RESUMO
Interaction of cancer cells with their microenvironment generated by stromal cells is essential for tumor cell survival and influences the localization of tumor growth. Here we demonstrate that hedgehog ligands secreted by bone-marrow, nodal and splenic stromal cells function as survival factors for malignant lymphoma and plasmacytoma cells derived from transgenic Emu-Myc mice or isolated from humans with these malignancies. Hedgehog pathway inhibition in lymphomas induced apoptosis through downregulation of Bcl2, but was independent of p53 or Bmi1 expression. Blockage of hedgehog signaling in vivo inhibited expansion of mouse lymphoma cells in a syngeneic mouse model and reduced tumor mass in mice with fully developed disease. Our data indicate that stromally induced hedgehog signaling may provide an important survival signal for B- and plasma-cell malignancies in vitro and in vivo. Disruption of this interaction by hedgehog pathway inhibition could provide a new strategy in lymphoma and multiple myeloma therapy.
Assuntos
Proteínas Hedgehog/metabolismo , Linfoma de Células B/metabolismo , Transdução de Sinais , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Proteínas Hedgehog/genética , Humanos , Ligantes , Linfoma de Células B/genética , Linfoma de Células B/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Fenótipo , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2 , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Células Estromais/metabolismo , Taxa de Sobrevida , Transativadores/genética , Transativadores/metabolismo , Alcaloides de Veratrum/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína GLI1 em Dedos de ZincoRESUMO
Through scaffold morphing of a known Smoothened antagonist Antag691, a series of novel phenyl imidazole derivatives were developed. Structure-activity-relationship studies and lead optimization led to the discovery of potent, selective and orally bioavailable Smoothened antagonist 19 that is suitable for in vivo studies.
Assuntos
Desenho de Fármacos , Imidazóis/síntese química , Imidazóis/farmacocinética , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Área Sob a Curva , Humanos , Imidazóis/química , Imidazóis/farmacologia , Concentração Inibidora 50 , Camundongos , Ligação Proteica/efeitos dos fármacos , Ratos , Receptor Smoothened , Relação Estrutura-AtividadeRESUMO
Epigenetic dysregulation is an emerging hallmark of cancers. We developed a high-information-content mass spectrometry approach to profile global histone modifications in human cancers. When applied to 115 lines from the Cancer Cell Line Encyclopedia, this approach identified distinct molecular chromatin signatures. One signature was characterized by increased histone 3 lysine 36 (H3K36) dimethylation, exhibited by several lines harboring translocations in NSD2, which encodes a methyltransferase. A previously unknown NSD2 p.Glu1099Lys (p.E1099K) variant was identified in nontranslocated acute lymphoblastic leukemia (ALL) cell lines sharing this signature. Ectopic expression of the variant induced a chromatin signature characteristic of NSD2 hyperactivation and promoted transformation. NSD2 knockdown selectively inhibited the proliferation of NSD2-mutant lines and impaired the in vivo growth of an NSD2-mutant ALL xenograft. Sequencing analysis of >1,000 pediatric cancer genomes identified the NSD2 p.E1099K alteration in 14% of t(12;21) ETV6-RUNX1-containing ALLs. These findings identify NSD2 as a potential therapeutic target for pediatric ALL and provide a general framework for the functional annotation of cancer epigenomes.
Assuntos
Cromatina/genética , Histona-Lisina N-Metiltransferase/genética , Histonas/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Repressoras/genética , Animais , Sequência de Bases , Linhagem Celular Tumoral , Criança , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Camundongos , Camundongos SCID , Células NIH 3T3 , Transplante de Neoplasias , Análise de Sequência de DNA , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Several small molecule antagonists for Smoothened (Smo) have been developed, and achieved promising preclinical efficacy in cancers that are dependent on Hedgehog (Hh) signaling. However, in a recent clinical study, a drug-resistant D473H SMO mutant was identified that is thought to be responsible for cancer relapse in a patient with medulloblastoma. Here, we report two Smo antagonists that bind to distinct sites, as compared to known antagonists and agonists, and inhibit both wild-type and mutant Smo. These findings provide an insight of the ligand-binding sites of Smo and a basis for the development of potential therapeutics for tumors with drug-resistant Smo mutations.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Mutantes/antagonistas & inibidores , Mutação , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Camundongos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptor SmoothenedRESUMO
The blockade of aberrant hedgehog (Hh) signaling has shown promise for therapeutic intervention in cancer. A cell-based phenotypic high-throughput screen was performed, and the lead structure (1) was identified as an inhibitor of the Hh pathway via antagonism of the Smoothened receptor (Smo). Structure-activity relationship studies led to the discovery of a potent and specific Smoothened antagonist N-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)biphenyl-3-carboxamide (5m, NVP-LDE225), which is currently in clinical development.