Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 44
Filtrar
1.
Molecules ; 27(23)2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36500607

RESUMO

BRAF is a serine/threonine kinase frequently mutated in human cancers. BRAFV600E mutated protein is targeted through the use of kinase inhibitors which are approved for the treatment of melanoma; however, their long-term efficacy is hampered by resistance mechanisms. The PROTAC-induced degradation of BRAFV600E has been proposed as an alternative strategy to avoid the onset of resistance. In this study, we designed a series of compounds where the BRAF kinase inhibitor encorafenib was conjugated to pomalidomide through different linkers. The synthesized compounds maintained their ability to inhibit the kinase activity of mutated BRAF with IC50 values in the 40-88 nM range. Selected compounds inhibited BRAFV600E signaling and cellular proliferation of A375 and Colo205 tumor cell lines. Compounds 10 and 11, the most active of the series, were not able to induce degradation of mutated BRAF. Docking and molecular dynamic studies, conducted in comparison with the efficient BRAF degrader P5B, suggest that a different orientation of the linker bearing the pomalidomide substructure, together with a decreased mobility of the solvent-exposed part of the conjugates, could explain this behavior.


Assuntos
Quimera de Direcionamento de Proteólise , Proteínas Proto-Oncogênicas B-raf , Humanos , Sulfonamidas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Mutação
2.
Cancers (Basel) ; 14(15)2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35954355

RESUMO

Cancer is a complex disease arising from a homeostatic imbalance of cell-intrinsic and microenvironment-related mechanisms. A multimodal approach to treat cancer that includes surgery, chemotherapy, and radiation therapy often fails in achieving tumor remission and produces unbearable side effects including secondary malignancies. Novel strategies have been implemented in the past decades in order to replace conventional chemotherapeutics with targeted, less toxic drugs. Up to now, scientists have relied on results achieved in animal research before proceeding to clinical trials. However, the high failure rate of targeted drugs in early phase trials leaves no doubt about the inadequacy of those models. In compliance with the need of reducing, and possibly replacing, animal research, studies have been conducted in vitro with advanced cellular models that more and more mimic the tumor in vivo. We will here review those methods that allow for the 3D reconstitution of the tumor and its microenvironment and the implementation of the organ-on-a-chip technology to study minimal organ units in disease progression. We will make specific reference to the usability of these systems as predictive cancer models and report on recent applications in high-throughput screenings of innovative and targeted drug compounds.

3.
Cancers (Basel) ; 14(10)2022 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-35626078

RESUMO

Malignant tumors originate from a combination of genetic alterations, which induce activation of oncogenes and inactivation of oncosuppressor genes, ultimately resulting in uncontrolled growth and neoplastic transformation. Chemotherapy prevents the abnormal proliferation of cancer cells, but it also affects the entire cellular network in the human body with heavy side effects. For this reason, the ultimate aim of cancer therapy remains to selectively kill cancer cells while sparing their normal counterparts. Nanoparticle formulations have the potential to achieve this aim by providing optimized drug delivery to a pathological site with minimal accumulation in healthy tissues. In this review, we will first describe the characteristics of recently developed nanoparticles and how their physical properties and targeting functionalization are exploited depending on their therapeutic payload, route of delivery, and tumor type. Second, we will analyze how nanoparticles can overcome multidrug resistance based on their ability to combine different therapies and targeting moieties within a single formulation. Finally, we will discuss how the implementation of these strategies has led to the generation of nanoparticle-based cancer vaccines as cutting-edge instruments for cancer immunotherapy.

4.
Front Oncol ; 12: 771418, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35251961

RESUMO

The treatment of unresectable cholangiocarcinoma (CCA) is limited by the development of resistance to conventional first-line chemotherapy based on gemcitabine (GEM). In addition, a prior treatment with GEM frequently induces cross-resistance to other drugs employed in the second-line. Paclitaxel (PTX) is now emerging as an alternative option for the management of advanced/metastatic CCA. In the present work, we evaluate the antitumor activity of PTX in preclinical models of multidrug-resistant intrahepatic cholangiocarcinoma (iCCA). In vitro, PTX decreases tumor cell viability by affecting the cell cycle and inducing apoptosis and impairs the stem cell compartment. In vivo, a therapeutic regimen containing albumin-bound nanoparticle (Nab)-PTX overcomes drug resistance resulting in delayed tumor growth, impaired organization of the tumor vasculature, and reduced glucose uptake. Together, our results provide a rationale to consider PTX-based regimens in patients with iCCA who became refractory to conventional therapies.

