RESUMEN
While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).
RESUMEN
The safety and efficacy of CAR T-cell therapy is not well described in older patients, a population that has higher frailty and co-morbidities. In this multicenter retrospective study, we evaluated clinical outcomes along with frailty and geriatric characteristics such as comorbidities, polypharmacy, falls, neuropathy, organ dysfunction, and performance status in younger (<65 years) versus older (≥65 years) patients who received commercial idecabtagene vicleucel (ide-cel). A total of 156 patients (n=75, ≥65 years) were infused with ide-cel by data cut-off. In older patients (median age: 69 years, range: 65-83 years; 66.7% frail; 77.3% did not meet KarMMa eligibility criteria), with a median follow-up duration of 14.2 months, best overall response rate (ORR) was 86.7%, which was comparable to pivotal KarMMa study results (ORR: 73%). Median progression-free survival (PFS) and overall survival (OS) in older patients were 9.1 months and 26.5 months, respectively. Grade 3 or higher cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were observed in 1% and 4% of older patients, respectively. Compared to younger patients, the older patients had significantly higher prevalence of frailty, geriatric characteristics such as polypharmacy (5+ drugs; 97%), 4+ comorbidities (69%), and organ dysfunction (35%) (p<0.05). The safety and efficacy of ide-cel therapy were similar in younger and older patients. Frailty and geriatric characteristics such as polypharmacy, comorbidities, and organ dysfunction in older patients did not confer an inferior overall outcome.
RESUMEN
We evaluated patients with relapsed multiple myeloma with renal impairment (RI) treated with standard of care idecabtagene vicleucel (ide-cel), as outcomes with chimeric antigen receptor (CAR) T-cell therapy are unknown in this population. RI was defined as creatinine clearance (CrCl) <50 mL/min. CrCl of <30 mL/min or dialysis dependence were defined as severe RI. The study cohort included 214 patients, 28 (13%) patients with RI, including 11 patients severe RI (dialysis, N=1). Patients with RI were older, more likely to be female and had higher likelihood of having Revised International Staging System stage 3 disease. Rates and severity of cytokine release syndrome (89% vs. 84%, grade ≥3: 7% vs. 2%) and immune effector cell-associated neurotoxicity syndrome (23% vs. 20%) were similar in patients with and without RI, respectively. Patients with RI had higher incidence of short-term grade ≥3 cytopenias, although cytopenias were similar by 3 months following CAR T-cell therapy. Renal function did not worsen after CAR T-cell therapy in patients with RI. Response rates (93% vs. 82%) and survival outcomes (median progression-free survival: 9 vs. 8 months; P=0.26) were comparable in patients with and without RI, respectively. Treatment with ide-cel is feasible in patients with RI, with a comparable safety and efficacy profile as patients without RI, with notable exception of higher short-term high-grade cytopenias.
Asunto(s)
Citopenia , Mieloma Múltiple , Neoplasias de Células Plasmáticas , Receptores Quiméricos de Antígenos , Insuficiencia Renal , Humanos , Femenino , Masculino , Mieloma Múltiple/complicaciones , Mieloma Múltiple/terapia , Inmunoterapia Adoptiva/efectos adversos , Tratamiento Basado en Trasplante de Células y TejidosRESUMEN
Despite recent advancement of treatment strategies in multiple myeloma (MM), patients with relapsed/refractory MM disease, particularly after triple-class refractoriness, continue to have poor prognosis. Chimeric antigen receptor (CAR-T) cells were developed and applied to improve outcomes in this setting, and two products, idecabtagene vicleucel and ciltacabtagene autoleucel, both targeting B-cell maturation antigen, have been approved by the Food and Drug Administration in the United States and European Medicines Agency in Europe. Both have shown unprecedented clinical outcomes with high response rate and prolonged progression-free survival and overall survival in this patient population with grim prognosis. Currently, further investigations are ongoing for CAR-T targeting different tumor antigens such as G protein-coupled receptor, class C, group 5, member D or with different combinations of intracellular signaling domains, as well as fourth-generation CAR-T with antigen-unrestricted inducible cytokines. Although CAR-T therapies hold hopes and enthusiasm from the myeloma community, several hurdles remain before these treatments become available for all patients in need. These barriers include CAR-T-cell manufacturing availability, access to administering centers, financial cost, caregivers' availability, and socioeconomic and racial disparities. Expanding clinical trial eligibility criteria and real-world data collection and analysis is crucial to understand the efficacy and safety of CAR-T in the patient cohort who tends to be excluded from current trials.
