RESUMEN
The TAM (TYRO3, MERTK, and AXL) family of receptor tyrosine kinases are pleiotropic regulators of adult tissue homeostasis maintaining organ integrity and self-renewal. Disruption of their homeostatic balance fosters pathological conditions like autoinflammatory or degenerative diseases including rheumatoid arthritis, lupus erythematodes, or liver fibrosis. Moreover, TAM receptors exhibit prominent cell-transforming properties, promoting tumor progression, metastasis, and therapy resistance in various cancer entities. Emerging evidence shows that TAM receptors are involved in bone homeostasis by regulating osteoblastic bone formation and osteoclastic bone resorption. Therefore, TAM receptors emerge as new key players of the regulatory cytokine network of osteoblasts and osteoclasts and represent accessible targets for pharmacologic therapy for a broad set of different bone diseases, including primary and metastatic bone tumors, rheumatoid arthritis, or osteoporosis.
Asunto(s)
Artritis Reumatoide , Enfermedades Óseas , Resorción Ósea , Adulto , Humanos , Osteoblastos , Osteoclastos , OsteogénesisRESUMEN
We analyzed the predictive potential of pretreatment soluble carbonic anhydrase IX levels (sCAIX) for the efficacy of bevacizumab in the phase III neoadjuvant GeparQuinto trial. sCAIX was determined by enzyme-linked immunosorbent assay (ELISA). Correlations between sCAIX and pathological complete response (pCR), disease-free and overall survival (DFS, OS) were assessed with logistic and Cox proportional hazard regression models using bootstrapping for robust estimates and internal validation. 1,160 HER2-negative patient sera were analyzed, of whom 577 received bevacizumab. Patients with low pretreatment sCAIX had decreased pCR rates (12.1 vs. 20.1%, p = 0.012) and poorer DFS (adjusted 5-year DFS 71.4 vs. 80.5 months, p = 0.010) compared to patients with high sCAIX when treated with neoadjuvant chemotherapy (NCT). For patients with low sCAIX, pCR rates significantly improved upon addition of bevacizumab to NCT (12.1 vs. 20.4%; p = 0.017), which was not the case in patients with high sCAIX (20.1% for NCT vs. 17.0% for NCT-B, p = 0.913). When analyzing DFS we found that bevacizumab improved 5-year DFS for patients with low sCAIX numerically but not significantly (71.4 vs. 78.5 months; log rank 0.234). In contrast, addition of bevacizumab worsened 5-year DFS for patients with high sCAIX (81 vs. 73.6 months, log-rank 0.025). By assessing sCAIX levels we identified a patient cohort in breast cancer that is potentially undertreated with NCT alone. Bevacizumab improved pCR rates in this group, suggesting sCAIX is a predictive biomarker for bevacizumab with regards to treatment response. Our data also show that bevacizumab is not beneficial in patients with high sCAIX.
Asunto(s)
Antígenos de Neoplasias/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/enzimología , Anhidrasa Carbónica IX/sangre , Adulto , Anciano , Bevacizumab/administración & dosificación , Biomarcadores de Tumor/sangre , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Docetaxel/administración & dosificación , Epirrubicina/administración & dosificación , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Adulto JovenRESUMEN
Although inhibitors of bromodomain and extra terminal domain (BET) proteins show promising clinical activity in different hematologic malignancies, a systematic analysis of the consequences of pharmacological BET inhibition on healthy hematopoietic (stem) cells is urgently needed. We found that JQ1 treatment decreases the numbers of pre-, immature and mature B cells while numbers of early pro-B cells remain constant. In addition, JQ1 treatment increases apoptosis in T cells, all together leading to reduced cellularity in thymus, bone marrow and spleen. Furthermore, JQ1 induces proliferation of long-term hematopoietic stem cells, thereby increasing stem cell numbers. Due to increased numbers, JQ1-treated hematopoietic stem cells engrafted better after stem cell transplantation and repopulated the hematopoietic system significantly faster after sublethal myeloablation. As quantity and functionality of hematopoietic stem cells determine the duration of life-threatening myelosuppression, BET inhibition might benefit patients in myelosuppressive conditions.
