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Enfortumab vedotin is a fully human monoclonal antibody directed to Nectin-4 and conjugated to monomethyl auristatin E (MMAE), approved for treatment of previously treated locally advanced or metastatic urothelial carcinoma (mUC). This population analysis characterized pharmacokinetics of enfortumab vedotin and free (unconjugated) MMAE, identified covariates affecting pharmacokinetics, and evaluated weight-based dosing for enfortumab vedotin. Exposure-response analyses characterized relationships between enfortumab vedotin and free MMAE exposures and efficacy/safety endpoints. Data from 748 patients with locally advanced or mUC in 5 clinical studies were analyzed using nonlinear mixed-effects modeling. Patients received enfortumab vedotin 0.50-1.25 mg/kg every 3 weeks or on days 1, 8, and 15 of a 28-day cycle. Relevant covariates retained in final models were evaluated for clinical relevance to enfortumab vedotin and free MMAE exposures. Although some covariates produced differences in exposure, the magnitude of changes was not clinically meaningful. Simulations indicated weight-based dosing yielded more consistent exposures across body weight groups vs. a hypothetical fixed-dose regimen of enfortumab vedotin 95 mg (calculated for median body weight, 75 kg). Exposure-response analysis showed average enfortumab vedotin concentrations were not a statistically significant predictor of overall survival (hazard ratio 0.91, 95% confidence interval: 0.72-1.14; P = 0.41); all exposure quartiles had a greater median overall survival than chemotherapy (11.0-12.6 vs. 9.0 months). Enfortumab vedotin and free MMAE exposures were statistically significant predictors of grade ≥ 3 treatment-related adverse events (both P < 0.0001). This analysis supports enfortumab vedotin 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle.
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BACKGROUND: Limited data exist for global prevalence of claudin 18 isoform 2 (CLDN18.2) positivity and association of CLDN18.2 status with clinical and tumor characteristics in patients with locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. We report prevalence of CLDN18.2 positivity (phase 3; SPOTLIGHT, NCT03504397; GLOW, NCT03653507) and concordance of CLDN18.2 status between a subset of pair-matched tumor samples (phase 2, ILUSTRO, NCT03505320; phase 1, NCT03528629) from clinical studies of zolbetuximab. METHODS: Tumor samples from patients with LA unresectable or mG/GEJ adenocarcinoma were tested for CLDN18.2 status by immunohistochemistry. Human epidermal growth factor receptor 2 (HER2) expression was tested per central or local assessment. RESULTS: Across SPOTLIGHT and GLOW, the prevalence of CLDN18.2 positivity (≥ 75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining) was 38.4%. Prevalence was similar in gastric versus GEJ adenocarcinoma samples and regardless of collection method (biopsy versus resection) or collection site (primary versus metastatic). CLDN18.2 positivity was most prevalent in patients with diffuse-type tumors. In ILUSTRO and the phase 1 study, concordance of CLDN18.2 positivity was 61.1% between archival (i.e., any time before treatment) and baseline (i.e., ≤ 3 months before first treatment) samples, and concordance of any CLDN18 staining (≥ 1% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining) was 88.9%. CONCLUSIONS: CLDN18.2 was a highly prevalent biomarker in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma. CLDN18.2 positivity remained relatively stable over time in many patients. Biomarker testing for CLDN18.2 should be considered in standard clinical practice in these patients.
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Adenocarcinoma , Claudinas , Neoplasias Esofágicas , Unión Esofagogástrica , Neoplasias Gástricas , Humanos , Adenocarcinoma/patología , Adenocarcinoma/metabolismo , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Unión Esofagogástrica/patología , Claudinas/metabolismo , Masculino , Femenino , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/metabolismo , Isoformas de Proteínas , Prevalencia , AdultoRESUMEN
Enfortumab vedotin is an antibody-drug conjugate comprised of a human monoclonal antibody directed to Nectin-4 and monomethyl auristatin E (MMAE), a microtubule-disrupting agent. The objectives of this review are to summarize the clinical pharmacology of enfortumab vedotin monotherapy and demonstrate that the appropriate dose has been selected for clinical use. Pharmacokinetics (PK) of enfortumab vedotin (antibody-drug conjugate and total antibody) and free MMAE were evaluated in five clinical trials of patients with locally advanced or metastatic urothelial carcinoma (n = 748). Intravenous enfortumab vedotin 0.5-1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle showed linear, dose-proportional PK. No significant differences in exposure or safety of enfortumab vedotin and free MMAE were observed in mild, moderate, or severe renal impairment versus normal renal function. Patients with mildly impaired versus normal hepatic function had a 37% increase in area under the concentration-time curve (0-28 days), a 31% increase in maximum concentration of free MMAE, and a similar adverse event profile. No clinically significant PK differences were observed based on race/ethnicity with weight-based dosing, and no clinically meaningful QT prolongation was observed. Concomitant use with dual P-glycoprotein and strong cytochrome P450 3A4 inhibitors may increase MMAE exposure and the risk of adverse events. Approximately 3% of patients developed antitherapeutic antibodies against enfortumab vedotin 1.25 mg/kg. These findings support enfortumab vedotin 1.25 mg/kg monotherapy on days 1, 8, and 15 of a 28-day cycle. No dose adjustments are required for patients with renal impairment or mild hepatic impairment, or by race/ethnicity.
