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1.
Blood ; 137(6): 788-800, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32785655

RESUMO

MALT1 inhibitors are promising therapeutic agents for B-cell lymphomas that are dependent on constitutive or aberrant signaling pathways. However, a potential limitation for signal transduction-targeted therapies is the occurrence of feedback mechanisms that enable escape from the full impact of such drugs. Here, we used a functional genomics screen in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) cells treated with a small molecule irreversible inhibitor of MALT1 to identify genes that might confer resistance or enhance the activity of MALT1 inhibition (MALT1i). We find that loss of B-cell receptor (BCR)- and phosphatidylinositol 3-kinase (PI3K)-activating proteins enhanced sensitivity, whereas loss of negative regulators of these pathways (eg, TRAF2, TNFAIP3) promoted resistance. These findings were validated by knockdown of individual genes and a combinatorial drug screen focused on BCR and PI3K pathway-targeting drugs. Among these, the most potent combinatorial effect was observed with PI3Kδ inhibitors against ABC-DLBCLs in vitro and in vivo, but that led to an adaptive increase in phosphorylated S6 and eventual disease progression. Along these lines, MALT1i promoted increased MTORC1 activity and phosphorylation of S6K1-T389 and S6-S235/6, an effect that was only partially blocked by PI3Kδ inhibition in vitro and in vivo. In contrast, simultaneous inhibition of MALT1 and MTORC1 prevented S6 phosphorylation, yielded potent activity against DLBCL cell lines and primary patient specimens, and resulted in more profound tumor regression and significantly improved survival of ABC-DLBCLs in vivo compared with PI3K inhibitors. These findings provide a basis for maximal therapeutic impact of MALT1 inhibitors in the clinic, by disrupting feedback mechanisms that might otherwise limit their efficacy.


Assuntos
Antineoplásicos/uso terapêutico , Retroalimentação Fisiológica/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Receptores de Antígenos de Linfócitos B/imunologia , Receptores Toll-Like/imunologia , Animais , Antineoplásicos/farmacologia , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/fisiologia , Proteínas de Neoplasias/fisiologia , Organoides/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , RNA Interferente Pequeno/genética , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Dev Cell ; 57(2): 228-245.e6, 2022 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-35016014

RESUMO

Although overwhelming plasma membrane integrity loss leads to cell lysis and necrosis, cells can tolerate a limited level of plasma membrane damage, undergo ESCRT-III-mediated repair, and survive. Here, we find that cells which undergo limited plasma membrane damage from the pore-forming actions of MLKL, GSDMD, perforin, or detergents experience local activation of PKCs through Ca2+ influx at the damage sites. S660-phosphorylated PKCs subsequently activate the TAK1/IKKs axis and RelA/Cux1 complex to trigger chemokine expressions. We observe that in late-stage cancers, cells with active MLKL show expression of CXCL8. Similar expression induction is also found in ischemia-injured kidneys. Chemokines generated in this manner are also indispensable for recruiting immune cells to the dead and dying cells. This plasma membrane integrity-sensing pathway is similar to the well-established yeast cell wall integrity signaling pathway at molecular level, and this suggests an evolutionary conserved mechanism to respond to the cellular barrier damage.


Assuntos
Membrana Celular/metabolismo , Quimiocinas/fisiologia , Proteína Quinase C/fisiologia , Animais , Apoptose/fisiologia , Membrana Celular/fisiologia , Quimiocinas/genética , Quimiocinas/imunologia , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Necrose/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Fosforilação , Proteína Quinase C/metabolismo , Proteínas Quinases/metabolismo , Proteínas Quinases/fisiologia , Transdução de Sinais
3.
Sci Adv ; 8(7): eabl6083, 2022 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-35171671

RESUMO

Although DNA damage is intricately linked to metabolism, the metabolic alterations that occur in response to DNA damage are not well understood. We use a DNA repair-deficient model of ERCC1-XPF in Caenorhabditis elegans to gain insights on how genotoxic stress drives aging. Using multi-omic approach, we discover that nuclear DNA damage promotes mitochondrial ß-oxidation and drives a global loss of fat depots. This metabolic shift to ß-oxidation generates acetyl-coenzyme A to promote histone hyperacetylation and an associated change in expression of immune-effector and cytochrome genes. We identify the histone acetyltransferase MYS-1, as a critical regulator of this metabolic-epigenetic axis. We show that in response to DNA damage, polyunsaturated fatty acids, especially arachidonic acid (AA) and AA-related lipid mediators, are elevated and this is dependent on mys-1. Together, these findings reveal that DNA damage alters the metabolic-epigenetic axis to drive an immune-like response that can promote age-associated decline.


