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PURPOSE: Antibodies against insulin-like growth factor (IGF) type 1 receptor have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC family member YES has been shown to mediate IGF type 1 receptor (IGF-1R) antibody acquired resistance, and cotargeting IGF-1R and YES resulted in sustained responses in murine RMS models. We conducted a phase I trial of the anti-IGF-1R antibody ganitumab combined with dasatinib, a multi-kinase inhibitor targeting YES, in patients with RMS (NCT03041701). PATIENTS AND METHODS: Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib dose was 60 mg/m2/dose (max 100 mg) oral once daily [dose level (DL)1] or 60 mg/m2/dose (max 70 mg) twice daily (DL2). A 3+3 dose escalation design was used, and maximum tolerated dose (MTD) was determined on the basis of cycle 1 dose-limiting toxicities (DLT). RESULTS: Thirteen eligible patients, median age 18 years (range 8-29) enrolled. Median number of prior systemic therapies was 3; all had received prior radiation. Of 11 toxicity-evaluable patients, 1/6 had a DLT at DL1 (diarrhea) and 2/5 had a DLT at DL2 (pneumonitis, hematuria) confirming DL1 as MTD. Of nine response-evaluable patients, one had a confirmed partial response for four cycles, and one had stable disease for six cycles. Genomic studies from cell-free DNA correlated with disease response. CONCLUSIONS: The combination of dasatinib 60 mg/m2/dose daily and ganitumab 18 mg/kg every 2 weeks was safe and tolerable. This combination had a disease control rate of 22% at 5 months.
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Rabdomiossarcoma , Quinases da Família src , Humanos , Animais , Camundongos , Criança , Adolescente , Adulto Jovem , Adulto , Dasatinibe/efeitos adversos , Fator de Crescimento Insulin-Like I , Receptor IGF Tipo 1 , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dose Máxima TolerávelRESUMO
Data-driven basic, translational, and clinical research has resulted in improved outcomes for children, adolescents, and young adults (AYAs) with pediatric cancers. However, challenges in sharing data between institutions, particularly in research, prevent addressing substantial unmet needs in children and AYA patients diagnosed with certain pediatric cancers. Systematically collecting and sharing data from every child and AYA can enable greater understanding of pediatric cancers, improve survivorship, and accelerate development of new and more effective therapies. To accomplish this goal, the Childhood Cancer Data Initiative (CCDI) was launched in 2019 at the National Cancer Institute. CCDI is a collaborative community endeavor supported by a 10-year, $50-million (in US dollars) annual federal investment. CCDI aims to learn from every patient diagnosed with a pediatric cancer by designing and building a data ecosystem that facilitates data collection, sharing, and analysis for researchers, clinicians, and patients across the cancer community. For example, CCDI's Molecular Characterization Initiative provides comprehensive clinical molecular characterization for children and AYAs with newly diagnosed cancers. Through these efforts, the CCDI strives to provide clinical benefit to patients and improvements in diagnosis and care through data-focused research support and to build expandable, sustainable data resources and workflows to advance research well past the planned 10 years of the initiative. Importantly, if CCDI demonstrates the success of this model for pediatric cancers, similar approaches can be applied to adults, transforming both clinical research and treatment to improve outcomes for all patients with cancer.
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Neoplasias , Adolescente , Estados Unidos/epidemiologia , Humanos , Criança , Adulto Jovem , Neoplasias/terapia , Ecossistema , Coleta de Dados , National Cancer Institute (U.S.)RESUMO
PURPOSE: Succinate dehydrogenase (dSDH)-deficient tumors, including pheochromocytoma/paraganglioma, hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinoma (HLRCC-RCC), and gastrointestinal stromal tumors (GIST) without KIT or platelet-derived growth factor receptor alpha mutations are often resistant to cytotoxic chemotherapy, radiotherapy, and many targeted therapies. We evaluated guadecitabine, a dinucleotide containing the DNA methyltransferase inhibitor decitabine, in these patient populations. PATIENTS AND METHODS: Phase II study of guadecitabine (subcutaneously, 45 mg/m2/day for 5 consecutive days, planned 28-day cycle) to assess clinical activity (according to RECISTv.1.1) across three strata of patients with dSDH GIST, pheochromocytoma/paraganglioma, or HLRCC-RCC. A Simon optimal two-stage design (target response rate 30% rule out 5%) was used. Biologic correlates (methylation and metabolites) from peripheral blood mononuclear cells (PBMC), serum, and urine were analyzed. RESULTS: Nine patients (7 with dSDH GIST, 1 each with paraganglioma and HLRCC-RCC, 6 females and 3 males, age range 18-57 years) were enrolled. Two patients developed treatment-limiting neutropenia. No partial or complete responses were observed (range 1-17 cycles of therapy). Biologic activity assessed as global demethylation in PBMCs was observed. No clear changes in metabolite concentrations were observed. CONCLUSIONS: Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity. Although 4 of 9 patients had prolonged stable disease, there were no objective responses. Thus, guadecitabine did not meet the target of 30% response rate across dSDH tumors at this dose, although signs of biologic activity were noted.
