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Clinical trials conducted by the Intergroup Rhabdomyosarcoma (RMS) Study Group and the Children's Oncology Group have been pivotal to establishing current standards for diagnosis and therapy for RMS. Recent advancements in understanding the biology and clinical behavior of RMS have led to more nuanced approaches to diagnosis, risk stratification, and treatment. The complexities introduced by these advancements, coupled with the rarity of RMS, pose challenges to conducting large-scale phase 3 clinical trials to evaluate new treatment strategies for RMS. Given these challenges, systematic planning of future clinical trials in RMS is paramount to address pertinent questions regarding the therapeutic efficacy of drugs, biomarkers of response, treatment-related toxicity, and patient quality of life. Herein, the authors outline the proposed strategic approach of the Children's Oncology Group Soft Tissue Sarcoma Committee to the next generation of RMS clinical trials, focusing on five themes: improved novel agent identification and preclinical to clinical translation, more efficient trial development and implementation, expanded opportunities for knowledge generation during trials, therapeutic toxicity reduction and quality of life, and patient engagement.
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BACKGROUND: Childhood cancer survivors are at high risk for developing new cancers (such as cervical and anal cancer) caused by persistent infection with the human papillomavirus (HPV). HPV vaccination is effective in preventing the infections that lead to these cancers, but HPV vaccine uptake is low among young cancer survivors. Lack of a healthcare provider recommendation is the most common reason that cancer survivors fail to initiate the HPV vaccine. Strategies that are most successful in increasing HPV vaccine uptake in the general population focus on enhancing healthcare provider skills to effectively recommend the vaccine, and reducing barriers faced by the young people and their parents in receiving the vaccine. This study will evaluate the effectiveness and implementation of an evidence-based healthcare provider-focused intervention (HPV PROTECT) adapted for use in pediatric oncology clinics, to increase HPV vaccine uptake among cancer survivors 9 to 17 years of age. METHODS: This study uses a hybrid type 1 effectiveness-implementation approach. We will test the effectiveness of the HPV PROTECT intervention using a stepped-wedge cluster-randomized trial across a multi-state sample of pediatric oncology clinics. We will evaluate implementation (provider perspectives regarding intervention feasibility, acceptability and appropriateness in the pediatric oncology setting, provider fidelity to intervention components and change in provider HPV vaccine-related knowledge and practices [e.g., providing vaccine recommendations, identifying and reducing barriers to vaccination]) using a mixed methods approach. DISCUSSION: This multisite trial will address important gaps in knowledge relevant to the prevention of HPV-related malignancies in young cancer survivors by testing the effectiveness of an evidence-based provider-directed intervention, adapted for the pediatric oncology setting, to increase HPV vaccine initiation in young cancer survivors receiving care in pediatric oncology clinics, and by procuring information regarding intervention delivery to inform future implementation efforts. If proven effective, HPV PROTECT will be readily disseminable for testing in the larger pediatric oncology community to increase HPV vaccine uptake in cancer survivors, facilitating protection against HPV-related morbidities for this vulnerable population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04469569, prospectively registered on July 14, 2020.
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Alphapapillomavirus , Supervivientes de Cáncer , Neoplasias , Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Adolescente , Cuidados Posteriores , Niño , Humanos , Papillomaviridae , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/prevención & control , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Biliary rhabdomyosarcoma (RMS) is the most common biliary tumor in children. The biliary tract is classified as a favorable primary site. Therefore, patients with localized biliary RMS were included in two consecutive low-risk studies, D9602 and ARST0331, by the Children's Oncology Group (COG). The outcome for these patients treated with low-risk therapy has not been reported. PROCEDURE: Patients with biliary RMS enrolled on COG low-risk trials D9602 or ARST0331 were analyzed. All patients received systemic chemotherapy and those with Group II (microscopic residual) or Group III (macroscopic residual) disease received 36-50.4 Gy adjuvant radiotherapy (RT). Delayed primary excision (DPE) was allowed on both studies. RESULTS: Seventeen patients with biliary RMS were treated on D9602 (n = 7) or ARST0331 (n = 10). Median age was 3.5 years (range 1.7-10.3). Ten (59%) patients had tumors >5 cm and 14 (82%) had Group III disease. Fifteen (88%) patients received RT. The 5-year event-free survival (EFS) and overall survival (OS) were 70.6% (95% confidence interval [CI]: 46.9-94.3%) and 76.5% (95% CI: 54.6-98.4%), respectively. The majority of patients (80%) who received RT did not have disease recurrence while both patients who did not receive RT had local relapse. Five (36%) of 14 patients with Group III disease underwent DPE; two experienced a local relapse. In the nine patients without DPE, two developed local relapse. CONCLUSIONS: Patients with localized biliary RMS treated on low-risk studies had suboptimal outcomes. These patients may benefit from therapy on intermediate-risk studies.