5.
Pharmaceuticals (Basel) ; 14(2)2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33671476

RESUMO

Evolution of nanomedicine is the re-design of synthetic and biological carriers to implement novel theranostic platforms. In recent years, bacteriophage research favors this process, which has opened up new roads in drug and gene delivery studies. By displaying antibodies, peptides, or proteins on the surface of different bacteriophages through the phage display technique, it is now possible to unravel specific molecular determinants of both cancer cells and tumor-associated microenvironmental molecules. Downstream applications are manifold, with peptides being employed most of the times to functionalize drug carriers and improve their therapeutic index. Bacteriophages themselves were proven, in this scenario, to be good carriers for imaging molecules and therapeutics as well. Moreover, manipulation of their genetic material to stably vehiculate suicide genes within cancer cells substantially changed perspectives in gene therapy. In this review, we provide examples of how amenable phages can be used as anticancer agents, especially because their systemic administration is possible. We also provide some insights into how their immunogenic profile can be modulated and exploited in immuno-oncology for vaccine production.

6.
Molecules ; 25(4)2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32075083

RESUMO

Phage display is a nanotechnology with limitless potential, first developed in 1985 and still awaiting to reach its peak. Awarded in 2018 with the Nobel Prize for Chemistry, the method allows the isolation of high-affinity ligands for diverse substrates, ranging from recombinant proteins to cells, organs, even whole organisms. Personalized therapeutic approaches, particularly in oncology, depend on the identification of new, unique, and functional targets that phage display, through its various declinations, can certainly provide. A fast-evolving branch in cancer research, immunotherapy is now experiencing a second youth after being overlooked for years; indeed, many reports support the concept of immunotherapy as the only non-surgical cure for cancer, at least in some settings. In this review, we describe literature reports on the application of peptide phage display to cancer immunotherapy. In particular, we discuss three main outcomes of this procedure: (i) phage display-derived peptides that mimic cancer antigens (mimotopes) and (ii) antigen-carrying phage particles, both as prophylactic and/or therapeutic vaccines, and (iii) phage display-derived peptides as small-molecule effectors of immune cell functions. Preclinical studies demonstrate the efficacy and vast potential of these nanosized tools, and their clinical application is on the way.


Assuntos
Antígenos de Neoplasias/imunologia , Técnicas de Visualização da Superfície Celular/métodos , Neoplasias/terapia , Biblioteca de Peptídeos , Antígenos de Neoplasias/uso terapêutico , Humanos , Fatores Imunológicos/imunologia , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Ligantes , Nanotecnologia/tendências , Neoplasias/imunologia
7.
J Immunol ; 202(4): 1079-1087, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30635394

RESUMO

An unbalance between Abs that recognize an autoantigen (idiotypes; IDs) and Igs that bind such Abs (anti-IDs) is considered a functional event in autoimmune disorders. We investigated the presence of an ID/anti-ID network in celiac disease (CD), a condition in which antitissue transglutaminase 2 (TG2) Abs are suspected to contribute to CD pathogenesis. To characterize the ID side, we reproduced by in vitro yeast display the intestine-resident Abs from CD and control patients. These TG2-specific IDs were used to identify potential anti-IDs in the serum. We observed elevated titers of anti-IDs in asymptomatic patients with predisposition to CD and demonstrated that anti-ID depletion from the serum restores a detectable humoral response against TG2. Our study provides an alternative approach to quantify CD-related autoantibodies in cases that would be defined "negative serology" with current diagnostic applications. Therefore, we suggest that developments of this technology could be designed for perspective routine tests.


Assuntos
Anticorpos Anti-Idiotípicos/imunologia , Autoanticorpos/imunologia , Doença Celíaca/imunologia , Glutens/genética , Idiótipos de Imunoglobulinas/imunologia , Intestinos/imunologia , Adolescente , Adulto , Autoanticorpos/sangue , Doença Celíaca/genética , Criança , Pré-Escolar , Feminino , Proteínas de Ligação ao GTP/imunologia , Proteínas de Ligação ao GTP/metabolismo , Glutens/imunologia , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Intestinos/patologia , Masculino , Pessoa de Meia-Idade , Proteína 2 Glutamina gama-Glutamiltransferase , Transglutaminases/imunologia , Transglutaminases/metabolismo , Adulto Jovem
8.
JAMA Neurol ; 76(4): 492-500, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30476961