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Anticuerpos Monoclonales , Inmunoconjugados , Nectinas , Humanos , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Inmunoconjugados/farmacocinética , Inmunoconjugados/administración & dosificación , Inmunoconjugados/farmacología , Inmunoconjugados/efectos adversos , Inmunoconjugados/uso terapéutico , Oligopéptidos/farmacocinética , Oligopéptidos/administración & dosificación , Oligopéptidos/uso terapéutico , Oligopéptidos/farmacología , Oligopéptidos/efectos adversos , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Relación Dosis-Respuesta a Droga , Carcinoma de Células Transicionales/tratamiento farmacológico , Antineoplásicos/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
BACKGROUND AND OBJECTIVE: In comparison to chemotherapy, enfortumab vedotin (EV) prolonged overall survival in patients with previously treated advanced urothelial carcinoma in EV-301. The objective of the present study was to assess patient experiences of EV versus chemotherapy using patient-reported outcome (PRO) analysis of health-related quality of life (HRQoL). METHODS: For patients in the phase 3 EV-301 trial randomized to EV or chemotherapy we assessed responses to the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline, weekly for the first 12 wk, and then every 12 wk until discontinuation. We analyzed the QLQ-C30 change from baseline to week 12, the confirmed improvement rate, and the time to improvement or deterioration. KEY FINDINGS AND LIMITATIONS: Baseline PRO compliance rates were 91% for the EV arm (n = 301) and 89% for the chemotherapy arm (n = 307); the corresponding average rates from baseline to week 12 were 70% and 67%. Patients receiving EV versus chemotherapy had reduced pain (difference in change from baseline to week 12: -5.7, 95% confidence interval [CI] -10.8 to -0.7; p = 0.027) and worsening appetite loss (7.3, 95% CI 0.90-13.69; p = 0.026). Larger proportions of patients in the EV arm reported HRQoL improvement from baseline than in the chemotherapy arm; the odds of a confirmed improvement across ten QLQ-C30 function/symptom scales were 1.67 to 2.76 times higher for EV than for chemotherapy. Patients in the EV arm had a shorter time to first confirmed improvement in global health status (GHS)/QoL, fatigue, pain, and physical, role, emotional, and social functioning (all p < 0.05). EV delayed the time to first confirmed deterioration in GHS/QoL (p = 0.027), but worsening appetite loss occurred earlier (p = 0.009) in comparison to chemotherapy. CONCLUSIONS AND CLINICAL IMPLICATIONS: HRQoL with EV was maintained, and deterioration in HRQoL was delayed with EV in comparison to chemotherapy. Better results with EV were reported for some scales, with the greatest difference observed for pain. These findings reinforce the EV safety and efficacy outcomes and benefits observed in EV-301. PATIENT SUMMARY: Patients with previously treated advanced cancer of the urinary tract receiving the drug enfortumab vedotin maintained their HRQoL in comparison to patients treated with chemotherapy. The EV-301 trial is registered on ClinicalTrials.gov as NCT03474107 and on EudraCT as 2017-003344-21.
