RESUMEN
Stereoselective fluorination is investigated as a method for modulating the properties of a cyclic RGD-containing tetrapeptide. Three key outcomes of fluorination are assessed: (i) the effect on peptide cyclisation efficiency; (ii) the ability to fine-tune the molecular conformation; and (iii) the effect on the cyclic peptides' biological activity. Fluorination is found to exert pronounced effects against all three criteria.
RESUMEN
Oncology has benefited from an increasingly growing number of groundbreaking innovations over the last decade. Targeted therapies, biotherapies, and the most recent immunotherapies all contribute to increase the number of therapeutic options for cancer patients. Consequently, substantial improvements in clinical outcomes for some disease with dismal prognosis such as lung carcinoma or melanoma have been achieved. Of note, the latest innovations in targeted therapies or biotherapies do not preclude the use of standard cytotoxic agents, mostly used in combination. Importantly, and despite the rise of bioguided (a.k.a. precision) medicine, the administration of chemotherapeutic agents still relies on the maximum tolerated drug (MTD) paradigm, a concept inherited from theories conceptualized nearly half a century ago. Alternative dosing schedules such as metronomic regimens, based upon the repeated and regular administration of low doses of chemotherapeutic drugs, and adaptive therapy (i.e. modulating the dose and frequency of cytotoxics administration to control disease progression rather than eradicate it at all cost) have emerged as possible strategies to improve response rates while reducing toxicities. The recent changes in paradigm in the way we theorize cancer biology and evolution, metastatic spreading and tumor ecology, alongside the recent advances in the field of immunotherapy, have considerably strengthened the interest for these alternative approaches. This paper aims at reviewing the recent evolutions in the field of theoretical biology of cancer and computational oncology, with a focus on the consequences these changes have on the way we administer chemotherapy. Here, we advocate for the development of model-guided strategies to refine doses and schedules of chemotherapy administration in order to achieve precision medicine in oncology.
Asunto(s)
Administración Metronómica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Modelos Teóricos , Neoplasias/tratamiento farmacológico , Medicina de Precisión , Animales , Antineoplásicos/administración & dosificación , Humanos , Neoplasias/etiología , Neoplasias/metabolismo , Neoplasias/patología , Medicina de Precisión/métodosRESUMEN
Phenoxodiol, an analogue of the isoflavone natural product daidzein, is a potent anti-cancer agent that has been investigated for the treatment of hormone dependent cancers. This molecular scaffold was reacted with different primary amines and secondary amines under different Mannich conditions to yield either benzoxazine or aminomethyl substituted analogues. These processes enabled the generation of a diverse range of analogues that were required for structure-activity relationship (SAR) studies. The resulting Mannich bases exhibited prominent anti-proliferative effects against SHEP neuroblastoma and MDA-MB-231 breast adenocarcinoma cell lines. Further cytotoxicity studies against MRC-5 normal lung fibroblast cells showed that the isoflavene analogues were selective towards cancer cells.
