RESUMO
PURPOSE: Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862), a microtubule-destabilizing agent. The goal of this study (NCT02895360) was to characterize the safety, tolerability and antitumor activity of lisavanbulin administered as a 48-hour intravenous (IV) infusion at the recommended Phase 2 dose (RP2D) of 70 mg/m2. Results from the Phase 1 dose-escalation portion of the study identifying the RP2D have been previously reported. Here, we present the findings from the Phase 2a portion of this study. Methods. This multi-center, open-label study included patients with ovarian, fallopian-tube, or primary peritoneal cancer that was either platinum-resistant or refractory (11 patients), or with first recurrence of glioblastoma (12 patients). Lisavanbulin was administered as a 48-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle. Results. Lisavanbulin was well tolerated in both patient cohorts. Thirteen patients (56.5%) developed 49 adverse events assessed as related to study treatment. The majority were mild or moderate; four were grade 3/4. Sixteen SAEs were reported in nine patients (39.1%), with none considered related to study treatment. No AEs led to permanent treatment discontinuation. Three patients in the ovarian cancer cohort had stable disease with lesion size reductions after two cycles of treatment; in the glioblastoma cohort, one patient showed partial response with a > 90% glioblastoma area reduction as best response, and one patient had stable disease after eight cycles of treatment. Conclusion. This study demonstrated a favorable safety and tolerability profile of 48-hour continuous IV infusion of lisavanbulin in patients with solid extracranial tumors or glioblastoma. Clinicaltrials.gov registration: NCT02895360.
Assuntos
Glioblastoma , Neoplasias Ovarianas , Humanos , Feminino , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologiaRESUMO
Derazantinib (DZB) is an inhibitor of the fibroblast growth factor receptors 1-3 (FGFRi) with similar potency against colony-stimulating factor receptor-1 (CSF1R), a protein important in the recruitment and function of tumor-associated macrophages. DZB inhibited pCSF1R in the macrophage cell line RAW264.7, and tumor cells GDM-1 and DEL, and had the same potency in HeLa cells transiently over-expressing FGFR2. DZB exhibited similar potency against pCSF1R expressed by isolated murine macrophages, but as in the cell lines, specific FGFRi were without significant CSF1R activity. DZB inhibited growth of three tumor xenograft models with reported expression or amplification of CSF1R, whereas the specific FGFRi, pemigatinib, had no efficacy. In the FGFR-driven syngeneic breast tumor-model, 4T1, DZB was highly efficacious causing tumor stasis. A murine PD-L1 antibody was without efficacy in this model, but combined with DZB, increased efficacy against the primary tumor and further reduced liver, spine and lung metastases. Immunohistochemistry of primary 4T1 tumors showed that the combination favored an antitumor immune infiltrate by strongly increasing cytotoxic T, natural killer and T-helper cells. Similar modulation of the tumor microenvironment was observed in an FGFR-insensitive syngeneic bladder model, MBT-2. These data confirm CSF1R as an important oncology target for DZB and provide mechanistic insight for the ongoing clinical trials, in which DZB is combined with the PD-L1 antibody, atezolizumab.
Assuntos
Antígeno B7-H1 , Receptores de Fator Estimulador de Colônias , Humanos , Camundongos , Animais , Receptores de Fator Estimulador de Colônias/metabolismo , Antígeno B7-H1/metabolismo , Células HeLa , Ligantes , Macrófagos , Apoptose , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Derazantinib (DZB) is an inhibitor of fibroblast growth factor receptors 1-3 (FGFR1-3), with additional activity against colony-stimulating-factor-1 receptor (CSF1R). We have profiled the activity of DZB in gastric cancer (GC) as monotherapy and combined with paclitaxel, and explored means of stratifying patients for treatment. The antiproliferative potency of DZB in vitro was quantified in 90 tumor cell lines and shown to correlate significantly with FGFR expression (<0.01) but not with FGFR DNA copy-number (CN) or FGFR mutations. In four GC cell lines in vitro , little or no synergy was observed with paclitaxel. In athymic nude mice, bearing cell-line derived xenografts (CDX) or patient-derived xenograft (PDX) GC models, DZB efficacy correlated highly significantly with FGFR gene expression ( r2 = 0.58; P = 0.0003; n = 18), but not FGFR mutations or DNA-CN. In FGFR-driven GC models, DZB had comparable efficacy to three other FGFR inhibitors and was more efficacious than paclitaxel. DZB had dose-dependent plasma pharmacokinetics but showed low brain penetration at all doses. GC models (one CDX and six PDX) were tested for sensitivity to the combination of DZB and paclitaxel and characterized by immunohistochemistry. The combination showed synergy (5) or additivity (2), and no antagonism, with synergy significantly associated ( P < 0.05) with higher levels of M2-type macrophages. The association of strong efficacy of the combination in vivo with M2 macrophages, which are known to express CSF1R, and the absence of synergy in vitro is consistent with the tumor microenvironment also being a factor in DZB efficacy and suggests additional means by which DZB could be stratified for cancer treatment in the clinic.