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Neoplasias del Sistema Biliar/terapia , Rabdomiosarcoma/terapia , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/radioterapia , Neoplasias del Sistema Biliar/cirugía , Niño , Preescolar , Manejo de la Enfermedad , Femenino , Humanos , Masculino , Neoplasia Residual/etiología , Radioterapia Adyuvante , Rabdomiosarcoma/tratamiento farmacológico , Rabdomiosarcoma/radioterapia , Rabdomiosarcoma/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: The role of adjuvant radiotherapy (RT) remains unclear in patients with localized, completely resected (group I) alveolar rhabdomyosarcoma (ARMS). PROCEDURE: Patients with group I ARMS enrolled on any one of three prior Children's Oncology Group (COG) clinical trials (D9602, D9803, or ARST0531) were analyzed. All patients received systemic chemotherapy and 36 Gy adjuvant RT (if given) to the primary site at week 12 or week 4 for D9602/D9803 and ARST0531, respectively. RESULTS: Thirty-six patients with group I ARMS were treated on D9602 (n = 6), D9803 (n = 17), or ARST0531 (n = 13), of whom 24 (67%) were male. The median age was 4.1 years (range, 0.8-45.8). Twenty (56%) patients had an unfavorable primary site, and 10 (28%) had tumors > 5 cm. FOXO1-fusion status was negative, positive, and unknown in 10 (28%), 15 (42%), and 11 (30%) tumors, respectively. Twenty-two (61%) patients received RT. Overall, the four-year event-free survival (EFS) and overall survival (OS) were 70.8% and 88.3%, respectively. Patients with FOXO1 positivity who received RT had superior EFS compared with those who did not (77.8% vs 16.7%; P = 0.03). Among 10 patients who were FOXO1 negative, the outcome was similar with or without RT. CONCLUSIONS: Although limited by a small sample size, data from this study support the routine use of adjuvant RT in patients with FOXO1-positive disease even after complete resection. Additionally, omitting adjuvant RT is rational for patients with FOXO1-negative ARMS and will be prospectively investigated in the current COG trial ARST1431.
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Quimioradioterapia Adyuvante , Rabdomiosarcoma Alveolar/mortalidad , Rabdomiosarcoma Alveolar/terapia , Adolescente , Adulto , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Group 3 tumors account for approximately 25-30% of medulloblastomas and have the worst prognosis. UAB30 is a novel synthetic rexinoid shown to have limited toxicities in humans and significant efficacy in the pediatric neuroectodermal tumor, neuroblastoma. We hypothesized that treatment with UAB30 would decrease tumorigenicity in medulloblastoma patient-derived xenografts (PDXs). METHODS: Three group 3 medulloblastoma PDXs (D341, D384 and D425) were utilized. Cell viability, proliferation, migration and invasion assays were performed after treatment with UAB30 or 13-cis-retinoic acid (RA). Cell cycle analysis was completed using flow cytometry. A flank model, a cerebellar model, and a model of leptomeningeal metastasis using human medulloblastoma PDX cells was used to assess the in vivo effects of UAB30 and RA. RESULTS: UAB30 treatment led to cell differentiation and decreased medulloblastoma PDX cell viability, proliferation, migration and invasion and G1 cell cycle arrest in all three PDXs similar to RA. UAB30 and RA treatment of mice bearing medulloblastoma PDX tumors resulted in a significant decrease in tumor growth and metastasis compared to vehicle treated animals. CONCLUSIONS: UAB30 decreased viability, proliferation, and motility in group 3 medulloblastoma PDX cells and significantly decreased tumor growth in vivo in a fashion similar to RA, suggesting that further investigations into the potential therapeutic application of UAB30 for medulloblastoma are warranted.