Asunto(s)
Isoflavonas , Bases de Mannich/síntesis química , Bases de Mannich/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Isoflavonas/síntesis química , Isoflavonas/química , Isoflavonas/toxicidad , Bases de Mannich/química , Bases de Mannich/toxicidad , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Fifteen novel 2-substituted isoflavenes were synthesised via nucleophilic addition to isoflavylium salts. Twelve of the newly synthesised isoflavenes, along with the unsubstituted parent isoflavene, were tested in cell viability assays against the SHEP neuroblastoma and MDA-MB-231 breast adenocarcinoma cell lines. While the 2-substituted isoflavenes displayed a range of anti-proliferative activities, in most cases they were less active that the unsubstituted isoflavene (IC50=9.9 µM vs SHEP; IC50=33 µM vs MDA-MB-231). However, compound 7f, derived from the reaction between isoflavylium salt 5 and para-methoxyacetophenone, showed improved anti-proliferative activity against breast cancer cells (IC50=7.6 µM). Furthermore, compound 7f, as well as analogues 7a, 7c, 11d and 14, inhibited the production of interleukin-6 in LPS-activated RAW 264.7 cells.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/farmacología , Flavonoides/farmacología , Interleucina-6/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Flavonoides/síntesis química , Flavonoides/química , Humanos , Interleucina-6/biosíntesis , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
In 2008, 72% of cancer deaths occurred in low-income and middle-income countries, where, although there is a lower incidence of cancer than in high-income countries, survival rates are also low. Many patients are sent home to die, and an even larger number of patients do not have access to treatment facilities. New constraint-adapted therapeutic strategies are therefore urgently needed. Metronomic chemotherapy--the chronic administration of chemotherapy at low, minimally toxic doses on a frequent schedule of administration, with no prolonged drug-free breaks--has recently emerged as a potential strategy to control advanced or refractory cancer and represents an alternative for patients with cancer living in developing countries. This low-cost, well-tolerated, and easy to access strategy is an attractive therapeutic option in resource-limited countries. Moreover, combined with drug repositioning, additional anticancer effects can be achieved, ultimately resulting in improved cancer control while maintaining minimum cost of treatment. In this Personal View, we will briefly review the rationale behind the combination of metronomic chemotherapy and drug repositioning-an approach we term metronomics. We assess the clinical experience obtained with this kind of anticancer treatment and describe potential new developments in countries with limited resources. We also highlight the need for adapted clinical study endpoints and innovative models of collaboration between for-profit and non-profit organisations, to address the growing problem of cancer in resource-limited countries.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/economía , Países en Desarrollo/economía , Costos de los Medicamentos , Accesibilidad a los Servicios de Salud/economía , Neoplasias/tratamiento farmacológico , Neoplasias/economía , Administración Metronómica , Conducta Cooperativa , Ahorro de Costo , Análisis Costo-Beneficio , Reposicionamiento de Medicamentos/economía , Humanos , Relaciones Interinstitucionales , Neoplasias/mortalidad , Resultado del TratamientoRESUMEN
Drug development in oncology is highly challenging, with less than 5% success rate in clinical trials. This alarming figure points out the need to study in more details the multiple biological effects of drugs in specific contexts. Indeed, the comprehensive assessment of drug poly-pharmacology can provide insights into their therapeutic and adverse effects, to optimize their utilization and maximize the success rate of clinical trials. Recent technological advances have made possible in-depth investigation of drug poly-pharmacology. This review first highlights high-throughput methodologies that have been used to unveil new mechanisms of action of existing drugs. Then, we discuss how emerging chemo-proteomics strategies allow effectively dissecting the poly-pharmacology of drugs in an unsupervised manner.
Asunto(s)
Neoplasias , Polifarmacia , Proteómica , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
The anti-angiogenic activity of chemotherapy is both dose- and schedule-dependent. While conventional maximum tolerated dose (MTD) chemotherapy exerts only mild and reversible anti-angiogenic effects, low-dose metronomic (LDM) chemotherapy was developed to specifically target tumour angiogenesis. However, the long-term effects of either MTD or LDM chemotherapy on vascular endothelial cells have never been investigated. Here, we demonstrated that repeated exposure to MTD and LDM chemotherapy differentially impact on the angiogenic potential and chemosensitivity of immortalized endothelial cells. Repeated MTD vinblastine treatment of vascular endothelial cells led to an increased proliferation rate and resistance to paclitaxel. In contrast, repeated LDM treatment with vinblastine or etoposide impaired the angiogenic potential of endothelial cells and increased their chemosensitivity. This effect was associated with a significant decrease in ßII- and ßIII-tubulin expression. Functional analysis using siRNA showed that silencing the expression of ßIII-tubulin in endothelial cells significantly decreased their capacity to form vascular structures and increased their sensitivity to the anti-angiogenic and vascular-disrupting effects of chemotherapy, whereas silencing ßII-tubulin expression had no effect. Collectively our results show that LDM chemotherapy impairs the angiogenic potential of endothelial cells while increasing their chemosensitivity-an effect at least in part mediated by the down-regulation of ßIII-tubulin expression. Furthermore, our study suggests that ßIII-tubulin represents an attractive therapeutic target to increase the anti-angiogenic effects of chemotherapy and overall anti-tumour efficacy.