Asunto(s)
Antineoplásicos/farmacología , Azepinas/farmacología , Autorrenovación de las Células/efectos de los fármacos , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Proteínas/antagonistas & inhibidores , Triazoles/farmacología , Animales , Apoptosis/efectos de los fármacos , Linfocitos B/citología , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Biomarcadores , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia de Injerto/efectos de los fármacos , Hematopoyesis , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/efectos de la radiación , Inmunofenotipificación , Ratones , Fenotipo , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismoRESUMEN
Patients with t(1;19)-positive acute lymphoblastic leukemia (ALL) are prone to central nervous system (CNS) relapses, and expression of the TAM (Tyro3, Axl, and Mer) receptor Mer is upregulated in these leukemias. We examined the functional role of Mer in the CNS in preclinical models and performed correlative studies in 64 t(1;19)-positive and 93 control pediatric ALL patients. ALL cells were analyzed in coculture with human glioma cells and normal rat astrocytes: CNS coculture caused quiescence and protection from methotrexate toxicity in Mer(high) ALL cell lines, which was antagonized by short hairpin RNA-mediated knockdown of Mer. Mer expression was upregulated, prosurvival Akt and mitogen-activated protein kinase signaling were activated, and secretion of the Mer ligand Galectin-3 was stimulated. Mer(high) t(1;19) primary cells caused CNS involvement to a larger extent in murine xenografts than in their Mer(low) counterparts. Leukemic cells from Mer(high) xenografts showed enhanced survival in coculture. Treatment of Mer(high) patient cells with the Mer-specific inhibitor UNC-569 in vivo delayed leukemia onset, reduced CNS infiltration, and prolonged survival of mice. Finally, a correlation between high Mer expression and CNS positivity upon initial diagnosis was observed in t(1;19) patients. Our data provide evidence that Mer is associated with survival in the CNS in t(1;19)-positive ALL, suggesting a role as a diagnostic marker and therapeutic target.
Asunto(s)
Sistema Nervioso Central/metabolismo , Regulación Leucémica de la Expresión Génica , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogénicas/genética , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/genética , Animales , Antimetabolitos Antineoplásicos/farmacología , Astrocitos/citología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Proteínas Sanguíneas , Estudios de Casos y Controles , Supervivencia Celular , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/patología , Niño , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 19 , Técnicas de Cocultivo , Femenino , Galectina 3/genética , Galectina 3/metabolismo , Galectinas , Glioma/genética , Glioma/metabolismo , Glioma/patología , Humanos , Metotrexato/farmacología , Ratones , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Cultivo Primario de Células , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/metabolismo , Transducción de Señal , Translocación Genética , Células Tumorales Cultivadas , Tirosina Quinasa c-MerRESUMEN
Acute myeloid leukemia (AML) represents a clonal disease of hematopoietic progenitors characterized by acquired heterogenous genetic changes that alter normal mechanisms of proliferation, self-renewal, and differentiation.(1) Although 40% to 45% of patients younger than 65 years of age can be cured with current therapies, only 10% of older patients reach long-term survival.(1) Because only very few novel AML drugs were approved in the past 2 decades, there is an urgent need to identify novel targets and therapeutic strategies to treat underserved AML patients. We report here that Axl, a member of the Tyro3, Axl, Mer receptor tyrosine kinase family,(2-4) represents an independent prognostic marker and therapeutic target in AML. AML cells induce expression and secretion of the Axl ligand growth arrest-specific gene 6 (Gas6) by bone marrow-derived stromal cells (BMDSCs). Gas6 in turn mediates proliferation, survival, and chemoresistance of Axl-expressing AML cells. This Gas6-Axl paracrine axis between AML cells and BMDSCs establishes a chemoprotective tumor cell niche that can be abrogated by Axl-targeting approaches. Axl inhibition is active in FLT3-mutated and FLT3 wild-type AML, improves clinically relevant end points, and its efficacy depends on presence of Gas6 and Axl. Axl inhibition alone or in combination with chemotherapy might represent a novel therapeutic avenue for AML.
