RESUMEN
The standard of care for advanced or metastatic urothelial carcinoma (mUC) was historically identified with platinum-based chemotherapy. Thanks to the advances in biological and genetic knowledge and technologies, new therapeutic agents have emerged in this setting recently: the immune checkpoint inhibitors and the fibroblast growth factor receptor inhibitors as the target therapy for patients harboring alterations in the fibroblast growth factor receptor (FGFR) pathway. However, chasing a tumor's tendency to recur and progress, a new class of agents has more recently entered the scene, with promising results. Antibody-drug conjugates (ADCs) are in fact the latest addition, with enfortumab vedotin being the first to receive accelerated approval by the U.S. Food and Drug Administration in December 2019, followed by sacituzumab govitecan. Many other ADCs are still under investigation. ADCs undoubtedly represent the new frontier, with the potential of transforming the management of mUC treatment in the future. Therefore, we reviewed the landscape of mUC treatment options, giving an insight into the molecular basis and mechanisms, and evaluating new therapeutic strategies in the perspective of more and more personalized treatments.
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Inmunoconjugados , Humanos , Inmunoconjugados/uso terapéutico , Metástasis de la Neoplasia , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Terapia Molecular Dirigida/métodos , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/metabolismo , Camptotecina/análogos & derivadosAsunto(s)
Antineoplásicos Fitogénicos , Camptotheca , Camptotecina , Especies en Peligro de Extinción , Magnoliopsida , Humanos , Antineoplásicos Fitogénicos/aislamiento & purificación , Asia , Árboles/química , Camptotheca/química , Magnoliopsida/química , Camptotecina/aislamiento & purificación , FitomejoramientoRESUMEN
Liver cancer is the third leading cause of cancer deaths globally. The use of Hydroxycamptothecin (HCPT) as a first-line chemotherapeutic agent for liver, lung, and gastric cancers is often hampered by its low activity, limited targeting, and poor water solubility. This results in a low accumulation of HCPT in tumor cells, as well as the inability to maintain continuous treatment. Consequently, there is an urgent need to develop an accessory method that can enhance the therapeutic efficacy of HCPT while exhibiting good biocompatibility and targeted delivery ability. To address this critical issue, an enzyme-triggered supramolecular nanocarrier, refer as SCD/LCC SNCs, has been successfully developed, leveraging the aggregation of the negatively charged sulfate-modified ß-CDs and positively charged lauroylcholine chloride (LCC). This nanocarrier demonstrates acetylcholinesterase (LCC) triggered decomposition behavior, making it a promising drug carrier for HCPT. The cellular assays conducted have demonstrated that HCPT loaded into these SCD/LCC SNCs exhibit reduced cytotoxicity towards normal cells while maintaining robust tumor inhibitory activity and inducing apoptosis. Therefore, this study offers a promising strategy for the effective use of HCPT in the treatment of liver cancer.
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Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Camptotecina/farmacología , Camptotecina/química , Camptotecina/análogos & derivados , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/química , Apoptosis/efectos de los fármacos , Portadores de Fármacos/química , Antineoplásicos/farmacología , Antineoplásicos/química , Sistemas de Liberación de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacos , Nanopartículas/química , Supervivencia Celular/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Células Hep G2RESUMEN
BACKGROUND: Camptothecin (CPT) is one of the frequently used small chemotherapy drugs for treating hepatocellular carcinoma (HCC), but its clinical application is limited due to severe toxicities and acquired resistance. Combined chemo-gene therapy has been reported to be an effective strategy for counteracting drug resistance while sensitizing cancer cells to cytotoxic agents. Thus, we hypothesized that combining CPT with miR-145 could synergistically suppress tumor proliferation and enhance anti-tumor activity. METHODS: Lactobionic acid (LA) modified lipid nanoparticles (LNPs) were developed to co-deliver CPT and miR-145 into asialoglycoprotein receptors-expressing HCC in vitro and in vivo. We evaluated the synergetic antitumor effect of miR-145 and CPT using CCK8, Western blotting, apoptosis and wound scratch assay in vitro, and the mechanisms underlying the synergetic antitumor effects were further investigated. Tumor inhibitory efficacy, safety evaluation and MRI-visible ability were assessed using diethylnitrosamine (DEN) + CCl4-induced HCC mouse model. RESULTS: The LA modification improved the targeting delivery of cargos to HCC cells and tissues. The LA-CMGL-mediated co-delivery of miR-145 and CPT is more effective on tumor inhibitory than LA-CPT-L or LA-miR-145-L treatment alone, both in vitro and in vivo, with almost no side effects during the treatment period. Mechanistically, miR-145 likely induces apoptosis by targeting SUMO-specific peptidase 1 (SENP1)-mediated hexokinase (HK2) SUMOylation and glycolysis pathways and, in turn, sensitizing the cancer cells to CPT. In vitro and in vivo tests confirmed that the loaded Gd-DOTA served as an effective T1-weighted contrast agent for noninvasive tumor detection as well as real-time monitoring of drug delivery and biodistribution. CONCLUSIONS: The LA-CMGL-mediated co-delivery of miR-145 and CPT displays a synergistic therapy against HCC. The novel MRI-visible, actively targeted chemo-gene co-delivery system for HCC therapy provides a scientific basis and a useful idea for the development of HCC treatment strategies in the future.