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Neoplasias das Glândulas Suprarrenais , Produtos Biológicos , Carcinoma de Células Renais , Tumores do Estroma Gastrointestinal , Neoplasias Renais , Paraganglioma , Feocromocitoma , Masculino , Feminino , Adulto , Humanos , Criança , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Succinato Desidrogenase/genética , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Tumores do Estroma Gastrointestinal/genética , Leucócitos Mononucleares/metabolismo , Paraganglioma/tratamento farmacológico , Paraganglioma/genéticaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/terapia , Imunoterapia , Osteossarcoma/terapia , Neoplasias Ósseas/patologia , Neoplasias Ósseas/cirurgia , Humanos , Terapia Neoadjuvante , Osteossarcoma/patologia , Osteossarcoma/secundário , Osteossarcoma/cirurgia , Medicina de Precisão , Prognóstico , Taxa de SobrevidaRESUMO
Over the past few years, the field of pediatric cancer has experienced a shift in momentum, and this has led to new and exciting findings that have relevance beyond pediatric malignancies. Here we present the current status of key aspects of pediatric cancer research. We have focused on genetic and epigenetic drivers of disease, cellular origins of different pediatric cancers, disease models, the tumor microenvironment, and cellular immunotherapies.
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Pesquisa Biomédica/métodos , Epigenômica , Genômica/métodos , Imunoterapia , Neoplasias/diagnóstico , Neoplasias/terapia , Criança , Humanos , Neoplasias/genéticaRESUMO
BACKGROUND: In preclinical Ewing sarcoma (ES) models, poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors were identified as a potential therapeutic strategy with synergy in combination with cytotoxic agents. This study evaluated the safety and dosing of the PARP1/2 inhibitor niraparib (NIR) with temozolomide (TMZ; arm 1) or irinotecan (IRN; arm 2) in patients with pretreated ES. METHODS: Eligible patients in arm 1 received continuous NIR daily and escalating TMZ (days 2-6 [D2-6]) in cohort A. Subsequent patients received intermittent NIR dosing (cohort B), with TMZ re-escalation in cohort C. In arm 2, patients were assigned to NIR (days 1-7 [D1-7]) and escalating doses of IRN (D2-6). RESULTS: From July 2014 to May 2018, 29 eligible patients (23 males and 6 females) were enrolled in arms 1 and 2, which had 7 dose levels combined. Five patients experienced at least 1 dose-limiting toxicity (DLT) in arm 1 (grade 4 [G4] neutropenia for >7 days or G4 thrombocytopenia), and 3 patients experienced at least 1 DLT in arm 2 (grade 3 [G3] colitis, G3 anorexia, or G3 alanine aminotransferase elevation). The maximum tolerated dose was NIR at 200 mg every day on D1-7 plus TMZ at 30 mg/m2 every day on D2-6 (arm 1) or NIR at 100 mg every day on D1-7 plus IRN at 20 mg/m2 every day on D2-6 (arm 2). One confirmed partial response was observed in arm 2; the median progression-free survival was 9.0 weeks (95% CI, 7.0-10.1 weeks) and 16.3 weeks (95% CI, 5.1-69.7 weeks) in arms 1 and 2, respectively. The median decrease in tumor poly(ADP-ribose) activity was 89% (range, 83%-98%). CONCLUSIONS: The combination of NIR and TMZ or IRN was tolerable, but at lower doses in comparison with conventional cytotoxic combinations. A triple-combination study of NIR, IRN, and TMZ has commenced.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Adulto , Alanina Transaminase/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Irinotecano/uso terapêutico , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Temozolomida/administração & dosagem , Temozolomida/efeitos adversos , Trombocitopenia/induzido quimicamente , Adulto JovemRESUMO
