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1.
Pediatr Blood Cancer ; 67(7): e28284, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32333633

RESUMEN

BACKGROUND: VTP-50469 is a potent inhibitor of the menin-MLL1 interaction and is implicated in signaling downstream of EWSR1-FLI1. PROCEDURE: VTP-50469 was evaluated against seven Ewing sarcoma (EwS) xenograft models and in vitro against EwS cell lines. RESULTS: VTP-50469 showed limited antitumor activity, statistically significantly slowing tumor progression in four tumor models but with no evidence of tumor regression. In vitro, the IC50 concentration was 10 nM for the mixed lineage leukemia (MLL)-rearranged leukemia cell line MV4;11, but > 3 µM for EwS cell lines. CONCLUSIONS: In contrast to its high level of activity against MLL1-rearranged leukemia xenografts, VTP-50469 shows little activity against EwS models.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias Óseas/tratamiento farmacológico , N-Metiltransferasa de Histona-Lisina/efectos de los fármacos , Proteína de la Leucemia Mieloide-Linfoide/efectos de los fármacos , Proteínas Proto-Oncogénicas/efectos de los fármacos , Sarcoma de Ewing/tratamiento farmacológico , Animales , Antineoplásicos/metabolismo , Neoplasias Óseas/patología , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Femenino , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Ratones , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Pediatría , Proteínas Proto-Oncogénicas/metabolismo , Sarcoma de Ewing/patología , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Pediatr Blood Cancer ; 66(8): e27820, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31099166

RESUMEN

BACKGROUND: Entinostat, a selective class I histone deacetylase inhibitor, has been reported to enhance the activity of cytotoxic agents and suppress expression of PAX3-FOXO1 in alveolar rhabdomyosarcoma (ARMS). PROCEDURES: Entinostat was tested against three rhabdomyosarcoma cell lines using 96-hour drug exposure. Entinostat alone or in binary combination with vincristine, actinomycin D or cyclophosphamide was tested in ARMS and two embryonal rhabdomyosarcoma (ERMS) xenograft models. Tumor growth was measured at weekly intervals. Drug-induced changes in acetylated histone H3(K9) and entinostat pharmacokinetics were determined. RESULTS: In vitro, the IC50 concentration of entinostat ranged from 280 to 1300 nM. In vivo, entinostat significantly inhibited the growth of only Rh10 xenografts. For most studies, entinostat did not potentiate the activity of the cytotoxic agent. Exceptions included the vincristine and entinostat combination for Rh10 and the entinostat and actinomycin D combination for Rh10 and Rh18, although the effects were modest. For Rh18, the combination of entinostat with vincristine showed evidence of an antagonistic interaction compared with single-agent vincristine. Pharmacokinetic studies showed the average Cmax was 569.4 ng/mL (1.51 µM) with Tmax at 15 minutes, and total exposure (AUC0-12 h ) was 435.6 h × ng/mL. Entinostat treatment increased acetylated histone H3. CONCLUSIONS: Entinostat demonstrated modest antitumor activity in only one of four models at dose and shedule that gave drug exposures relevant to human treatment. The addition of entinostat to standard-of-care cytotoxic agents was in most instances no more effective than the cytotoxic agents used alone. Entinostat demonstrated target inhibition with increased histone 2A acetylation.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Nivel de Atención , Animales , Benzamidas/administración & dosificación , Neoplasias de la Mama/patología , Ciclofosfamida/administración & dosificación , Dactinomicina/administración & dosificación , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Piridinas/administración & dosificación , Células Tumorales Cultivadas , Vincristina/administración & dosificación , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Pediatr Blood Cancer ; 65(2)2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29080385