Asunto(s)
Células de la Médula Ósea/metabolismo , Leucemia Mieloide Aguda/metabolismo , Comunicación Paracrina/fisiología , Proteínas Proto-Oncogénicas/metabolismo , Receptor Cross-Talk/fisiología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Animales , Antineoplásicos/farmacocinética , Western Blotting , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Ratones , Pronóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Células del Estroma/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa del Receptor AxlRESUMEN
Ample clinical and preclinical evidence indicates that macrophages interact with tumor cells as well as with virtually all populations of host cells present in the tumor microenvironment. This crosstalk can strongly promote malignancy, but also has in principle the potential to inhibit tumor growth. Thus, it is of the utmost importance to improve our understanding of the mechanisms driving the pro- and antimalignant behavior of tumor-associated macrophages (TAMs) in order to develop better anticancer therapies. In this review, we discuss the biological consequences of reciprocal interactions between TAMs, cancer cells, endothelial cells, fibroblasts and other leukocyte subfractions within tumors. It was recently elucidated that tumors specifically educate macrophages to secrete growth arrest-specific gene 6 (Gas6), the common ligand of the Tyro3, Axl, Mer receptor (TAMR) family. In turn, Gas6 fosters tumor growth by promoting cancer cell proliferation. Therefore, the Gas6-TAMR axis might represent a novel target for disrupting tumor-macrophage crosstalk. We summarize here what is known about TAMR and their ligands in (human) cancer biology. In order to shed more light on the role of macrophages in human cancer, we additionally provide an overview of what is currently known about the prognostic impact of TAMs in human cancer.
Asunto(s)
Macrófagos/fisiología , Proteínas Tirosina Quinasas Receptoras/fisiología , Microambiente Tumoral/fisiología , Células Endoteliales/patología , Células Endoteliales/fisiología , Femenino , Fibroblastos/patología , Fibroblastos/fisiología , Humanos , Péptidos y Proteínas de Señalización Intercelular/fisiología , Leucocitos/patología , Leucocitos/fisiología , Ligandos , Macrófagos/clasificación , Macrófagos/inmunología , Macrófagos/patología , Masculino , Modelos Biológicos , Neoplasias/patología , Neoplasias/fisiopatología , Pronóstico , Proteína S/fisiologíaRESUMEN
Despite enormous efforts to improve therapeutic options, pancreatic cancer remains a fatal disease and is expected to become the second leading cause of cancer-related deaths in the next decade. Previous research identified lipid metabolic pathways to be highly enriched in pancreatic ductal adenocarcinoma (PDAC) cells. Thereby, cholesterol uptake and synthesis promotes growth advantage to and chemotherapy resistance for PDAC tumor cells. Here, we demonstrate that high-density lipoprotein (HDL)-mediated efficient cholesterol removal from cancer cells results in PDAC cell growth reduction and induction of apoptosis in vitro. This effect is driven by an HDL particle composition-dependent interaction with SR-B1 and ABCA1 on cancer cells. AAV-mediated overexpression of APOA1 and rHDL injections decreased PDAC tumor development in vivo. Interestingly, plasma samples from pancreatic-cancer patients displayed a significantly reduced APOA1-to-SAA1 ratio and a reduced cholesterol efflux capacity compared with healthy donors. We conclude that efficient, HDL-mediated cholesterol depletion represents an interesting strategy to interfere with the aggressive growth characteristics of PDAC.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/genética , Proliferación Celular , Colesterol/metabolismo , Humanos , Neoplasias Pancreáticas/metabolismo , Neoplasias PancreáticasRESUMEN
The fine equilibrium of bone homeostasis is maintained by bone-forming osteoblasts and bone-resorbing osteoclasts. Here, we show that TAM receptors MERTK and TYRO3 exert reciprocal effects in osteoblast biology: Osteoblast-targeted deletion of MERTK promotes increased bone mass in healthy mice and mice with cancer-induced bone loss, whereas knockout of TYRO3 in osteoblasts shows the opposite phenotype. Functionally, the interaction of MERTK with its ligand PROS1 negatively regulates osteoblast differentiation via inducing the VAV2-RHOA-ROCK axis leading to increased cell contractility and motility while TYRO3 antagonizes this effect. Consequently, pharmacologic MERTK blockade by the small molecule inhibitor R992 increases osteoblast numbers and bone formation in mice. Furthermore, R992 counteracts cancer-induced bone loss, reduces bone metastasis and prolongs survival in preclinical models of multiple myeloma, breast- and lung cancer. In summary, MERTK and TYRO3 represent potent regulators of bone homeostasis with cell-type specific functions and MERTK blockade represents an osteoanabolic therapy with implications in cancer and beyond.
