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1.
Clin Cancer Res ; 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35552383

RESUMO

PURPOSE: Prostate specific membrane antigen (PSMA) targeting therapies such as Lutetium-177 (177Lu)-PSMA-617 are impacting outcomes from metastatic castration-resistant prostate cancer (mCRPC). However, a significant subset of patients have prostate cancer cells lacking PSMA expression raising concerns about treatment resistance attributable at least in part to heterogeneous PSMA expression. We have previously demonstrated an association between high PSMA expression and DNA damage repair defects in mCRPC biopsies, and therefore hypothesized that DNA damage upregulates PSMA expression. EXPERIMENTAL DESIGN: To test this relationship between PSMA and DNA damage we conducted a screen of 147 anticancer agents (NCI/NIH FDA-approved anticancer "Oncology Set") and treated tumor cells with repeated ionizing irradiation. RESULTS: The topoisomerase-2 inhibitors, daunorubicin and mitoxantrone, were identified from the screen to upregulate PSMA protein expression in castration-resistant LNCaP95 cells; this result was validated in vitro in LNCaP, LNCaP95 and 22Rv1 cell lines, and in vivo using an mCRPC patient-derived xenograft model CP286 identified to have heterogeneous PSMA expression. Since double strand DNA break induction by topoisomerase-2 inhibitors upregulated PSMA, we next studied the impact of ionizing radiation on PSMA expression; this also upregulated PSMA protein expression in a dose-dependent fashion. CONCLUSIONS: The results presented herein are the first, to our knowledge, to demonstrate that PSMA is upregulated in response to double-strand DNA damage by anticancer treatment. These data support the study of rational combinations that maximize the antitumor activity of PSMA targeted therapeutic strategies by upregulating PSMA.

2.
Infect Dis Ther ; 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35445964

RESUMO

Interferon (IFN) therapies are used to treat a variety of infections and diseases and could be used to treat SARS-CoV-2. However, optimal use and timing of IFN therapy to treat SARS-CoV-2 is not well documented. We aimed to synthesize available evidence to understand whether interferon therapy should be recommended for treatment compared to a placebo or standard of care in adult patients. We reviewed literature comparing outcomes of randomized control trials that used IFN therapy for adults diagnosed with SARS-CoV-2 between 2019 and 2021. Data were extracted from 11 of 669 screened studies. Evidence of IFN effectiveness was mixed. Five studies reported that IFN was a better therapy than the control, four found no or minimal difference between IFN and the control, and two concluded that IFN led to worse patient outcomes than the control. Evidence was difficult to compare because of high variability in outcome measures, intervention types and administration, subtypes of IFNs used and timing of interventions. We recommend standardized indicators and reporting for IFN therapy for SARS-CoV-2 to improve evidence synthesis and generation. While IFN therapy has the potential to be a viable treatment for SARS-CoV-2, especially when combined with antivirals and early administration, the lack of comparable of study outcomes prevents evidence synthesis and uptake.

3.
Am J Trop Med Hyg ; 2022 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-35263710

RESUMO

Fluvoxamine is widely prescribed as an antidepressant. Recent studies show the drug may have a clinical benefit in treating COVID-19. We aimed to perform a meta-analysis of the existing randomized trials of fluvoxamine compared with placebo on the early treatment of COVID-19 patients. We included only randomized clinical trials enrolling ambulatory patients with early-stage disease (symptoms > 7 days) for the prevention of hospitalization. We searched MEDLINE, and clinicaltrials.gov databases to identify trials and extract data with clarifications from the study investigators. We performed a fixed-effects meta-analysis and sensitivity analyses via R to evaluate the pooled estimate of hospitalization. We included three randomized trials: STOP COVID 1 and 2, and the TOGETHER Trial. The studies included a total of 2,196 patients. The STOP COVID trials measured clinical deterioration whereas the TOGETHER Trial measured hospitalization as the primary outcome. All trials reported on hospitalization up to day 28. The meta-analysis results show that patients receiving fluvoxamine were 31% less likely to experience clinical deterioration or hospitalization compared with placebo (risk ratio, 0.69; 95% CI, 0.54-0.88). A sensitivity analysis using the definition of hospitalization resulted in a risk reduction of 21% (95% CI, 0.60-1.03). Data from three randomized controlled trials show that fluvoxamine was associated with a reduction in the primary outcome measure (either clinical deterioration or composite outcome of hospitalization or extended emergency setting observation), although analysis of hospitalization-only was not statistically significant. More evidence from future trials is still needed to support the findings of this meta-analysis.