Assuntos
Paclitaxel , Receptores de Fatores de Crescimento de Fibroblastos , Neoplasias Gástricas , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Camundongos Nus , Paclitaxel/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Microambiente Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: BAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents. METHODS: This two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. The MTD was determined using a modified accelerated titration design in phase I. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D). RESULTS: Seventy-three patients received BAL101553 at doses of 15-80 mg/m2 (phase 1, n = 24; phase 2a, n = 49). The MTD was 60 mg/m2; DLTs observed at doses ≥60 mg/m2 were reversible Grade 2-3 gait disturbance with Grade 2 peripheral sensory neuropathy. In phase 2a, asymptomatic myocardial injury was observed at doses ≥45 mg/m2. The RP2D for 2-h intravenous infusion was 30 mg/m2. The overall disease control rate was 26.3% in the efficacy population. CONCLUSIONS: The RP2D for 2-h infusion of BAL101553 was well tolerated. Dose-limiting neurological and myocardial side effects were consistent with the agent's vascular-disrupting properties. CLINICAL TRIAL REGISTRATION: EudraCT: 2010-024237-23.
Assuntos
Benzimidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Oxidiazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Progressão da Doença , Feminino , Humanos , Infusões Intravenosas , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Oxidiazóis/efeitos adversos , Oxidiazóis/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Fuso Acromático/efeitos dos fármacos , Reino UnidoRESUMO
Purpose BAL101553, the prodrug of the microtubule-destabilizer BAL27862, previously showed signs of antitumor activity when administered as a 2-h infusion, but its use was limited by vascular toxicity. We investigated an alternative dosing strategy aimed at improving the safety profile of BAL101553. Methods This multicenter, open-label, Phase 1 dose-escalation study used a 3 + 3 design to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and antitumor activity of BAL101553 administered as a 48-h IV infusion on Days 1, 8, and 15 of a 28-day cycle. Patients received oral BAL101553 on Days 15-21 of cycle 2 to assess oral bioavailability. Results BAL101553 was well tolerated at doses up to ≤70 mg/m2. Three grade 3 DLTs occurred: hypotension (70 mg/m2), hyponatremia and neutropenia (both 90 mg/m2). The MTD for 48-h IV BAL101553 was 70 mg/m2. At this dose level, the AUC for BAL27862 was 8580 ng.h/mL and the Cmax was 144 ng/mL. No apparent dose-related effects on blood pressure were observed with 48-h BAL101553 IV infusion. BAL27862 oral bioavailability was >80%. Conclusions Continuous 48-h IV BAL101553 infusion achieved higher exposure of the BAL27862 active metabolite than a 2-h infusion at the RP2D and did not cause vascular toxicity. Clinicaltrials.gov registration: NCT02895360.
Assuntos
Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Oxidiazóis/uso terapêutico , Pró-Fármacos/uso terapêutico , Administração Oral , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Benzimidazóis/efeitos adversos , Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Feminino , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Microtúbulos , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/metabolismo , Oxidiazóis/efeitos adversos , Oxidiazóis/sangue , Oxidiazóis/farmacocinética , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Resultado do TratamentoRESUMO
Human glioblastoma (GBM) is a highly aggressive, invasive and hypervascularised malignant brain cancer. Individual circulating tumour cells (CTCs) are sporadically found in GBM patients, yet it is unclear whether multicellular CTC clusters are generated in this disease and whether they can bypass the physical hurdle of the blood-brain barrier. Here, we assessed CTC presence and composition at multiple time points in 13 patients with progressing GBM during an open-label phase 1/2a study with the microtubule inhibitor BAL101553. We observe CTC clusters ranging from 2 to 23 cells and present at multiple sampling time points in a GBM patient with pleomorphism and extensive necrosis, throughout disease progression. Exome sequencing of GBM CTC clusters highlights variants in 58 cancer-associated genes including ATM, PMS2, POLE, APC, XPO1, TFRC, JAK2, ERBB4 and ALK. Together, our findings represent the first evidence of the presence of CTC clusters in GBM.