Asunto(s)
Mieloma Múltiple , Receptores Quiméricos de Antígenos , Humanos , Mieloma Múltiple/terapia , Receptores Quiméricos de Antígenos/genética , Inmunoterapia Adoptiva , Citocinas , Europa (Continente)RESUMEN
Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.
Asunto(s)
Linfoma de Células B Grandes Difuso , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Inmunoterapia Adoptiva/métodos , Linfocitos T , Antígenos CD19/genética , Microambiente TumoralRESUMEN
Idecabtagene vicleucel (ide-cel) was FDA-approved in March 2021 for the treatment of relapsed/refractory multiple myeloma after 4 lines of therapy. On the KarMMa trial, grade ≥ 3 cytopenias and infections were common. We sought to characterize cytopenias and infections within 100 days after ide-cel in the standard-of-care (SOC) setting. This multi-center retrospective study included 52 patients who received SOC ide-cel; 47 reached day-90 follow-up. Data were censored at day 100. Grade ≥ 3 cytopenia was present among 65% of patients at day 30 and 40% of patients at day 90. Granulocyte colony stimulating factor (G-CSF) was administered to 88%, packed red blood cell transfusions to 63%, platelet transfusions to 42%, thrombopoietin (TPO) agonists to 21%, intravenous immunoglobulin to 13%, and CD34+ stem cell boosts to 8%. At day 100, 19% and 13% of patients had ongoing use of TPO agonists and G-CSF, respectively. Infections occurred in 54% of patients and were grade ≥ 3 in 23%. Earlier infections in the first 30 days were typically bacterial (68%) and severe (50%). Later infections between days 31 and 100 were 50% bacterial and 42% viral; only 13% were grade ≥ 3. On univariate analysis, high pre-CAR-T marrow myeloma burden (≥ 50%), circulating plasma cells at pre-lymphodepletion (LD), and grade ≥ 3 anemia at pre-LD were associated with grade ≥ 3 cytopenia at both days 30 and 90. Longer time from last bridging treatment to LD was the only significant risk factor for infection.
Asunto(s)
Anemia , Mieloma Múltiple , Receptores Quiméricos de Antígenos , Trombocitopenia , Humanos , Mieloma Múltiple/terapia , Estudios Retrospectivos , Nivel de Atención , Factor Estimulante de Colonias de GranulocitosRESUMEN
PURPOSE OF REVIEW: The field of multiple myeloma treatment has entered a new era with antibody-based approaches in clinical practice. In this review, we focus on the clinical approaches of utilizing antibody-based modality, specifically monoclonal antibodies, antibody-drug conjugates, and bispecific T-cell antibodies in the treatment of multiple myeloma. RECENT FINDINGS: Three monoclonal antibodies (daratumumab, isatuximab, elotuzumab) and one anti-BCMA (B-cell maturation antigen) antibody-drug conjugate (belantamab mafodotin) have been approved by the FDA in the last 5 years for the treatment of multiple myeloma. There are many ongoing clinical trials using novel targets and constructs, including bispecific antibodies against BCMA, GPRC5D, and FCRH5. In addition to exploring efficacy, there are ongoing efforts to overcome the resistance to therapy. Antibody-based therapy has improved the outcomes of patients with multiple myeloma and has been incorporated in the standard of care. We expect to see novel targets and constructs that can achieve a deeper and more durable response while minimizing toxicity, as well as better strategies for toxicity management for existing agents. We also expect that antibody-based strategies will be used in earlier lines of therapy in the future.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Molecular Dirigida , Mieloma Múltiple/tratamiento farmacológico , Anticuerpos Biespecíficos/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Vías de Administración de Medicamentos , Resistencia a Antineoplásicos , Humanos , Inmunoconjugados/administración & dosificación , Terapia Molecular Dirigida/efectos adversos , Terapia Molecular Dirigida/métodos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/etiología , Mieloma Múltiple/mortalidad , Recurrencia , RetratamientoRESUMEN