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Camptotecina , Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , Nanopartículas , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Animales , Ratones , MicroARNs/genética , MicroARNs/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Humanos , Nanopartículas/química , Camptotecina/farmacología , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Camptotecina/uso terapéutico , Imagen por Resonancia Magnética/métodos , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Lípidos/química , LiposomasRESUMEN
Triple-negative breast cancer (TNBC) represents a major therapeutic challenge due to its heterogeneous and aggressive phenotype, and limited target-specific treatment options. The trophoblast cell surface antigen (Trop-2), a transmembrane glycoprotein overexpressed in various cancers, has emerged as a promising target for TNBC. Sacituzumab govitecan (SG), an antibody-drug conjugate (ADC) that targets Trop-2, has recently entered treatment algorithms for advanced and metastatic TNBC, independently from Trop-2 expression status, with manageable toxicity. Despite the impressive results, questions remain unsolved regarding its efficacy, safety profile, and Trop-2 biological role in cancer. Currently, Trop-2 cannot be designated as a predictive biomarker in SG treatment, albeit its expression correlates with disease outcome, yet its levels are not uniform across all TNBCs. Additionally, data regarding Trop-2 expression variations in primary and metastatic sites, and its interplay with other biomarkers are still ambiguous but mandatory in light of future applications of SG in other indications and settings. This poses the questions of a careful evaluation of the efficacy and toxicity profile of SG in such early stages of disease, and in personalized and combinatorial strategies. Research and clinical data are mandatory to address SG drawbacks and minimize its benefits, to realize its full potential as therapeutic agent in different epithelial tumors.
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Anticuerpos Monoclonales Humanizados , Antígenos de Neoplasias , Camptotecina , Moléculas de Adhesión Celular , Inmunoconjugados , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Camptotecina/efectos adversos , Femenino , Inmunoconjugados/uso terapéutico , Inmunoconjugados/efectos adversos , Antígenos de Neoplasias/inmunología , Moléculas de Adhesión Celular/metabolismo , Biomarcadores de Tumor , Animales , Investigación Biomédica TraslacionalRESUMEN
BACKGROUND: The liver is affected by two groups of malignant tumours: primary liver cancers and liver metastases. Liver metastases are significantly more common than primary liver cancer, and five-year survival after radical surgical treatment of liver metastases ranges from 28% to 50%, depending on primary cancer site. However, R0 resection (resection for cure) is not feasible in most people; therefore, other treatments have to be considered in the case of non-resectability. One possible option is based on the concept that the blood supply to hepatic tumours originates predominantly from the hepatic artery. Transarterial chemoembolisation (TACE) of the peripheral branches of the hepatic artery can be achieved by administering a chemotherapeutic drug followed by vascular occlusive agents and can lead to selective necrosis of the cancer tissue while leaving normal liver parenchyma virtually unaffected. The entire procedure can be performed without infusion of chemotherapy and is then called bland transarterial embolisation (TAE). These procedures are usually applied over a few sessions. Another possible treatment option is systemic chemotherapy which, in the case of colorectal cancer metastases, is most commonly performed using FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) and FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) regimens applied in multiple sessions over a long period of time. These therapies disrupt the cell cycle, leading to death of rapidly dividing malignant cells. Current guidelines determine the role of TAE and TACE as non-curative treatment options applicable in people with liver-only or liver-dominant metastatic disease that is unresectable or non-ablatable, and in people who have failed systemic chemotherapy. Regarding the treatment modalities in people with colorectal cancer liver metastases, we found no systematic reviews comparing the efficacy of TAE or TACE versus systemic chemotherapy. OBJECTIVES: To evaluate the beneficial and harmful effects of transarterial embolisation (TAE) or transarterial chemoembolisation (TACE) compared with systemic chemotherapy in people with liver-dominant unresectable colorectal cancer liver metastases. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, and three additional databases up to 4 April 2024. We also searched two trials registers and the European Medicines Agency database and checked reference lists of retrieved publications. SELECTION CRITERIA: We included randomised clinical trials assessing beneficial and harmful effects of TAE or TACE versus systemic chemotherapy in adults (aged 18 years or older) with colorectal cancer liver metastases. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were all-cause mortality; overall survival (time to mortality); and any adverse events or complications. Our secondary outcomes were cancer mortality; health-related quality of life; progression-free survival; proportion of participants dying or surviving with progression of the disease; time to progression of liver metastases; recurrence of liver metastases; and tumour response measures (complete response, partial response, stable disease, and progressive disease). For the purpose of the review and to perform necessary analyses, whenever possible, we converted survival rates to mortality rates, as this was our primary outcome. For the analysis of dichotomous outcomes, we used the risk ratio (RR); for continuous outcomes, we used the mean difference; and for time to event outcomes, we calculated hazard ratios (HRs), all with 95% confidence intervals (CI). We used the standardised mean difference with 95% CIs when the trials used different instruments. We used GRADE to assess the certainty of evidence for each outcome. We based our conclusions on outcomes analysed at the longest follow-up. MAIN RESULTS: We included three trials with 118 participants randomised to TACE versus 120 participants to systemic chemotherapy. Four participants were excluded; one due to disease progression prior to treatment and three due to decline in health. The trials reported data on one or more outcomes. Two trials were performed in China and one in Italy. The trials differed in terms of embolisation techniques and chemotherapeutic agents. Follow-up ranged from 12 months to 50 months. TACE may reduce mortality at longest follow-up (RR 0.86, 95% CI 0.79 to 0.94; 3 trials, 234 participants; very low-certainty evidence), but the evidence is very uncertain. TACE may have little to no effect on overall survival (time to mortality) (HR 0.61, 95% CI 0.37 to 1.01; 1 trial, 70 participants; very low-certainty evidence), any adverse events or complications (3 trials, 234 participants; very low-certainty evidence), health-related quality of life (2 trials, 154 participants; very low-certainty evidence), progression-free survival (1 trial, 70 participants; very low-certainty evidence), and tumour response measures (presented as the overall response rate) (RR 1.81, 95% CI 1.11 to 2.96; 3 trials, 234 participants; very low-certainty evidence), but the evidence is very uncertain. No trials reported cancer mortality, proportion of participants dying or surviving with progression of the disease, and recurrence of liver metastases. We found no trials comparing the effects of TAE versus systemic chemotherapy in people with colorectal cancer liver metastases. AUTHORS' CONCLUSIONS: The evidence regarding effectiveness of TACE versus systemic chemotherapy in people with colorectal cancer liver metastases is of very low certainty and is based on three trials. Our confidence in the results is limited due to the risk of bias, inconsistency, indirectness, and imprecision. It is very uncertain whether TACE confers benefits with regard to reduction in mortality, overall survival (time to mortality), reduction in adverse events or complications, improvement in health-related quality of life, improvement in progression-free survival, and tumour response measures (presented as the overall response rate). Data on cancer mortality, proportion of participants dying or surviving with progression of the disease, and recurrence of liver metastases are lacking. We found no trials assessing TAE versus systemic chemotherapy. More randomised clinical trials are needed to strengthen the body of evidence and provide insight into the benefits and harms of TACE or TAE in comparison with systemic chemotherapy in people with liver metastases from colorectal cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica , Quimioembolización Terapéutica , Neoplasias Colorrectales , Fluorouracilo , Leucovorina , Neoplasias Hepáticas , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Quimioembolización Terapéutica/métodos , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Arteria Hepática , Compuestos Organoplatinos/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Camptotecina/uso terapéutico , Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificaciónAsunto(s)
Neoplasias de la Mama , Camptotecina , Medicina Estatal , Trastuzumab , Humanos , Trastuzumab/uso terapéutico , Trastuzumab/economía , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/economía , Femenino , Medicina Estatal/economía , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Camptotecina/economía , Costos de los Medicamentos , Inmunoconjugados/uso terapéutico , Inmunoconjugados/economía , Reino Unido/epidemiología , Antineoplásicos Inmunológicos/economía , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Análisis Costo-BeneficioRESUMEN
Preclinical studies have demonstrated that liposomal irinotecan (CPT-11), a topoisomerase I inhibitor, has broad activity against adult cancers, including pancreatic, gastric, colon, lung, glioma, ovarian, and breast cancer. Encapsulation of irinotecan into liposomes can modify its pharmacokinetic properties dramatically. Also, the pharmacokinetic profiles of liposomal drug formulations are not fully understood; thus, bioanalytical methods are needed to separate and quantify nonencapsulated vs. encapsulated concentrations. In this study, two robust, specific, and sensitive LC-MS/MS methods were developed and validated to separate and quantify the nonencapsulated CPT-11 (NE-CPT-11) from the sum-total CPT-11 (T-CPT-11) and its major metabolite, SN-38, in human plasma after intravenous administration of liposomal irinotecan. NE-CPT-11 and SN-38 were separated from plasma samples by using solid-phase extraction, and T-CPT-11 was measured by protein precipitation. The liposomal CPT-11 formulation was unstable during sample storage and handling, resulting in elevated NE-CPT-11 concentration. To improve the stability of liposomal CPT-11, a cryoprotectant solution was added to human plasma samples prior to storage and processing. CPT-11, SN-38, and their respective internal standards, CPT-11-d10 and SN-38-d3, were chromatographically separated on a reversed-phase C18 analytical column. The drugs were detected on a triple quadrupole mass spectrometer in the positive MRM ion mode by monitoring the transitions 587.3 > 124.1 (CPT-11) and 393.0 > 349.1 (SN-38). The calibration curves demonstrated a good fit across the concentration ranges of 10-5000 ng/mL for T-CPT-11, 2.5-250 ng/mL for NE-CPT-11, and 1-500 ng/mL for SN-38. The accuracy and precision were within the acceptable limits, matrix effects were nonsignificant, recoveries were consistent and reproducible, and the analytes were stable under all tested storage conditions. Finally, the LC-MS/MS methods were successfully applied in a phase I clinical pharmacokinetic study of nanoliposomal irinotecan (Onivyde®) in pediatric patients with recurrent solid malignancies or Ewing sarcoma.
