criteria. SVR was associated with improved 5-year RFS (92% vs 77%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 92%, and 82%, and 5-year RFS of 93%, 94%, and 87%, respectively. Among 427 HCV treatment-naïve patients (no previous interferon therapy), patients who achieved SVR with DAAs had improved 5-year RFS (93% vs 76%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 93%, and 78% (P < 0.01) and 5-year RFS of 93%, 100%, and 83% (P = 0.01). CONCLUSIONS: The optimal timing of DAA therapy appears to be 0 to 3 months after LT for HCV-associated HCC, given increased rates of SVR and improved RFS. Delayed administration after transplant should be avoided. A prospective randomized controlled trial is warranted to validate these results.


Assuntos
Antivirais/administração & dosagem , Carcinoma Hepatocelular/cirurgia , Hepatite C Crônica/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Idoso , Benzimidazóis/administração & dosagem , Carbamatos/administração & dosagem , Carcinoma Hepatocelular/virologia , Esquema de Medicação , Combinação de Medicamentos , Feminino , Fluorenos/administração & dosagem , Hepatite C Crônica/complicações , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Humanos , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Pirrolidinas/administração & dosagem , Quinoxalinas/administração & dosagem , Estudos Retrospectivos , Sofosbuvir/administração & dosagem , Sulfonamidas/administração & dosagem , Resposta Viral Sustentada
16.
Br J Cancer ; 125(10): 1365-1376, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34588615

RESUMO

BACKGROUND: There is no effective therapy for patients with malignant pleural mesothelioma (MPM) who progressed to platinum-based chemotherapy and immunotherapy. METHODS: We aimed to investigate the antitumor activity of CDK4/6 inhibitors using in vitro and in vivo preclinical models of MPM. RESULTS: Based on publicly available transcriptomic data of MPM, patients with CDK4 or CDK6 overexpression had shorter overall survival. Treatment with abemaciclib or palbociclib at 100 nM significantly decreased cell proliferation in all cell models evaluated. Both CDK4/6 inhibitors significantly induced G1 cell cycle arrest, thereby increasing cell senescence and increased the expression of interferon signalling pathway and tumour antigen presentation process in culture models of MPM. In vivo preclinical studies showed that palbociclib significantly reduced tumour growth and prolonged overall survival using distinct xenograft models of MPM implanted in athymic mice. CONCLUSIONS: Treatment of MPM with CDK4/6 inhibitors decreased cell proliferation, mainly by promoting cell cycle arrest at G1 and by induction of cell senescence. Our preclinical studies provide evidence for evaluating CDK4/6 inhibitors in the clinic for the treatment of MPM.


Assuntos
Aminopiridinas/administração & dosagem , Benzimidazóis/administração & dosagem , Quinase 4 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/genética , Mesotelioma Maligno/tratamento farmacológico , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Idoso , Aminopiridinas/farmacologia , Animais , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Mesotelioma Maligno/genética , Mesotelioma Maligno/metabolismo , Camundongos , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Clin Cancer Res ; 27(21): 5801-5809, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34376533