Asunto(s)
Antineoplásicos/farmacología , Endotelio Vascular/efectos de los fármacos , Neovascularización Patológica/prevención & control , Antineoplásicos/administración & dosificación , Secuencia de Bases , Western Blotting , Línea Celular Transformada , Cartilla de ADN , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Endotelio Vascular/citología , Silenciador del Gen , Humanos , Reacción en Cadena de la Polimerasa , ARN Interferente Pequeño , Tubulina (Proteína)/metabolismoRESUMEN
Isoflavene-propranolol hybrid molecules were developed as potentially novel anti-tumour agents. Isoflavene itself has potent anti-cancer activity while propranolol can enhance anti-proliferative and anti-angiogenic properties of 5-fluorouracil and paclitaxel. The hybrids were produced via nucleophilic addition of substituted amine groups to a dioxiran intermediate, which was in turn generated from the Williamson-type reaction of isoflavene with (±)-epichlorohydrin. These analogues were tested in anti-cancer cell viability assays against SHEP neuroblastoma and MDA-MB-231 breast adenocarcinoma cell lines, and were found to exhibit potent anti-proliferative activities. These compounds also displayed anti-angiogenic and anti-proliferative effects in HMEC-1 human microvascular endothelial cell lines. Notably, the most potent hybrid molecules synthesized in this work showed enhanced potency against cancer cell lines compared to either isoflavene or propranolol alone, while retaining significant selectivity for cancer cells over MRC-5 normal lung fibroblast cells.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Isoflavonas/química , Isoflavonas/farmacología , Propranolol/química , Propranolol/farmacología , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Isoflavonas/síntesis química , Neuroblastoma/tratamiento farmacológico , Propranolol/síntesis químicaRESUMEN
Recently, a holistic approach to oncology that integrates a whole-body understanding of the etiology and dynamics of cancer and the development of new therapies has been proposed. Herein we discuss how this concept is also relevant to pediatric oncology, with the caveat of specificities that must be considered.
Asunto(s)
Oncología Médica , Neoplasias , Niño , Humanos , Neoplasias/genética , Neoplasias/terapiaRESUMEN
Brain tumors are an important cause of suffering and death. Glioblastoma are the most frequent primary tumors of the central nervous system in adults. They are associated with a very poor prognosis, since only 10% of GBM patients survive 5 years after diagnosis. Medulloblastoma are the most frequent brain malignancies in childhood; they affect the cerebellum in children under 10 years of age in 75% of cases. The current multimodal treatment comes at the expense of serious and often long-lasting side effects. Herein, we propose the synthesis of a library of novel alkoxyamines as anticancer drug candidates. The most efficient molecule, ALK4, was selected based on its ability to inhibit both survival and migration of GBM and MB cells in 2D cultures and in 3D tumor spheroids. A fluorescent derivative was used to show the early cytosolic accumulation of ALK4 in tumor cells. Spontaneous homolysis of ALK4 led to the release of alkyl radicals, which triggered the generation of reactive oxygen species, fragmentation of the mitochondrial network and ultimately apoptosis. To control its homolytic process, the selected alkoxyamine was bioconjugated to a peptide selectively recognized by matrix metalloproteases. This bioconjugate, named ALK4-MMPp, successfully inhibited survival, proliferation, and invasion of GBM and MB tumor micromasses. We further developed innovative brain and cerebellum organotypic models to monitor treatment response over time. It confirmed that ALK4-MMPp significantly impaired tumor progression, while no significant damage was observed on normal brain tissue. Lastly, we showed that ALK4-MMPp was well-tolerated in vivo by zebrafish embryos. This study provides a new strategy to control the activation of alkoxyamines, and revealed the bioconjugate ALK4-MMPp bioconjugate as a good anticancer drug candidate.