RESUMO

Importance: Cerebral cavernous malformations (CCMs) are vascular lesions of the brain that may lead to hemorrhage, seizures, and neurologic deficits. Most are linked to loss-of-function mutations in 1 of 3 genes, namely CCM1 (originally called KRIT1), CCM2 (MGC4607), or CCM3 (PDCD10), that can either occur as sporadic events or are inherited in an autosomal dominant pattern with incomplete penetrance. Familial forms originate from germline mutations, often have multiple intracranial lesions that grow in size and number over time, and cause an earlier and more severe presentation. Despite active preclinical research on a few pharmacologic agents, clinical translation has been slow. Open surgery and, in some cases, stereotactic radiosurgery remain the only effective treatments, but these options are limited by lesion accessibility and are associated with nonnegligible rates of morbidity and mortality. Observations: We discuss the limits of CCM management and introduce findings from in vitro and in vivo studies that provide insight into CCM pathogenesis and indicate molecular mechanisms as potential therapeutic targets. These studies report dysregulated cellular pathways shared between CCM, cardiovascular diseases, and cancer. They also suggest the potential effectiveness of proper drug repurposing in association with, or as an alternative to, targeted interventions. Conclusions and Relevance: We propose methods to exploit specific molecular pathways to design patient-tailored therapeutic approaches in CCM, with the aim to alter its natural progression. In this scenario, the lack of effective pharmacologic options remains a critical barrier that poses an unfulfilled and urgent medical need.


Assuntos
Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Hemangioma Cavernoso do Sistema Nervoso Central/tratamento farmacológico , Animais , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/fisiopatologia , Hemangioma Cavernoso do Sistema Nervoso Central/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Hemangioma Cavernoso do Sistema Nervoso Central/fisiopatologia , Humanos
9.
JCI Insight ; 3(24)2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30568038

RESUMO

The 78-kDa glucose-regulated protein (GRP78) is an ER molecular chaperone that aids in protein folding and secretion. However, pathological conditions that cause ER stress can promote the relocalization of GRP78 to the cell surface (csGRP78), where it acts as a signaling receptor to promote cancer progression. csGRP78 also possesses antigenic properties, leading to the production of anti-GRP78 autoantibodies, which contribute to tumor growth. In contrast, the presence and role of anti-GRP78 autoantibodies in atherosclerosis is unknown. Here, we show that atherosclerotic-prone ApoE-/- mice develop circulating anti-GRP78 autoantibodies that bind to csGRP78 on lesion-resident endothelial cells. Moreover, GRP78-immunized ApoE-/- mice exhibit a marked increase in circulating anti-GRP78 autoantibody titers that correlated with accelerated lesion growth. Mechanistically, engagement of anti-GRP78 autoantibodies with csGRP78 on human endothelial cells activated NF-κB, thereby inducing the expression of ICAM-1 and VCAM-1, a process blocked by NF-κB inhibitors. Disrupting the autoantibody/csGRP78 complex with enoxaparin, a low-molecular-weight heparin, reduced the expression of adhesion molecules and attenuated lesion growth. In conclusion, anti-GRP78 autoantibodies play a crucial role in atherosclerosis development, and disruption of the interaction between anti-GRP78 autoantibodies and csGRP78 represents a therapeutic strategy.


Assuntos
Aterosclerose/metabolismo , Autoanticorpos/metabolismo , Células Endoteliais/metabolismo , Proteínas de Choque Térmico/metabolismo , Animais , Aterosclerose/patologia , Autoimunidade/fisiologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Chaperona BiP do Retículo Endoplasmático , Feminino , Proteínas de Choque Térmico/genética , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , NF-kappa B/metabolismo , Deficiências na Proteostase , RNA Mensageiro/metabolismo , Transdução de Sinais , Molécula 1 de Adesão de Célula Vascular/metabolismo
10.
J Biol Chem ; 292(51): 21180-21192, 2017 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-29066620