OBJECTIVES: Functional imaging presents a non-invasive process that may capture the hyper-metabolic nature of red bone marrow in myeloproliferative neoplasms, such as polycythemia vera (PV). METHODS: This study analyzed the FDG-PET/CT scans (n=12) of six patients diagnosed with PV and six age-sex matched controls using a quantitative global analysis methodology. RESULTS: All PV patients had elevated activities in the bone marrow of each skeletal structure as compared to matched controls with respect to mean standardized uptake value (femoral neck p=0.01, lumbar spine p=0.02, pelvis p=0.002, sternum p=0.04). Notable variations in splenic uptake were observed among the treated and untreated PV patients. CONCLUSION: Our study exemplifies the potential utility of PET in reflecting hyperactive bone marrow activity related to PV. Future studies may further substantiate and elaborate on the use of PET-derived metabolic data in PV.
RESUMEN
Heart failure (HF) is a chronic medical condition affecting an estimated 1-2% of the world's population, and as many as 10% of patients age 65 and above. Among patients with HF, iron deficiency (ID) has an estimated prevalence of 30-83%, often without concomitant anemia. Thus, ID in HF is often underdiagnosed unless actively sought after. ID in HF has been shown to be an independent contributor of increased mortality, hospitalization, and early readmission compared with HF patients without ID or HF patients with anemia without ID. Previous trials suggest that intravenous iron supplementation for patients with chronic HF and ID with or without anemia has resulted in improved functional outcomes and quality of life; however, the role of iron supplementation in patients hospitalized with HF has not been well characterized. In this retrospective analysis conducted in a large urban health system, we show that of the greater than 10,000 patients admitted for HF in 1 year, only 158 patients underwent screening for ID. Of these, 109 met criteria for ID. Despite intravenous iron being the standard of care for treatment of ID in HF patients, only 23 patients received this therapy. These data suggest that iron deficiency, despite having major implications in HF, is not being adequately evaluated during hospitalizations for HF. Further, if ID is identified, it is not being appropriately addressed, as per current treatment guidelines.
Asunto(s)
Insuficiencia Cardíaca , Hospitalización , Hierro , Calidad de Vida , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Humanos , Hierro/administración & dosificación , Deficiencias de Hierro , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging was conceived in the early 1970 by investigators at the University of Pennsylvania as a research technique to measure brain metabolism and function by employing a non-invasive imaging approach. Soon after the introduction of whole-body PET instruments, 18F-FDG was utilized in the assessment of a variety of solid tumors and certain hematological malignancies. Yet, the role of 18F-FDG in assessing benign and uncommon malignant disorders of the bone marrow has not been investigated to a great extent. Fluorine-18-FDG as a molecular probe has the proven capacity to reflect the abnormal glycolytic activities inherent to a variety of disorders, where such information may serve as a guide to the clinical course of the respective disease. Recent efforts have studied bone marrow and extra-medullary disease activity in certain malignancies like chronic lymphocytic leukemia. Nonetheless, few studies have explored the role of 18F-FDG in assessing the metabolic basis of benign disorders of red marrow. Moreover, the introduction of novel imaging analysis schemes in recent years has allowed for the global assessment of red marrow disease, which can provide a superior means for characterizing the systemic nature and burden of these disorders. Accordingly, semi-quantitative global analysis techniques as applied to the skeletal structures in 18F-FDG PET may provide a tool to better understand these complex marrow abnormalities. Functional imaging of red bone marrow may also reveal critical information specifically regarding the extra-medullary extension of such hematological disorders that cannot be assessed by other diagnostic or imaging techniques. Myleoproliferative neoplasms (MPN) are an apt category of hematological disease that confer significantly altered systemic metabolic rates of hematopoietic stem cells (HSC) in the marrow, as such they are primed for exploration with 18F-FDG PET. The hallmark of such disorders involves the