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Antineoplásicos/farmacología , Carcinogénesis/efectos de los fármacos , Neoplasias Cerebelosas/tratamiento farmacológico , Ácidos Grasos Insaturados/farmacología , Meduloblastoma/tratamiento farmacológico , Carcinomatosis Meníngea/tratamiento farmacológico , Naftalenos/farmacología , Animales , Carcinogénesis/patología , Células Cultivadas , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/fisiopatología , Femenino , Humanos , Isotretinoína/farmacología , Meduloblastoma/patología , Meduloblastoma/fisiopatología , Carcinomatosis Meníngea/patología , Carcinomatosis Meníngea/fisiopatología , Ratones Desnudos , Trasplante de Neoplasias , Distribución Aleatoria , Receptores X Retinoide/agonistas , Receptores X Retinoide/metabolismoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Tumores Neuroendocrinos/tratamiento farmacológico , Tumor Rabdoide/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Carboplatino/administración & dosificación , Niño , Etopósido/administración & dosificación , Etopósido/análogos & derivados , Humanos , Neoplasias Hepáticas/secundario , Masculino , Clasificación del Tumor , Tumores Neuroendocrinos/patología , Compuestos Organofosforados/administración & dosificación , Tumor Rabdoide/patología , Resultado del TratamientoRESUMEN
BACKGROUND: Sarcomas are a heterogenous collection of bone and soft tissue tumors. The heterogeneity of these tumors makes it difficult to standardize treatment. CDK 4/6 inhibitors are a family of targeted agents which limit cell cycle progression and have been shown to be upregulated in sarcomas. In the current preclinical study, we evaluated the effects of lerociclib, a CDK4/6 inhibitor, on pediatric sarcomas in vitro and in 3D bioprinted tumors. METHODS: The effects of lerociclib on viability, proliferation, cell cycle, motility, and stemness were assessed in established sarcoma cell lines, U-2 OS and MG-63, as well as sarcoma patient-derived xenografts (PDXs). 3D printed biotumors of each of the U-2 OS, MG-63, and COA79 cells were utilized to study the effects of lerociclib on tumor growth ex vivo. RESULTS: CDK 4/6, as well as the intermediaries retinoblastoma protein (Rb) and phosphorylated Rb were identified as targets in the four sarcoma cell lines. Lerociclib treatment induced cell cycle arrest, decreased proliferation, motility, and stemness of sarcoma cells. Treatment with lerociclib decreased sarcoma cell viability in both traditional 2D culture as well as 3D bioprinted microtumors. CONCLUSIONS: Inhibition of CDK 4/6 activity with lerociclib was efficacious in traditional 2D sarcoma cell culture as well as in 3D bioprints. Lerociclib holds promise and warrants further investigation as a novel therapeutic strategy for management of these heterogenous groups of tumors.
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Antineoplásicos , Sarcoma , Niño , Humanos , Sarcoma/tratamiento farmacológico , Sarcoma/patología , Inhibidores de Proteínas Quinasas/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proteína de Retinoblastoma/metabolismo , Proteína de Retinoblastoma/farmacología , Proteína de Retinoblastoma/uso terapéutico , Fosforilación , Línea Celular Tumoral , Proliferación Celular , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/uso terapéuticoRESUMEN
BACKGROUND: Pediatric gastroenteropancreatic neuroendocrine tumors are exceedingly rare, resulting in most pediatric treatment recommendations being based on data derived from adults. Trametinib is a kinase inhibitor that targets MEK1/2 and has been employed in the treatment of cancers harboring mutations in the Ras pathway. METHODS: We utilized an established human pediatric gastroenteropancreatic neuroendocrine-like tumor patient-derived xenograft (PDX) with a known NRAS mutation to study the effects of MEK inhibition. We evaluated the effects of trametinib on proliferation, motility, and tumor growth in vivo. We created an intraperitoneal metastatic model of this PDX, characterized both the phenotype and the genotype of the metastatic PDX and again, investigated the effects of MEK inhibition. RESULTS: We found target engagement with decreased ERK1/2 phosphorylation with trametinib treatment. Trametinib led to decreased in vitro cell growth and motility, and decreased tumor growth and increased animal survival in a murine flank tumor model. Finally, we demonstrated that trametinib was able to significantly decrease gastroenteropancreatic neuroendocrine intraperitoneal tumor metastasis. CONCLUSIONS: The results of these studies support the further investigation of MEK inhibition in pediatric NRAS mutated solid tumors.