4.
N Engl J Med ; 386(18): 1721-1731, 2022 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-35353979

RESUMO

BACKGROUND: The efficacy of ivermectin in preventing hospitalization or extended observation in an emergency setting among outpatients with acutely symptomatic coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is unclear. METHODS: We conducted a double-blind, randomized, placebo-controlled, adaptive platform trial involving symptomatic SARS-CoV-2-positive adults recruited from 12 public health clinics in Brazil. Patients who had had symptoms of Covid-19 for up to 7 days and had at least one risk factor for disease progression were randomly assigned to receive ivermectin (400 µg per kilogram of body weight) once daily for 3 days or placebo. (The trial also involved other interventions that are not reported here.) The primary composite outcome was hospitalization due to Covid-19 within 28 days after randomization or an emergency department visit due to clinical worsening of Covid-19 (defined as the participant remaining under observation for >6 hours) within 28 days after randomization. RESULTS: A total of 3515 patients were randomly assigned to receive ivermectin (679 patients), placebo (679), or another intervention (2157). Overall, 100 patients (14.7%) in the ivermectin group had a primary-outcome event, as compared with 111 (16.3%) in the placebo group (relative risk, 0.90; 95% Bayesian credible interval, 0.70 to 1.16). Of the 211 primary-outcome events, 171 (81.0%) were hospital admissions. Findings were similar to the primary analysis in a modified intention-to-treat analysis that included only patients who received at least one dose of ivermectin or placebo (relative risk, 0.89; 95% Bayesian credible interval, 0.69 to 1.15) and in a per-protocol analysis that included only patients who reported 100% adherence to the assigned regimen (relative risk, 0.94; 95% Bayesian credible interval, 0.67 to 1.35). There were no significant effects of ivermectin use on secondary outcomes or adverse events. CONCLUSIONS: Treatment with ivermectin did not result in a lower incidence of medical admission to a hospital due to progression of Covid-19 or of prolonged emergency department observation among outpatients with an early diagnosis of Covid-19. (Funded by FastGrants and the Rainwater Charitable Foundation; TOGETHER ClinicalTrials.gov number, NCT04727424.).


Assuntos
Anti-Infecciosos , COVID-19 , Ivermectina , Adulto , Assistência Ambulatorial , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/uso terapêutico , Teorema de Bayes , COVID-19/tratamento farmacológico , Método Duplo-Cego , Hospitalização , Humanos , Ivermectina/efeitos adversos , Ivermectina/uso terapêutico , SARS-CoV-2 , Resultado do Tratamento
5.
Am J Trop Med Hyg ; 106(2): 389-393, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34996047

RESUMO

In response to the COVID-19 pandemic, clinical research groups across the world developed trial protocols to evaluate the safety and efficacy of treatments for COVID-19. Despite this initial enthusiasm, only a small portion of these protocols were implemented. Of those implemented, a fraction successfully recruited their target sample size to analyze and disseminate findings. More than a year and a half into the COVID-19 pandemic, only a few clinical trials evaluating treatments for COVID-19 have generated new evidence. Productive randomized platform clinical trials evaluating COVID-19 treatments may attribute their success to intentional investments in developing resilient clinical trial infrastructures. Health system resiliency discourse provides a conceptual framework for characterizing attributes for withstanding shocks. This framework may also be useful for contextualizing the attributes of productive clinical trials evaluating COVID-19 therapies. We characterize the successful attributes and lessons learned in developing the TOGETHER Trial infrastructure using a health system resiliency framework. This framework may be considered by clinical trialists aiming to build resilient trial infrastructures capable of responding rapidly and efficiently to global health threats.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Atenção à Saúde/organização & administração , Eficiência Organizacional , Humanos , SARS-CoV-2
6.
Cancer Res ; 81(24): 6207-6218, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34753775