RESUMO

PURPOSE: In MONARCH 2, abemaciclib plus fulvestrant significantly prolonged progression-free survival (PFS) and overall survival (OS) versus placebo plus fulvestrant in patients with hormone receptor positive (HR+), HER2- advanced breast cancer. This exploratory analysis assessed the efficacy of abemaciclib plus fulvestrant across subgroups of patients receiving study therapy as first- or second-line treatment for metastatic disease. PATIENTS AND METHODS: Improvements were estimated using Cox models, and a test of interactions of subgroups with treatment was performed. RESULTS: The benefit in PFS [first-line, HR, 0.57; 95% confidence interval (CI), 0.45-0.73; second-line, HR, 0.48; 95% CI, 0.36-0.64] and OS (first-line, HR, 0.85; 95% CI, 0.64-1.14; second-line, HR, 0.66; 95% CI, 0.46-0.94) was observed across both subgroups, consistent with the intent-to-treat (ITT) population. In first-line patients (abemaciclib arm, n = 265; placebo arm, n = 133), the numerically largest effect on PFS and OS was observed in patients with primary resistance to endocrine therapy (ET; PFS, HR, 0.40; 95% CI, 0.26-0.63; OS, HR, 0.58; 95% CI, 0.35-0.97) and visceral disease (PFS, HR, 0.54; 95% CI, 0.39-0.73; OS, HR, 0.82; 95% CI, 0.58-1.20). In second-line patients (abemaciclib arm, n = 170; placebo arm, n = 86), a numerical benefit in PFS and OS was observed across primary and secondary ET resistance, with numerically more pronounced effects observed in patients with visceral disease (PFS, HR, 0.39; 95% CI, 0.27-0.57; OS, HR, 0.51; 95% CI, 0.33-0.81). Prolongation of time to second disease progression, time to chemotherapy, and chemotherapy-free survival was observed in both subgroups. CONCLUSIONS: Consistent with the ITT population, a benefit in PFS and OS was observed across the first- and second-line subgroups in MONARCH 2.


Assuntos
Aminopiridinas/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Benzimidazóis/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Fulvestranto/administração & dosagem , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Combinação de Medicamentos , Feminino , Humanos , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Receptor ErbB-2/análise , Resultado do Tratamento
18.
J Steroid Biochem Mol Biol ; 214: 105979, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34438041

RESUMO

Chemotherapy is a standard therapeutic option for triple-negative breast cancer (TNBC); however, its effectiveness is often compromised by drug-related toxicity and resistance development. Herein, we aimed to evaluate whether an improved antineoplastic effect could be achieved in vitro and in vivo in TNBC by combining dovitinib, a multi-kinase inhibitor, with calcitriol, a natural anticancer hormone. In vitro, cell proliferation and cell-cycle distribution were studied by sulforhodamine B-assays and flow cytometry. In vivo, dovitinib/calcitriol effects on tumor growth, angiogenesis, and endothelium activation were evaluated in xenografted mice by caliper measures, Itgb3/VEGFR2-immunohistochemistry and 99mTc-Ethylenediamine-N,N-diacetic acid/hydrazinonicotinamyl-Glu[cyclo(Arg-Gly-Asp-D-Phe-Lys)]2 (99mTc-RGD2)-tumor uptake. The drug combination elicited a synergistically improved antiproliferative effect in TNBC-derived cells, which allowed a 7-fold and a 3.3-fold dovitinib dose-reduction in MBCDF-Tum and HCC-1806 cells, respectively. Mechanistically, the co-treatment induced a cell cycle profile suggestive of cell death and DNA damage (accumulation of cells in SubG1, S, and G2/M phases), increased the number of multinucleated cells and inhibited tumor growth to a greater extent than each compound alone. Tumor uptake of 99mTc-RGD2 was reduced by dovitinib, suggesting angiogenesis inhibition, which was corroborated by decreased endothelial cell growth, tumor-vessel density and VEGFR2 expression. In summary, calcitriol synergized dovitinib anticancer effects in vitro and in vivo, allowing for a significant dose-reduction of dovitinib while maintaining its antiproliferative potency. Our results suggest the beneficial convergence of independent antitumor mechanisms of dovitinib and calcitriol to inhibit TNBC-tumor growth.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Calcitriol/farmacologia , Oligopeptídeos/química , Quinolonas/farmacologia , Tecnécio/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Benzimidazóis/administração & dosagem , Calcitriol/administração & dosagem , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Relação Dose-Resposta a Droga , Feminino , Humanos , Concentração Inibidora 50 , Integrina beta3/metabolismo , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neovascularização Patológica , Quinolonas/administração & dosagem , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
19.
Eur J Cancer ; 154: 35-45, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34243076