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Anticuerpos Monoclonales , Carcinoma de Células Transicionales , Medición de Resultados Informados por el Paciente , Calidad de Vida , Humanos , Masculino , Femenino , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/patología , Anticuerpos Monoclonales/uso terapéutico , Anciano , Persona de Mediana Edad , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversosRESUMEN
BACKGROUND: Enfortumab vedotin (EV) is an antibody-drug conjugate showing significant overall survival (OS) benefit versus chemotherapy for patients with previously treated locally advanced or metastatic urothelial carcinoma (la/mUC) in EV-301. This subgroup analysis was conducted to further analyze the efficacy and safety in a Japanese population. METHODS: In the open-label, phase 3 EV-301 trial, patients with la/mUC were randomized 1:1 to EV 1.25 mg/kg on Days 1, 8, and 15 for 28-day cycles or investigator-preselected standard chemotherapy (SC; docetaxel or paclitaxel for patients in Japan) on Day 1 of each 21-day cycle. Primary endpoint was OS and secondary efficacy endpoints included progression-free survival (PFS) and overall response rate (ORR). Safety/tolerability was also evaluated. RESULTS: As of the July 15, 2020 cut-off date for the interim analysis, the Japanese subgroup included 86 patients (EV: n = 36; SC: n = 50). Median OS was 15.18 months for EV and 10.55 months for SC (HR: 0.437 [95% CI: 0.209, 0.914]). Median PFS was 6.47 months for EV and 5.39 months for SC (HR: 0.464 [95% CI: 0.258, 0.835]). Confirmed ORR was 34.4% for EV and 21.3% for SC. A higher proportion of patients receiving SC versus EV had treatment-related adverse events (TRAEs; 97.9% vs. 91.7%, respectively), including grade ≥ 3 TRAEs (75.0% vs. 63.9%). CONCLUSIONS: This subgroup analysis confirmed that EV, with consistent efficacy and safety/tolerability in the EV-301 Japanese subgroup and overall study population, represents an important treatment option for previously treated patients with la/mUC.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Carcinoma de Células Transicionales/patología , Pueblos del Este de Asia , Neoplasias de la Vejiga Urinaria/patología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: Patients with advanced urothelial carcinoma have poor overall survival after platinum-containing chemotherapy and programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor treatment. METHODS: We conducted a global, open-label, phase 3 trial of enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-containing chemotherapy and had had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor. Patients were randomly assigned in a 1:1 ratio to receive enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight on days 1, 8, and 15 of a 28-day cycle) or investigator-chosen chemotherapy (standard docetaxel, paclitaxel, or vinflunine), administered on day 1 of a 21-day cycle. The primary end point was overall survival. RESULTS: A total of 608 patients underwent randomization; 301 were assigned to receive enfortumab vedotin and 307 to receive chemotherapy. As of July 15, 2020, a total of 301 deaths had occurred (134 in the enfortumab vedotin group and 167 in the chemotherapy group). At the prespecified interim analysis, the median follow-up was 11.1 months. Overall survival was longer in the enfortumab vedotin group than in the chemotherapy group (median overall survival, 12.88 vs. 8.97 months; hazard ratio for death, 0.70; 95% confidence interval [CI], 0.56 to 0.89; P = 0.001). Progression-free survival was also longer in the enfortumab vedotin group than in the chemotherapy group (median progression-free survival, 5.55 vs. 3.71 months; hazard ratio for progression or death, 0.62; 95% CI, 0.51 to 0.75; P<0.001). The incidence of treatment-related adverse events was similar in the two groups (93.9% in the enfortumab vedotin group and 91.8% in the chemotherapy group); the incidence of events of grade 3 or higher was also similar in the two groups (51.4% and 49.8%, respectively). CONCLUSIONS: Enfortumab vedotin significantly prolonged survival as compared with standard chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based treatment and a PD-1 or PD-L1 inhibitor. (Funded by Astellas Pharma US and Seagen; EV-301 ClinicalTrials.gov number, NCT03474107.).
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Moléculas de Adhesión Celular/antagonistas & inhibidores , Neoplasias Urológicas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Resistencia a Antineoplásicos , Femenino , Humanos , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Proteína 2 Ligando de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Supervivencia sin Progresión , Análisis de Supervivencia , Neoplasias Urológicas/mortalidad , Neoplasias Urológicas/patología , Urotelio/patologíaRESUMEN
Bromodomain and extraterminal domain (BET) proteins, which are important epigenetic readers, are often dysregulated in cancer. While a number of BET inhibitors are currently in early phase clinical trials, BET inhibitors show limited single-agent activity. The purpose of this study is to determine if Quercetin, a naturally occurring polyphenolic flavonoid often found abundant in fruits and vegetables, can enhance the anti-tumor effects of BET inhibitors. The efficacy of the combination was evaluated in vitro and in a xenograft model of pancreatic cancer. Co-treatment with BET inhibitors and Quercetin promoted apoptosis, decreased sphere-forming ability by cancer cells, and decreased cell proliferation. We found that hnRNPA1, a nuclear protein known to control mRNA export and mRNA translation of anti-apoptotic proteins, mediates some anti-tumor effects by Quercetin. Additionally, we show that combining BET inhibitors with Quercetin or hnRNPA1 knockdown decreased the anti-apoptotic protein Survivin. Significantly, Quercetin decreased hnRNPA1 in vivo and enhanced the effects of BET inhibitors at suppressing tumor growth. Together, these results demonstrate that Quercetin enhances the efficacy of BET inhibitors by suppressing hnRNPA1, and identify combination therapy with Quercetin and BET inhibitors for the treatment of cancer patients.