RESUMO

It has been recognized for decades that ERBB signaling is important in prostate cancer, but targeting ERBB receptors as a therapeutic strategy for prostate cancer has been ineffective clinically. However, we show here that membranous HER3 protein is commonly highly expressed in lethal prostate cancer, associating with reduced time to castration resistance (CR) and survival. Multiplex immunofluorescence indicated that the HER3 ligand NRG1 is detectable primarily in tumor-infiltrating myelomonocytic cells in human prostate cancer; this observation was confirmed using single-cell RNA sequencing of human prostate cancer biopsies and murine transgenic prostate cancer models. In castration-resistant prostate cancer (CRPC) patient-derived xenograft organoids with high HER3 expression as well as mouse prostate cancer organoids, recombinant NRG1 enhanced proliferation and survival. Supernatant from murine bone marrow-derived macrophages and myeloid-derived suppressor cells promoted murine prostate cancer organoid growth in vitro, which could be reversed by a neutralizing anti-NRG1 antibody and ERBB inhibition. Targeting HER3, especially with the HER3-directed antibody-drug conjugate U3-1402, exhibited antitumor activity against HER3-expressing prostate cancer. Overall, these data indicate that HER3 is commonly overexpressed in lethal prostate cancer and can be activated by NRG1 secreted by myelomonocytic cells in the tumor microenvironment, supporting HER3-targeted therapeutic strategies for treating HER3-expressing advanced CRPC. SIGNIFICANCE: HER3 is an actionable target in prostate cancer, especially with anti-HER3 immunoconjugates, and targeting HER3 warrants clinical evaluation in prospective trials.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Biomarcadores Tumorais/metabolismo , Camptotecina/análogos & derivados , Neuregulina-1/metabolismo , Organoides/patologia , Neoplasias da Próstata/patologia , Receptor ErbB-3/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Camptotecina/farmacologia , Proliferação de Células , Seguimentos , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Neuregulina-1/genética , Organoides/efeitos dos fármacos , Organoides/metabolismo , Prognóstico , Estudos Prospectivos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Science ; 374(6564): 216-224, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34618582

RESUMO

The microbiota comprises the microorganisms that live in close contact with the host, with mutual benefit for both counterparts. The contribution of the gut microbiota to the emergence of castration-resistant prostate cancer (CRPC) has not yet been addressed. We found that androgen deprivation in mice and humans promotes the expansion of defined commensal microbiota that contributes to the onset of castration resistance in mice. Specifically, the intestinal microbial community in mice and patients with CRPC was enriched for species capable of converting androgen precursors into active androgens. Ablation of the gut microbiota by antibiotic therapy delayed the emergence of castration resistance even in immunodeficient mice. Fecal microbiota transplantation (FMT) from CRPC mice and patients rendered mice harboring prostate cancer resistant to castration. In contrast, tumor growth was controlled by FMT from hormone-sensitive prostate cancer patients and Prevotella stercorea administration. These results reveal that the commensal gut microbiota contributes to endocrine resistance in CRPC by providing an alternative source of androgens.


Assuntos
Androgênios/biossíntese , Bactérias/metabolismo , Microbioma Gastrointestinal/fisiologia , Interações entre Hospedeiro e Microrganismos , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/microbiologia , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/uso terapêutico , Animais , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/genética , Linhagem Celular Tumoral , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Neoplasias Experimentais , Prevotella/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Simbiose , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Nucl Med ; 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385339

RESUMO

Despite significant advances in prostate cancer therapeutic development over the last two decades, metastatic prostate cancer remains a lethal disease. Prostate-specific membrane antigen (PSMA), which is markedly overexpressed by prostate cancer cells, including at metastatic sites, but have low normal tissue expression, has emerged as an important theranostic target for these diseases. Both beta-emitting and alpha-emitting PSMA-targeted radionuclide therapy (RNT) are in clinical development. Several of these agents have already shown promising activity, however, a significant subset of patients have primary resistant disease and secondary resistance invariably occurs. Further, the effect of these therapies on healthy organs limit their therapeutic window. Elucidating the biology of PSMA as well as characterising the pharmacokinetic and pharmacodynamic properties of PSMA-targeted RNT will facilitate therapeutic approaches aimed at improving efficacy and safety. In this review, we provide an overview of existing PSMA-targeting RNT and an update on novel combinatorial approaches.