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Camptotecina , Estabilidad de Medicamentos , Irinotecán , Liposomas , Neoplasias , Espectrometría de Masas en Tándem , Humanos , Irinotecán/farmacocinética , Irinotecán/sangre , Liposomas/química , Liposomas/sangre , Espectrometría de Masas en Tándem/métodos , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Camptotecina/sangre , Camptotecina/administración & dosificación , Niño , Neoplasias/tratamiento farmacológico , Neoplasias/sangre , Reproducibilidad de los Resultados , Límite de Detección , Femenino , Modelos Lineales , Cromatografía Liquida/métodos , Masculino , AdolescenteRESUMEN
Antibody-drug conjugates (ADCs) have demonstrated effectiveness in treating various cancers, particularly exhibiting specificity in targeting human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Recent advancements in phase 3 clinical trials have broadened current understanding of ADCs, especially trastuzumab deruxtecan, in treating other HER2-expressing malignancies. This expansion of knowledge has led to the US Food and Drug Administration's approval of trastuzumab deruxtecan for HER2-positive and HER2-low breast cancer, HER2-positive gastric cancer, and HER2-mutant nonsmall cell lung cancer. Concurrent with the increasing use of ADCs in oncology, there is growing concern among health care professionals regarding the rise in the incidence of interstitial lung disease or pneumonitis (ILD/p), which is associated with anti-HER2 ADC therapy. Studies on anti-HER2 ADCs have reported varying ILD/p mortality rates. Consequently, it is crucial to establish guidelines for the diagnosis and management of ILD/p in patients receiving anti-HER2 ADC therapy. To this end, a panel of Chinese experts was convened to formulate a strategic approach for the identification and management of ILD/p in patients treated with anti-HER2 ADC therapy. This report presents the expert panel's opinions and recommendations, which are intended to guide the management of ILD/p induced by anti-HER2 ADC therapy in clinical practice.
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Inmunoconjugados , Enfermedades Pulmonares Intersticiales , Receptor ErbB-2 , Humanos , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/inducido químicamente , China , Inmunoconjugados/uso terapéutico , Inmunoconjugados/efectos adversos , Neumonía/tratamiento farmacológico , Femenino , Consenso , Trastuzumab/uso terapéutico , Trastuzumab/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Camptotecina/análogos & derivadosRESUMEN
BACKGROUND: Trastuzumab deruxtecan has shown encouraging activity in patients with treatment-refractory HER2-positive, RAS wild-type and BRAF wild-type metastatic colorectal cancer. Dose optimisation and further antitumour assessments in patients with RAS mutations and those with previous anti-HER2 therapy are warranted. We aimed to evaluate two doses of trastuzumab deruxtecan (5·4 mg/kg and 6·4 mg/kg) to establish the recommended dose in patients with pretreated HER2-positive, RAS wild-type or mutant metastatic colorectal cancer. METHODS: DESTINY-CRC02 was a multicentre, randomised, two-stage, two-arm, phase 2 study done in 53 research hospitals and medical centres in Australia, Belgium, France, Italy, Japan, South Korea, Spain, Taiwan, the UK, and the USA. Eligible patients were aged 18 years and older or 20 years and older (depending on region) with pretreated pathologically documented, unresectable, recurrent, or metastatic HER2-positive, and RAS wild-type or mutant colorectal cancer. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and have received previous chemotherapy, and anti-EGFR, anti-VEGF, or anti-PD-L1 therapy, if clinically indicated. In stage 1, patients were randomly assigned (1:1), via a secure interactive response technology system, to receive 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan administered intravenously every 21 days. Stratification factors were ECOG performance status, HER2 status, and RAS status. In stage 2, patients were assigned into the 5·4 mg/kg treatment group only. The primary endpoint was confirmed objective response rate by blinded independent central review, assessed in all patients for whom treatment was assigned (full analysis set). Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04744831, and is ongoing (not recruiting). FINDINGS: Between March 5, 2021, and March 29, 2022, 135 patients were centrally screened, 122 of whom were enrolled. In stage 1, 40 patients each were randomly assigned to receive trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg. In stage 2, an additional 42 patients were enrolled in the 5·4 mg/kg group. 64 (52%) participants were male and 58 (48%) were female. The median duration of follow-up was 8·9 months (IQR 6·7-10·5) in the 5·4 mg/kg group and 10·3 months (5·9-12·7) in the 6·4 mg/kg group. The confirmed objective response rate by blinded independent central review was 37·8% (31/82 [95% CI 27·3-49·2]) in the 5·4 mg/kg group and 27·5% (11/40 [14·6-43·9]) in the 6·4 mg/kg group. 34 (41%) of 83 patients in the 5·4 mg/kg group and 19 (49%) of 39 in the 6·4 mg/kg group had grade 3 or worse drug-related treatment-emergent adverse events. The most common grade 3 or worse drug-related treatment-emergent adverse events were neutrophil count decreased (13 [16%] of 83 patients), anaemia (six [7%]), nausea (six [7%]), and white blood cell count decreased (five [6%]) in the 5·4 mg/kg group; and were neutrophil count decreased (10 [26%] of 39 patients), anaemia (eight [21%]), platelet count decreased (four [10%]), and white blood cell count decreased (four [10%]) in the 6·4 mg/kg group. Drug-related serious adverse events occurred in 11 (13%) of 83 patients in the 5·4 mg/kg group and six (15%) of 39 patients in the 6·4 mg/kg group; the most common in the 5·4 mg/kg group was nausea (three [4%] patients) and the most common in the 6·4 mg/kg group were fatigue (two [5%] patients), neutropenia (two [5%]), and thrombocytopenia (two [5%]). A drug-related treatment-emergent adverse event related to death occurred in one (1%) patient in the 5·4 mg/kg group (due to hepatic failure). Adjudicated drug-related interstitial lung disease or pneumonitis events were observed in seven (8%) patients in the 5·4 mg/kg group (all grade 1 or 2) and in five (13%) patients in the 6·4 mg/kg group (four grade 1 or 2; one grade 5). INTERPRETATION: The promising antitumour activity and favourable safety profile support trastuzumab deruxtecan 5·4 mg/kg as the optimal single-agent dose for patients with pretreated HER2-positive metastatic colorectal cancer, including those with RAS mutations, previous anti-HER2 therapy, or both. FUNDING: Daiichi Sankyo and AstraZeneca.