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Acetanilidas/farmacología , Antineoplásicos/farmacología , Azepinas/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Ribonucleoproteína Nuclear Heterogénea A1/metabolismo , Quercetina/farmacología , Triazoles/farmacología , Animales , Línea Celular Tumoral , Femenino , Humanos , Ratones Desnudos , Ratas , Survivin/metabolismoRESUMEN
BET inhibitors (BETi), which target transcription of key oncogenic genes, are currently being evaluated in early-phase clinical trials. However, because BETis show limited single-agent activity, there is increasing interest in identifying signaling pathways to enhance the efficacy of BETis. Here, we demonstrate increased MNK kinase-dependent eIF4E phosphorylation following treatment with BETis, indicating activation of a prosurvival feedback mechanism in response to BETis. BET PROTACs, which promote degradation of BET proteins, also induced eIF4E phosphorylation in cancer cells. Mechanistically, we show that the effect of BETis on MNK-eIF4E phosphorylation was mediated by p38 MAPKs. We also show that BETis suppressed RacGAP1 to induce Rac signaling-mediated eIF4E phosphorylation. Significantly, MNK inhibitors and MNK1/2 knockdown enhanced the efficacy of BETis in suppressing proliferation of cancer cells in vitro and in a syngeneic mouse model. Together, these results demonstrate a novel prosurvival feedback signaling induced by BETis, providing a mechanistic rationale for combination therapy with BET and MNK inhibitors for synergistic inhibition of cancer cells.
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Acetanilidas/administración & dosificación , Compuestos de Anilina/administración & dosificación , Azepinas/administración & dosificación , Factor 4E Eucariótico de Iniciación/metabolismo , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Proteínas Serina-Treonina Quinasas/metabolismo , Purinas/administración & dosificación , Neoplasias de la Tiroides/tratamiento farmacológico , Triazoles/administración & dosificación , Acetanilidas/farmacología , Compuestos de Anilina/farmacología , Animales , Azepinas/farmacología , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Factor 4E Eucariótico de Iniciación/antagonistas & inhibidores , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Ratones , Fosforilación/efectos de los fármacos , Purinas/farmacología , Transducción de Señal , Neoplasias de la Tiroides/metabolismo , Triazoles/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Glycogen Synthase Kinase-3ß (GSK-3ß), a serine/threonine protein kinase, has been implicated as a potential therapeutic target in human cancer. The objective of the present study was to evaluate aberrant expression of GSK-3ß as a potential biomarker in human breast and head and neck cancers. Nuclear/cytosolic fractionation, immunoblotting and immunohistochemical staining was used to study the expression of GSK-3ß in human breast and head and neck cancer. Aberrant nuclear accumulation of GSK-3ß in five human breast cancer cell lines was demonstrated and in 89/128 (70%) human breast carcinomas, whereas no detectable expression of GSK-3ß was found in benign breast tissue. Nuclear GSK-3ß expression was associated with HER-2 positive tumors (P=0.02) and non-triple negative breast carcinomas (P=0.0001), although nuclear GSK-3ß was observed in some samples across all breast cancer subtypes. Aberrant nuclear expression of GSK-3ß was found in 11/15 (73%) squamous cell head and neck carcinomas, whereas weak or no detectable expression of GSK-3ß was found in benign salivary gland and other benign head and neck tissues. These results support the hypothesis that aberrant nuclear GSK-3ß may represent a potential target for the clinical treatment of human breast and squamous cell carcinoma.
