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1.
Nat Chem Biol ; 10(11): 977-83, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25242553

RESUMO

Aberrant signaling through the Axl receptor tyrosine kinase has been associated with a myriad of human diseases, most notably metastatic cancer, identifying Axl and its ligand Gas6 as important therapeutic targets. Using rational and combinatorial approaches, we engineered an Axl 'decoy receptor' that binds Gas6 with high affinity and inhibits its function, offering an alternative approach from drug discovery efforts that directly target Axl. Four mutations within this high-affinity Axl variant caused structural alterations in side chains across the Gas6-Axl binding interface, stabilizing a conformational change on Gas6. When reformatted as an Fc fusion, the engineered decoy receptor bound Gas6 with femtomolar affinity, an 80-fold improvement compared to binding of the wild-type Axl receptor, allowing effective sequestration of Gas6 and specific abrogation of Axl signaling. Moreover, increased Gas6 binding affinity was critical and correlative with the ability of decoy receptors to potently inhibit metastasis and disease progression in vivo.


Assuntos
Engenharia Genética , Fragmentos Fc das Imunoglobulinas/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/farmacologia , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Sítios de Ligação , Progressão da Doença , Relação Dose-Resposta a Droga , Humanos , Fragmentos Fc das Imunoglobulinas/química , Fragmentos Fc das Imunoglobulinas/isolamento & purificação , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Peptídeos e Proteínas de Sinalização Intercelular/química , Camundongos , Modelos Moleculares , Mutação/genética , Metástase Neoplásica/tratamento farmacológico , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Relação Estrutura-Atividade , Receptor Tirosina Quinase Axl
2.
Nat Rev Drug Discov ; 23(3): 201-217, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38092952

RESUMO

The TAM receptor family of TYRO3, AXL and MERTK regulates tissue and immune homeostasis. Aberrant TAM receptor signalling has been linked to a range of diseases, including cancer, fibrosis and viral infections. Specifically, the dysregulation of TAM receptors can enhance tumour growth and metastasis due to their involvement in multiple oncogenic pathways. For example, TAM receptors have been implicated in the epithelial-mesenchymal transition, maintaining the stem cell phenotype, immune modulation, proliferation, angiogenesis and resistance to conventional and targeted therapies. Therapeutically, multiple TAM receptor inhibitors are in preclinical and clinical development for cancers and other indications, with those targeting AXL being the most clinically advanced. Although there has been notable clinical advancement in recent years, challenges persist. This Review aims to provide both biological and clinical insights into the current therapeutic landscape of TAM receptor inhibitors, and evaluates their potential for the treatment of cancer and non-malignant diseases.


Assuntos
Neoplasias , Receptores Proteína Tirosina Quinases , Humanos , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptor Tirosina Quinase Axl , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , c-Mer Tirosina Quinase/genética , c-Mer Tirosina Quinase/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
3.
J Exp Med ; 219(9)2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-35881112

RESUMO

Disease relapse and treatment-induced immunotoxicity pose significant clinical challenges for patients with hematological cancers. Here, we reveal distinctive requirements for neutralizing TNF receptor ligands APRIL and BAFF and their receptor activity in MM and DLBCL, impacting protein translation and production in MM cells and modulating the translation efficiency of the ATM interactor (ATMIN/ACSIZ). Therapeutically, we investigated the use of BCMA decoy receptor (sBCMA-Fc) as an inhibitor of APRIL and BAFF. While wild-type sBCMA-Fc effectively blocked APRIL signaling in MM, it lacked activity in DLBCL due to its weak BAFF binding. To expand the therapeutic utility of sBCMA-Fc, we engineered an affinity-enhanced mutant sBCMA-Fc fusion molecule (sBCMA-Fc V3) 4- and 500-fold stronger in binding to APRIL and BAFF, respectively. The mutant sBCMA-Fc V3 clone significantly enhanced antitumor activity against both MM and DLBCL. Importantly, we also demonstrated an adequate toxicity profile and on-target mechanism of action in nonhuman primate studies.