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Neoplasias Colorrectales , Receptor ErbB-2 , Trastuzumab , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Trastuzumab/uso terapéutico , Trastuzumab/administración & dosificación , Femenino , Masculino , Receptor ErbB-2/genética , Persona de Mediana Edad , Anciano , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Camptotecina/administración & dosificación , Adulto , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Mutación , InmunoconjugadosAsunto(s)
Camptotecina , Neoplasias Colorrectales , Inmunoconjugados , Metástasis de la Neoplasia , Receptor ErbB-2 , Trastuzumab , Humanos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Inmunoconjugados/administración & dosificación , Inmunoconjugados/uso terapéutico , Receptor ErbB-2/metabolismo , Trastuzumab/administración & dosificación , Trastuzumab/uso terapéuticoRESUMEN
AIMS: Fruquintinib is a selective small molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3 recently approved in the United States (US) for the treatment of adult patients with metastatic colorectal cancer (CRC) who have previously been treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type and medically appropriate, anti-epidermal growth factor receptor therapy. This study aimed to estimate the 5-year budget impact of fruquintinib from a US payer perspective (commercial and Medicare). MATERIALS AND METHODS: A budget impact model was developed to compare two scenarios: a reference scenario in which patients received regorafenib, trifluridine/tipiracil, or trifluridine/tipiracil with bevacizumab and an alternative scenario in which patients received reference scenario treatments or fruquintinib. Market shares were evenly divided across available options. A 5-year time horizon and a hypothetical health plan of 1 million members was assumed. The model included epidemiological inputs to estimate the eligible population; clinical inputs for treatment duration, progression-free survival, overall survival, and adverse event (AE) frequency; and cost inputs for treatment, AEs, disease management, subsequent therapy, and terminal care costs. Budget impact was reported as total, per member per year (PMPY), and per member per month (PMPM). RESULTS: The model estimated an eligible population of 194 patients (39 per year) over 5 years. In the base case, the estimated 5-year budget impact of fruquintinib was $4,077,073 ($0.82 PMPY and 0.07 PMPM) for a commercial health plan. During the first year, the estimated budget impact was $627,570 ($0.63 PMPY and 0.05 PMPM). Results were robust across sensitivity analyses. PMPM costs from the Medicare perspective were greater than the base-case (commercial) ($0.17 vs. $0.07) due to higher incidence of CRC in that population. CONCLUSIONS: Fruquintinib is associated with a low budget impact for payers based on proposed thresholds in the US.
Fruquintinib is a treatment for metastatic colorectal cancer that has progressed after or not responded to multiple guideline-recommended therapies. This budget impact analysis was conducted to estimate the added costs a health plan would incur over a 5-year period if it chose to cover this therapy. The analysis found that the per plan member per month cost of covering fruquintinib was $0.07 for a United States commercial health plan and $0.17 for Medicare.