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As immunotherapies including tyrosine kinase inhibitors become more widely used for the treatment of a variety of malignancies, it is important for prescribers and patients to understand the potential adverse effects associated with these drugs. It is especially important to understand the potentially fatal side effects associated with these drugs to further determine risk factors for their development. The review presents a case of posterior reversible encephalopathy syndrome with concomitant Takotsubo cardiomyopathy, associated with use of lenvatinib therapy for thyroid cancer. It discusses the interventions performed and outcome. Potential mechanisms for development of these rare adverse effects, as well as cases in which these adverse effects are seen with use of other tyrosine-kinase inhibitors will be presented. It is important to continue to report these side effects, and further studies are needed to elucidate potential risk factors for their development, as well as to determine prognosis after development.
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Immunotherapy is emerging as a promising option for lung cancer treatment. Various endothelial adhesion molecules, such as integrin and selectin, as well as various cellular barrier molecules such as desmosome and tight junctions, regulate T-cell infiltration in the tumor microenvironment. However, little is known regarding how these molecules affect immune cells in patients with lung cancer. We demonstrated for the first time that overexpression of endothelial adhesion molecules and cellular barrier molecule genes was linked to differential infiltration of particular immune cells in non-small cell lung cancer. Overexpression of endothelial adhesion molecule genes is associated with significantly lower infiltration of activated CD4 and CD8 T-cells, but higher infiltration of activated B-cells and regulatory T-cells. In contrast, overexpression of desmosome genes was correlated with significantly higher infiltration of activated CD4 and CD8 T-cells, but lower infiltration of activated B-cells and regulatory T-cells in lung adenocarcinoma. This inverse relation of immune cells aligns with previous studies of tumor-infiltrating B-cells inhibiting T-cell activation. Although overexpression of endothelial adhesion molecule or cellular barrier molecule genes alone was not predictive of overall survival in our sample, these genetic signatures may serve as biomarkers of immune exclusion, or resistance to T-cell mediated immunotherapy.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Moléculas de Adhesión Celular/genética , Expresión Génica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos B/patología , Biomarcadores , Carcinoma de Pulmón de Células no Pequeñas/patología , Desmosomas/metabolismo , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/patología , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Modelos Biológicos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/patología , Microambiente Tumoral/inmunologíaRESUMEN
Glioblastoma multiforme is the most common malignant primary central nervous system neoplasm in adults. It has a very aggressive natural history with a median overall survival estimated at 14.6 months despite multimodality treatment. Extracranial metastases are very rare with few case reports published to date. We report the case of a 65-year-old male who underwent maximal safe resection for a newly diagnosed brain mass after presentation with new neurologic symptoms. He then received standard postsurgical adjuvant treatment for glioblastoma. Subsequently, he underwent another resection for early progressive disease. Several months later, he was hospitalized for new-onset musculoskeletal complaints. Additional investigation revealed new metastatic osseous lesions which were initially felt to be a new malignancy. The patient opted for supportive care and died 12 days later. Despite choosing no treatment, he elected to undergo a bone biopsy to understand the new underlying process. Results were that of metastatic GBM and were reported after the patient expired. Physicians caring for patients with GBM and new nonneurologic symptoms may contemplate body imaging.
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The tumor microenvironment is a vital feature of oncogenesis and tumor progression. There are several parallels between cancer cells and early developmental stem cells, including their plasticity and signaling mechanisms. In early fetal development, Nodal is expressed for endodermal and mesodermal differentiation. This expression has been shown reemerge in the setting of epithelial cancers, such as breast and melanoma. High Nodal expression correlates to an aggressive tumor grade in these malignancies. Nodal signal begins with its interaction with its coreceptor, Cripto-1, leading to activation of Smad2/Smad3 and ultimately downstream transcription and translation. Lefty is the natural inhibitor of Nodal and controls Nodal signaling during fetal development. However, cancer cells lack the presence of Lefty, thus leading to uncontrolled tumor growth. Given this understanding, inhibition of the Nodal pathway offers a new novel therapeutic target in oncology. Mol Cancer Ther; 16(5); 787-92. ©2017 AACR.