Asunto(s)
Proteínas Proto-Oncogénicas , Proteínas Tirosina Quinasas Receptoras , Ratones , Animales , Tirosina Quinasa c-Mer/genética , Tirosina Quinasa c-Mer/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Homeostasis , Proteínas PortadorasRESUMEN
Pulmonary arterial hypertension (PAH), is a fatal disease characterized by a pseudo-malignant phenotype. We investigated the expression and the role of the receptor tyrosine kinase Axl in experimental (i.e., monocrotaline and Su5416/hypoxia treated rats) and clinical PAH. In vitro Axl inhibition by R428 and Axl knock-down inhibited growth factor-driven proliferation and migration of non-PAH and PAH PASMCs. Conversely, Axl overexpression conferred a growth advantage. Axl declined in PAECs of PAH patients. Axl blockage inhibited BMP9 signaling and increased PAEC apoptosis, while BMP9 induced Axl phosphorylation. Gas6 induced SMAD1/5/8 phosphorylation and ID1/ID2 increase were blunted by BMP signaling obstruction. Axl association with BMPR2 was facilitated by Gas6/BMP9 stimulation and diminished by R428. In vivo R428 aggravated right ventricular hypertrophy and dysfunction, abrogated BMPR2 signaling, elevated pulmonary endothelial cell apoptosis and loss. Together, Axl is a key regulator of endothelial BMPR2 signaling and potential determinant of PAH.
Asunto(s)
Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Regulación de la Expresión Génica , Hipertensión Arterial Pulmonar/genética , Proteínas Tirosina Quinasas Receptoras/deficiencia , Inhibidores de la Angiogénesis/farmacología , Animales , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/metabolismo , Indoles/farmacología , Masculino , Monocrotalina/farmacología , Pirroles/farmacología , Ratas Endogámicas WKY , Ratas Sprague-DawleyRESUMEN
BCR-ABL negative myeloproliferative neoplasms (MPNs) consist of essential thrombocythemia, polycythemia vera, and myelofibrosis. The majority of patients harbor the JAK2-activating mutation V617F. JAK2 inhibitors were shown to reduce symptom burden and splenomegaly in MPN patients. However, treatment options are limited after failure of JAK2 inhibitors. AXL, a member of the TAM family of receptor tyrosine kinases, mediates survival and therapy resistance of different myeloid cancers including acute myeloid leukemia and chronic myeloid leukemia. We studied the relevance of AXL as a target in MPN using primary patient cells and preclinical disease models. We found that AXL is abundantly activated in MPN cells and that its ligand growth arrest-specific gene 6 is upregulated in MPN patients. Pharmacologic and genetic blockade of AXL impaired viability, decreased proliferation and increased apoptosis of MPN cells. Interestingly, ruxolitinib treatment induced increased phosphorylation of AXL indicating that activation of AXL might mediate resistance to ruxolitinib. Consistently, the AXL inhibitor bemcentinib exerted additive effects with ruxolitinib via impaired STAT3, STAT5, and AKT signaling. Both agents had activity when employed alone and exerted an additive effect on survival and splenomegaly in vivo. Moreover, bemcentinib treatment normalized red blood cell count and hemoglobin levels in vivo. Thus, our data indicate that AXL inhibition represents a novel treatment option in MPN warranting clinical investigation.
RESUMEN
Influenza during pregnancy can affect the health of offspring in later life, among which neurocognitive disorders are among the best described. Here, we investigate whether maternal influenza infection has adverse effects on immune responses in offspring. We establish a two-hit mouse model to study the effect of maternal influenza A virus infection (first hit) on vulnerability of offspring to heterologous infections (second hit) in later life. Offspring born to influenza A virus infected mothers are stunted in growth and more vulnerable to heterologous infections (influenza B virus and MRSA) than those born to PBS- or poly(I:C)-treated mothers. Enhanced vulnerability to infection in neonates is associated with reduced haematopoetic development and immune responses. In particular, alveolar macrophages of offspring exposed to maternal influenza have reduced capacity to clear second hit pathogens. This impaired pathogen clearance is partially reversed by adoptive transfer of alveolar macrophages from healthy offspring born to uninfected dams. These findings suggest that maternal influenza infection may impair immune ontogeny and increase susceptibility to early life infections of offspring.