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Protocolos de Quimioterapia Combinada Antineoplásica , Benzofuranos , Bevacizumab , Neoplasias Colorrectales , Piridinas , Timina , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Benzofuranos/uso terapéutico , Benzofuranos/economía , Estados Unidos , Bevacizumab/uso terapéutico , Bevacizumab/economía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Piridinas/uso terapéutico , Piridinas/economía , Trifluridina/uso terapéutico , Trifluridina/economía , Presupuestos , Quinazolinas/uso terapéutico , Quinazolinas/economía , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/economía , Uracilo/análogos & derivados , Uracilo/uso terapéutico , Uracilo/economía , Compuestos Organoplatinos/uso terapéutico , Compuestos Organoplatinos/economía , Análisis Costo-Beneficio , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Camptotecina/economía , Antineoplásicos/economía , Antineoplásicos/uso terapéutico , Irinotecán/uso terapéutico , Irinotecán/economía , Medicare , Fluorouracilo/uso terapéutico , Fluorouracilo/economía , Oxaliplatino/uso terapéutico , Oxaliplatino/economía , Receptores de Factores de Crecimiento Endotelial Vascular , Modelos Económicos , Combinación de Medicamentos , PirrolidinasRESUMEN
Sacituzumab Govitecan (SG) is an antibody-drug conjugate that has demonstrated efficacy in patients with TROP-2 expressing epithelial cancers. In a xenograft model of intracranial breast cancer, SG inhibited tumor growth and increased mouse survival. We conducted a prospective window-of-opportunity trial (NCT03995706) at the University of Texas Health Science Center at San Antonio to examine the intra-tumoral concentrations and intracranial activity of SG in patients undergoing craniotomy for breast cancer with brain metastases (BCBM) or recurrent glioblastoma (rGBM). We enrolled 25 patients aged ≥18 years diagnosed with BCBM and rGBM to receive a single intravenous dose of SG at 10 mg/kg given one day before resection and continued on days 1 and 8 of 21-day cycles following recovery. The PFS was 8 months and 2 months for BCBM and rGBM cohorts, respectively. The OS was 35.2 months and 9.5 months, respectively. Grade≥3 AE included neutropenia (28%), hypokalemia (8%), seizure (8%), thromboembolic event (8%), urinary tract infection (8%) and muscle weakness of the lower limb (8%). In post-surgical tissue, the median total SN-38 was 249.8 ng/g for BCBM and 104.5 ng/g for rGBM, thus fulfilling the primary endpoint. Biomarker analysis suggests delivery of payload by direct release at target site and that hypoxic changes do not drive indirect release. Secondary endpoint of OS was 35.2 months for the BCBM cohort and 9.5 months for rGBM. Non-planned exploratory endpoint of ORR was 38% for BCBM and 29%, respectively. Exploratory endpoint of Trop-2 expression was observed in 100% of BCBM and 78% of rGBM tumors. In conclusion, SG was found to be well tolerated with adequate penetration into intracranial tumors and promising preliminary activity within the CNS. Trial Registration: Trial (NCT03995706) enrolled at Clinical Trials.gov as Neuro/Sacituzumab Govitecan/Breast Brain Metastasis/Glioblastoma/Ph 0: https://clinicaltrials.gov/study/NCT03995706?cond=NCT03995706 .
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Anticuerpos Monoclonales Humanizados , Neoplasias Encefálicas , Neoplasias de la Mama , Glioblastoma , Inmunoconjugados , Recurrencia Local de Neoplasia , Humanos , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Adulto , Anciano , Inmunoconjugados/uso terapéutico , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Estudios Prospectivos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Antígenos de Neoplasias/metabolismo , Moléculas de Adhesión Celular/metabolismoRESUMEN
Patients with right-sided metastatic colon carcinoma have a significantly worse prognosis than those with left-sided colorectal cancer (CRC), regardless of treatment. The aim of the prospective IVOPAK II study was to implement an interdisciplinary guideline-conform personalized CRC palliative therapy of metastatic colorectal carcinoma and to improve the overall survival (OS) by multidisciplinary approach via secondary metastatic resection. We present the efficacy data of first-line treatment and the benefit of interdisciplinary collaboration of right-sided metastatic colon carcinoma patients: n â =â 25. RAS mutation: n â =â 20 (80%): received systemic first-line treatment: FOLFIRI plus bevacizumab. All-RAS-wildtype: n â =â 5 (20%): received systemic first-line treatment: FOLFIRI plus cetuximab. Last date evaluation: 31 January 2024. Median age: 59.6â years (range 42-71), men/women: 14/11. Eastern Cooperative Oncology Group (ECOG) index: 0/1/2â :â 11/10/4. Evaluable for response: n â =â 25. Complete response: n â =â 0, partial response: n â =â 14 (56%), stable disease: n â =â 8 (32%), progressive disease: n â =â 3 (12%), early tumor shrinkage: n â =â 13 (52%), estimates progression-free survival: 13â months (95% CI 8-17â months), estimated OS: 48â months (95% CI 25-71â months), median follow-up: 26â months (1-61â months), no evidence of disease: n â =â 4 (16%). A chemotherapy doublette regimen with FOLFIRI plus a biological as first-line treatment shows promising efficacy and secondary metastatic resection after interdisciplinary discussion was associated with a survival benefit in right-sided metastatic colon carcinoma.
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Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina , Neoplasias del Colon , Fluorouracilo , Leucovorina , Humanos , Masculino , Femenino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano , Neoplasias del Colon/patología , Neoplasias del Colon/tratamiento farmacológico , Adulto , Fluorouracilo/administración & dosificación , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Camptotecina/uso terapéutico , Estudios Prospectivos , Biomarcadores de Tumor/genética , Bevacizumab/administración & dosificación , Bevacizumab/uso terapéutico , Cetuximab/administración & dosificación , Cetuximab/uso terapéutico , Mutación , Tasa de SupervivenciaRESUMEN
Trastuzumab deruxtecan (T-DXd) is a novel anti-HER2 antibody-drug conjugate formed by the combination of trastuzumab and deruxtecan. It is used in human epidermal growth factor 2 receptor (HER2) mutant breast, stomach and colorectal cancers as well as non-small cell lung cancer (NSCLC). The 58-year-old denovo metastatic NSCLC patient we will discuss here progressed with newly developing brain metastasis under first-line carboplatin/paclitaxel treatment. After next generation sequencing revealed a mutation in the ERBB2 gene located in exon 20, we administered T-DXd to our patient. While a significant improvement was observed in the clinical condition of the patient after one course of treatment, brain metastases were found to be in complete response in control screening after four courses of treatment. Systemic screening with PET/computed tomography showed nearly complete regression of the primary lesion, metastatic lymphadenopathies, and surrenal metastases. T-DXd may be successfully used in HER2 mutant metastatic NSCLC patients. In addition, it can also be successfully used in patients with central nervous system metastases with or without cranial radiotherapy.