9.
Eur Urol Focus ; 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34167925

RESUMO

CONTEXT: Prostate-specific membrane antigen (PSMA) is a promising, novel theranostic target in advanced prostate cancer (PCa). Multiple PSMA-targeted therapies are currently in clinical development, with some agents showing impressive antitumour activity, although optimal patient selection and therapeutic resistance remain ongoing challenges. OBJECTIVE: To review the biology of PSMA and recent advances in PSMA-targeted therapies in PCa, and to discuss potential strategies for patient selection and further therapeutic development. EVIDENCE ACQUISITION: A comprehensive literature search was performed using PubMed and review of American Society of Clinical Oncology and European Society of Medical Oncology annual meeting abstracts up to April 2021. EVIDENCE SYNTHESIS: PSMA is a largely extracellular protein that is frequently, but heterogeneously, expressed by PCa cells. PSMA expression is associated with disease progression, worse clinical outcomes and the presence of tumour defects in DNA damage repair (DDR). PSMA is also expressed by other cancer cell types and is implicated in glutamate and folate metabolism. It may confer a tumour survival advantage in conditions of cellular stress. PSMA regulation is complex, and recent studies have shed light on interactions with androgen receptor, PI3K/Akt, and DDR signalling. A phase 2 clinical trial has shown that 177Lu-PSMA-617 causes tumour shrinkage and delays disease progression in a significant subset of patients with metastatic castration-resistant PCa in comparison to second-line chemotherapy. Numerous novel PSMA-targeting immunotherapies, small molecules, and antibody therapies are currently in clinical development, including in earlier stages of PCa, with emerging evidence of antitumour activity. To date, the regulation and function of PSMA in PCa cells remain poorly understood. CONCLUSIONS: There has been rapid recent progress in PSMA-targeted therapies for the management of advanced PCa. Dissection of PSMA biology will help to identify biomarkers for and resistance mechanisms to these therapies and facilitate further therapeutic development to improve PCa patient outcomes. PATIENT SUMMARY: There have been major advances in the development of therapies targeting a molecule, PSMA, in PCa. Radioactive molecules targeting PSMA can cause tumour shrinkage and delay progression in some patients with lethal disease. Future studies are needed to determine which patients are most likely to respond, and how other treatments can be combined with therapies targeting PSMA so that more patients may benefit.

10.
Br J Cancer ; 125(5): 625-626, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33859342

RESUMO

KRAS mutations drive a wide variety of cancers. Drugs targeting the protein product of KRASG12C mutations are currently being evaluated show preliminary efficacy in clinical trials. A clinical trial of VS-6766, a dual RAF-MEK inhibitor, has reported early single agent activity in non-G12C mutated KRAS driven cancers.


Assuntos
Neoplasias/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Humanos , Terapia de Alvo Molecular , Mutação , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
11.
Eur Urol ; 79(6): 736-746, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33678520

RESUMO

BACKGROUND: CD38, a druggable ectoenzyme, is involved in the generation of adenosine, which is implicated in tumour immune evasion. Its expression and role in prostate tumour-infiltrating immune cells (TIICs) have not been elucidated. OBJECTIVE: To characterise CD38 expression on prostate cancer (PC) epithelial cells and TIICs, and to associate this expression with clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: RNAseq from 159 patients with metastatic castration-resistant prostate cancer (mCRPC) in the International Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF) cohort and 171 mCRPC samples taken from 63 patients in the Fred Hutchinson Cancer Research Centre cohort were analysed. CD38 expression was immunohistochemically scored by a validated assay on 51 castration-resistant PC (CRPC) and matching, same-patient castration-sensitive PC (CSPC) biopsies obtained between 2016 and 2018, and was associated with retrospectively collected clinical data. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: mCRPC transcriptomes were analysed for associations between CD38 expression and gene expression signatures. Multiplex immunofluorescence determined CD38 expression in PC biopsies. Differences in CD38+ TIIC densities between CSPC and CRPC biopsies were analysed using a negative binomial mixed model. Differences in the proportions of CD38+ epithelial cells between non-matched benign prostatic epithelium and PC were compared using Fisher's exact test. Differences in the proportions of biopsies containing CD38+ tumour epithelial cells between matched CSPC and CRPC biopsies were compared by McNemar's test. Univariable and multivariable survival analyses were performed using Cox regression models. RESULTS AND LIMITATIONS: CD38 mRNA expression in mCRPC was most significantly associated with upregulated immune signalling pathways. CD38 mRNA expression was associated with interleukin (IL)-12, IL-23, and IL-27 signalling signatures as well as immunosuppressive adenosine signalling and T cell exhaustion signatures. CD38 protein was frequently expressed on phenotypically diverse TIICs including B cells and myeloid cells, but largely absent from tumour epithelial cells. CD38+ TIIC density increased with progression to CRPC and was independently associated with worse overall survival. Future studies are required to dissect TIIC CD38 function. CONCLUSIONS: CD38+ prostate TIICs associate with worse survival and immunosuppressive mechanisms. The role of CD38 in PC progression warrants investigation as insights into its functions may provide rationale for CD38 targeting in lethal PC. PATIENT SUMMARY: CD38 is expressed on the surface of white blood cells surrounding PC cells. These cells may impact PC growth and treatment resistance. Patients with PC with more CD38-expressing white blood cells are more likely to die earlier.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Adenosina , Humanos , Masculino , Próstata , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , RNA Mensageiro , Estudos Retrospectivos
12.
Cancer Discov ; 11(1): 80-91, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32988960