RESUMEN
BACKGROUND: Pharmacological synergisms are an attractive anticancer strategy. However, with more than 5000 approved-drugs and compounds in clinical development, identifying synergistic treatments represents a major challenge. METHODS: High-throughput screening was combined with target deconvolution and functional genomics to reveal targetable vulnerabilities in glioblastoma. The role of the top gene hit was investigated by RNA interference, transcriptomics and immunohistochemistry in glioblastoma patient samples. Drug combination screen using a custom-made library of 88 compounds in association with six inhibitors of the identified glioblastoma vulnerabilities was performed to unveil pharmacological synergisms. Glioblastoma 3D spheroid, organotypic ex vivo and syngeneic orthotopic mouse models were used to validate synergistic treatments. FINDINGS: Nine targetable vulnerabilities were identified in glioblastoma and the top gene hit RRM1 was validated as an independent prognostic factor. The associations of CHK1/MEK and AURKA/BET inhibitors were identified as the most potent amongst 528 tested pairwise drug combinations and their efficacy was validated in 3D spheroid models. The high synergism of AURKA/BET dual inhibition was confirmed in ex vivo and in vivo glioblastoma models, without detectable toxicity. INTERPRETATION: Our work provides strong pre-clinical evidence of the efficacy of AURKA/BET inhibitor combination in glioblastoma and opens new therapeutic avenues for this unmet medical need. Besides, we established the proof-of-concept of a stepwise approach aiming at exploiting drug poly-pharmacology to unveil druggable cancer vulnerabilities and to fast-track the identification of synergistic combinations against refractory cancers. FUNDING: This study was funded by institutional grants and charities.
Asunto(s)
Antineoplásicos , Glioblastoma , Animales , Ratones , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Aurora Quinasa A , Sinergismo Farmacológico , Línea Celular Tumoral , Antineoplásicos/farmacología , Combinación de MedicamentosRESUMEN
Rhabdomyosarcoma (RMS) is the main form of pediatric soft-tissue sarcoma. Its cure rate has not notably improved in the last 20 years following relapse, and the lack of reliable preclinical models has hampered the design of new therapies. This is particularly true for highly heterogeneous fusion-negative RMS (FNRMS). Although methods have been proposed to establish FNRMS organoids, their efficiency remains limited to date, both in terms of derivation rate and ability to accurately mimic the original tumor. Here, we present the development of a next-generation 3D organoid model derived from relapsed adult and pediatric FNRMS. This model preserves the molecular features of the patients' tumors and is expandable for several months in 3D, reinforcing its interest to drug combination screening with longitudinal efficacy monitoring. As a proof-of-concept, we demonstrate its preclinical relevance by reevaluating the therapeutic opportunities of targeting apoptosis in FNRMS from a streamlined approach based on transcriptomic data exploitation.
Asunto(s)
Antineoplásicos , Rabdomiosarcoma , Adulto , Humanos , Niño , Recurrencia Local de Neoplasia/tratamiento farmacológico , Rabdomiosarcoma/tratamiento farmacológico , Rabdomiosarcoma/patología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Organoides/patología , Muerte CelularRESUMEN
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA-mutations showed increased sensitivity to ONC201, while those harboring TP53-mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.
RESUMEN
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA mutations showed increased sensitivity to ONC201, whereas those harboring TP53 mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992. SIGNIFICANCE: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib.