BACKGROUND: Osteosarcoma (OS), the most common bone tumor in children and adolescents, has high rates of metastasis leading to poor survival. Leucine-rich repeat containing 15 (LRRC15), a transmembrane protein whose expression is modulated by TGFß, was recently shown to be highly expressed on the surface of OS tumor cells. Here, we evaluate a novel antibody-drug conjugate (ADC) targeting LRRC15 in OS human cell lines and murine xenografts. We compare this new ADC, which is conjugated to the anthracycline derivative PNU-159682 (PNU), to a previously studied LRRC15 ADC that is conjugated to the tubulin inhibitor monomethyl auristatin E (MMAE), since anthracyclines are standard of care in OS. PROCEDURE: We evaluated LRRC15 expression in OS cells using Western blots and flow cytometry, and analyzed the epigenetic landscape of the LRRC15 locus using chromatin immunoprecipitation. Efficacy of ADCs on cell growth was analyzed by IncuCyte live cell imaging. Intramuscular xenograft tumor growth was assessed by bioluminescence imaging and hematoxylin and eosin staining. RESULTS: LRRC15-PNU is more effective at inhibiting growth in vitro and in vivo than an isotype antibody control or the LRRC15-MMAE ADC in two high LRRC15 expressing OS cell lines. Low expressing cell lines are not sensitive to either ADC. Importantly, cells with low LRRC15 expression are amenable to re-expression after TGFß treatment, suggesting a potential to sensitize insensitive OS cells to LRRC15 ADC treatment. In vivo, LRRC15-PNU had cure rates of 40-100% in OS xenograft models. CONCLUSIONS: Overall, LRRC15-directed ADCs are a promising new avenue for OS treatment.
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Antineoplásicos/farmacologia , Doxorrubicina/análogos & derivados , Imunoconjugados/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Osteossarcoma/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Humanos , Camundongos , Camundongos SCID , Metástase Neoplásica/tratamento farmacológico , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Moduladores de Tubulina/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. The primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. Patients and Methods. Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175 mg orally, once daily, for up to thirteen 28-day cycles. RESULTS: Thirty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (p=0.47). Median OS was not reached in either arm. CONCLUSIONS: Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. There is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated.
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Rhabdomyosarcoma is the most common childhood soft-tissue sarcoma, yet patients with metastatic or recurrent disease continue to do poorly, indicating a need for new treatments. The SRC family tyrosine kinase YES1 is upregulated in rhabdomyosarcoma and is necessary for growth, but clinical trials using single agent dasatinib, a SRC family kinase inhibitor, have failed in sarcomas. YAP1 (YES-associated protein) is highly expressed in rhabdomyosarcoma, driving growth and survival when the upstream Hippo tumor suppressor pathway is silenced, but efforts to pharmacologically inhibit YAP1 have been unsuccessful. Here we demonstrate that treatment of rhabdomyosarcoma with DNA methyltransferase inhibitor (DNMTi) upregulates Hippo activators RASSF1 and RASSF5 by promoter demethylation, activating canonical Hippo signaling and increasing inactivation of YAP1 by phosphorylation. Treatment with DNMTi decreased rhabdomyosarcoma cell growth and increased apoptosis and differentiation, an effect partially rescued by expression of constitutively active YAP (S127A), suggesting the effects of DNMTi treatment are, in part, due to Hippo-dependent inhibition of YAP1. In addition, YES1 and YAP1 interacted in the nucleus of rhabdomyosarcoma cells, and genetic or pharmacologic suppression of YES1 resulted in cytoplasmic retention of YAP1 and decreased YAP1 target gene expression, suggesting YES1 regulates YAP1 in a Hippo-independent manner. Combined treatment with DNMTi and dasatinib targeted both Hippo-dependent and Hippo-independent regulation of YAP1, ablating rhabdomyosarcoma cell growth in vitro and trending toward decreased tumor growth in vivo. These results show that the mechanisms regulating YAP1 in rhabdomyosarcoma can be inhibited by combinatorial therapy of DNMTi and dasatinib, laying the groundwork for future clinical investigations. SIGNIFICANCE: This study elucidates the signaling pathways that regulate the oncogenic protein YAP1 and identifies a combination therapy to target these pathways in the childhood tumor rhabdomyosarcoma.