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Neoplasias Encefálicas , Camptotecina , Carcinoma de Pulmón de Células no Pequeñas , Exones , Neoplasias Pulmonares , Receptor ErbB-2 , Trastuzumab , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Trastuzumab/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Receptor ErbB-2/genética , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Inmunoconjugados/uso terapéutico , Mutación , Femenino , Masculino , Antineoplásicos Inmunológicos/uso terapéuticoRESUMEN
Colorectal cancer (CRC) remains one of the most prevalent malignant tumors of the digestive system, yet the availability of safe and effective chemotherapeutic agents for clinical use remains limited. Camptothecin (CPT) and its derivatives, though approved for cancer treatment, have encountered significant challenges in clinical application due to their low bioavailability and high systemic toxicity. Strategic modification at the 7-position of CPT enables the development of novel CPT derivatives with high activity. In the present study, a series of compounds incorporating aminoureas, amino thioureas, and acylamino thioureas as substituents at the 7-position were screened. These compounds were subsequently evaluated for their cytotoxicity against the human gastric cancer (GC) cell line AGS and the CRC cell line HCT116. Two derivatives, XSJ05 (IC50 = 0.006 ± 0.003 µM) and XSJ07 (IC50 = 0.013 ± 0.003 µM), exhibited remarkably effective anti-CRC activity, being better than TPT. In addition, they have a better safety profile. In vitro mechanistic studies revealed that XSJ05 and XSJ07 exerted their inhibitory effects on CRC cell proliferation by suppressing the activity of topoisomerase I (Topo I). This suppression triggers DNA double-strand breaks, leads to DNA damage and subsequently causes CRC cells to arrest in the G2/M phase. Ultimately, the cells undergo apoptosis. Collectively, these findings indicate that XSJ05 and XSJ07 possess superior activity coupled with favorable safety profiles, suggesting their potential as lead compounds for the development of CRC therapeutics.
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Antineoplásicos , Apoptosis , Camptotecina , Proliferación Celular , Neoplasias Colorrectales , ADN-Topoisomerasas de Tipo I , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Topoisomerasa I , Humanos , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa I/síntesis química , Camptotecina/farmacología , Camptotecina/química , Camptotecina/síntesis química , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , ADN-Topoisomerasas de Tipo I/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Estructura Molecular , Apoptosis/efectos de los fármacos , Tiourea/farmacología , Tiourea/química , Tiourea/síntesis química , Línea Celular TumoralRESUMEN
DNA-protein crosslinks (DPCs) are toxic lesions that inhibit DNA related processes. Post-translational modifications (PTMs), including SUMOylation and ubiquitylation, play a central role in DPC resolution, but whether other PTMs are also involved remains elusive. Here, we identify a DPC repair pathway orchestrated by poly-ADP-ribosylation (PARylation). Using Xenopus egg extracts, we show that DPCs on single-stranded DNA gaps can be targeted for degradation via a replication-independent mechanism. During this process, DPCs are initially PARylated by PARP1 and subsequently ubiquitylated and degraded by the proteasome. Notably, PARP1-mediated DPC resolution is required for resolving topoisomerase 1-DNA cleavage complexes (TOP1ccs) induced by camptothecin. Using the Flp-nick system, we further reveal that in the absence of PARP1 activity, the TOP1cc-like lesion persists and induces replisome disassembly when encountered by a DNA replication fork. In summary, our work uncovers a PARP1-mediated DPC repair pathway that may underlie the synergistic toxicity between TOP1 poisons and PARP inhibitors.
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Reparación del ADN , Replicación del ADN , ADN-Topoisomerasas de Tipo I , Poli(ADP-Ribosa) Polimerasa-1 , Poli ADP Ribosilación , Animales , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/genética , ADN-Topoisomerasas de Tipo I/metabolismo , Xenopus laevis , Ubiquitinación , Humanos , ADN/metabolismo , Daño del ADN , Camptotecina/farmacología , Procesamiento Proteico-Postraduccional , ADN de Cadena Simple/metabolismo , Proteínas de Xenopus/metabolismoRESUMEN
Recently, the sortilin receptor (SORT1) was found to be preferentially over-expressed on the surface of many cancer cells, which makes SORT1 a novel anticancer target. The SORT1 binding proprietary peptide TH19P01 could achieve the SORT1-mediated cancer cell binding and subsequent internalization. Inspired by the peptide-drug conjugate (PDC) strategy, the TH19P01-camptothecin (CPT) conjugates were designed, efficiently synthesized, and evaluated for their anticancer potential in this study. The water solubility, in vitro anticancer activity, time-kill kinetics, cellular uptake, anti-migration activity, and hemolysis effects were systematically estimated. Besides, in order to monitor the release of CPT from conjugates in real-time, the CPT/Dnp-based "turn on" hybrid peptide was designed, which indicted that CPT could be sustainably released from the hybrid peptide in both human serum and cancer cellular environments. Strikingly, compared with free CPT, the water solubility, cellular uptake, and selectivity towards cancer cells of hybrid peptide LYJ-2 have all been significantly enhanced. Moreover, unlike free CPT or TH19P01, LYJ-2 exhibited selective anti-proliferative and anti-migration effects against SORT1-positive MDA-MB-231 cells. Collectively, this study not only established efficient strategies to improve the solubility and anticancer potential of chemotherapeutic agent CPT, but also provided important references for the future development of TH19P01 based PDCs targeting SORT1.