RESUMO

Targeting the ataxia telangiectasia and RAD3-related (ATR) enzyme represents a promising anticancer strategy for tumors with DNA damage response (DDR) defects and replication stress, including inactivation of ataxia telangiectasia mutated (ATM) signaling. We report the dose-escalation portion of the phase I first-in-human trial of oral ATR inhibitor BAY 1895344 intermittently dosed 5 to 80 mg twice daily in 21 patients with advanced solid tumors. The MTD was 40 mg twice daily 3 days on/4 days off. Most common adverse events were manageable and reversible hematologic toxicities. Partial responses were achieved in 4 patients and stable disease in 8 patients. Median duration of response was 315.5 days. Responders had ATM protein loss and/or deleterious ATM mutations and received doses ≥40 mg twice daily. Overall, BAY 1895344 is well tolerated, with antitumor activity against cancers with certain DDR defects, including ATM loss. An expansion phase continues in patients with DDR deficiency. SIGNIFICANCE: Oral BAY 1895344 was tolerable, with antitumor activity in heavily pretreated patients with various advanced solid tumors, particularly those with ATM deleterious mutations and/or loss of ATM protein; pharmacodynamic results supported a mechanism of action of increased DNA damage. Further study is warranted in this patient population.See related commentary by Italiano, p. 14.This article is highlighted in the In This Issue feature, p. 1.


Assuntos
Ataxia Telangiectasia , Neoplasias , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Dano ao DNA , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores de Proteínas Quinases/efeitos adversos
13.
Clin Cancer Res ; 27(2): 566-574, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-32988971

RESUMO

PURPOSE: Cyclin-dependent kinase 12 (CDK12) aberrations have been reported as a biomarker of response to immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). Herein, we characterize CDK12-mutated mCRPC, presenting clinical, genomic, and tumor-infiltrating lymphocyte (TIL) data. EXPERIMENTAL DESIGN: Patients with mCRPC consented to the molecular analyses of diagnostic and mCRPC biopsies. Genomic analyses involved targeted next-generation (MiSeq; Illumina) and exome sequencing (NovaSeq; Illumina). TILs were assessed by validated immunocytochemistry coupled with deep learning-based artificial intelligence analyses including multiplex immunofluorescence assays for CD4, CD8, and FOXP3 evaluating TIL subsets. The control group comprised a randomly selected mCRPC cohort with sequencing and clinical data available. RESULTS: Biopsies from 913 patients underwent targeted sequencing between February 2015 and October 2019. Forty-three patients (4.7%) had tumors with CDK12 alterations. CDK12-altered cancers had distinctive features, with some revealing high chromosomal break numbers in exome sequencing. Biallelic CDK12-aberrant mCRPCs had shorter overall survival from diagnosis than controls [5.1 years (95% confidence interval (CI), 4.0-7.9) vs. 6.4 years (95% CI, 5.7-7.8); hazard ratio (HR), 1.65 (95% CI, 1.07-2.53); P = 0.02]. Median intratumoral CD3+ cell density was higher in CDK12 cancers, although this was not statistically significant (203.7 vs. 86.7 cells/mm2; P = 0.07). This infiltrate primarily comprised of CD4+FOXP3- cells (50.5 vs. 6.2 cells/mm2; P < 0.0001), where high counts tended to be associated with worse survival from diagnosis (HR, 1.64; 95% CI, 0.95-2.84; P = 0.077) in the overall population. CONCLUSIONS: CDK12-altered mCRPCs have worse prognosis, with these tumors surprisingly being primarily enriched for CD4+FOXP3- cells that seem to associate with worse outcome and may be immunosuppressive.See related commentary by Lotan and Antonarakis, p. 380.