Assuntos
Linfoma Difuso de Grandes Células B , Mieloma Múltiplo , Animais , Fator Ativador de Células B/genética , Antígeno de Maturação de Linfócitos B/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/terapia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Transdução de Sinais , Proteína Transmembrana Ativadora e Interagente do CAML , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
4.
Clin Cancer Res ; 27(15): 4435-4448, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34011561

RESUMO

PURPOSE: Ovarian cancer represents a major clinical hurdle for immune checkpoint blockade (ICB), with reported low patient response rates. We found that the immune checkpoint ligand PD-L2 is robustly expressed in patient samples of ovarian cancers and other malignancies exhibiting suboptimal response to ICB but not in cancers that are ICB sensitive. Therefore, we hypothesize that PD-L2 can facilitate immune escape from ICB through incomplete blockade of the PD-1 signaling pathway. EXPERIMENTAL DESIGN: We engineered a soluble form of the PD-1 receptor (sPD-1) capable of binding and neutralizing both PD-L2 and PD-L1 with ×200 and ×10,000 folds improvement in binding affinity over wild-type PD-1 leading to superior inhibition of ligand-mediated PD-1 activities. RESULTS: Both in vitro and in vivo analyses performed in this study demonstrated that the high-affinity sPD-1 molecule is superior at blocking both PD-L1- and PD-L2-mediated immune evasion and reducing tumor growth in immune-competent murine models of ovarian cancer. CONCLUSIONS: The data presented in this study provide justification for using a dual targeting, high-affinity sPD-1 receptor as an alternative to PD-1 or PD-L1 therapeutic antibodies for achieving superior therapeutic efficacy in cancers expressing both PD-L2 and PD-L1.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Proteína 2 Ligante de Morte Celular Programada 1/antagonistas & inibidores , Animais , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Camundongos
5.
Cell Death Dis ; 11(2): 102, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029721

RESUMO

Despite the fact that Otto H. Warburg discovered the Warburg effect almost one hundred years ago, why cancer cells waste most of the glucose carbon as lactate remains an enigma. Warburg proposed a connection between the Warburg effect and cell dedifferentiation. Hypoxia is a common tumor microenvironmental stress that induces the Warburg effect and blocks tumor cell differentiation. The underlying mechanism by which this occurs is poorly understood, and no effective therapeutic strategy has been developed to overcome this resistance to differentiation. Using a neuroblastoma differentiation model, we discovered that hypoxia repressed cell differentiation through reducing cellular acetyl-CoA levels, leading to reduction of global histone acetylation and chromatin accessibility. The metabolic switch triggering this global histone hypoacetylation was the induction of pyruvate dehydrogenase kinases (PDK1 and PDK3). Inhibition of PDKs using dichloroacetate (DCA) restored acetyl-CoA generation and histone acetylation under hypoxia. Knocking down PDK1 induced neuroblastoma cell differentiation, highlighting the critical role of PDK1 in cell fate control. Importantly, acetate or glycerol triacetate (GTA) supplementation restored differentiation markers expression and neuron differentiation under hypoxia. Moreover, ATAC-Seq analysis demonstrated that hypoxia treatment significantly reduced chromatin accessibility at RAR/RXR binding sites, which can be restored by acetate supplementation. In addition, hypoxia-induced histone hypermethylation by increasing 2-hydroxyglutarate (2HG) and reducing α-ketoglutarate (αKG). αKG supplementation reduced histone hypermethylation upon hypoxia, but did not restore histone acetylation or differentiation markers expression. Together, these findings suggest that diverting pyruvate flux away from acetyl-CoA generation to lactate production is the key mechanism that Warburg effect drives dedifferentiation and tumorigenesis. We propose that combining differentiation therapy with acetate/GTA supplementation might represent an effective therapy against neuroblastoma.


Assuntos
Acetatos/farmacologia , Antineoplásicos/farmacologia , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Neuroblastoma/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Efeito Warburg em Oncologia/efeitos dos fármacos , Acetilação , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Humanos , Masculino , Camundongos , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Crescimento Neuronal/efeitos dos fármacos , Piruvato Desidrogenase Quinase de Transferência de Acetil/genética , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Hipóxia Tumoral , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cancer Res ; 79(22): 5758-5768, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31585940