excess production of particular cellular components in blood. After a period of excess production, scar tissue may develop in place of the HSC leading to myleofibrosis and decreased hematopoietic activity. One of the least studied disorders within the larger category of MPN with respect to the nuclear medicine is polycythemia. Polycythemia may be either primary, polycythemia vera (PV), or secondary. PV involves a JAK2+ in HSC which allows for the excessive proliferation of immature erythrocytes and depressed erythropoietin levels as a result. Secondary polycythemia occurs in response to decreased oxygen intake, often as a result of smoking, which results in increased erythropoietin and hematocrit levels. Primary and secondary polycythemia lead to an increase in overall red marrow activity and a diffusion of active red marrow into the appendicular skeleton. Clinical presentation often includes redness or irritation of the skin along with headache, fatigue and excessive bleeding. Based upon the mentioned precedent, it is evident that PET imaging with 18F-FDG and other tracers will play a meaningful role in assessing diffuse bone marrow disorders such as hematological malignancies and myeloproliferative abnormalities. Semi-quantification studies of global bone marrow activity in such an application will be a vital means in accurately assessing the systematic nature and global burden of such benign hematological disorders such a polycythemia. Accordingly, the derived metabolic data projects to be a useful tool in the prospective clinical and scientific aspects of the diagnosis of these benign hematological disorders and the assessment of disease progression in light of relevant biological treatments. Given the nature of the disease and the enumerated capabilities of 18F-FDG PET it is expected that one would be able to capture the systematic abnormalities inherent to the disease. Moreover, the handful of case studies supports this possibility. Three case studies have all illustrated diffuse elevated 18F-FDG uptake throughout the axial and appendicular skeleton that reflects the hyper-metabolic red bone marrow as related to polycythemia. Moreover, the use of various functional imaging tracers, in addition to 18F-FDG, may indirectly reflect hypermetabolism in red bone marrow through abnormal tracer accumulation in the skeletons of patients. The whole body 18F-FDG scan of a JAK2+ PV patient before treatment (a) as compared to a matched subject (b) is found below; of note is the PV patient's elevated uptake in the pelvis, femur and spine.
Asunto(s)
Policitemia/diagnóstico por imagen , Tomografía de Emisión de Positrones , Fluorodesoxiglucosa F18 , Humanos , RadiofármacosRESUMEN
BACKGROUND: Pericardial effusions in systemic sclerosis (SSc) may present as acute or chronic with or without clinical symptoms. Best treatment is unknown and whether patients receive medical therapy or a surgical procedure is clinician-dependent. OBJECTIVE: To describe the clinical characteristics, treatment, and outcomes of patients with SSc and clinically symptomatic pericardial effusions treated in the inpatient setting. METHODS: We evaluated all SSc admissions over a 10-year period to a tertiary care hospital which has a dedicated SSc clinic. Patients who had a clinically symptomatic pericardial effusion were evaluated based on their demographics, disease pattern, and medical or surgical management. RESULTS: From January 2005 till October 2015, there were 462 SSc admissions with 32 (6.9%) of them being for a clinically symptomatic pericardial effusion in 23 unique patients. Eleven (47%) of these patients had right heart failure, seventeen (74%) had pulmonary arterial hypertension (PAH), and 4 (17%) had tamponade physiology. Five (22%) patients were treated by a surgical procedure, while eighteen (78%) patients had medical therapy. Patients who received medical therapy tended to be older, have a lower serum Cr level, and more likely have right heart failure. CONCLUSION: Clinically symptomatic pericardial effusion is a rare cause for hospital admissions in SSc, with a high percentage of these patients having PAH. Medical therapy tends to be reserved for older patients with right heart failure, while surgical therapy was more likely in patients with higher serum Cr levels.