RESUMO

Tumor cells display on their surface several molecular chaperones that normally reside in the endoplasmic reticulum. Because this display is unique to cancer cells, these chaperones are attractive targets for drug development. Previous epitope-mapping of autoantibodies (AutoAbs) from prostate cancer patients identified the 78-kDa glucose-regulated protein (GRP78) as one such target. Although we previously showed that anti-GRP78 AutoAbs increase tissue factor (TF) procoagulant activity on the surface of tumor cells, the direct effect of TF activation on tumor growth was not examined. In this study, we explore the interplay between the AutoAbs against cell surface-associated GRP78, TF expression/activity, and prostate cancer progression. First, we show that tumor GRP78 expression correlates with disease stage and that anti-GRP78 AutoAb levels parallel prostate-specific antigen concentrations in patient-derived serum samples. Second, we demonstrate that these anti-GRP78 AutoAbs target cell-surface GRP78, activating the unfolded protein response and inducing tumor cell proliferation through a TF-dependent mechanism, a specific effect reversed by neutralization or immunodepletion of the AutoAb pool. Finally, these AutoAbs enhance tumor growth in mice bearing human prostate cancer xenografts, and heparin derivatives specifically abrogate this effect by blocking AutoAb binding to cell-surface GRP78 and decreasing TF expression/activity. Together, these results establish a molecular mechanism in which AutoAbs against cell-surface GRP78 drive TF-mediated tumor progression in an experimental model of prostate cancer. Heparin derivatives counteract this mechanism and, as such, represent potentially appealing compounds to be evaluated in well-designed translational clinical trials.


Assuntos
Autoanticorpos/metabolismo , Membrana Celular/metabolismo , Proteínas de Choque Térmico/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Tromboplastina/agonistas , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Autoanticorpos/análise , Autoanticorpos/toxicidade , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/imunologia , Membrana Celular/patologia , Proliferação de Células/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/uso terapêutico , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Gradação de Tumores , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/uso terapêutico , Estadiamento de Neoplasias , Próstata/efeitos dos fármacos , Próstata/imunologia , Próstata/patologia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Distribuição Aleatória , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapêutico , Propriedades de Superfície , Tromboplastina/análise , Tromboplastina/metabolismo , Carga Tumoral/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Proc Natl Acad Sci U S A ; 114(30): 8065-8070, 2017 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-28698375

RESUMO

Osteosarcoma occurs predominantly in children and young adults. High-grade tumors require multidisciplinary treatment consisting of chemotherapy in the neoadjuvant and adjuvant settings, along with surgical intervention. Despite this approach, death from respiratory failure secondary to the development and progression of pulmonary metastases remains a significant problem. Here, we identify the IL-11 receptor α subunit (IL-11Rα) as a cell surface marker of tumor progression that correlates with poor prognosis in patients with osteosarcoma. We also show that both IL-11Rα and its ligand, IL-11, are specifically up-regulated in human metastatic osteosarcoma cell lines; engagement of this autocrine loop leads to tumor cell proliferation, invasion, and anchorage-independent growth in vitro. Consistently, IL-11Rα promotes lung colonization by human metastatic osteosarcoma cells in vivo in an orthotopic mouse model. Finally, we evaluate the IL-11Rα-targeted proapoptotic agent bone metastasis-targeting peptidomimetic (BMTP-11) in preclinical models of primary intratibial osteosarcomas, observing marked inhibition of both tumor growth and lung metastases. This effect was enhanced when BMTP-11 was combined with the chemotherapeutic drug gemcitabine. Our combined data support the development of approaches targeting IL-11Rα, and establish BMTP-11 as a leading drug candidate for clinical translation in patients with high-risk osteosarcoma.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Subunidade alfa de Receptor de Interleucina-11/antagonistas & inibidores , Osteossarcoma/tratamento farmacológico , Peptídeos/uso terapêutico , Animais , Comunicação Autócrina , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Masculino , Camundongos Nus , Metástase Neoplásica , Osteossarcoma/metabolismo , Peptídeos/farmacologia , Pesquisa Translacional Biomédica
13.
Sci Rep ; 7(1): 4243, 2017 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-28652618