RESUMO

Angiogenesis is a hallmark of cancer that promotes tumor progression and metastasis. However, antiangiogenic agents have limited efficacy in cancer therapy due to the development of resistance. In clear cell renal cell carcinoma (ccRCC), AXL expression is associated with antiangiogenic resistance and poor survival. Here, we establish a role for GAS6/AXL signaling in promoting the angiogenic potential of ccRCC cells through the regulation of the plasminogen receptor S100A10. Genetic and therapeutic inhibition of AXL signaling in ccRCC tumor xenografts reduced tumor vessel density and growth under the renal capsule. GAS6/AXL signaling activated the expression of S100A10 through SRC to promote plasmin production, endothelial cell invasion, and angiogenesis. Importantly, treatment with the small molecule AXL inhibitor cabozantinib or an ultra-high affinity soluble AXL Fc fusion decoy receptor (sAXL) reduced the growth of a pazopanib-resistant ccRCC patient-derived xenograft. Moreover, the combination of sAXL synergized with pazopanib and axitinib to reduce ccRCC patient-derived xenograft growth and vessel density. These findings highlight a role for AXL/S100A10 signaling in mediating the angiogenic potential of ccRCC cells and support the combination of AXL inhibitors with antiangiogenic agents for advanced ccRCC. SIGNIFICANCE: These findings show that angiogenesis in renal cell carcinoma (RCC) is regulated through AXL/S100A10 signaling and support the combination of AXL inhibitors with antiangiogenic agents for the treatment of RCC.


Assuntos
Anexina A2/metabolismo , Carcinoma de Células Renais/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Renais/metabolismo , Neovascularização Patológica/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas S100/metabolismo , Animais , Carcinoma de Células Renais/patologia , Linhagem Celular , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Rim/metabolismo , Rim/patologia , Neoplasias Renais/patologia , Camundongos , Camundongos Knockout , Neovascularização Patológica/patologia , Transdução de Sinais/fisiologia , Receptor Tirosina Quinase Axl
7.
J Clin Invest ; 127(1): 183-198, 2017 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-27893463

RESUMO

The AXL receptor and its activating ligand, growth arrest-specific 6 (GAS6), are important drivers of metastasis and therapeutic resistance in human cancers. Given the critical roles that GAS6 and AXL play in refractory disease, this signaling axis represents an attractive target for therapeutic intervention. However, the strong picomolar binding affinity between GAS6 and AXL and the promiscuity of small molecule inhibitors represent important challenges faced by current anti-AXL therapeutics. Here, we have addressed these obstacles by engineering a second-generation, high-affinity AXL decoy receptor with an apparent affinity of 93 femtomolar to GAS6. Our decoy receptor, MYD1-72, profoundly inhibited disease progression in aggressive preclinical models of human cancers and induced cell killing in leukemia cells. When directly compared with the most advanced anti-AXL small molecules in the clinic, MYD1-72 achieved superior antitumor efficacy while displaying no toxicity. Moreover, we uncovered a relationship between AXL and the cellular response to DNA damage whereby abrogation of AXL signaling leads to accumulation of the DNA-damage markers γH2AX, 53BP1, and RAD51. MYD1-72 exploited this relationship, leading to improvements upon the therapeutic index of current standard-of-care chemotherapies in preclinical models of advanced pancreatic and ovarian cancer.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Leucemia/tratamento farmacológico , Neoplasias Experimentais/tratamento farmacológico , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Histonas/genética , Histonas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Leucemia/metabolismo , Camundongos , Camundongos Nus , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Receptor Tirosina Quinase Axl
8.
Sci Transl Med ; 6(236): 236ra64, 2014 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-24828078