Asunto(s)
Derrame Pericárdico/complicaciones , Esclerodermia Sistémica/complicaciones , Adulto , Anciano , Demografía , Femenino , Humanos , Hipertensión Pulmonar , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Sickle-cell disease (SCD) leads to recurrent vaso-occlusive crises, chronic end-organ damage, and resultant physical, psychological, and social disabilities. Although hematopoietic stem-cell transplantation (HSCT) is potentially curative for SCD, this procedure is associated with well-recognized morbidity and mortality and thus is ideally offered only to patients at high risk of significant complications. However, it is difficult to identify patients at high risk before significant complications have occurred, and once patients experience significant organ damage, they are considered poor candidates for HSCT. In turn, patients who have experienced long-term organ toxicity from SCD such as renal or liver failure may be candidates for solid-organ transplantation (SOT); however, the transplanted organs are at risk of damage by the original disease. Thus, dual HSCT and organ transplantation could simultaneously replace the failing organ and eliminate the underlying disease process. Advances in HSCT conditioning such as reduced-intensity regimens and alternative donor selection may expand both the feasibility of and potential donor pool for transplantation. This review summarizes the current state of HSCT and organ transplantation in SCD and discusses future directions and the clinical feasibility of dual HSCT/SOT.
Asunto(s)
Anemia de Células Falciformes/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Órganos/métodos , Trasplante de Células Madre Hematopoyéticas/tendencias , Humanos , Trasplante de Órganos/tendencias , Donantes de TejidosAsunto(s)
Anticuerpos Monoclonales/efectos adversos , Encefalitis/inducido químicamente , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Encefalitis/tratamiento farmacológico , Femenino , Humanos , Persona de Mediana Edad , Esteroides/uso terapéutico , Resultado del TratamientoRESUMEN
A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Modelos Animales de Enfermedad , Imagen Multimodal , Nanotecnología , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Sistemas de Liberación de Medicamentos , Femenino , Rayos Infrarrojos , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Resonancia por Plasmón de SuperficieRESUMEN
Circulating cancer cells can putatively colonize distant organs to form metastases or to reinfiltrate primary tumors themselves through a process termed "tumor self-seeding." Here we exploit this biological attribute to deliver tumor necrosis factor alpha (TNF), a potent antitumor cytokine, directly to primary and metastatic tumors in a mechanism that we have defined as "tumor self-targeting." For this purpose, we genetically engineered mouse mammary adenocarcinoma (TSA), melanoma (B16-F10), and Lewis lung carcinoma cells to produce and release murine TNF. In a series of intervention trials, systemic administration of TNF-expressing tumor cells was associated with reduced growth of both primary tumors and metastatic colonies in immunocompetent mice. We show that these malignant cells home to tumors, locally release TNF, damage neovascular endothelium, and induce massive cancer cell apoptosis. We also demonstrate that such tumor-cell-mediated delivery avoids or minimizes common side effects often associated with TNF-based therapy, such as acute inflammation and weight loss. Our study provides proof of concept that genetically modified circulating tumor cells may serve as targeted vectors to deliver anticancer agents. In a clinical context, this unique paradigm represents a personalized approach to be translated into applications potentially using patient-derived circulating tumor cells as self-targeted vectors for drug delivery.