Assuntos
Benzimidazóis/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Células Neoplásicas Circulantes/patologia , Oxidiazóis/administração & dosagem , Animais , Benzimidazóis/farmacologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Contagem de Células , Análise por Conglomerados , Progressão da Doença , Feminino , Redes Reguladoras de Genes/efeitos dos fármacos , Variação Genética , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Masculino , Camundongos , Mutação , Células Neoplásicas Circulantes/química , Células Neoplásicas Circulantes/efeitos dos fármacos , Oxidiazóis/farmacologia , Sequenciamento do Exoma , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
ERBB receptor tyrosine kinases have important roles in human cancer. In particular, the expression or activation of epidermal growth factor receptor and ERBB2 are altered in many epithelial tumours, and clinical studies indicate that they have important roles in tumour aetiology and progression. Accordingly, these receptors have been intensely studied to understand their importance in cancer biology and as therapeutic targets, and many ERBB inhibitors are now used in the clinic. We will discuss the significance of these receptors as clinical targets, in particular the molecular mechanisms underlying response.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Receptor ErbB-2/fisiologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/imunologia , Transdução de Sinais/efeitos dos fármacosRESUMO
This study prospectively compared the effect of secondary prophylaxis to episodic treatment on target joint (TJ) range of motion (ROM), number of joint haemorrhages and new TJ development in patients with moderate or severe haemophilia. Two-hundred and eighty-six males, 17% in prophylaxis, 83% in episodic treatment group, participating in the Centers for Disease Control and Prevention's Universal Data Collection project, fulfilled inclusion criteria: age >2 years at enrollment, free of TJs at enrollment, developed at least one TJ after enrollment, and received either prophylaxis or episodic treatment continuously for two follow-up visits after TJ development. The outcomes of interest - percentage change in TJ ROM, number of joint haemorrhages and new TJ development, were modelled using multivariate linear, Poisson and logistic regression techniques respectively. Individuals who received secondary prophylaxis in comparison to episodic treatment were younger at TJ development (P < 0.01); there was no difference in the decrease in TJ ROM between the two groups (P = 0.9). Factors significantly associated with a higher rate of haemarthroses included episodic treatment, severe haemophilia, age >5 years at TJ development, obesity and inhibitor negative status. Secondary prophylaxis significantly decreased haemarthroses but was not associated with a significant improvement in TJ ROM or with new TJ development.
Assuntos
Hemartrose/prevenção & controle , Hemofilia A/complicações , Adolescente , Adulto , Idoso , Centers for Disease Control and Prevention, U.S. , Criança , Pré-Escolar , Comorbidade , Fator IX/imunologia , Fator IX/uso terapêutico , Fator VIII/imunologia , Fator VIII/uso terapêutico , Seguimentos , Infecções por HIV/epidemiologia , Hemartrose/epidemiologia , Hemartrose/etiologia , Hemartrose/reabilitação , Hemofilia A/tratamento farmacológico , Hemofilia A/epidemiologia , Hepatite B/epidemiologia , Hepatite C/epidemiologia , Humanos , Isoanticorpos/análise , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Amplitude de Movimento Articular , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , Recuperação de Função Fisiológica , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
Microtubules are major components of the cellular cytoskeleton, ubiquitously founded in all eukaryotic cells. They are involved in mitosis, cell motility, intracellular protein and organelle transport, and maintenance of cytoskeletal shape. Avanbulin (BAL27862) is a microtubule-targeted agent (MTA) that promotes tumor cell death by destabilization of microtubules. Due to its unique binding to the colchicine site of tubulin, differently from other MTAs, avanbulin has previously shown activity in solid tumor cell lines. Its prodrug, lisavanbulin (BAL101553), has shown early signs of clinical activity, especially in tumors with high EB1 expression. Here, we assessed the preclinical anti-tumor activity of avanbulin in diffuse large B cell lymphoma (DLBCL) and the pattern of expression of EB1 in DLBCL cell lines and clinical specimens. Avanbulin showed a potent in vitro anti-lymphoma activity, which was mainly cytotoxic with potent and rapid apoptosis induction. Median IC50 was around 10 nM in both ABC and GCB-DLBCL. Half of the cell lines tested showed an induction of apoptosis already in the first 24 h of treatment, the other half in the first 48 h. EB1 showed expression in DLBCL clinical specimens, opening the possibility for a cohort of patients that could potentially benefit from treatment with lisavanbulin. These data show the basis for further preclinical and clinical evaluation of lisavanbulin in the lymphoma field.