RESUMO

BACKGROUND: Addition of veliparib to carboplatin-paclitaxel, with continuation of veliparib monotherapy if carboplatin-paclitaxel was discontinued, improved progression-free survival (PFS) in patients with germline BRCA-associated locally advanced/metastatic HER2- breast cancer and ≤2 lines of previous cytotoxic therapy for metastatic disease in BROCADE3. A pre-planned subgroup analysis evaluated efficacy and safety in patients without previous cytotoxic therapy for metastatic disease. METHODS: Patients were randomised 2:1 to receive veliparib (120 mg orally BID) or placebo on days -2 to 5. Carboplatin (AUC 6) was administered on day 1, and paclitaxel (80 mg/m2) on days 1, 8 and 15 (21-day cycles). Patients discontinuing carboplatin-paclitaxel for reasons besides progression could continue veliparib/placebo monotherapy (300 mg BID, increasing to 400 mg BID if tolerated) until progression. The primary end-point was PFS assessed by investigator. RESULTS: Of 509 patients in the intention-to-treat population (98.6% female; mean age 47, standard deviation 11), 413 (81%) had no previous cytotoxic therapy for metastatic disease (274, veliparib; 139, placebo). In the first-line subgroup, median PFS was 16.6 months (95% confidence interval [CI] 13.4-18.7) versus 13.1 months (95% CI 11.4-14.5) for the veliparib versus control groups (hazard ratio 0.70, 95% CI 0.54-0.89, P = .004). More patients were alive and progression-free at 2 years (36% versus 23.2%) and 3 years (27.9% versus 13.3%) in the veliparib versus control group. Adverse events unrelated to progression leading to study drug discontinuation occurred in 25 (9.1%) and 8 (5.8%) patients. CONCLUSIONS: Veliparib with carboplatin-paclitaxel led to durable disease control among first-line patients, suggesting a benefit of this treatment approach in early lines. CLINICAL TRIAL REGISTRATION: NCT02163694.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Receptor ErbB-2/análise
20.
Mol Cancer Ther ; 20(9): 1680-1691, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34158347

RESUMO

We analyzed the efficacy and mechanistic interactions of PARP inhibition (PARPi; olaparib) and CDK4/6 inhibition (CDK4/6i; palbociclib or abemaciclib) combination therapy in castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) models. We demonstrated that combined olaparib and palbociblib or abemaciclib treatment resulted in synergistic suppression of the p-Rb1-E2F1 signaling axis at the transcriptional and posttranslational levels, leading to disruption of cell-cycle progression and inhibition of E2F1 gene targets, including genes involved in DDR signaling/damage repair, antiapoptotic BCL-2 family members (BCL-2 and MCL-1), CDK1, and neuroendocrine differentiation (NED) markers in vitro and in vivo In addition, olaparib + palbociclib or olaparib + abemaciclib combination treatment resulted in significantly greater growth inhibition and apoptosis than either single agent alone. We further showed that PARPi and CDK4/6i combination treatment-induced CDK1 inhibition suppressed p-S70-BCL-2 and increased caspase cleavage, while CDK1 overexpression effectively prevented the downregulation of p-S70-BCL-2 and largely rescued the combination treatment-induced cytotoxicity. Our study defines a novel combination treatment strategy for CRPC and NEPC and demonstrates that combination PARPi and CDK4/6i synergistically promotes suppression of the p-Rb1-E2F1 axis and E2F1 target genes, including CDK1 and NED proteins, leading to growth inhibition and increased apoptosis in vitro and in vivo Taken together, our results provide a molecular rationale for PARPi and CDK4/6i combination therapy and reveal mechanism-based clinical trial opportunities for men with NEPC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Diferenciação Celular , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Tumores Neuroectodérmicos/tratamento farmacológico , Poli(ADP-Ribose) Polimerases/química , Neoplasias da Próstata/tratamento farmacológico , Aminopiridinas/administração & dosagem , Animais , Apoptose , Benzimidazóis/administração & dosagem , Ciclo Celular , Proliferação de Células , Humanos , Masculino , Camundongos , Camundongos Nus , Tumores Neuroectodérmicos/metabolismo , Tumores Neuroectodérmicos/patologia , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Piridinas/administração & dosagem , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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