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Invasive aspergillosis is a known complication in patients with hematologic malignancies. Tracheopleural fistulas are very rare and reported in immunocompromised adults. We present a case of invasive pulmonary aspergillosis with tracheopleural fistula in a pediatric patient with a history of rhabdomyosarcoma and macrophage activation syndrome. This case highlights the importance of recognizing life-threatening fungal infections and coordinating surgical subspecialities for patient care.
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BACKGROUND: Neuroblastoma arises from aberrancies in neural stem cell differentiation. PIM kinases contribute to cancer formation, but their precise role in neuroblastoma tumorigenesis is poorly understood. In the current study, we evaluated the effects of PIM kinase inhibition on neuroblastoma differentiation. METHODS: Versteeg database query assessed the correlation between PIM gene expression and the expression of neuronal stemness markers and relapse free survival. PIM kinases were inhibited with AZD1208. Viability, proliferation, motility were measured in established neuroblastoma cells lines and high-risk neuroblastoma patient-derived xenografts (PDXs). qPCR and flow cytometry detected changes in neuronal stemness marker expression after AZD1208 treatment. RESULTS: Database query showed increased levels of PIM1, PIM2, or PIM3 gene expression were associated with higher risk of recurrent or progressive neuroblastoma. Increased levels of PIM1 were associated with lower relapse free survival rates. Higher levels of PIM1 correlated with lower levels of neuronal stemness markers OCT4, NANOG, and SOX2. Treatment with AZD1208 resulted in increased expression of neuronal stemness markers. CONCLUSIONS: Inhibition of PIM kinases differentiated neuroblastoma cancer cells toward a neuronal phenotype. Differentiation is a key component of preventing neuroblastoma relapse or recurrence and PIM kinase inhibition provides a potential new therapeutic strategy for this disease.
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Recurrencia Local de Neoplasia , Neuroblastoma , Humanos , Proliferación Celular , Proteínas Proto-Oncogénicas c-pim-1/genética , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Diferenciación Celular , Fenotipo , Neuroblastoma/tratamiento farmacológico , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
BACKGROUND: The tumor suppressor, protein phosphatase 2A (PP2A), is downregulated in hepatoblastoma. We aimed to examine the effects of two novel compounds of the tricyclic sulfonamide class, ATUX-3364 (3364) and ATUX-8385 (8385), designed to activate PP2A without causing immunosuppression, on human hepatoblastoma. METHODS: An established human hepatoblastoma cell line, HuH6, and a human hepatoblastoma patient-derived xenograft, COA67, were treated with increasing doses of 3364 or 8385, and viability, proliferation, cell cycle and motility were investigated. Cancer cell stemness was evaluated by real-time PCR and tumorsphere forming ability. Effects on tumor growth were examined using a murine model. RESULTS: Treatment with 3364 or 8385 significantly decreased viability, proliferation, cell cycle progression and motility in HuH6 and COA67 cells. Both compounds significantly decreased stemness as demonstrated by decreased abundance of OCT4, NANOG, and SOX2 mRNA. The ability of COA67 to form tumorspheres, another sign of cancer cell stemness, was significantly diminished by 3364 and 8385. Treatment with 3364 resulted in decreased tumor growth in vivo. CONCLUSION: Novel PP2A activators, 3364 and 8385, decreased hepatoblastoma proliferation, viability, and cancer cell stemness in vitro. Animals treated with 3364 had decreased tumor growth. These data provide evidence for further investigation of PP2A activating compounds as hepatoblastoma therapeutics.
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Hepatoblastoma , Neoplasias Hepáticas , Humanos , Animales , Ratones , Hepatoblastoma/tratamiento farmacológico , Hepatoblastoma/genética , Hepatoblastoma/metabolismo , Neoplasias Hepáticas/genética , Proteína Fosfatasa 2/metabolismo , Proteína Fosfatasa 2/farmacología , Proteína Fosfatasa 2/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Línea Celular Tumoral , Proliferación CelularRESUMEN
The use of three-dimensional (3D) bioprinting has remained at the forefront of tissue engineering and has recently been employed for generating bioprinted solid tumors to be used as cancer models to test therapeutics. In pediatrics, neural crest-derived tumors are the most common type of extracranial solid tumors. There are only a few tumor-specific therapies that directly target these tumors, and the lack of new therapies remains detrimental to improving the outcomes for these patients. The absence of more efficacious therapies for pediatric solid tumors, in general, may be due to the inability of the currently employed preclinical models to recapitulate the solid tumor phenotype. In this study, we utilized 3D bioprinting to generate neural crest-derived solid tumors. The bioprinted tumors consisted of cells from established cell lines and patient-derived xenograft tumors mixed with a 6% gelatin/1% sodium alginate bioink. The viability and morphology of the bioprints were analyzed via bioluminescence and immunohisto chemistry, respectively. We compared the bioprints to traditional twodimensional (2D) cell culture under conditions such as hypoxia and therapeutics. We successfully produced viable neural crest-derived tumors that retained the histology and immunostaining characteristics of the original parent tumors. The bioprinted tumors propagated in culture and grew in orthotopic murine models. Furthermore, compared to cells grown in traditional 2D culture, the bioprinted tumors were resistant to hypoxia and chemotherapeutics, suggesting that the bioprints exhibited a phenotype that is consistent with that seen clinically in solid tumors, thus potentially making this model superior to traditional 2D culture for preclinical investigations. Future applications of this technology entail the potential to rapidly print pediatric solid tumors for use in high-throughput drug studies, expediting the identification of novel, individualized therapies.
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Cancer is the leading cause of death by disease in children, and over 15% of pediatric cancer-related mortalities are due to neuroblastoma. Current treatment options for neuroblastoma remain suboptimal as they often have significant toxicities, are associated with long-term side effects, and result in disease relapse in over half of children with high-risk disease. There is a dire need for new therapies, and oncolytic viruses may represent an effective solution. Oncolytic viruses attack tumor cells in two ways: direct infection of tumor cells leading to cytolysis, and production of a debris field that stimulates an anti-tumor immune response. Our group has previously shown that M002, an oncolytic herpes simplex virus (oHSV), genetically engineered to express murine interleukin-12 (mIL-12), was effective at targeting and killing long term passage tumor cell lines. In the current study, we investigated M002 in three neuroblastoma patient-derived xenografts (PDXs). PDXs better recapitulate the human condition, and these studies were designed to gather robust data for translation to a clinical trial. We found that all three PDXs expressed viral entry receptors, and that the virus actively replicated in the cells. M002 caused significant tumor cell death in 2D culture and 3D bioprinted tumor models. Finally, the PDXs displayed variable susceptibility to M002, with a more profound effect on high-risk neuroblastoma PDXs compared to low-risk PDX. These findings validate the importance of incorporating PDXs for preclinical testing of oncolytic viral therapeutics and showcase a novel technique, 3D bioprinting, to test therapies in PDXs. Collectively, our data indicate that oHSVs effectively target high-risk neuroblastoma, and support the advancement of this therapy to the clinical setting.
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BACKGROUND: Protein phosphatase 2A (PP2A) functions as an inhibitor of cancer cell proliferation, and its tumor suppressor function is attenuated in many cancers. Previous studies utilized FTY720, an immunomodulating compound known to activate PP2A, and demonstrated a decrease in the malignant phenotype in neuroblastoma. We wished to investigate the effects of two novel PP2A activators, ATUX-792 (792) and DBK-1154 (1154). METHODS: Long-term passage neuroblastoma cell lines and human neuroblastoma patient-derived xenograft (PDX) cells were used. Cells were treated with 792 or 1154, and viability, proliferation, and motility were examined. The effect on tumor growth was investigated using a murine flank tumor model. RESULTS: Treatment with 792 or 1154 resulted in PP2A activation, decreased cell survival, proliferation, and motility in neuroblastoma cells. Immunoblotting revealed a decrease in MYCN protein expression with increasing concentrations of 792 and 1154. Treatment with 792 led to tumor necrosis and decreased tumor growth in vivo. CONCLUSIONS: PP2A activation with 792 or 1154 decreased survival, proliferation, and motility of neuroblastoma in vitro and tumor growth in vivo. Both compounds resulted in decreased expression of the oncogenic protein MYCN. These findings indicate a potential therapeutic role for these novel PP2A activators in neuroblastoma.