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Proteínas Adaptadoras del Transporte Vesicular , Antineoplásicos , Camptotecina , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Camptotecina/farmacología , Camptotecina/química , Camptotecina/síntesis química , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Péptidos/química , Péptidos/farmacología , Péptidos/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Movimiento Celular/efectos de los fármacosRESUMEN
Background: A successful immune response against tumors depends on various cellular processes. Hence, there is an urgent need to construct a proficient nanoplatform for immunotherapy that can concurrently regulate the activities of various cells participating in the immune process. We have developed zeolitic imidazolate framework-8 (ZIF-8) formula, with good pH sensitivity, which is conducive to the release of drugs in the tumor site (acidic environment) and significantly improves immunotherapy. This is achieved through the coordinated action of different therapeutic agents, such as the photothermal agent polydopamine (PDA), the chemodrug camptothecin (CPT), and the immunomodulator 1-methyl-D-tryptophan (1-MT). Materials and Methods: In this study, we evaluated the antitumor effect of PDA/(CPT + 1-MT) @ZIF-8 (PCMZ) nanoparticles (NPs) in vitro and in vivo and investigated the molecular mechanism of PCMZ NPs in tumor suppression via photothermal-chemo-immunotherapy. Results: MTT and Annexin V-FITC/PI double staining apoptosis test showed that PCMZ NPs could induce apoptosis of 4T1 cell, and PCMZ NPs could cause 4T1 cell necrosis under 808 nm laser irradiation. The objective is to establish a unilateral breast cancer model in mice and investigate the effect of PCMZ NPs on tumor growth and tumor suppression in tumor bearing mice. The results showed that PCMZ NPs showed good heating effect in vivo and effectively inhibited tumor growth under 808 nm laser irradiation. In addition, PCMZ NPs could induce the immunogenic death of tumor cells, promote the maturation of DCs, inhibit IDO pathway, and finally differentiate T cells into cytotoxic T cells and helper T cells, so as to effectively activate the anti-tumor immune response. Conclusion: The PCMZ NPs, possessing good photothermal conversion capabilities due to join of PDA, effectively overcome two main challenges in immunotherapy: insufficient stimulation of the immune response and evasion of the immune system. This provides a robust platform against invasive cancer and recurrent tumors.
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Camptotecina , Inmunoterapia , Indoles , Ratones Endogámicos BALB C , Polímeros , Triptófano , Zeolitas , Animales , Indoles/química , Indoles/farmacología , Zeolitas/química , Zeolitas/farmacología , Inmunoterapia/métodos , Triptófano/química , Triptófano/farmacología , Triptófano/análogos & derivados , Ratones , Concentración de Iones de Hidrógeno , Línea Celular Tumoral , Femenino , Polímeros/química , Polímeros/farmacología , Camptotecina/química , Camptotecina/farmacología , Nanopartículas/química , Apoptosis/efectos de los fármacos , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Humanos , Terapia Fototérmica/métodos , Imidazoles/química , Imidazoles/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Terapia CombinadaRESUMEN
BACKGROUND: Accurate estimation of cell viability is crucial in various applications such as cytotoxicity testing and routine cell culture on both industrial and laboratory scales. For this, the real-time monitoring of cell status would be beneficial. Conventional cell-based assays for cell viability have limitations in sensitivity and time-effectiveness. Analysis of cell-free DNA (cfDNA) in (culture) media is a good alternative as cfDNA release are a well-known phenomenon during cell death. RESULTS: We demonstrate a direct digital PCR (dPCR) method to estimate cell viability by analyzing cfDNA in media during induced cell death. After validating the duplex dPCR method for short and long amplicons of the SMAD4 and RPP30 loci, we determined that a media volume of 2 µL is feasible to measure the target DNA copy number with minimal negative effects on amplification. dPCR inhibition was evident with a higher media volume per reaction targeting long amplicons. Next, we applied our dPCR method using media cfDNA and other conventional methods to the monitoring of camptothecin (CPT)-induced cell death. Copy numbers increased significantly after 4 h of CPT treatment, showing a fold change of approximately 4-6 compared to the controls. Cell-based assays such as the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay and annexin V/7-AAD assay also indicated increased cell death at 4 h, but the trypan blue exclusion assay did not. SIGNIFICANCE: The developed media cfDNA direct dPCR method allows for efficient measurements of the degree of cell viability. Unlike other conventional cell-based assays, our method has advantages of no loss of cultured cells and the ability to implement online analysis. Accurate and sensitive media cfDNA analysis using dPCR can be adopted in various applications such as determining cytotoxicity levels in large-scale bioreactors or screening for effective anticancer drugs.