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Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Azacitidina/análogos & derivados , Terapia de Alvo Molecular , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Rabdomiossarcoma/tratamento farmacológico , Transdução de Sinais , Fatores de Transcrição/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Apoptose , Azacitidina/farmacologia , Proliferação de Células , Criança , Feminino , Regulação Neoplásica da Expressão Gênica , Via de Sinalização Hippo , Humanos , Camundongos , Camundongos SCID , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Sinalização YAPRESUMO
Fibroblast growth factor receptor 4 (FGFR4) aberrant expression and activity have been linked to the pathogenesis of a variety of cancers including rhabdomyosarcomas (RMS). We found that treatment of alveolar rhabdomyosarcoma (aRMS) cells with Guadecitabine (SGI-110), a next-generation DNA methyltransferase inhibitor (DNMTi), resulted in a significant reduction of FGFR4 protein levels, 5â¯days post treatment. Chromatin immunoprecipitation-sequencing (ChIP-seq) in aRMS cells revealed attenuation of the H3K4 mono-methylation across the FGFR4 super enhancer without changes in tri-methylation of either H3K4 or H3K27. These changes were associated with a significant reduction in FGFR4 transcript levels in treated cells. These decreases in H3K4me1 in the FGFR4 super enhancer were also associated with a 240-fold increase in KDM5B (JARID1B) mRNA levels. Immunoblot and immunofluorescent studies also revealed a significant increase in the KDM5B protein levels after treatment in these cells. KDM5B is the only member of KDM5 (JARID1) family of histone lysine demethylases that catalyzes demethylation of H3K4me1. These data together suggest a pleiotropic effect of DNMTi therapy in aRMS cells, converging to significantly lower FGFR4 protein levels in these cells.
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Antineoplásicos/farmacologia , Azacitidina/análogos & derivados , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Rabdomiossarcoma Alveolar/tratamento farmacológico , Azacitidina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sequenciamento de Cromatina por Imunoprecipitação , Regulação para Baixo/efeitos dos fármacos , Elementos Facilitadores Genéticos , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Lisina/metabolismo , Proteínas Nucleares/metabolismo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética , Proteínas Repressoras/metabolismo , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Alveolar/metabolismo , Rabdomiossarcoma Alveolar/patologiaRESUMO
Despite a growing body of knowledge about the genomic landscape of Ewing sarcoma, translation of basic discoveries into targeted therapies and significant clinical gains has remained elusive. Recent insights have revealed that the oncogenic transcription factor EWS-FLI1 can impact Ewing sarcoma cellular metabolism, regulating expression of 3-phosphoglycerate dehydrogenase (PHGDH), the first enzyme in de novo serine synthesis. Here, we have examined the importance of serine metabolism in Ewing sarcoma tumorigenesis and evaluated the therapeutic potential of targeting serine metabolism in preclinical models of Ewing sarcoma. We show that PHGDH knockdown resulted in decreased Ewing sarcoma cell proliferation, especially under serine limitation, and significantly inhibited xenograft tumorigenesis in preclinical orthotopic models of Ewing sarcoma. In addition, the PHGDH inhibitor NCT-503 caused a dose-dependent decrease in cellular proliferation. Moreover, we report a novel drug combination in which nicotinamide phosphoribosyltransferase (NAMPT) inhibition, which blocks production of the PHGDH substrate NAD+, synergized with NCT-503 to abolish Ewing sarcoma cell proliferation and tumor growth. Furthermore, we show that serine deprivation inhibited Ewing sarcoma cell proliferation and tumorigenesis, indicating that Ewing sarcoma cells depend on exogenous serine in addition to de novo serine synthesis. Our findings suggest that serine metabolism is critical for Ewing sarcoma tumorigenesis, and that targeting metabolic dependencies should be further investigated as a potential therapeutic strategy for Ewing sarcoma. In addition, the combination strategy presented herein may have broader clinical applications in other PHGDH-overexpressing cancers as well.