RESUMO

Cytoskeletal-associated proteins play an active role in coordinating the adhesion and migration machinery in cancer progression. To identify functional protein networks and potential inhibitors, we screened an internalizing phage (iPhage) display library in tumor cells, and selected LGRFYAASG as a cytosol-targeting peptide. By affinity purification and mass spectrometry, intracellular annexin A2 was identified as the corresponding binding protein. Consistently, annexin A2 and a cell-internalizing, penetratin-fused version of the selected peptide (LGRFYAASG-pen) co-localized and specifically accumulated in the cytoplasm at the cell edges and cell-cell contacts. Functionally, tumor cells incubated with LGRFYAASG-pen showed disruption of filamentous actin, focal adhesions and caveolae-mediated membrane trafficking, resulting in impaired cell adhesion and migration in vitro. These effects were paralleled by a decrease in the phosphorylation of both focal adhesion kinase (Fak) and protein kinase B (Akt). Likewise, tumor cells pretreated with LGRFYAASG-pen exhibited an impaired capacity to colonize the lungs in vivo in several mouse models. Together, our findings demonstrate an unrecognized functional link between intracellular annexin A2 and tumor cell adhesion, migration and in vivo grafting. Moreover, this work uncovers a new peptide motif that binds to and inhibits intracellular annexin A2 as a candidate therapeutic lead for potential translation into clinical applications.


Assuntos
Anexina A2/genética , Proteína-Tirosina Quinases de Adesão Focal/genética , Neoplasias/genética , Proteínas Proto-Oncogênicas c-akt/genética , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/metabolismo , Animais , Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Citosol/efeitos dos fármacos , Citosol/metabolismo , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Neoplasias/patologia , Biblioteca de Peptídeos , Peptídeos/farmacologia , Fosforilação , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Cancer Res ; 77(12): 3144-3150, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28428279

RESUMO

Human prostate cancer often metastasizes to bone, but the biological basis for such site-specific tropism remains largely unresolved. Recent work led us to hypothesize that this tropism may reflect pathogenic interactions between RAGE, a cell surface receptor expressed on malignant cells in advanced prostate cancer, and proteinase 3 (PR3), a serine protease present in inflammatory neutrophils and hematopoietic cells within the bone marrow microenvironment. In this study, we establish that RAGE-PR3 interaction mediates homing of prostate cancer cells to the bone marrow. PR3 bound to RAGE on the surface of prostate cancer cells in vitro, inducing tumor cell motility through a nonproteolytic signal transduction cascade involving activation and phosphorylation of ERK1/2 and JNK1. In preclinical models of experimental metastasis, ectopic expression of RAGE on human prostate cancer cells was sufficient to promote bone marrow homing within a short timeframe. Our findings demonstrate how RAGE-PR3 interactions between human prostate cancer cells and the bone marrow microenvironment mediate bone metastasis during prostate cancer progression, with potential implications for prognosis and therapeutic intervention. Cancer Res; 77(12); 3144-50. ©2017 AACR.


Assuntos
Antígenos de Neoplasias/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mieloblastina/metabolismo , Invasividade Neoplásica/patologia , Neoplasias da Próstata/patologia , Microambiente Tumoral/fisiologia , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Neoplasias Ósseas/secundário , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Xenoenxertos , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias da Próstata/metabolismo
16.
Proc Natl Acad Sci U S A ; 113(45): 12780-12785, 2016 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-27791177

RESUMO

Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging and tumor treatment by selective activation of the prodrug ganciclovir at tumor sites. Translation of this AAVP system is expected simultaneously to image, monitor, and treat the IBC phenotype and possibly other aggressive (e.g., invasive and/or metastatic) subtypes of breast cancer, based on the inducible cell-surface expression of the stress-response chaperone GRP78, and possibily other cell-surface receptors in human tumors.

17.
Proc Natl Acad Sci U S A ; 113(45): 12786-12791, 2016 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-27791181

RESUMO

Aggressive variant prostate cancers (AVPC) are a clinically defined group of tumors of heterogeneous morphologies, characterized by poor patient survival and for which limited diagnostic and treatment options are currently available. We show that the cell surface 78-kDa glucose-regulated protein (GRP78), a receptor that binds to phage-display-selected ligands, such as the SNTRVAP motif, is a candidate target in AVPC. We report the presence and accessibility of this receptor in clinical specimens from index patients. We also demonstrate that human AVPC cells displaying GRP78 on their surface could be effectively targeted both in vitro and in vivo by SNTRVAP, which also enabled specific delivery of siRNA species to tumor xenografts in mice. Finally, we evaluated ligand-directed strategies based on SNTRVAP-displaying adeno-associated virus/phage (AAVP) particles in mice bearing MDA-PCa-118b, a patient-derived xenograft (PDX) of castration-resistant prostate cancer bone metastasis that we exploited as a model of AVPC. For theranostic (a merging of the terms therapeutic and diagnostic) studies, GRP78-targeting AAVP particles served to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) gene, which has a dual function as a molecular-genetic sensor/reporter and a cell suicide-inducing transgene. We observed specific and simultaneous PET imaging and treatment of tumors in this preclinical model of AVPC. Our findings demonstrate the feasibility of GPR78-targeting, ligand-directed theranostics for translational applications in AVPC.