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Despite increasing incidence, treatment for hepatoblastoma has not changed significantly over the past 20 years. Chemotherapeutic strategies continue to rely on cisplatin, as it remains the most active single agent against hepatoblastoma. However, chemoresistance remains a significant challenge with 54-80% of patients developing resistance to chemotherapy after 4-5 cycles of treatment. Stem cell-like cancer cells (SCLCCs) are a subset of cells thought to play a role in chemoresistance and disease recurrence. We have previously demonstrated that Proviral Integration site for Moloney murine leukemia virus (PIM) kinases, specifically PIM3, play a role in hepatoblastoma cell proliferation and tumor growth and maintain the SCLCC phenotype. Here, we describe the development of a cisplatin-resistant hepatoblastoma xenograft model of the human HuH6 cell line and a patient-derived xenograft, COA67. We provide evidence that these cisplatin-resistant cells are enriched for SCLCCs and express PIM3 at higher levels than cisplatin-naïve cells. We demonstrate that PIM inhibition with AZD1208 sensitizes cisplatin-resistant hepatoblastoma cells to cisplatin, enhances cisplatin-mediated apoptosis, and decreases the SCLCC phenotype seen with cisplatin resistance. Together, these findings indicate that PIM inhibition may be a promising adjunct in the treatment of hepatoblastoma to effectively target SCLCCs and potentially decrease chemoresistance and subsequent disease relapse.
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Antineoplásicos/farmacología , Cisplatino/farmacología , Resistencia a Antineoplásicos , Hepatoblastoma/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Compuestos de Bifenilo/farmacología , Línea Celular Tumoral , Cisplatino/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/genética , Activación Enzimática , Expresión Génica , Hepatoblastoma/tratamiento farmacológico , Hepatoblastoma/etiología , Hepatoblastoma/patología , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/patología , Ratones , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Fenotipo , Proteínas Proto-Oncogénicas c-pim-1/genética , Tiazolidinas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Investigation of the mechanisms responsible for aggressive neuroblastoma and its poor prognosis is critical to identify novel therapeutic targets and improve survival. Enhancer of Zeste Homolog 2 (EZH2) is known to play a key role in supporting the malignant phenotype in several cancer types and knockdown of EZH2 has been shown to decrease tumorigenesis in neuroblastoma cells. We hypothesized that the EZH2 inhibitor, GSK343, would affect cell proliferation and viability in human neuroblastoma. We utilized four long-term passage neuroblastoma cell lines and two patient-derived xenolines (PDX) to investigate the effects of the EZH2 inhibitor, GSK343, on viability, motility, stemness and in vivo tumor growth. Immunoblotting confirmed target knockdown. Treatment with GSK343 led to significantly decreased neuroblastoma cell viability, migration and invasion, and stemness. GSK343 treatment of mice bearing SK-N-BE(2) neuroblastoma tumors resulted in a significant decrease in tumor growth compared to vehicle-treated animals. GSK343 decreased viability, and motility in long-term passage neuroblastoma cell lines and decreased stemness in neuroblastoma PDX cells. These data demonstrate that further investigation into the mechanisms responsible for the anti-tumor effects seen with EZH2 inhibitors in neuroblastoma cells is warranted.
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Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Neuroblastoma/patología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Ratones , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Novel therapies are needed for patients with hepatoblastoma because of an increasing incidence of disease and poor prognosis for advanced, refractory, and recurrent disease. PIM kinases promote tumorigenesis in hepatoblastoma. A novel PIM inhibitor, PIM447, has shown promise in inhibiting oncogenesis in hematologic and lymphoid malignancies. We hypothesized that PIM inhibition with PIM447 would result in decreased tumorigenesis in hepatoblastoma. METHODS: The effects of PIM447 on hepatoblastoma viability, proliferation, motility, apoptosis, and tumor cell stemness were assessed in HuH6, a human hepatoblastoma cell line, and COA67, a human hepatoblastoma patient-derived xenograft. RESULTS: PIM447 significantly decreased the viability, proliferation, and motility of HuH6 and COA67 cells. Apoptosis significantly increased following PIM447 treatment. PIM447 had a significant impact on tumor cell stemness as evidenced by decreased expression of CD133 and reduced ability of HuH6 and COA67 cells to form tumorspheres. Furthermore, combining PIM447 with cisplatin resulted in a significant decrease in cell viability compared to either treatment alone. CONCLUSION: We showed that PIM447 inhibits oncogenesis and potentiates the effects of cisplatin in hepatoblastoma and, therefore, warrants further investigation as a potential therapeutic agent for hepatoblastoma.