Asunto(s)
Neoplasias Experimentales/terapia , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Apoptosis , Carcinoma Pulmonar de Lewis/patología , Carcinoma Pulmonar de Lewis/secundario , Carcinoma Pulmonar de Lewis/terapia , Ingeniería Celular , Línea Celular Tumoral , Tratamiento Basado en Trasplante de Células y Tejidos , Sistemas de Liberación de Medicamentos , Endotelio Vascular/patología , Femenino , Humanos , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/secundario , Neoplasias Mamarias Experimentales/terapia , Melanoma Experimental/patología , Melanoma Experimental/secundario , Melanoma Experimental/terapia , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neoplasias Experimentales/patología , Neoplasias Experimentales/secundario , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapéutico , Transducción Genética , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Prostate cancer antigen 3 (PCA3) is the most specific prostate cancer biomarker but its function remains unknown. Here we identify PRUNE2, a target protein-coding gene variant, which harbors the PCA3 locus, thereby classifying PCA3 as an antisense intronic long noncoding (lnc)RNA. We show that PCA3 controls PRUNE2 levels via a unique regulatory mechanism involving formation of a PRUNE2/PCA3 double-stranded RNA that undergoes adenosine deaminase acting on RNA (ADAR)-dependent adenosine-to-inosine RNA editing. PRUNE2 expression or silencing in prostate cancer cells decreased and increased cell proliferation, respectively. Moreover, PRUNE2 and PCA3 elicited opposite effects on tumor growth in immunodeficient tumor-bearing mice. Coregulation and RNA editing of PRUNE2 and PCA3 were confirmed in human prostate cancer specimens, supporting the medical relevance of our findings. These results establish PCA3 as a dominant-negative oncogene and PRUNE2 as an unrecognized tumor suppressor gene in human prostate cancer, and their regulatory axis represents a unique molecular target for diagnostic and therapeutic intervention.
Asunto(s)
Antígenos de Neoplasias/genética , Intrones/genética , Proteínas de Neoplasias/genética , Neoplasias de la Próstata/genética , ARN Largo no Codificante/genética , Proteínas Supresoras de Tumor/genética , Adenosina Desaminasa/genética , Adenosina Desaminasa/metabolismo , Animales , Antígenos de Neoplasias/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Células HeLa , Humanos , Immunoblotting , Células MCF-7 , Masculino , Ratones SCID , Datos de Secuencia Molecular , Proteínas de Neoplasias/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Unión Proteica , Interferencia de ARN , Precursores del ARN/genética , Precursores del ARN/metabolismo , ARN Largo no Codificante/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Supresoras de Tumor/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Angiogenesis is fundamental to tumorigenesis and an attractive target for therapeutic intervention against cancer. We have recently demonstrated that CD13 (aminopeptidase N) expressed by nonmalignant host cells of unspecified types regulate tumor blood vessel development. Here, we compare CD13 wild-type and null bone marrow-transplanted tumor-bearing mice to show that host CD13(+) bone marrow-derived cells promote cancer progression via their effect on angiogenesis. Furthermore, we have identified CD11b(+)CD13(+) myeloid cells as the immune subpopulation directly regulating tumor blood vessel development. Finally, we show that these cells are specifically localized within the tumor microenvironment and produce proangiogenic soluble factors. Thus, CD11b(+)CD13(+) myeloid cells constitute a population of bone marrow-derived cells that promote tumor progression and metastasis and are potential candidates for the development of targeted antiangiogenic drugs.
Asunto(s)
Inductores de la Angiogénesis/metabolismo , Células de la Médula Ósea/metabolismo , Antígenos CD13 , Células Mieloides/metabolismo , Neoplasias Experimentales/metabolismo , Neovascularización Patológica/metabolismo , Animales , Células de la Médula Ósea/patología , Antígeno CD11b , Línea Celular Tumoral , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Células Mieloides/patología , Metástasis de la Neoplasia , Neoplasias Experimentales/patología , Neoplasias Experimentales/terapia , Neovascularización Patológica/patologíaRESUMEN
Phage display screening allows the study of functional protein-protein interactions at the cell surface, but investigating intracellular organelles remains a challenge. Here we introduce internalizing-phage libraries to identify clones that enter mammalian cells through a receptor-independent mechanism and target-specific organelles as a tool to select ligand peptides and identify their intracellular receptors. We demonstrate that penetratin, an antennapedia-derived peptide, can be displayed on the phage envelope and mediate receptor-independent uptake of internalizing phage into cells. We also show that an internalizing-phage construct displaying an established mitochondria-specific localization signal targets mitochondria, and that an internalizing-phage random peptide library selects for peptide motifs that localize to different intracellular compartments. As a proof-of-concept, we demonstrate that one such peptide, if chemically fused to penetratin, is internalized receptor-independently, localizes to mitochondria, and promotes cell death. This combinatorial platform technology has potential applications in cell biology and drug development.