RESUMO
INTRODUCTION: Strategies to improve the efficacy of endocrine agents in breast cancer (BC) therapy and to delay the onset of resistance include concomitant targeting of the estrogen receptor alpha (ER) and the mammalian target of rapamycin complex 1 (mTORC1), which regulate cell-cycle progression and are supported by recent clinical results. METHODS: BC cell lines expressing aromatase (AROM) and modeling endocrine-sensitive (MCF7-AROM1) and human epidermal growth factor receptor 2 (HER2)-dependent de novo resistant disease (BT474-AROM3) and long-term estrogen-deprived (LTED) MCF7 cells that had acquired resistance associated with HER2 overexpression were treated in vitro and as subcutaneous xenografts with everolimus (RAD001-mTORC1 inhibitor), in combination with tamoxifen or letrozole. End points included proliferation, cell-cycle arrest, cell signaling, and effects on ER-mediated transactivation. RESULTS: Everolimus caused a concentration-dependent decrease in proliferation in all cell lines, which was associated with reductions in S6 phosphorylation. Everolimus plus letrozole or tamoxifen enhanced the antiproliferative effect and G1-accumulation compared with monotherapy, as well as increased phosphorylation (Ser10) and nuclear accumulation of p27 and pronounced dephosphorylation of Rb. Sensitivity was greatest to everolimus in the LTED cells but was reduced by added estrogen. Increased pAKT occurred in all circumstances with everolimus and, in the BT474 and LTED cells, was associated with increased pHER3. Decreased ER transactivation suggested that the effectiveness of everolimus might be partly related to interrupting cross-talk between growth-factor signaling and ER. In MCF7-AROM1 xenografts, letrozole plus everolimus showed a trend toward enhanced tumor regression, versus the single agents. In BT474-AROM3 xenografts, everolimus alone was equally effective at reducing tumor volume as were the combination therapies. CONCLUSIONS: The results provide mechanistic support for recent positive clinical data on the combination of everolimus and endocrine therapy, as well as data on potential routes of escape via enhanced HER2/3 signaling. This merits investigation for further improvements in treatment efficacy.
Assuntos
Antineoplásicos Hormonais/farmacologia , Nitrilas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Sirolimo/análogos & derivados , Tamoxifeno/farmacologia , Triazóis/farmacologia , Animais , Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Nucléolo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Everolimo , Feminino , Humanos , Letrozol , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Complexos Multiproteicos/antagonistas & inibidores , Complexos Multiproteicos/metabolismo , Nitrilas/administração & dosagem , Fosforilação , Inibidores de Proteínas Quinases/administração & dosagem , Transporte Proteico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-3/metabolismo , Receptores de Estrogênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/administração & dosagem , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Tamoxifeno/administração & dosagem , Triazóis/administração & dosagem , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
NVP-BEZ235 is a dual PI3K/mTOR inhibitor currently in phase I clinical trials. We profiled this compound against a panel of breast tumor cell lines to identify the patient populations that would benefit from such treatment. In this setting, NVP-BEZ235 selectively induced cell death in cell lines presenting either HER2 amplification and/or PIK3CA mutation, but not in cell lines with PTEN loss of function or KRAS mutations, for which resistance could be attributed, in part to ERK pathway activity. An in depth analysis of death markers revealed that the cell death observed upon NVP-BEZ235 treatment could be recapitulated with other PI3K inhibitors and that this event is linked to active PARP cleavage indicative of an apoptotic process. Moreover, the effect seemed to be partly independent of the caspase-9 executioner and mitochondrial activated caspases, suggesting an alternate route for apoptosis induction by PI3K inhibitors. Overall, this study will provide guidance for patient stratification for forthcoming breast cancer phase II trials for NVP-BEZ235.
Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Genes erbB-2 , Imidazóis/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Quinolinas/farmacologia , Apoptose/genética , Apoptose/fisiologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caspase 9/metabolismo , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/fisiologia , Inibidores Enzimáticos/farmacologia , Feminino , Amplificação de Genes , Genes erbB-2/efeitos dos fármacos , Humanos , Mutação , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TORRESUMO
BACKGROUND: Glioblastoma (GBM) is an incurable disease with few approved therapeutic interventions. Radiation therapy (RT) and temozolomide (TMZ) remain the standards of care. The efficacy and optimal deployment schedule of the orally bioavailable small-molecule tumor checkpoint controller lisavanbulin alone, and in combination with, standards of care were assessed using a panel of IDH-wildtype GBM patient-derived xenografts. METHODS: Mice bearing intracranial tumors received lisavanbulin +/-RT +/-TMZ and followed for survival. Lisavanbulin concentrations in plasma and brain were determined by liquid chromatography with tandem mass spectrometry, while flow cytometry was used for cell cycle analysis. RESULTS: Lisavanbulin monotherapy showed significant benefit (P < .01) in 9 of 14 PDXs tested (median survival extension 9%-84%) and brain-to-plasma ratios of 1.3 and 1.6 at 2- and 6-hours postdose, respectively, validating previous data suggesting significant exposure in the brain. Prolonged lisavanbulin dosing from RT start until moribund was required for maximal benefit (GBM6: median survival lisavanbulin/RT 90 vs. RT alone 69 days, P = .0001; GBM150: lisavanbulin/RT 143 days vs. RT alone 73 days, P = .06). Similar observations were seen with RT/TMZ combinations (GBM39: RT/TMZ/lisavanbulin 502 days vs. RT/TMZ 249 days, P = .0001; GBM26: RT/TMZ/lisavanbulin 172 days vs. RT/TMZ 121 days, P = .04). Immunohistochemical analyses showed a significant increase in phospho-histone H3 with lisavanbulin treatment (P = .01). CONCLUSIONS: Lisavanbulin demonstrated excellent brain penetration, significant extension of survival alone or in RT or RT/TMZ combinations, and was associated with mitotic arrest. These data provide a strong clinical rationale for testing lisavanbulin in combination with RT or RT/TMZ in GBM patients.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Animais , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Xenoenxertos , Humanos , Camundongos , Microtúbulos/metabolismo , Microtúbulos/patologia , Temozolomida/uso terapêuticoRESUMO
The aim was to determine the potential of the allosteric mammalian target of rapamycin inhibitor, everolimus, to act in combination with cytotoxic anticancer compounds in vitro and in vivo. A concomitant combination in vitro showed no evidence of antagonism, but enhanced the antiproliferative effects (additive to synergistic) with cisplatin, doxorubicin, 5-fluorouracil, gemcitabine, paclitaxel, and patupilone. Everolimus (1-5 mg/kg/d orally) was evaluated for antitumor activity in vivo alone or in combination with suboptimal cytotoxic doses using athymic nude mice bearing subcutaneous human H-596 lung, KB-31 cervical, or HCT-116 colon tumor xenografts. Everolimus monotherapy was very well tolerated and caused inhibition of tumor growth, rather than regression, and this was associated with a dose-dependent decline in tumor pS6 levels, a key downstream protein of mammalian target of rapamycin. At the doses used, the cytotoxics inhibited tumor growth and caused tolerable body-weight loss. Concomitant combinations of cisplatin, doxorubicin, paclitaxel, or patupilone with everolimus produced cooperative antitumor effects, in some cases producing regressions without clinically significant increases in toxicity. In contrast, combinations with gemcitabine and 5-fluorouracil were less well tolerated. Alternative administration schedules were tested for cisplatin, gemcitabine, or paclitaxel combined with everolimus: these did not dramatically affect cisplatin or gemcitabine activity or tolerability but were antagonistic for paclitaxel. Everolimus showed promising maintenance activity after treatment with doxorubicin or paclitaxel ceased. Overall, the results confirm that everolimus is an effective, well-tolerated suppressor of experimental human tumor growth, and although it did not show strong potentiation of efficacy, antitumor activity in vivo was increased without marked increases in toxicity, supporting clinical use of everolimus as a partner for conventional cytotoxics.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Epotilonas/administração & dosagem , Everolimo , Feminino , Fluoruracila/administração & dosagem , Células HCT116 , Humanos , Camundongos , Camundongos Nus , Paclitaxel/administração & dosagem , Paclitaxel/antagonistas & inibidores , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Ensaios Antitumorais Modelo de Xenoenxerto , GencitabinaRESUMO
Loss of PTEN function leads to activation of phosphoinositide 3-kinase (PI3K) signaling and Akt. Clinical trials are now testing whether mammalian target of rapamycin (mTOR) inhibition is useful in treating PTEN-null cancers. Here, we report that mTOR inhibition induced apoptosis of epithelial cells and the complete reversal of a neoplastic phenotype in the prostate of mice expressing human AKT1 in the ventral prostate. Induction of cell death required the mitochondrial pathway, as prostate-specific coexpression of BCL2 blocked apoptosis. Thus, there is an mTOR-dependent survival signal required downstream of Akt. Bcl2 expression, however, only partially restored intraluminal cell growth in the setting of mTOR inhibition. Expression profiling showed that Hif-1 alpha targets, including genes encoding most glycolytic enzymes, constituted the dominant transcriptional response to AKT activation and mTOR inhibition. These data suggest that the expansion of AKT-driven prostate epithelial cells requires mTOR-dependent survival signaling and activation of HIF-1 alpha, and that clinical resistance to mTOR inhibitors may emerge through BCL2 expression and/or upregulation of HIF-1 alpha activity.