Assuntos
Inteligência Artificial , Neoplasias da Próstata , Quinases Ciclina-Dependentes , Genômica , Humanos , Masculino , Prognóstico , Microambiente Tumoral
15.
Lancet Oncol ; 21(11): 1478-1488, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33128873

RESUMO

BACKGROUND: CH5126766 (also known as VS-6766, and previously named RO5126766), a novel MEK-pan-RAF inhibitor, has shown antitumour activity across various solid tumours; however, its initial development was limited by toxicity. We aimed to investigate the safety and toxicity profile of intermittent dosing schedules of CH5126766, and the antitumour activity of this drug in patients with solid tumours and multiple myeloma harbouring RAS-RAF-MEK pathway mutations. METHODS: We did a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study at the Royal Marsden National Health Service Foundation Trust (London, UK). Patients were eligible for the study if they were aged 18 years or older, had cancers that were refractory to conventional treatment or for which no conventional therapy existed, and if they had a WHO performance status score of 0 or 1. For the dose-escalation phase, eligible patients had histologically or cytologically confirmed advanced or metastatic solid tumours. For the basket dose-expansion phase, eligible patients had advanced or metastatic solid tumours or multiple myeloma harbouring RAS-RAF-MEK pathway mutations. During the dose-escalation phase, we evaluated three intermittent oral schedules (28-day cycles) in patients with solid tumours: (1) 4·0 mg or 3·2 mg CH5126766 three times per week; (2) 4·0 mg CH5126766 twice per week; and (3) toxicity-guided dose interruption schedule, in which treatment at the recommended phase 2 dose (4·0 mg CH5126766 twice per week) was de-escalated to 3 weeks on followed by 1 week off if patients had prespecified toxic effects (grade 2 or worse diarrhoea, rash, or creatinine phosphokinase elevation). In the basket dose-expansion phase, we evaluated antitumour activity at the recommended phase 2 dose, determined from the dose-escalation phase, in biomarker-selected patients. The primary endpoints were the recommended phase 2 dose at which no more than one out of six patients had a treatment-related dose-limiting toxicity, and the safety and toxicity profile of each dosing schedule. The key secondary endpoint was investigator-assessed response rate in the dose-expansion phase. Patients who received at least one dose of the study drug were evaluable for safety and patients who received one cycle of the study drug and underwent baseline disease assessment were evaluable for response. This trial is registered with ClinicalTrials.gov, NCT02407509. FINDINGS: Between June 5, 2013, and Jan 10, 2019, 58 eligible patients were enrolled to the study: 29 patients with solid tumours were included in the dose-escalation cohort and 29 patients with solid tumours or multiple myeloma were included in the basket dose-expansion cohort (12 non-small-cell lung cancer, five gynaecological malignancy, four colorectal cancer, one melanoma, and seven multiple myeloma). Median follow-up at the time of data cutoff was 2·3 months (IQR 1·6-3·5). Dose-limiting toxicities included grade 3 bilateral retinal pigment epithelial detachment in one patient who received 4·0 mg CH5126766 three times per week, and grade 3 rash (in two patients) and grade 3 creatinine phosphokinase elevation (in one patient) in those who received 3·2 mg CH5126766 three times per week. 4·0 mg CH5126766 twice per week (on Monday and Thursday or Tuesday and Friday) was established as the recommended phase 2 dose. The most common grade 3-4 treatment-related adverse events were rash (11 [19%] patients), creatinine phosphokinase elevation (six [11%]), hypoalbuminaemia (six [11%]), and fatigue (four [7%]). Five (9%) patients had serious treatment-related adverse events. There were no treatment-related deaths. Eight (14%) of 57 patients died during the trial due to disease progression. Seven (27% [95% CI 11·6-47·8]) of 26 response-evaluable patients in the basket expansion achieved objective responses. INTERPRETATION: To our knowledge, this is the first study to show that highly intermittent schedules of a RAF-MEK inhibitor has antitumour activity across various cancers with RAF-RAS-MEK pathway mutations, and that this inhibitor is tolerable. CH5126766 used as a monotherapy and in combination regimens warrants further evaluation. FUNDING: Chugai Pharmaceutical.