RESUMO

Radiation-induced gastrointestinal (GI) toxicity can be a major source of morbidity and mortality after radiation exposure. There is an unmet need for effective preventative or mitigative treatments against the potentially fatal diarrhea and water loss induced by radiation damage to the GI tract. We report that prolyl hydroxylase inhibition by genetic knockout or pharmacologic inhibition of all PHD (prolyl hydroxylase domain) isoforms by the small-molecule dimethyloxallyl glycine (DMOG) increases hypoxia-inducible factor (HIF) expression, improves epithelial integrity, reduces apoptosis, and increases intestinal angiogenesis, all of which are essential for radioprotection. HIF2, but not HIF1, is both necessary and sufficient to prevent radiation-induced GI toxicity and death. Increased vascular endothelial growth factor (VEGF) expression contributes to the protective effects of HIF2, because inhibition of VEGF function reversed the radioprotection and radiomitigation afforded by DMOG. Additionally, mortality from abdominal or total body irradiation was reduced even when DMOG was given 24 hours after exposure. Thus, prolyl hydroxylase inhibition represents a treatment strategy to protect against and mitigate GI toxicity from both therapeutic radiation and potentially lethal radiation exposures.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Lesões por Radiação/tratamento farmacológico , Aminoácidos Dicarboxílicos/química , Animais , Apoptose , Peso Corporal , Linhagem Celular Tumoral , Quelantes/química , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/efeitos da radiação , Regulação da Expressão Gênica , Hematócrito , Heterozigoto , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos , Camundongos Knockout , Inibidores de Prolil-Hidrolase/química , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Estrutura Terciária de Proteína , Lesões por Radiação/prevenção & controle , Fator A de Crescimento do Endotélio Vascular/química
9.
Clin Cancer Res ; 19(8): 2107-16, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-23470966

RESUMO

PURPOSE: The major cause of morbidity in breast cancer is development of metastatic disease, for which few effective therapies exist. Because tumor cell dissemination is often an early event in breast cancer progression and can occur before diagnosis, new therapies need to focus on targeting established metastatic disease in secondary organs. We report an effective therapy based on targeting cell surface-localized glucose-regulated protein 78 (GRP78). GRP78 is expressed normally in the endoplasmic reticulum, but many tumors and disseminated tumor cells are subjected to environmental stresses and exhibit elevated levels of GRP78, some of which are localized at the plasma membrane. EXPERIMENTAL DESIGN AND RESULTS: Here, we show that matched primary tumors and metastases from patients who died from advanced breast cancer also express high levels of GRP78. We used a peptidomimetic targeting strategy that uses a known GRP78-binding peptide fused to a proapoptotic moiety [designated bone metastasis targeting peptide 78 (BMTP78)] and show that it can selectively kill breast cancer cells that express surface-localized GRP78. Furthermore, in preclinical metastasis models, we show that administration of BMTP78 can inhibit primary tumor growth as well as prolong overall survival by reducing the extent of outgrowth of established lung and bone micrometastases. CONCLUSIONS: The data presented here provide strong evidence that it is possible to induce cell death in established micrometastases by peptide-mediated targeting of cell surface-localized GRP in advanced breast cancers. The significance to patients with advanced breast cancer of a therapy that can reduce established metastatic disease should not be underestimated.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Proteínas de Choque Térmico/metabolismo , Micrometástase de Neoplasia/prevenção & controle , Peptídeos/farmacologia , Sequência de Aminoácidos , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Chaperona BiP do Retículo Endoplasmático , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Dados de Sequência Molecular , Peptídeos/administração & dosagem , Peptídeos/metabolismo , Ligação Proteica , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Proc Natl Acad Sci U S A ; 104(34): 13762-7, 2007 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-17690249

RESUMO

MYB (the human ortholog of c-myb) is expressed in a high proportion of human breast tumors, and that expression correlates strongly with estrogen receptor (ER) positivity. This may reflect the fact that MYB is a target of estrogen/ER signaling. Because in many cases MYB expression appears to be regulated by transcriptional attenuation or pausing in the first intron, we first investigated whether this mechanism was involved in estrogen/ER modulation of MYB. We found that this was the case and that estrogen acted directly to relieve attenuation due to sequences within the first intron, specifically, a region potentially capable of forming a stem-loop structure in the transcript and an adjacent poly(dT) tract. Secondly, given the involvement of MYB in hematopoietic and colon tumors, we also asked whether MYB was required for the proliferation of breast cancer cells. We found that proliferation of ER(+) but not ER(-) breast cancer cell lines was inhibited when MYB expression was suppressed by using either antisense oligonucleotides or RNA interference. Our results show that MYB is an effector of estrogen/ER signaling and provide demonstration of a functional role of MYB in breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Estrogênios/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myb/metabolismo , Receptores de Estrogênio/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Genes Reporter/genética , Humanos , Proteínas Proto-Oncogênicas c-myb/genética , Interferência de RNA , RNA Mensageiro/genética , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/genética
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