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Carcinogénesis/genética , Terapia Molecular Dirigida , Neoplasias/genética , Proteína Nodal/genética , Diferenciación Celular/genética , Proteínas Ligadas a GPI/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Factores de Determinación Derecha-Izquierda/genética , Proteínas de Neoplasias/genética , Neoplasias/tratamiento farmacológico , Transducción de Señal , Proteína Smad2/genética , Proteína smad3/genética , Microambiente Tumoral/genéticaRESUMEN
Small-cell lung cancer (SCLC) is distinguished from non-small-cell lung cancer by its rapid growth and more frequent metastases. Although patients with SCLC are highly responsive to chemotherapy and radiation therapy, long-term prognosis remains poor, with relapse and disease recurrence occurring in almost all cases. Whereas combination chemotherapies continue to be the standard of care in extensive-stage SCLC, there is value in exploring whether immune-checkpoint inhibition is an effective treatment strategy, given the durable responses in non-small-cell lung cancer. Data from SCLC trials have shown clinical activity and response to cytotoxic T-lymphocyte antigen-4 protein and programmed cell death-1 blockade, suggesting that antibodies targeting these pathways may be effective in improving survival outcome. However, data on clinical activity by programmed cell death-1 ligand expression in SCLC are not widely available. Limited data indicate that programmed cell death-1 ligand expression may not be an ideal biomarker for patient selection. Continued research is necessary to better optimize patient selection and response to therapy.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Inmunoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/terapia , Humanos , Neoplasias Pulmonares/inmunología , Pronóstico , Carcinoma Pulmonar de Células Pequeñas/inmunologíaRESUMEN
The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) is a tyrosine kinase signaling pathway that has a fundamental role in many biologic processes including embryonic development, tissue regeneration, and angiogenesis. Increasing evidence indicates that this pathway plays a critical role in oncogenesis via gene amplification, activating mutations, or translocation in tumors of various histologies. With multiplex sequencing technology, the detection of FGFR aberrations has become more common and is tied to cancer cell proliferation, resistance to anticancer therapies, and neoangiogenesis. Inhibition of FGFR signaling appears promising in preclinical studies, suggesting a pathway of clinical interest in the development of targeted therapy. Phase I trials have demonstrated a manageable toxicity profile. Currently, there are multiple FGFR inhibitors under study with many non-selective (multi-kinase) inhibitors demonstrating limited clinical responses. As we progress from the first generation of non-selective drugs to the second generation of selective FGFR inhibitors, it is clear that FGFR aberrations do not behave uniformly across cancer types; thus, a deeper understanding of biomarker strategies is undoubtedly warranted. This review aims to consolidate data from recent clinical trials with a focus on selective FGFR inhibitors. As Phase II clinical trials emerge, concentration on patient selection as it pertains to predicting response to therapy, feasible methods for overcoming toxicity, and the likelihood of combination therapies should be utilized. We will also discuss qualities that may be desirable in future generations of FGFR inhibitors, with the hope that overcoming these current barriers will expedite the availability of this novel class of medications.
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Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Humanos , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Transducción de SeñalRESUMEN
Genomic analysis of tumor tissue is the standard technique for identifying DNA alterations in malignancies. Genomic analysis of circulating tumor cell-free DNA (cfDNA) represents a relatively non-invasive method of assessing genomic alterations using peripheral blood. We compared the concordance of genomic alterations between cfDNA and tissue biopsies in this retrospective study. Twenty-eight patients with advanced solid tumors with paired next-generation sequencing tissue and cfDNA biopsies were identified. Sixty-five genes were common to both assays. Concordance was defined as the presence or absence of the identical genomic alteration(s) in a single gene on both molecular platforms. Including all aberrations, the average number of alterations per patient for tissue and cfDNA analysis was 4.82 and 2.96, respectively. When eliminating alterations not detectable in the cfDNA assay, mean number of alterations for tissue and cfDNA was 3.21 and 2.96, respectively. Overall, concordance was 91.9-93.9%. However, the concordance rate decreased to 11.8-17.1% when considering only genes with reported genomic alterations in either assay. Over 50% of mutations detected in either technique were not detected using the other biopsy technique, indicating a potential complementary role of each assay. Across 5 genes (TP53, EGFR, KRAS, APC, CDKN2A), sensitivity and specificity were 59.1% and 94.8%, respectively. Potential explanations for the lack of concordance include differences in assay platform, spatial and temporal factors, tumor heterogeneity, interval treatment, subclones, and potential germline DNA contamination. These results highlight the importance of prospective studies to evaluate concordance of genomic findings between distinct platforms that ultimately may inform treatment decisions.