Asunto(s)
Infecciones Bacterianas/inmunología , Virus de la Influenza A/inmunología , Infecciones por Orthomyxoviridae/virología , Parto , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Femenino , Hematopoyesis , Humanos , Gripe Humana/inmunología , Pulmón/inmunología , Macrófagos Alveolares , Ratones , Ratones Endogámicos C57BL , Madres , Poli I-C , EmbarazoRESUMEN
It is well-known that sex hormones can directly and indirectly influence immune cell function. Different studies support a suppressive role of androgens on different components of the immune system by decreasing antibody production, T cell proliferation, NK cytotoxicity, and stimulating the production of anti-inflammatory cytokines. Androgen receptors have also been detected in many different cells of hematopoietic origin leading to direct effects of their ligands on the development and function of the immune system. The immunosuppressive properties of androgens could contribute to gender dimorphisms in autoimmune and infectious disease and thereby also hamper immune surveillance of tumors. Consistently, females generally are more prone to autoimmunity, while relatively less susceptible to infections, and have lower incidence and mortality of the majority of cancers compared to males. Some studies show that androgen deprivation therapy (ADT) can induce expansion of naïve T cells and increase T-cell responses. Emerging clinical data also reveal that ADT might enhance the efficacy of various immunotherapies including immune checkpoint blockade. In this review, we will discuss the potential role of androgens and their receptors in the immune responses in the context of different diseases. A particular focus will be on cancer, highlighting the effect of androgens on immune surveillance, tumor biology and on the efficacy of anti-cancer therapies including emerging immune therapies.
Asunto(s)
Andrógenos/inmunología , Vigilancia Inmunológica/inmunología , Neoplasias/inmunología , Receptores Androgénicos/inmunología , Animales , Femenino , Humanos , Masculino , Autotolerancia/inmunologíaRESUMEN
It has previously been demonstrated that 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] administration, whether in cell cultures or in vivo to rats, increases glial cell line-derived neurotrophic factor (GDNF) expression levels, suggesting that this hormone may have beneficial effects in neurodegenerative disorders. This study was carried out to explore the effects of 1,25(OH)(2)D(3) administration in a 6-OHDA-lesioned rat model of Parkinson's disease on GDNF and tyrosine hydroxylase (TH) expression in substantia nigra (SN) and striatum. Two groups of animals received 1,25(OH)(2)D(3) intraperitoneally, the first group 7 days before the unilateral injection of 6-OHDA into the medial forebrain bundle (MFB) and the second group 21 days (days 21-28) after the unilateral injection of 6-OHDA. Animals of both groups were sacrificed on day 28. In addition, two other groups received a unilateral injection of either saline or 6-OHDA into the MFB. Rats were killed, and the SN and striatum were then removed for GDNF and TH determination. Striatal GDNF protein expression was increased on the ipsilateral with respect to the contralateral side after 6-OHDA injection alone as well as in 1,25(OH)(2)D(3)-treated rats before or after 6-OHDA administration. As expected, 6-OHDA injection induced an ipsilateral decrease in TH-immunopositive neuronal cell bodies and axonal terminals in the SN and striatum. However, treatment with 1,25(OH)(2)D(3) before and after 6-OHDA injection partially restored TH expression in SN. These data suggest that 1,25(OH)(2)D(3) may help to prevent dopaminergic neuron damage.
Asunto(s)
Calcitriol/administración & dosificación , Cuerpo Estriado/efectos de los fármacos , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Enfermedad de Parkinson Secundaria/metabolismo , Sustancia Negra/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismo , Animales , Western Blotting , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Expresión Génica/efectos de los fármacos , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Inmunohistoquímica , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/ultraestructura , Oxidopamina , Enfermedad de Parkinson Secundaria/inducido químicamente , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sustancia Negra/metabolismoRESUMEN
Cancer represents a leading cause of death with continuously increasing incidence worldwide. Many solid cancer types in non-reproductive organs are significantly more frequent and deadly in males compared to females. This sex-biased difference is also present in hematologic malignancies. In this review, we present an overview about sex differences in cancer with a focus on leukemia. We discuss mechanisms potentially underlying the observed sex-biased imbalance in cancer incidence and outcome including sex hormones, sex chromosomes, and immune responses. Besides affecting the pathobiology of cancers, sex differences can also influence drug responses, most notably those to immune checkpoint blockers. Therefore, sex should become a relevant factor in clinical trial design in order to avoid over- or under-treatment of one sex.