Assuntos
Reparo do DNA , Histonas , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Dano ao DNA , Histonas/metabolismo , Metabolismo dos Lipídeos
4.
Mol Cancer Ther ; 21(6): 999-1009, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35405743

RESUMO

One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model for human CAR T-cell therapy. Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3-specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3. After refining activation, transduction, and expansion methods, we confirmed target killing in a tumor spheroid three-dimensional assay. We designed a B7-H3 canine CAR T-cell and achieved consistently high levels of transduction efficacy, expansion, and in vitro tumor killing. Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine. Immune response, clinical parameters, and manifestation were closely monitored after treatments and were shown to resemble that of humans. No severe adverse events were observed. In summary, we demonstrated that similar to human cancers, B7-H3 can serve as a target for canine solid tumors. We successfully generated highly functional canine B7-H3-specific CAR T-cell products using a production protocol that closely models human CAR T-cell production procedure. The treatment regimen that we designed was confirmed to be safe in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment.


Assuntos
Receptores de Antígenos Quiméricos , Sarcoma , Animais , Antígenos B7 , Linhagem Celular Tumoral , Cães , Humanos , Sarcoma/tratamento farmacológico , Linfócitos T , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Mech Ageing Dev ; 200: 111573, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34562508

RESUMO

Although the link between DNA damage and aging is well accepted, the role of different DNA repair proteins on functional/physiological aging is not well-defined. Here, using Caenorhabditis elegans, we systematically examined the effect of three DNA repair genes involved in key genome stability pathways. We assayed multiple health proxies including molecular, functional and resilience measures to define healthspan. Loss of XPF-1/ERCC-1, a protein involved in nucleotide excision repair (NER), homologous recombination (HR) and interstrand crosslink (ICL) repair, showed the highest impairment of functional and stress resilience measures along with a shortened lifespan. brc-1 mutants, with a well-defined role in HR and ICL are short-lived and highly sensitive to acute stressors, specifically oxidative stress. In contrast, ICL mutant, fcd-2 did not impact lifespan or most healthspan measures. Our efforts also uncover that DNA repair mutants show high sensitivity to oxidative stress with age, suggesting that this measure could act as a primary proxy for healthspan. Together, these data suggest that impairment of multiple DNA repair genes can drive functional/physiological aging. Further studies to examine specific DNA repair genes in a tissue specific manner will help dissect the importance and mechanistic role of these repair systems in biological aging.


Assuntos
Envelhecimento/fisiologia , Proteínas de Caenorhabditis elegans/genética , DNA Helicases/genética , Reparo do DNA/fisiologia , Longevidade/genética , Reparo de DNA por Recombinação/fisiologia , Animais , Caenorhabditis elegans , Dano ao DNA , Instabilidade Genômica , Humanos , Mutação , Estresse Oxidativo/fisiologia
6.
Sci Transl Med ; 6(224): 224ra25, 2014 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-24553386

RESUMO

We report on 16 patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL) that we treated with autologous T cells expressing the 19-28z chimeric antigen receptor (CAR) specific to the CD19 antigen. The overall complete response rate was 88%, which allowed us to transition most of these patients to a standard-of-care allogeneic hematopoietic stem cell transplant (allo-SCT). This therapy was as effective in high-risk patients with Philadelphia chromosome-positive (Ph(+)) disease as in those with relapsed disease after previous allo-SCT. Through systematic analysis of clinical data and serum cytokine levels over the first 21 days after T cell infusion, we have defined diagnostic criteria for a severe cytokine release syndrome (sCRS), with the goal of better identifying the subset of patients who will likely require therapeutic intervention with corticosteroids or interleukin-6 receptor blockade to curb the sCRS. Additionally, we found that serum C-reactive protein, a readily available laboratory study, can serve as a reliable indicator for the severity of the CRS. Together, our data provide strong support for conducting a multicenter phase 2 study to further evaluate 19-28z CAR T cells in B-ALL and a road map for patient management at centers now contemplating the use of CAR T cell therapy.


Assuntos
Transplante de Células , Imunoterapia , Leucemia de Células B/terapia , Linfócitos T/imunologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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