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Adenocarcinoma/diagnóstico , Ácidos Nucleicos Libres de Células/análisis , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias Pulmonares/diagnóstico , Mutación/genética , Adenocarcinoma/genética , Proteína de la Poliposis Adenomatosa del Colon/genética , Biopsia , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Inhibidor p18 de las Quinasas Dependientes de la Ciclina/genética , Receptores ErbB/genética , Femenino , Genoma , Humanos , Neoplasias Pulmonares/genética , Masculino , Patología Molecular , Proteínas Proto-Oncogénicas p21(ras)/genética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Immunotherapy has emerged as a promising treatment modality in cancer therapy. With improved understanding of how to tip the balance of immune homeostasis, novel therapeutics targeting immune checkpoints have been developed, with durable responses observed in multiple solid tumors, including melanoma, renal cell carcinoma, and non-small-cell lung cancer. Clinical trials have reported favorable responses using programmed cell death-1 protein receptor (PD-1)/programmed cell death-1 protein ligand (PD-L1) blockade as monotherapy and most impressively in combinatorial trials with cytotoxic T-lymphocyte antigen-4 protein blockade. Nonetheless, a clinical benefit has not been observed in all patients. Therefore, identifying the ideal biomarkers for patient selection would be of great value in optimizing and personalizing immunotherapy. The utility of PD-L1 expression as a biomarker has varied in different clinical trials and immunohistochemistry assays. In addition, the response to immune checkpoint inhibition has been complicated by PD-L1 expression as a marker influenced by the dynamic tumor microenvironment. No consensus has yet been reached on whether PD-L1 expression is an ideal marker for patient selection. Recent research has shown promise for alternative markers, including T-cell immunohistochemistry, other immunologic markers, T-cell receptor clonality, and somatic mutational burden. However, additional studies are needed to assess the value of these as practical predictive biomarkers for patient selection and treatment response.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inmunoterapia/métodos , Neoplasias Pulmonares/tratamiento farmacológico , Antineoplásicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Biomarcadores de Tumor/inmunología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Selección de Paciente , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Microambiente TumoralRESUMEN
Aberrant activation of the Wingless-type (Wnt)/beta-catenin signaling pathway is associated with a variety of human cancers. Little is known regarding the role that Wnt ligands play in human carcinogenesis. To test whether a Wnt-1 signal is a survival factor in human cancer cells and thus may serve as a potential cancer therapeutic target, we investigated the effect of inhibition of Wnt-1 signaling in a variety of human cancer cell lines, including non small cell lung cancer, breast cancer, mesothelioma, and sarcoma. Both monoclonal antibody and RNA interference (RNAi) were used to inhibit Wnt-1 signaling. We found that incubation of a monoclonal anti-Wnt-1 antibody induced apoptosis and caused downstream protein changes in cancer cells overexpressing Wnt-1. In contrast, apoptosis was not detected in cells lacking or having minimal Wnt-1 expression after the antibody incubation. RNAi targeting of Wnt-1 in cancer cells overexpressing Wnt-1 demonstrated similar downstream protein changes and induction of apoptosis. The antibody also suppressed tumor growth in vivo. Our results indicate that both monoclonal anti-Wnt-1 antibody and Wnt-1 siRNA inhibit Wnt-1 signaling and can induce apoptosis in human cancer cells. These findings hold promise as a novel therapeutic strategy for cancer.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Apoptosis/fisiología , Proteínas Proto-Oncogénicas/metabolismo , Apoptosis/efectos de los fármacos , Western Blotting , División Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Etiquetado Corte-Fin in Situ , Análisis de Secuencia por Matrices de Oligonucleótidos , Pruebas de Precipitina , Proteínas Proto-Oncogénicas/inmunología , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Proteínas Wnt , Proteína Wnt1RESUMEN
SOCS-3 is a member of a newly discovered protein family that inhibits LIF-activated Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling in a negative auto-regulatory manner. In this study, we have cloned and characterized the promoter region of the human SOCS-3 gene. This region is approximately 1.1 kbp in length and consists of two putative STAT-binding elements, a G-rich element, and a putative TATA box. These elements are highly conserved in both murine and rat SOCS-3 promoters. Functional analysis of this region shows that the whole fragment (approximately 1.1 kbp) has high basal promoter activity and is responsive to growth factors. We also found that the wild type SOCS-3 promoter construct has significantly greater activity in non-small-cell lung cancer cell lines than in normal cells in accordance with STAT3 disregulation in these cells. Cloning of the human SOCS-3 promoter should help uncover mechanisms of regulation of the JAK-STAT pathway in human cancer.