RESUMEN

BACKGROUND: Integrating molecularly targeted agents with cytotoxic drugs used in curative treatment of pediatric cancers is complex. An evaluation was undertaken with the ERBB3/Her3-specific antibody patritumab (P) either alone or with the ERBB1/epidermal growth factor receptor inhibitor erlotinib (E) in combination with standard cytotoxic agents, cisplatin, vincristine, and cyclophosphamide, in pediatric sarcoma xenograft models that express receptors and ligands targeted by these agents. PROCEDURES: Tumor models were selected based upon ERBB3 expression and phosphorylation, and ligand (heregulin) expression. Patritumab, E, or these agents combined was evaluated without or with concomitant cytotoxic agents using procedures developed by the Pediatric Preclinical Testing Program. RESULTS: Full doses of cytotoxic agents were tolerated when combined with P, whereas dose reductions of 25% (vincristine, cisplatin) or 50% (cyclophosphamide) were required when combined with P + E. Patritumab, E alone, or in combination did not significantly inhibit growth of any tumor model, except for Rh18 xenografts (E alone). Patritumab had no single-agent activity and marginally enhanced the activity of vincristine and cisplatin only in Ewing sarcoma ES-4. P + E did not increase the antitumor activity of vincristine or cisplatin, whereas dose-reduced cyclophosphamide was significantly less active than cyclophosphamide administered at its maximum tolerated dose when combined with P + E. CONCLUSIONS: P had no single-agent activity, although it marginally potentiated the activity of vincristine and cisplatin in one of three models studied. However, the addition of E necessitated dose reduction of each cytotoxic agent, abrogating the enhancement observed with P alone.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Anticuerpos Neutralizantes/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Óseas/tratamiento farmacológico , Clorhidrato de Erlotinib/farmacología , Sarcoma de Ewing/tratamiento farmacológico , Animales , Anticuerpos Monoclonales Humanizados , Neoplasias Óseas/metabolismo , Anticuerpos ampliamente neutralizantes , Línea Celular Tumoral , Femenino , Humanos , Ratones , Ratones SCID , Receptor ErbB-3/antagonistas & inhibidores , Receptor ErbB-3/metabolismo , Sarcoma de Ewing/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Cancer Drug Resist ; 5: 80-89, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35450020

RESUMEN

Aim: Despite aggressive multiagent protocols, patients with metastatic rhabdomyosarcoma (RMS) have poor prognosis. In a recent high-risk trial (ARST0431), 25% of patients failed within the first year, while on therapy and 80% had tumor progression within 24 months. However, the mechanisms for tumor resistance are essentially unknown. Here we explore the use of preclinical models to develop resistance to complex chemotherapy regimens used in ARST0431. Methods: A Single Mouse Testing (SMT) protocol was used to evaluate the sensitivity of 34 RMS xenograft models to one cycle of vincristine, actinomycin D, cyclophosphamide (VAC) treatment. Tumor response was determined by caliper measurement, and tumor regression and event-free survival (EFS) were used as endpoints for evaluation. Treated tumors at regrowth were transplanted into recipient mice, and the treatment was repeated until tumors progressed during the treatment period (i.e., became resistant). At transplant, tumor tissue was stored for biochemical and omics analysis. Results: The sensitivity to VAC of 34 RMS models was determined. EFS varied from 3 weeks to > 20 weeks. Tumor models were classified as having intrinsic resistance, intermediate sensitivity, or high sensitivity to VAC therapy. Resistance to VAC was developed in multiple models after 2-5 cycles of therapy; however, there were examples where sensitivity remained unchanged after 3 cycles of treatment. Conclusion: The SMT approach allows for in vivo assessment of drug sensitivity and development of drug resistance in a large number of RMS models. As such, it provides a platform for assessing in vivo drug resistance mechanisms at a "population" level, simulating conditions in vivo that lead to clinical resistance. These VAC-resistant models represent "high-risk" tumors that mimic a preclinical phase 2 population and will be valuable for identifying novel agents active against VAC-resistant disease.