RESUMEN
Cell migration plays a crucial role in numerous cellular functions, and alterations in the regulation of cell migration are required for invasive transformation of a tumor cell. While the mechanistic process of actin-based migration has been well documented, little is known as to the specific function of the nonmuscle actin isoforms in mammalian cells. Here, we present a comprehensive examination of γ-actin's role in cell migration using an RNAi approach. The partial suppression of γ-actin expression in SH-EP neuroblastoma cells resulted in a significant decrease in wound healing and transwell migration. Similarly, the knockdown of γ-actin significantly reduced speed of motility and severely affected the cell's ability to explore, which was, in part, due to a loss of cell polarity. Moreover, there was a significant increase in the size and number of paxillin-containing focal adhesions, coupled with a significant decrease in phosphorylated paxillin in γ-actin-knockdown cells. In addition, there was a significant increase in the phosphorylation of cofilin and myosin regulatory light chain, suggesting an overactivated Rho-associated kinase (ROCK) signaling pathway in γ-actin-knockdown cells. The alterations in the phosphorylation of paxillin and myosin regulatory light chain were unique to γ-actin and not ß-actin knockdown. Inhibition of the ROCK pathway with the inhibitor Y-27632 restored the ability of γ-actin-knockdown cells to migrate. This study demonstrates γ-actin as a potential upstream regulator of ROCK mediated cell migration.
Asunto(s)
Actinas/metabolismo , Movimiento Celular/fisiología , Quinasas Asociadas a rho/metabolismo , Actinas/antagonistas & inhibidores , Actinas/genética , Amidas/farmacología , Secuencia de Bases , Línea Celular , Polaridad Celular/fisiología , Adhesiones Focales/fisiología , Técnicas de Silenciamiento del Gen , Humanos , Modelos Biológicos , Cadenas Ligeras de Miosina/metabolismo , Paxillin/metabolismo , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Interferencia de ARN , ARN Interferente Pequeño/genética , Transducción de Señal , Cicatrización de Heridas/fisiologíaRESUMEN
Differentially screening the Fr-PPIChem chemical library on the bromodomain and extra-terminal (BET) BRD4-BDII versus -BDI bromodomains led to the discovery of a BDII-selective tetrahydropyridothienopyrimidinone (THPTP)-based compound. Structure-activity relationship (SAR) and hit-to-lead approaches allowed us to develop CRCM5484, a potent inhibitor of BET proteins with a preferential and 475-fold selectivity for the second bromodomain of the BRD3 protein (BRD3-BDII) over its first bromodomain (BRD3-BDI). Its very low activity was demonstrated in various cell-based assays, corresponding with recent data describing other selective BDII compounds. However, screening on a drug sensitivity and resistance-profiling platform revealed its ability to modulate the anti-leukemic activity in combination with various FDA-approved and/or in-development drugs in a cell- and context-dependent differential manner. Altogether, the results confirm the originality of the THPTP molecular mode of action in the bromodomain (BD) cavity and its potential as a starting scaffold for the development of potent and selective bromodomain inhibitors.
Asunto(s)
Proteínas Nucleares , Factores de Transcripción , Proteínas de Ciclo Celular , Dominios Proteicos , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
BACKGROUND: Medulloblastoma is the most frequent brain malignancy of childhood. The current multimodal treatment comes at the expense of serious and often long-lasting side effects. Drug repurposing is a strategy to fast-track anti-cancer therapy with low toxicity. Here, we showed the ability of ß-blockers to potentiate radiotherapy in medulloblastoma with bad prognosis. METHODS: Medulloblastoma cell lines, patient-derived xenograft cells, 3D spheroids and an innovative cerebellar organotypic model were used to identify synergistic interactions between ß-blockers and ionising radiations. Gene expression profiles of ß-adrenergic receptors were analysed in medulloblastoma samples from 240 patients. Signaling pathways were explored by RT-qPCR, RNA interference, western blotting and RNA sequencing. Medulloblastoma cell bioenergetics were evaluated by measuring the oxygen consumption rate, the extracellular acidification rate and superoxide production. FINDINGS: Low concentrations of ß-blockers significantly potentiated clinically relevant radiation protocols. Although patient biopsies showed detectable expression of ß-adrenergic receptors, the ability of the repurposed drugs to potentiate ionising radiations did not result from the inhibition of the canonical signaling pathway. We highlighted that the efficacy of the combinatorial treatment relied on a metabolic catastrophe that deprives medulloblastoma cells of their adaptive bioenergetics capacities. This led to an overproduction of superoxide radicals and ultimately to an increase in ionising radiations-mediated DNA damages. INTERPRETATION: These data provide the evidence of the efficacy of ß-blockers as potentiators of radiotherapy in medulloblastoma, which may help improve the treatment and quality of life of children with high-risk brain tumours. FUNDING: This study was funded by institutional grants and charities.
Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Niño , Metabolismo Energético , Humanos , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/genética , Meduloblastoma/radioterapia , Calidad de Vida , Receptores Adrenérgicos beta/metabolismo , Receptores Adrenérgicos beta/uso terapéutico , SuperóxidosRESUMEN
Metronomic scheduling of anticancer treatment (MSAT) is progressively gaining interest after the antiangiogenic properties of metronomic chemotherapy and its potential to overcome drug resistance was initially described in 2000. MSAT has now grown beyond the anticipated scope of antiangiogenic chemotherapy, with accumulating evidence demonstrating that these treatments may also act by stimulating an antitumor immune response and could ultimately lead to reinduction of tumor dormancy. An increasing number of drugs, not initially developed as anticancer agents, are currently being used in metronomic protocols in order to increase treatment efficacy. Interestingly, these 'repositioned' agents can target cancer cells, the tumor vasculature or, more broadly, the tumor microenvironment. Malignant tumors are no longer regarded as simple congregations of cancer cells but as genuine tissues with various components such as blood vessels, fibroblasts, inflammatory cells and an extracellular matrix. These different components and their multiple interactions play a crucial role in tumor development and response to treatment. Therefore, future anticancer treatments will have to take into account the tumor microenvironment and aim to target the different cellular and molecular participants encompassed in a tumor, as well as their specific interactions. In this article, we explain why MSAT represents a very attractive strategy for developing next-generation multitarget therapies.
Asunto(s)
Antineoplásicos/administración & dosificación , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Antineoplásicos/farmacología , Biomarcadores de Tumor , Humanos , Neoplasias/metabolismo , Neoplasias/patología , Microambiente Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: Metronomic chemotherapy (MC) is defined as the frequent administration of chemotherapy at doses below the maximal tolerated dose and with no prolonged drug-free break. As off-patent chemotherapeutic drugs can be used and given the low toxicity profile of this approach, MC seems to be well adapted to low-income countries. OBJECTIVE: The aim of this study was to assess the efficacy and safety of a vincristine/cyclophosphamide/methotrexate MC regimen given to children with refractory cancer of various tumor types. METHODS: This prospective, pilot, single-center study evaluated the use of MC with a first cycle consisting of weekly vincristine (1.5 mg/m) on days 1, 8, 15, and 22, daily cyclophosphamide (25 mg/m) on days 1 to 21, and twice weekly methotrexate (15 mg/m) on days 21 to 42, followed by a 1-week break. For the following cycles, vincristine was administered only at weeks 1 and 5 of the cycle. This treatment was proposed to children with refractory cancer following treatments with the standard protocols available in our institution and to patients who were not eligible for the protocol. Adverse events were determined through laboratory analyses and investigator observations. RESULTS: From November 2008 to December 2009, 12 children (median age, 3.7 y; range, 2 to 7 y) were included. The most frequent diagnoses were Wilms tumors (6) and retinoblastoma (5). No objective response was observed, but 7 patients experienced disease stabilization (58%) and continued their treatment for 15 to 24 weeks. After a median follow-up of 39 weeks, 6 patients (50%) were alive. Most importantly, in 3 patients (25%), disease remained stable for at least 6 months after completion of treatment. One grade 4 anemia was observed in 1 patient and 1 grade 4 nonfebrile neutropenia in 1 patient. No other grade 3 or 4 toxicities were noted. CONCLUSION: The MC regimen that we report here was well tolerated and was associated with disease stabilization. Most importantly, stabilization could be maintained for over 6 additional months after completion of treatment in 3 patients. The potential of MC in children and young adults in low-income countries warrants further studies.