Assuntos
Apoptose/fisiologia , Células Epiteliais/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo , Animais , Sobrevivência Celular , Everolimo , Perfilação da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Imunossupressores/metabolismo , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Placebos , Próstata/citologia , Próstata/metabolismo , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sirolimo/análogos & derivados , Sirolimo/metabolismo , Serina-Treonina Quinases TOR , Fatores de Transcrição/genéticaRESUMO
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth via mTOR complex 1 (mTORC1), whose activation has been implicated in many human cancers. However, mTORC1's status in gastrointestinal tumors has not been characterized thoroughly. We have found that the mTORC1 pathway is activated with increased expression of the mTOR protein in intestinal polyps of the Apc(Delta716) heterozygous mutant mouse, a model for human familial adenomatous polyposis. An 8-week treatment with RAD001 (everolimus) suppressed the mTORC1 activity in these polyps and inhibited proliferation of the adenoma cells as well as tumor angiogenesis, which significantly reduced not only the number of polyps but also their size. beta-Catenin knockdown in the colon cancer cell lines reduced the mTOR level and thereby inhibited the mTORC1 signaling. These results suggest that the Wnt signaling contributes to mTORC1 activation through the increased level of mTOR and that the activation plays important roles in the intestinal polyp formation and growth. Indeed, long-term RAD001 treatment significantly reduced mortality of the Apc(Delta716) mice. Thus, we propose that the mTOR inhibitors may be efficacious for therapy and prevention of colonic adenomas and cancers with Wnt signaling activation.
Assuntos
Proteína da Polipose Adenomatosa do Colo/metabolismo , Pólipos Intestinais/metabolismo , Pólipos Intestinais/prevenção & controle , Transdução de Sinais , Fatores de Transcrição/metabolismo , Adenoma/irrigação sanguínea , Adenoma/tratamento farmacológico , Adenoma/patologia , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Proliferação de Células/efeitos dos fármacos , Everolimo , Feminino , Pólipos Intestinais/patologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Transgênicos , Complexos Multiproteicos , Proteínas , Transdução de Sinais/efeitos dos fármacos , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Taxa de Sobrevida , Serina-Treonina Quinases TOR , Proteínas Wnt/metabolismoRESUMO
Glioblastoma is a highly malignant brain tumor with no curative treatment options, and immune checkpoint blockade has not yet shown major impact. We hypothesized that drugs targeting mitosis might affect the tumor microenvironment and sensitize cancer cells to immunotherapy. We used 2 glioblastoma mouse models with different immunogenicity profiles, GL261 and SB28, to test the efficacy of antineoplastic and immunotherapy combinations. The spindle assembly checkpoint activator BAL101553 (lisavanbulin), agonistic anti-CD40 antibody, and double immune checkpoint blockade (anti-programmed cell death 1 and anti-cytotoxic T lymphocyte-associated protein 4; anti-PD-1 and anti-CTLA-4) were evaluated individually or in combination for treating orthotopic GL261 and SB28 tumors. Genomic and immunological analyses were used to predict and interpret therapy responsiveness. BAL101553 monotherapy increased survival in immune checkpoint blockade-resistant SB28 glioblastoma tumors and synergized with anti-CD40 antibody, in a T cell-independent manner. In contrast, the more immunogenic and highly mutated GL261 model responded best to anti-PD-1 and anti-CTLA-4 therapy and more modestly to BAL101553 and anti-CD40 combination. Our results show that BAL101553 is a promising therapeutic agent for glioblastoma and could synergize with innate immune stimulation. Overall, these data strongly support immune profiling of glioblastoma patients and preclinical testing of combination therapies with appropriate models for particular patient groups.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Mitose/efeitos dos fármacos , Oxidiazóis/uso terapêutico , Animais , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Alquilantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose , Benzimidazóis/farmacologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Antígenos CD40/imunologia , Antígeno CTLA-4/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/imunologia , Proteína HMGB1/metabolismo , Interferon gama/genética , Camundongos , Transplante de Neoplasias , Oxidiazóis/farmacologia , Receptor de Morte Celular Programada 1/imunologia , Taxa de Sobrevida , Temozolomida/uso terapêutico , Microambiente Tumoral/efeitos dos fármacosRESUMO