5.
Clin Cancer Res ; 28(17): 3836-3849, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35797217

RESUMEN

PURPOSE: We investigated why three patient-derived xenograft (PDX) childhood BRAFV600E-mutant brain tumor models are highly sensitive to trametinib. Mechanisms of acquired resistance selected in situ, and approaches to prevent resistance were also examined, which may translate to both low-grade glioma (LGG) molecular subtypes. EXPERIMENTAL DESIGN: Sensitivity to trametinib [MEK inhibitor (MEKi)] alone or in combination with rapamycin (TORC1 inhibitor), was evaluated in pediatric PDX models. The effect of combined treatment of trametinib with rapamycin on development of trametinib resistance in vivo was examined. PDX tissue and tumor cells from trametinib-resistant xenografts were characterized. RESULTS: In pediatric models TORC1 is activated through ERK-mediated inactivation of the tuberous sclerosis complex (TSC): consequently inhibition of MEK also suppressed TORC1 signaling. Trametinib-induced tumor regression correlated with dual inhibition of MAPK/TORC1 signaling, and decoupling TORC1 regulation from BRAF/MAPK control conferred trametinib resistance. In mice, acquired resistance to trametinib developed within three cycles of therapy in all three PDX models. Resistance to trametinib developed in situ is tumor-cell-intrinsic and the mechanism was tumor line specific. Rapamycin retarded or blocked development of resistance. CONCLUSIONS: In these three pediatric BRAF-mutant brain tumors, TORC1 signaling is controlled by the MAPK cascade. Trametinib suppressed both MAPK/TORC1 pathways leading to tumor regression. While low-dose intermittent rapamycin to enhance inhibition of TORC1 only modestly enhanced the antitumor activity of trametinib, it prevented or retarded development of trametinib resistance, suggesting future therapeutic approaches using rapamycin analogs in combination with MEKis that may be therapeutically beneficial in both KIAA1549::BRAF- and BRAFV600E-driven gliomas.


Asunto(s)
Neoplasias Encefálicas , Glioma , Diana Mecanicista del Complejo 1 de la Rapamicina , Piridonas , Pirimidinonas , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Modelos Animales de Enfermedad , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/metabolismo , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , Sirolimus
6.
J Clin Med ; 10(7)2021 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-33916592

RESUMEN

Developing new therapeutics for the treatment of childhood cancer has challenges not usually associated with adult malignancies. Firstly, childhood cancer is rare, with approximately 12,500 new diagnoses annually in the U.S. in children 18 years or younger. With current multimodality treatments, the 5-year event-free survival exceeds 80%, and 70% of patients achieve long-term "cure", hence the overall number of patients eligible for experimental drugs is small. Childhood cancer comprises many disease entities, the most frequent being acute lymphoblastic leukemias (25% of cancers) and brain tumors (21%), and each of these comprises multiple molecular subtypes. Hence, the numbers of diagnoses even for the more frequently occurring cancers of childhood are small, and undertaking clinical trials remains a significant challenge. Consequently, development of preclinical models that accurately represent each molecular entity can be valuable in identifying those agents or combinations that warrant clinical evaluation. Further, new regulations under the Research to Accelerate Cures and Equity for Children Act (RACE For Children Act) will change the way in which drugs are developed. Here, we will consider some of the limitations of preclinical models and consider approaches that may improve their ability to translate therapy to clinical trial more accurately.

7.
Clin Cancer Res ; 27(10): 2938-2946, 2021 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-33619171

RESUMEN

PURPOSE: Patients with relapsed pediatric solid malignancies have few therapeutic options, and many of these patients die of their disease. B7-H3 is an immune checkpoint protein encoded by the CD276 gene that is overexpressed in many pediatric cancers. Here, we investigate the activity of the B7-H3-targeting antibody-drug conjugate (ADC) m276-SL-PBD in pediatric solid malignancy patient-derived (PDX) and cell line-derived xenograft (CDX) models. EXPERIMENTAL DESIGN: B7-H3 expression was quantified by RNA sequencing and by IHC on pediatric PDX microarrays. We tested the safety and efficacy of m276-SL-PBD in two stages. Randomized trials of m276-SL-PBD of 0.5 mg/kg on days 1, 8, and 15 compared with vehicle were performed in PDX or CDX models of Ewing sarcoma (N = 3), rhabdomyosarcoma (N = 4), Wilms tumors (N = 2), osteosarcoma (N = 5), and neuroblastoma (N = 12). We then performed a single mouse trial in 47 PDX or CDX models using a single 0.5 m/kg dose of m276-SL-PBD. RESULTS: The vast majority of PDX and CDX samples studied showed intense membranous B7-H3 expression (median H-score 177, SD 52). In the randomized trials, m276-SL-PBD showed a 92.3% response rate, with 61.5% of models showing a maintained complete response (MCR). These data were confirmed in the single mouse trial with an overall response rate of 91.5% and MCR rate of 64.4%. Treatment-related mortality rate was 5.5% with late weight loss observed in a subset of models dosed once a week for 3 weeks. CONCLUSIONS: m276-SL-PBD has significant antitumor activity across a broad panel of pediatric solid tumor PDX models.


Asunto(s)
Antígenos B7/antagonistas & inhibidores , Inmunoconjugados/farmacología , Neoplasias/tratamiento farmacológico , Animales , Antígenos B7/genética , Línea Celular Tumoral , Niño , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunoconjugados/uso terapéutico , Ratones , Neoplasias/diagnóstico , Neoplasias/etiología , Neoplasias/metabolismo , Pediatría , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Cancer Chemother Pharmacol ; 85(2): 251-263, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31927611

RESUMEN

PURPOSE: Defining robust criteria for drug activity in preclinical studies allows for fewer animals per treatment group, and potentially allows for inclusion of additional cancer models that more accurately represent genetic diversity and, potentially, allows for tumor sensitivity biomarker identification. METHODS: Using a single-mouse design, 32 pediatric xenograft tumor models representing diverse pediatric cancer types [Ewing sarcoma (9), brain (4), rhabdomyosarcoma (10), Wilms tumor (4), and non-CNS rhabdoid tumors (5)] were evaluated for response to a single administration of pegylated-SN38 (PLX038A), a controlled-release PEGylated formulation of SN-38. Endpoints measured were percent tumor regression, and event-free survival (EFS). The correlation between response to PLX038A was compared to that for ten models treated with irinotecan (2.5 mg/kg × 5 days × 2 cycles), using a traditional design (10 mice/group). Correlations between tumor sensitivity, genetic mutations and gene expression were sought. Models showing no disease at week 20 were categorized as 'extreme responders' to PLX038A, whereas those with EFS less than 5 weeks were categorized as 'resistant'. RESULTS: The activity of PLX038A was evaluable in 31/32 models. PLX038A induced > 50% volume regressions in 25 models (78%). Initial tumor volume regression correlated only modestly with EFS (r2 = 0.238), but sensitivity to PLX038A was better correlated with response to irinotecan when one tumor hypersensitive to PLX038A was omitted (r2 = 0.6844). Mutations in 53BP1 were observed in three of six sensitive tumor models compared to none in resistant models (n = 6). CONCLUSIONS: This study demonstrates the feasibility of using a single-mouse design for assessing the antitumor activity of an agent, while encompassing greater genetic diversity representative of childhood cancers. PLX038A was highly active in most xenograft models, and tumor sensitivity to PLX038A was correlated with sensitivity to irinotecan, validating the single-mouse design in identifying agents with the same mechanism of action. Biomarkers that correlated with model sensitivity included wild-type TP53, or mutant TP53 but with a mutation in 53BP1, thus a defect in DNA damage response. These results support the value of the single-mouse experimental design.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Animales , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Irinotecán/farmacología , Ratones , Ratones SCID , Estudios Prospectivos , Proyectos de Investigación , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
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