Asunto(s)
Neoplasias Hematológicas/inmunología , Leucemia/inmunología , Caracteres Sexuales , Cromosomas Humanos/genética , Cromosomas Humanos/inmunología , Femenino , Hormonas Esteroides Gonadales/genética , Hormonas Esteroides Gonadales/inmunología , Neoplasias Hematológicas/epidemiología , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Humanos , Incidencia , Leucemia/epidemiología , Leucemia/genética , Leucemia/patología , Masculino , Cromosomas Sexuales/genética , Cromosomas Sexuales/inmunologíaRESUMEN
Intrinsic and adaptive resistance hampers the success of antiangiogenic therapies (AAT), especially in breast cancer where this treatment modality has proven largely ineffective. Therefore, novel strategies to improve the efficacy of AAT are warranted. Solid tumors such as breast cancer are characterized by a high infiltration of myeloid-derived suppressor cells (MDSC), which are key drivers of resistance to AAT. Therefore, we hypothesized that all-trans retinoic acid (ATRA), which induces differentiation of MDSC into mature cells, could improve the therapeutic effect of AAT. ATRA increased the efficacy of anti-VEGFR2 antibodies alone and in combination with chemotherapy in preclinical breast cancer models. ATRA reverted the anti-VEGFR2-induced accumulation of intratumoral MDSC, alleviated hypoxia, and counteracted the disorganization of tumor microvessels. Mechanistic studies indicate that ATRA treatment blocked the AAT-induced expansion of MDSC secreting high levels of vessel-destabilizing S100A8. Thus, concomitant treatment with ATRA holds the potential to improve AAT in breast cancer and possibly other tumor types.Significance: Increasing the therapeutic efficiency of antiangiogenic drugs by reducing resistance-conferring myeloid-derived suppressor cells might improve breast cancer treatment.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/12/3220/F1.large.jpg Cancer Res; 78(12); 3220-32. ©2018 AACR.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Células Supresoras de Origen Mieloide/efectos de los fármacos , Tretinoina/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Calgranulina A/metabolismo , Técnicas de Cultivo de Célula , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Línea Celular Tumoral/trasplante , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Ratones Endogámicos BALB C , Células Supresoras de Origen Mieloide/fisiología , Estabilidad Proteica/efectos de los fármacos , Resultado del Tratamiento , Tretinoina/uso terapéutico , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
Purpose: BCR-ABL kinase inhibitors are employed successfully for chronic myeloid leukemia (CML) treatment. However, resistant disease and persistence of BCR-ABL1-independent leukemia stem and progenitor cells (LSPC) remain clinical challenges. The receptor tyrosine kinase Axl can mediate survival and therapy resistance of different cancer cells. We investigated the therapeutic potential of Axl inhibition in CML.Experimental Design: We used primary cells from patients with CML and TKI-sensitive and -resistant BCR-ABL1+ CML cell lines and a novel ponatinib-resistant cell line KCL-22 PonR. We analyzed the effects of genetic and pharmacologic Axl blockade by the small-molecule Axl inhibitor BGB324 in vitro and in vivo In BCR-ABL1-unmutated cells, we also investigated BGB324 in combination with imatinib.Results: We demonstrate overexpression of Axl receptor tyrosine kinase in primary cells of patients with CML compared with healthy individuals and a further increase of Axl expression in BCR-ABL TKI-resistant patients. We show that Axl blockage decreased growth of BCR-ABL TKI-sensitive CML cells including CD34+ cells and exerts additive effects with imatinib via inhibition of Stat5 activation. BGB324 also inhibits BCR-ABL TKI-resistant cells, including T315I-mutated and ponatinib-resistant primary cells. BGB324 exerted therapeutic effects in BCR-ABL1 T315I-mutated and ponatinib-resistant preclinical mouse models. Notably, BGB324 does not inhibit BCR-ABL1 and consequently inhibits CML independent of BCR-ABL1 mutational status.Conclusions: Our data show that Axl inhibition has therapeutic potential in BCR-ABL TKI-sensitive as well as -resistant CML and support the need for clinical trials. Clin Cancer Res; 23(9); 2289-300. ©2016 AACR.