Assuntos
Cumarínicos/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Administração Oral , Adulto , Idoso , Cumarínicos/efeitos adversos , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Quinases raf/genética , Proteínas ras/genética
16.
Nat Rev Cancer ; 20(8): 455-469, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32546840

RESUMO

Prostate cancer is a major cause of cancer morbidity and mortality. Intra-prostatic inflammation is a risk factor for prostate carcinogenesis, with diet, chemical injury and an altered microbiome being causally implicated. Intra-prostatic inflammatory cell recruitment and expansion can ultimately promote DNA double-strand breaks and androgen receptor activation in prostate epithelial cells. The activation of the senescence-associated secretory phenotype fuels further 'inflammatory storms', with free radicals leading to further DNA damage. This drives the overexpression of DNA repair and tumour suppressor genes, rendering these genes susceptible to mutagenic insults, with carcinogenesis accelerated by germline DNA repair gene defects. We provide updates on recent advances in elucidating prostate carcinogenesis and explore novel therapeutic and prevention strategies harnessing these discoveries.


Assuntos
Carcinogênese/imunologia , Inflamação/imunologia , Próstata/imunologia , Neoplasias da Próstata/imunologia , Receptores Androgênicos/imunologia , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Doença Crônica , Quebras de DNA de Cadeia Dupla , Dano ao DNA/genética , Dano ao DNA/imunologia , Reparo do DNA/genética , Reparo do DNA/imunologia , Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/imunologia , Humanos , Inflamação/etiologia , Inflamação/genética , Masculino , Microbiota/imunologia , Obesidade/complicações , Obesidade/imunologia , Comunicação Parácrina/imunologia , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
17.
J Nucl Med ; 61(6): 857-865, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31732676

RESUMO

177Lu-PSMA-617 is a radioligand with high affinity for prostate-specific membrane antigen (PSMA), enabling targeted ß-irradiation of prostate cancer. We have previously reported favorable activity with low toxicity in a prospective phase II trial involving 30 men with metastatic castration-resistant prostate cancer. We now report their longer-term outcomes, including a 20-patient extension cohort and outcomes of subsequent systemic treatments after completion of trial therapy. Methods: Fifty patients with PSMA-avid metastatic castration-resistant prostate cancer who had progressed after standard therapies received up to 4 cycles of 177Lu-PSMA every 6 wk. Endpoints included prostate-specific antigen (PSA) response (Prostate Cancer Working Group 2), toxicity (Common Terminology Criteria for Adverse Events, version 4.03), imaging response, patient-reported health-related quality of life, progression-free survival, and overall survival. We also describe, as a novel finding, outcomes of men who subsequently progressed and had further systemic therapies, including 177Lu-PSMA. Results: Seventy-five men were screened to identify 50 patients eligible for treatment. Adverse prognostic features of the cohort included short median PSA doubling time (2.3 mo) and extensive prior treatment, including prior docetaxel (84%), cabazitaxel (48%), and abiraterone or enzalutamide (92%). The mean administered radioactivity was 7.5 GBq/cycle. A PSA decline of at least 50% was achieved in 32 of 50 patients (64%; 95% confidence interval [CI], 50%-77%), including 22 patients (44%; 95% CI, 30%-59%) with at least an 80% decrease. Of 27 patients with measurable soft-tissue disease, 15 (56%) achieved an objective response by RECIST 1.1. The most common toxicities attributed to 177Lu-PSMA were self-limiting G1-G2 dry mouth (66%), transient G1-G2 nausea (48%), G3-G4 thrombocytopenia (10%), and G3 anemia (10%). Brief Pain Inventory severity and interference scores decreased at all time points, including at the 3-mo follow-up, with a decrease of -1.2 (95% CI, -0.5 to -1.9; P = 0.001) and -1.0 (95% CI, -0.2 to -0.18; P = 0.013), respectively. At a median follow-up of 31.4 mo, median overall survival was 13.3 mo (95% CI, 10.5-18.7 mo), with a significantly longer survival of 18.4 mo (95% CI, 13.8-23.8 mo) in patients achieving a PSA decline of at least 50%. At progression after prior response, further 177Lu-PSMA was administered to 15 (30%) patients (median of 2 cycles commencing 359 d from enrollment), with a PSA decline of at least 50% in 11 patients (73%). Four of 21 patients (19%) receiving other systemic therapies on progression experienced a PSA decline of at least 50%. There were no unexpected adverse events with 177Lu-PSMA retreatment. Conclusion: This expanded 50-patient cohort of men with extensive prior therapy confirms our earlier report of high response rates, low toxicity, and improved quality of life with 177Lu-PSMA radioligand therapy. On progression, rechallenge 177Lu-PSMA demonstrated higher response rates than other systemic therapies.