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Neoplasias Ósseas/patologia , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Proteínas de Fusão Oncogênica/metabolismo , Fosfoglicerato Desidrogenase/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína EWS de Ligação a RNA/metabolismo , Sarcoma de Ewing/patologia , Serina/metabolismo , Animais , Apoptose , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Feminino , Humanos , Camundongos , Camundongos SCID , Proteínas de Fusão Oncogênica/genética , Proteína Proto-Oncogênica c-fli-1/genética , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
There is a need to develop novel approaches to improve the balance between efficacy and toxicity for transcription factor-targeted therapies. In this study, we exploit context-dependent differences in RNA polymerase II processivity as an approach to improve the activity and limit the toxicity of the EWS-FLI1-targeted small molecule, mithramycin, for Ewing sarcoma. The clinical activity of mithramycin for Ewing sarcoma is limited by off-target liver toxicity that restricts the serum concentration to levels insufficient to inhibit EWS-FLI1. In this study, we perform an siRNA screen of the druggable genome followed by a matrix drug screen to identify mithramycin potentiators and a synergistic "class" effect with cyclin-dependent kinase 9 (CDK9) inhibitors. These CDK9 inhibitors enhanced the mithramycin-mediated suppression of the EWS-FLI1 transcriptional program leading to a shift in the IC50 and striking regressions of Ewing sarcoma xenografts. To determine whether these compounds may also be liver protective, we performed a qPCR screen of all known liver toxicity genes in HepG2 cells to identify mithramycin-driven transcriptional changes that contribute to the liver toxicity. Mithramycin induces expression of the BTG2 gene in HepG2 but not Ewing sarcoma cells, which leads to a liver-specific accumulation of reactive oxygen species (ROS). siRNA silencing of BTG2 rescues the induction of ROS and the cytotoxicity of mithramycin in these cells. Furthermore, CDK9 inhibition blocked the induction of BTG2 to limit cytotoxicity in HepG2, but not Ewing sarcoma cells. These studies provide the basis for a synergistic and less toxic EWS-FLI1-targeted combination therapy for Ewing sarcoma.
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Antibióticos Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Plicamicina/farmacologia , Sarcoma de Ewing/tratamento farmacológico , Animais , Apoptose , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Nus , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: There are no known effective medical treatments for refractory MPNST. Inactivation of the NF1 tumor suppressor in MPNST results in upregulation of mTOR (mammalian target of rapamycin) signaling and angiogenesis, which contributes to disease progression. We conducted a phase II study for patients (pts) with refractory MPNST combining everolimus (10 mg PO once daily) with bevacizumab (10 mg/kg IV every 2 weeks) to determine the clinical benefit rate (CBR) (complete response, partial response (PR), or stable disease (SD) ≥ 4 months). PATIENTS AND METHODS: Patients ≥18 years old with chemotherapy refractory sporadic or NF1 MPNST were eligible. Tumor response was assessed after every 2 cycles (the WHO criteria). A two-stage design targeting a 25% CBR was used: if ≥ 1/15 pts in stage 1 responded, enrollment would be expanded by 10 pts, and if ≥ 4/25 patients had clinical benefit, the combination would be considered active. RESULTS: Twenty-five pts, 17 with NF1 and 8 with sporadic MPNST, enrolled. One of 15 pts in stage 1 had clinical benefit. Of 10 additional pts enrolled, 2 had clinical benefit. The median number of completed cycles was 3 (range 1-16). Adverse events were similar to those known for this combination. CONCLUSION: With a CBR of 12% (3/25), the combination of everolimus and bevacizumab did not reach the study's target response rate and is not considered active in refractory MPNST.