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Hepatoblastoma , Neoplasias Hepáticas , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica , Cisplatino/farmacología , Hepatoblastoma/tratamiento farmacológico , Hepatoblastoma/genética , Humanos , Neoplasias Hepáticas/tratamiento farmacológicoRESUMEN
INTRODUCTION: The poor therapeutic efficacy seen with current treatments for neuroblastoma may be attributed to stem cell-like cancer cells (SCLCCs), a subpopulation of cancer cells associated with poor prognosis and disease recurrence. Retinoic acid (RA) is a differentiating agent used as maintenance therapy for high-risk neuroblastoma but nearly half of children treated with RA relapse. We hypothesized that 6-Methyl-UAB30 (6-Me), a second-generation rexinoid recently developed with a favorable toxicity profile compared to RA, would reduce cancer cell stemness in human neuroblastoma patient-derived xenografts (PDXs). METHODS: Cells from three neuroblastoma PDXs were treated with 6-Me and proliferation, viability, motility, and cell-cycle progression were assessed. CD133 expression, sphere formation, and mRNA abundance of stemness and differentiation markers were evaluated using flow cytometry, in vitro extreme limiting dilution analysis, and real-time PCR, respectively. RESULTS: Treatment with 6-Me decreased proliferation, viability, and motility, and induced cell-cycle arrest and differentiation in all three neuroblastoma PDXs. In addition, 6-Me treatment led to decreased CD133 expression, decreased sphere-forming ability, and decreased mRNA abundance of Oct4, Nanog, and Sox2, indicating decreased cancer cell stemness. CONCLUSIONS: 6-Me decreased oncogenicity and reduced cancer cell stemness of neuroblastoma PDXs, warranting further exploration of 6-Me as potential novel therapy for neuroblastoma.
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Recurrencia Local de Neoplasia , Neuroblastoma , Diferenciación Celular , Línea Celular Tumoral , Proliferación Celular , Niño , Xenoinjertos , Humanos , Células Madre Neoplásicas , Neuroblastoma/tratamiento farmacológicoRESUMEN
Retinoic acid (RA) therapy has been utilized as maintenance therapy for high-risk neuroblastoma, but over half of patients treated with RA relapse. Neuroblastoma stem cell-like cancer cells (SCLCCs) are a subpopulation of cells characterized by the expression of the cell surface marker CD133 and are hypothesized to contribute to drug resistance and disease relapse. A novel rexinoid compound, 9-cis-UAB30 (UAB30), was developed having the same anti-tumor effects as RA but a more favorable toxicity profile. In the current study, we investigated the efficacy of UAB30 in neuroblastoma patient-derived xenografts (PDX). Two PDXs, COA3 and COA6, were utilized and alterations in the malignant phenotype were assessed following treatment with RA or UAB30. UAB30 significantly decreased proliferation, viability, and motility of both PDXs. UAB30 induced cell-cycle arrest as demonstrated by the significant increase in percentage of cells in G1 (COA6: 33.7⯱â¯0.7 vs. 43.3⯱â¯0.7%, control vs. UAB30) and decrease in percentage of cells in S phase (COA6: 44.7⯱â¯1.2 vs. 38.6⯱â¯1%, control vs. UAB30). UAB30 led to differentiation of PDX cells, as evidenced by the increase in neurite outgrowth and mRNA abundance of differentiation markers. CD133 expression was decreased by 40% in COA6 cells after UAB30. The ability to form tumorspheres and mRNA abundance of known stemness markers were also significantly decreased following treatment with UAB30, further indicating decreased cancer cell stemness. These results provide evidence that UAB30 decreased tumorigenicity and cancer cell stemness in neuroblastoma PDXs, warranting further exploration as therapy for high-risk neuroblastoma.