INTRODUCTION: This review evaluates the clinical role of fibroblast growth factor receptor 2 (FGFR2) inhibition with derazantinib in patients with intrahepatic cholangiocarcinoma (iCCA) harboring actionable oncogenic FGFR2 fusions/rearrangements, mutations and amplifications. FGFR inhibitors such as derazantinib are currently being evaluated to address the unmet medical need of patients with previously treated, locally advanced or metastatic iCCA harboring such genetic aberrations. AREAS COVERED: We summarize the pharmacokinetics, and the emerging safety and efficacy data of the investigational FGFR inhibitor derazantinib. We discuss the future directions of this novel therapeutic agent for iCCA. EXPERT OPINION: Derazantinib is a potent FGFR1â3 kinase inhibitor which also has activity against colony stimulating factor-1âreceptor (CSF1R) and vascular endothelial growfth factor receptorâ2 (VEGFR2), suggesting a potentially differentiated role in the treatment of patients with iCCA. Derazantinib has shown clinically meaningful efficacy with durable objective responses, supporting the therapeutic potential of derazantinib in previously treated patients with iCCA harboring FGFR2 fusions/rearrangements, mutations and amplifications. The clinical safety profile of derazantinib was well manageable and compared favorably to the FGFR inhibitor class, particularly with a low incidence of drug-related hand-foot syndrome, stomatitis, retinal and nail toxicity. These findings support the need for increased molecular profiling of cholangiocarcinoma patients.
Assuntos
Compostos de Anilina/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Quinazolinas/uso terapêutico , Compostos de Anilina/efeitos adversos , Compostos de Anilina/farmacologia , Animais , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Rearranjo Gênico , Humanos , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/efeitos adversos , Quinazolinas/farmacologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
PURPOSE: The Akt/mammalian target of rapamycin (mTOR) pathway is frequently activated in human cancers and plays an important role in small cell lung cancer (SCLC) biology. We investigated the potential of targeting mTOR signaling as a novel antitumor approach in SCLC. EXPERIMENTAL DESIGN: The expression of mTOR in patient specimens and in a panel of SCLC cell lines was analyzed. The effects on SCLC cell survival and downstream signaling were determined following mTOR inhibition by the rapamycin derivative RAD001 (Everolimus) or down-regulation by small interfering RNA. RESULTS: We found elevated expression of mTOR in patient specimens and SCLC cell lines, compared with normal lung tissue and normal lung epithelial cells. RAD001 treatment impaired basal and growth factor-stimulated cell growth in a panel of SCLC cell lines. Cells with increased Akt pathway activation were more sensitive to RAD001. Accordingly, a constitutive activation of the Akt/mTOR pathway was sufficient to sensitize resistant SCLC cells to the cytotoxic effect of RAD001. In the sensitive cells, RAD001 showed a strong additive effect to the proapoptotic action of the chemotherapeutic agent etoposide. Intriguingly, we observed low Bcl-2 family proteins levels in the SCLC cells with a constitutive Akt pathway activation, whereas an increased expression was detected in the RAD001-resistant SCLC cells. An antisense construct targeting Bcl-2 or a Bcl-2-specific inhibitor was able to sensitize resistant SCLC cells to RAD001. Moreover, SCLC tumor growth in vivo was significantly inhibited by RAD001. CONCLUSION: Together, our data show that inhibiting mTOR signaling with RAD001 potently disrupts growth and survival signaling in human SCLC cells.
Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Sirolimo/análogos & derivados , Animais , Carcinoma de Células Pequenas/patologia , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Resistencia a Medicamentos Antineoplásicos , Etoposídeo/farmacologia , Everolimo , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Proteínas Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/análise , Transdução de Sinais/fisiologia , Sirolimo/farmacologia , Fator de Células-Tronco/farmacologia , Serina-Treonina Quinases TORRESUMO
PURPOSE: Comparison of the antiangiogenic/vascular properties of the oral mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) and the vascular endothelial growth factor receptor (VEGFR) inhibitor vatalanib (PTK/ZK). EXPERIMENTAL DESIGN: Antiproliferative activity against various tumor histotypes and downstream effects on the mTOR pathway were measured in vitro. In vivo, antitumor activity, plasma, and tumor RAD001 levels were measured. Activity in several different angiogenic/vascular assays in vitro and in vivo was assessed and compared with PTK/ZK. RESULTS: RAD001 inhibited proliferation in vitro (IC50 values<1 nmol/L to >1 micromol/L), and in sensitive and insensitive tumor cells, pS6 kinase and 4E-BP1 were inhibited. Activity in vitro did not correlate with activity in vivo and significant responses were seen in tumors with IC50 values>10-fold higher than tumor RAD001 concentrations. In vitro, RAD001 inhibited the proliferation of VEGF-stimulated and fibroblast growth factor-stimulated human endothelial cells but not dermal fibroblasts and impaired VEGF release from both sensitive and insensitive tumor cells but did not inhibit migration of human endothelial cells. In vivo, in tumor models derived from either sensitive or insensitive cells, RAD001 reduced Tie-2 levels, the amount of mature and immature vessels, total plasma, and tumor VEGF. RAD001 did not affect blood vessel leakiness in normal vasculature acutely exposed to VEGF nor did it affect tumor vascular permeability (Ktrans) as measured by dynamic contrast-enhanced magnetic resonance imaging. However, the pan-VEGFR inhibitor PTK/ZK inhibited endothelial cell migration and vascular permeability but had less effect on mature vessels compared with RAD001. CONCLUSIONS: VEGFR and mTOR inhibitors show similar but also distinct effects on tumor vascular biology, which has implications for their clinical activity alone or in combination.
Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias Experimentais/irrigação sanguínea , Neovascularização Patológica/tratamento farmacológico , Ftalazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/química , Piridinas/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sirolimo/análogos & derivados , Inibidores da Angiogênese/farmacocinética , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Everolimo , Feminino , Humanos , Técnicas Imunoenzimáticas , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Ftalazinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Quinases/metabolismo , Piridinas/farmacocinética , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos WF , Receptor TIE-2/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Sirolimo/farmacocinética , Sirolimo/farmacologia , Serina-Treonina Quinases TOR , Distribuição Tecidual , Transplante Heterólogo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Inhibition of ErbB2 (HER2) with monoclonal antibodies, an effective therapy in some forms of breast cancer, is associated with cardiotoxicity, the pathophysiology of which is poorly understood. Recent data suggest, that dual inhibition of ErbB1 (EGFR) and ErbB2 signaling is more efficient in cancer therapy, however, cardiac safety of this therapeutic approach is unknown. We therefore tested an ErbB1-(CGP059326) and an ErbB1/ErbB2-(PKI166) tyrosine kinase inhibitor in an in-vitro system of adult rat ventricular cardiomyocytes and assessed their effects on 1. cell viability, 2. myofibrillar structure, 3. contractile function, and 4. MAPK- and Akt-signaling alone or in combination with Doxorubicin. Neither CGP nor PKI induced cardiomyocyte necrosis or apoptosis. PKI but not CGP caused myofibrillar structural damage that was additive to that induced by Doxorubicin at clinically relevant doses. These changes were associated with an inhibition of excitation-contraction coupling. PKI but not CGP decreased p-Erk1/2, suggesting a role for this MAP-kinase signaling pathway in the maintenance of myofibrils. These data indicate that the ErbB2 signaling pathway is critical for the maintenance of myofibrillar structure and function. Clinical studies using ErbB2-targeted inhibitors for the treatment of cancer should be designed to include careful monitoring for cardiac dysfunction.