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PURPOSE: Gastrointestinal stromal tumors (GIST) are resistant to cytotoxic chemotherapy and radiotherapy. Most GIST in children are wild-type for KIT and PDGFRA (WT GIST) and deficient in expression of succinate dehydrogenase (dSDH GIST). We tested the activity of vandetanib, an oral small-molecule inhibitor of VEGFR2, EGFR, and RET, in patients with dSDH GIST. PATIENTS AND METHODS: Phase II study of vandetanib (300 mg orally once daily to patients ≥18 years, and 100 mg/m2/dose to patients < 18 years) on a continuous dosing schedule (1 cycle = 28 days) to assess the clinical activity (partial and complete response rate RECIST v1.1) in patients with dSDH GIST. A Simon optimal two-stage design (target response rate 25%, rule out 5%) was used: If ≥1 of 9 patients in stage 1 responded, enrollment would be expanded to 24 patients, and if ≥3 of 24 responded, vandetanib would be considered active. RESULTS: Nine patients (7 female and 2 male; median age, 24 years; range, 11-52) with metastatic disease were enrolled. Three of the initial 5 adult patients developed treatment-modifying toxicities. After a protocol amendment, two adults received vandetanib at 200 mg/dose with improved tolerability. The two children (<18 years old) enrolled did not experience treatment-modifying toxicities. No partial or complete responses were observed (median number of cycles, 4; range, 2-18). CONCLUSIONS: Vandetanib at a dose of 300 mg daily was not well tolerated by adults with dSDH GIST. Two of 9 patients had prolonged stable disease, but no partial or complete responses were observed, and vandetanib is thus not considered active in dSDH GIST.
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Tumores do Estroma Gastrointestinal/tratamento farmacológico , Piperidinas/administração & dosagem , Quinazolinas/administração & dosagem , Succinato Desidrogenase/genética , Adolescente , Adulto , Criança , Intervalo Livre de Doença , Feminino , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Metástase Neoplásica , Piperidinas/efeitos adversos , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas c-kit/genética , Qualidade de Vida , Quinazolinas/efeitos adversos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Adulto JovemRESUMO
Altered cellular metabolism, including an increased dependence on aerobic glycolysis, is a hallmark of cancer. Despite the fact that this observation was first made nearly a century ago, effective therapeutic targeting of glycolysis in cancer has remained elusive. One potentially promising approach involves targeting the glycolytic enzyme lactate dehydrogenase (LDH), which is overexpressed and plays a critical role in several cancers. Here, we used a novel class of LDH inhibitors to demonstrate, for the first time, that Ewing sarcoma cells are exquisitely sensitive to inhibition of LDH. EWS-FLI1, the oncogenic driver of Ewing sarcoma, regulated LDH A (LDHA) expression. Genetic depletion of LDHA inhibited proliferation of Ewing sarcoma cells and induced apoptosis, phenocopying pharmacologic inhibition of LDH. LDH inhibitors affected Ewing sarcoma cell viability both in vitro and in vivo by reducing glycolysis. Intravenous administration of LDH inhibitors resulted in the greatest intratumoral drug accumulation, inducing tumor cell death and reducing tumor growth. The major dose-limiting toxicity observed was hemolysis, indicating that a narrow therapeutic window exists for these compounds. Taken together, these data suggest that targeting glycolysis through inhibition of LDH should be further investigated as a potential therapeutic approach for cancers such as Ewing sarcoma that exhibit oncogene-dependent expression of LDH and increased glycolysis. SIGNIFICANCE: LDHA is a pharmacologically tractable EWS-FLI1 transcriptional target that regulates the glycolytic dependence of Ewing sarcoma.
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Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Glicólise/efeitos dos fármacos , L-Lactato Desidrogenase/antagonistas & inibidores , Sarcoma de Ewing/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Camundongos SCID , Sarcoma de Ewing/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Overall survival rates for pediatric patients with high-risk or relapsed rhabdomyosarcoma (RMS) have not improved significantly since the 1980s. Recent studies have identified a number of targetable vulnerabilities in RMS, but these discoveries have infrequently translated into clinical trials. We propose streamlining the process by which agents are selected for clinical evaluation in RMS. We believe that strong consideration should be given to the development of combination therapies that add biologically targeted agents to conventional cytotoxic drugs. One example of this type of combination is the addition of the WEE1 inhibitor AZD1775 to the conventional cytotoxic chemotherapeutics, vincristine and irinotecan.