Asunto(s)
Benzocicloheptenos/administración & dosificación , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Triazoles/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Humanos , Mesilato de Imatinib/administración & dosificación , Imidazoles/administración & dosificación , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Ratones , Mutación , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Piridazinas/administración & dosificación , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Tirosina Quinasa del Receptor AxlRESUMEN
Head and neck squamous cell carcinomas (HNSCC) exhibiting resistance to the EGFR-targeting drug cetuximab poses a challenge to their effective clinical management. Here, we report a specific mechanism of resistance in this setting based upon the presence of a single nucleotide polymorphism encoding EGFR-K521 (K-allele), which is expressed in >40% of HNSCC cases. Patients expressing the K-allele showed significantly shorter progression-free survival upon palliative treatment with cetuximab plus chemotherapy or radiation. In several EGFR-mediated cancer models, cetuximab failed to inhibit downstream signaling or to kill cells harboring a high K-allele frequency. Cetuximab affinity for EGFR-K521 was reduced slightly, but ligand-mediated EGFR activation was intact. We found a lack of glycan sialyation on EGFR-K521 that associated with reduced protein stability, suggesting a structural basis for reduced cetuximab efficacy. CetuGEX, an antibody with optimized Fc glycosylation targeting the same epitope as cetuximab, restored HNSCC sensitivity in a manner associated with antibody-dependent cellular cytotoxicity rather than EGFR pathway inhibition. Overall, our results highlight EGFR-K521 expression as a key mechanism of cetuximab resistance to evaluate prospectively as a predictive biomarker in HNSCC patients. Further, they offer a preclinical rationale for the use of ADCC-optimized antibodies to treat tumors harboring this EGFR isoform. Cancer Res; 77(5); 1188-99. ©2016 AACR.
Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Cetuximab/farmacología , Receptores ErbB/genética , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Resistencia a Antineoplásicos , Femenino , Neoplasias de Cabeza y Cuello/enzimología , Neoplasias de Cabeza y Cuello/genética , Humanos , Ratones , Ratones Endogámicos NOD , Polimorfismo de Nucleótido Simple , Distribución Aleatoria , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Novel treatment options in acute myeloid leukemia (AML) are urgently needed; treatment has not changed significantly over the past decades and survival is still dismal, especially in elderly patients. Axl, a member of the Tyro3, Axl, Mer (TAM) receptor family, mediates proliferation and survival of AML cells and is upregulated upon cytostatic treatment. In addition, AML cells induce expression of the Axl ligand growth arrest-specific gene 6 (Gas6) in bone marrow stroma cells, which further amplifies their growth and therapy resistance. Interruption of Axl signaling by pharmacological approaches, including the small molecule Axl inhibitor BGB324, decreased disease burden and prolonged survival of AML mice. The Gas6-Axl pathway has translational relevance because Axl is expressed by approximately 50% of AML patients and Axl-targeting approaches can block growth of primary human AML cells. Thus, Axl represents a potential novel target in AML and BGB324 is now in clinical development.
Asunto(s)
Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Anciano , Humanos , Transducción de Señal , Tirosina Quinasa del Receptor AxlRESUMEN
Anti-angiogenic therapies were approved for different cancers. However, significant primary and secondary resistance hampers efficacy in several tumor types including breast cancer. Thus, we need to develop clinically applicable strategies to enhance efficacy of anti-angiogenic drugs.We report that anti-angiogenic therapies can induce upregulation of cyclooxygenase-2 (Cox-2) and of its product prostaglandin E2 (PGE2) in breast cancer models. Upon Cox-2 inhibition PGE2 levels were normalized and efficacy of anti-vascular endothelial growth factor receptor 2 (anti-VEGFR-2) antibodies and sunitinib was enhanced. Interestingly, both treatments exerted additive anti-angiogenic effects. Following Cox-2 inhibition, we observed reduced infiltration of tumors with cancer-associated fibroblasts (CAFs) and lower levels of pro-angiogenic factors active besides the VEGF axis including hepatocyte growth factor (HGF) and basic fibroblast growth factor (FGF2). Mechanistic studies indicated that Cox-2 inhibition reduced PGE2-induced migration and proliferation of CAFs via inhibiting phosphorylation of Akt.Hence, Cox-2 inhibition can increase efficacy of anti-angiogenic treatments and our findings might pave the road for clinical investigations of concomitant blockade of Cox-2 and VEGF-signaling.