Assuntos
Dipeptídeos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/radioterapia , Compostos Radiofarmacêuticos/uso terapêutico , Nanomedicina Teranóstica , Idoso , Idoso de 80 Anos ou mais , Dipeptídeos/efeitos adversos , Seguimentos , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Humanos , Lutécio , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/psicologia , Qualidade de Vida , Retratamento
18.
Eur J Cancer ; 124: 15-24, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31707280

RESUMO

Immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) have transformed the management of many malignancies. Although rare, immune-mediated myocarditis presents unique clinical challenges due to heterogenous presentation, potential life-threatening consequences, and the time-critical need to differentiate it from other causes of cardiac dysfunction. Increasingly, TKI are being combined with ICI to promote immune modulation and improve efficacy. However, these combinations are associated with more toxicities. This series describes six patients with advanced melanoma who developed immune-mediated myocarditis while receiving an anti-PD-1 antibody or an anti-PD-L1 antibody plus a mitogen-activated protein kinase inhibitor. It provides a review of their heterogenous clinical presentations, investigational findings and treatment outcomes. Presentations ranged from asymptomatic cardiac enzyme elevation to death due to heart failure. We highlight the role of cardiac MRI (CMRI), a sensitive and non-invasive tool for the early detection and subsequent monitoring of myocardial inflammation. Five of the six patients exhibited CMRI changes characteristic of myocarditis, including mid-wall myocardial oedema and late gadolinium enhancement in a non-coronary distribution. Critically, two of these patients had normal findings on echocardiogram. Of the five patients who received immunosuppression, four recovered from myocarditis and one died of cardiac failure. The sixth patient improved with cardiac failure management alone. Three of the four patients responding to ICI derived long-term benefit. Clinical vigilance, prompt multimodal diagnosis and multidisciplinary management are paramount for the treatment of immune-mediated myocarditis.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Imageamento por Ressonância Magnética , Miocardite/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Creatina Quinase/sangue , Diagnóstico Diferencial , Ecocardiografia , Feminino , Coração/diagnóstico por imagem , Coração/efeitos dos fármacos , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/imunologia , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/imunologia , Miocardite/sangue , Miocardite/induzido quimicamente , Miocardite/imunologia , Miocárdio/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia , Troponina T/sangue
19.
N Engl J Med ; 381(17): 1632-1643, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31566309

RESUMO

BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling. METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis. RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group. CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Carbamatos/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Progressão da Doença , Eletrocorticografia , Feminino , Humanos , Análise de Intenção de Tratamento , Irinotecano/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida
20.
Chin Clin Oncol ; 8(3): 23, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31311277

RESUMO

The Peter MacCallum Cancer Centre is strongly focused on the conduct of translational research in driving towards better outcomes for patients. Central to this is our clinical trials program, with a strategic focus on early phase trials. Our efforts in developing a world-class program focused on early phase trials have been critically dependent on the creation and collaboration with key networks: local, regional and global. In this paper, we will articulate how the early drug development landscape has evolved in Australia, and how and why collaboration has been such a critical enabler for us in driving success.


Assuntos
Institutos de Câncer/normas , /métodos , Humanos
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