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Protocolos de Quimioterapia Combinada Antineoplásica , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Rabdomiossarcoma , Criança , Humanos , Projetos de PesquisaRESUMO
Despite a growing body of knowledge about the genomic landscape and molecular pathogenesis of sarcomas, translation of basic discoveries into targeted therapies and significant clinical gains has remained elusive. Renewed interest in altered metabolic properties of cancer cells has led to an exploration of targeting metabolic dependencies as a novel therapeutic strategy. In this study, we have characterized the dependency of human pediatric sarcoma cells on key metabolic substrates and identified a mechanism of adaptation to metabolic stress by examining proliferation and bioenergetic properties of rhabdomyosarcoma and Ewing sarcoma cells under varying concentrations of glucose and glutamine. While all cell lines tested were completely growth-inhibited by lack of glucose, cells adapted to glutamine deprivation, and restored proliferation following an initial period of reduced growth. We show that expression of glutamine synthetase (GS), the enzyme responsible for de novo glutamine synthesis, increased during glutamine deprivation, and that pharmacological or shRNA-mediated GS inhibition abolished proliferation of glutamine-deprived cells, while having no effect on cells grown under normal culture conditions. Moreover, the GS substrates and glutamine precursors glutamate and ammonia restored proliferation of glutamine-deprived cells in a GS-dependent manner, further emphasizing the necessity of GS for adaptation to glutamine stress. Furthermore, pharmacological and shRNA-mediated GS inhibition significantly reduced orthotopic xenograft tumor growth. We also show that glutamine supports sarcoma nucleotide biosynthesis and optimal mitochondrial bioenergetics. Our findings demonstrate that GS mediates proliferation of glutamine-deprived pediatric sarcomas, and suggest that targeting metabolic dependencies of sarcomas should be further investigated as a potential therapeutic strategy.
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This corrects the article DOI: 10.1038/nm.4475.
RESUMO
Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in enhancer activity between primary and metastatic human tumors and between near isogenic pairs of highly lung metastatic and nonmetastatic osteosarcoma cell lines. We term these regions metastatic variant enhancer loci (Met-VELs). Met-VELs drive coordinated waves of gene expression during metastatic colonization of the lung. Met-VELs cluster nonrandomly in the genome, indicating that activity of these enhancers and expression of their associated gene targets are positively selected. As evidence of this causal association, osteosarcoma lung metastasis is inhibited by global interruptions of Met-VEL-associated gene expression via pharmacologic BET inhibition, by knockdown of AP-1 transcription factors that occupy Met-VELs, and by knockdown or functional inhibition of individual genes activated by Met-VELs, such as that encoding coagulation factor III/tissue factor (F3). We further show that genetic deletion of a single Met-VEL at the F3 locus blocks metastatic cell outgrowth in the lung. These findings indicate that Met-VELs and the genes they regulate play a functional role in metastasis and may be suitable targets for antimetastatic therapies.
Assuntos
Carcinogênese/genética , Elementos Facilitadores Genéticos/genética , Neoplasias Pulmonares/genética , Osteossarcoma/genética , Linhagem Celular Tumoral , Epigenômica , Regulação Neoplásica da Expressão Gênica , Genoma Humano/genética , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Metástase Neoplásica/genética , Osteossarcoma/patologia , Proteínas/antagonistas & inibidores , Proteínas/genética , Seleção Genética , Tromboplastina/genética , Fator de Transcrição AP-1/antagonistas & inibidores , Fator de Transcrição AP-1/genética , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: Worse chemotherapy response for neurofibromatosis type 1- (NF1-) associated compared to sporadic malignant peripheral nerve sheath tumors (MPNST) has been reported. METHODS: We evaluated the objective response (OR) rate of patients with AJCC Stage III/IV chemotherapy-naive NF1 MPNST versus sporadic MPNST after 4 cycles of neoadjuvant chemotherapy, 2 cycles of ifosfamide/doxorubicin, and 2 cycles of ifosfamide/etoposide. A Simon optimal two-stage design was used (target response rate 40%). RESULTS: 34 NF1 (median age 33 years) and 14 sporadic (median age 40 years) MPNST patients enrolled. Five of 28 (17.9%) evaluable NF1 MPNST patients had a partial response (PR), as did 4 of 9 (44.4%) patients with sporadic MPNST. Stable disease (SD) was achieved in 22 NF1 and 4 sporadic MPNST patients. In both strata, results in the initial stages met criteria for expansion of enrollment. Only 1 additional PR was observed in the expanded NF1 stratum. Enrollment was slower than expected and the trial closed before full accrual. CONCLUSIONS: This trial was not powered to detect differences in response rates between NF1 and sporadic MPNST. While the OR rate was lower in NF1 compared to sporadic MPNST, qualitative responses were similar, and disease stabilization was achieved in most patients.