18.
Am J Pathol ; 186(8): 2162-2170, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27317903

RESUMO

We previously isolated an IL-11-mimic motif (CGRRAGGSC) that binds to IL-11 receptor (IL-11R) in vitro and accumulates in IL-11R-expressing tumors in vivo. This synthetic peptide ligand was used as a tumor-targeting moiety in the rational design of BMTP-11, which is a drug candidate in clinical trials. Here, we investigated the specificity and accessibility of IL-11R as a target and the efficacy of BMTP-11 as a ligand-targeted drug in lung cancer. We observed high IL-11R expression levels in a large cohort of patients (n = 368). In matching surgical specimens (i.e., paired tumors and nonmalignant tissues), the cytoplasmic levels of IL-11R in tumor areas were significantly higher than in nonmalignant tissues (n = 36; P = 0.003). Notably, marked overexpression of IL-11R was observed in both tumor epithelial and vascular endothelial cell membranes (n = 301; P < 0.0001). BMTP-11 induced in vitro cell death in a representative panel of human lung cancer cell lines. BMTP-11 treatment attenuated the growth of subcutaneous xenografts and reduced the number of pulmonary tumors after tail vein injection of human lung cancer cells in mice. Our findings validate BMTP-11 as a pharmacologic candidate drug in preclinical models of lung cancer and patient-derived tumors. Moreover, the high expression level in patients with non-small cell lung cancer is a promising feature for potential translational applications.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/análise , Carcinoma/patologia , Neoplasias Pulmonares/patologia , Peptídeos/farmacologia , Receptores de Interleucina-11/biossíntese , Animais , Apoptose/efeitos dos fármacos , Carcinoma/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estudos Retrospectivos , Análise Serial de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Clin Cancer Res ; 22(19): 4923-4933, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27143691

RESUMO

PURPOSE: KRAS mutations confer adverse prognosis to colorectal cancer, and no targeted therapies have shown efficacy in this patient subset. Paracrine, nongenetic events induced by KRAS-mutant tumor cells are expected to result in specific deregulation and/or relocation of tumor microenvironment (TME) proteins, which in principle can be exploited as alternative therapeutic targets. EXPERIMENTAL DESIGN: A multimodal strategy combining ex vivo/in vitro phage display screens with deep-sequencing and bioinformatics was applied to uncover TME-specific targets in KRAS-mutant hepatic metastasis from colorectal cancer. Expression and localization of BCAM and LAMA5 were validated by immunohistochemistry in preclinical models of human hepatic metastasis and in a panel of human specimens (n = 71). The antimetastatic efficacy of two BCAM-mimic peptides was evaluated in mouse models. The role of BCAM in the interaction of KRAS-mutant colorectal cancer cells with TME cells was investigated by adhesion assays. RESULTS: BCAM and LAMA5 were identified as molecular targets within both tumor cells and TME of KRAS-mutant hepatic metastasis from colorectal cancer, where they were specifically overexpressed. Two BCAM-mimic peptides inhibited KRAS-mutant hepatic metastasis in preclinical models. Genetic suppression and biochemical inhibition of either BCAM or LAMA5 impaired adhesion of KRAS-mutant colorectal cancer cells specifically to endothelial cells, whereas adhesion to pericytes and hepatocytes was unaffected. CONCLUSIONS: These data show that the BCAM/LAMA5 system plays a functional role in the metastatic spreading of KRAS-mutant colorectal cancer by mediating tumor-TME interactions and as such represents a valuable therapeutic candidate for this large, currently untreatable patient group. Clin Cancer Res; 22(19); 4923-33. ©2016 AACR.


Assuntos
Moléculas de Adesão Celular/metabolismo , Neoplasias Colorretais/patologia , Laminina/metabolismo , Neoplasias Hepáticas/secundário , Sistema do Grupo Sanguíneo Lutheran/metabolismo , Invasividade Neoplásica/genética , Animais , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Endotélio Vascular/patologia , Xenoenxertos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Nus , Comunicação Parácrina/fisiologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Microambiente Tumoral/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA