Immunoproteasome Activity in Chronic Lymphocytic Leukemia as a Target of the Immunoproteasome-Selective Inhibitors.

Targeting proteasome with proteasome inhibitors (PIs) is an approved treatment strategy in multiple myeloma that has also been explored pre-clinically and clinically in other hematological malignancies. The approved PIs target both the constitutive and the immunoproteasome, the latter being present predominantly in cells of lymphoid origin. Therapeutic targeting of the immunoproteasome in cells with sole immunoproteasome activity may be selectively cytotoxic in malignant cells, while sparing the non-lymphoid tissues from the on-target PIs toxicity. Using activity-based probes to assess the proteasome activity profile and correlating it with the cytotoxicity assays, we identified B-cell chronic lymphocytic leukemia (B-CLL) to express predominantly immunoproteasome activity, which is associated with high sensitivity to approved proteasome inhibitors and, more importantly, to the immunoproteasome selective inhibitors LU005i and LU035i, targeting all immunoproteasome active subunits or only the immunoproteasome ß5i, respectively. At the same time, LU102, a proteasome ß2 inhibitor, sensitized B-CLL or immunoproteasome inhibitor-inherently resistant primary cells of acute myeloid leukemia, B-cell acute lymphoblastic leukemia, multiple myeloma and plasma cell leukemia to low doses of LU035i. The immunoproteasome thus represents a novel therapeutic target, which warrants further testing with clinical stage immunoproteasome inhibitors in monotherapy or in combinations.

Frequency and Genomic Aspects of Intrinsic Resistance to Vismodegib in Locally Advanced Basal Cell Carcinoma.

PURPOSE: Vismodegib is approved for the treatment of locally advanced basal cell carcinoma (laBCC), but some cases demonstrate intrinsic resistance (IR) to the drug. We sought to assess the frequency of IR to vismodegib in laBCC and its underlying genomic mechanisms. EXPERIMENTAL DESIGN: Response to vismodegib was evaluated in a cohort of 148 laBCC patients. Comprehensive genomic and transcriptomic profiling was performed in a subset of five intrinsically resistant BCC (IR-BCC). RESULTS: We identified that IR-BCC represents 6.1% of laBCC in the studied cohort. Prior treatment with chemotherapy was associated with IR. Genetic events that were previously associated with acquired resistance (AR) in BCC or medulloblastoma were observed in three out of five IR-BCC. However, IR-BCCs were distinct by highly rearranged polyploid genomes. Functional analyses identified hyperactivation of the HIPPO-YAP and WNT pathways at RNA and protein levels in IR-BCC. In vitro assay on the BCC cell line further confirmed that YAP1 overexpression increases the cell proliferation rate. CONCLUSIONS: IR to vismodegib is a rare event in laBCC. IR-BCCs frequently harbor resistance mutations in the Hh pathway, but also are characterized by hyperactivation of the HIPPO-YAP and WNT pathways.

HIV protease inhibitors for the treatment of multiple myeloma.

Outcomes in multiple myeloma (MM) patients have improved in recent years owing to the introduction of new drugs. Among them, proteasome inhibitors and immunomodulatory imide drugs have become central in the management of newly diagnosed and relapsed MM. However, resistance to these classes of agents develops in most patients and ultimately leads to death from relapsed/refractory disease. A need exists for new classes of antimyeloma drugs, especially ones that are active in the multirefractory setting. The conventional drug development process, which involves extensive preclinical and clinical testing prior to assessment of clinical activity, has fallen short in delivering adequately safe and active novel drug candidates. HIV protease inhibitors such as nelfinavir are safe, US Food and Drug Administration-approved agents that have been shown to have potent antimyeloma activity in both preclinical models and patients with refractory disease. The repurposing of HIV protease inhibitors for treatment of MM is promising in light of their antimyeloma activity in conjunction with their global availability, established safety, and relatively low cost. This review will summarize the preclinical and clinical data available on HIV protease inhibitors for the treatment of refractory MM.

Proteasome Inhibition in Multiple Myeloma: Head-to-Head Comparison of Currently Available Proteasome Inhibitors.

Proteasome inhibitors (PIs) are a backbone of multiple myeloma (MM) therapy. The proteasome harbors six proteolytically active subunits (ß1, ß2, ß5), while ß5 was identified as rate-limiting and is a primary target of clinically available PIs. The most effective pattern of subunit inhibition provided by these PIs for cytotoxic activity in MM is unknown. A head-to-head comparison of clinically available PIs shows that in the clinically relevant setting only the co-inhibition of ß1 or ß2 with ß5 activity achieves meaningful functional proteasome inhibition and cytotoxicity, while the selective ß2/ß5 inhibition of both constitutive and immunoproteasome is the most cytotoxic. In the long-term setting, selective inhibition of ß5 subunit is sufficient to induce cytotoxicity in PI-sensitive, but not in PI-resistant MM, and the ß5/ß2 co-inhibition is the most cytotoxic in PI-resistant MM. These results give a rational basis for selecting individual PIs for the treatment of MM.

Trombofilia primaria: mejoramiento del diagnóstico basado en evidencia / Thrombophilia: improving diagnosis with an evidence-based approach

El tromboembolismo venoso, que involucra que trombosis venosa profunda (TVP) y el tromboembolismo pulmonar (TEP)es uno de los síndromes con mayor morbi-mortalidad en pacientes ambulatorios y hospitalizados. Los factores de riesgogenéticos tienen un papel aún discutido en la génesis de enfermedades como la trombosis venosa profunda ya que existeuna gran variabilidad gen-gen y gen-ambiente. Existe debate desde hace muchos años sobre la utilidad de realizar estudiosgenéticos para detectar poblaciones de riesgo, sin embargo, la tendencia a medida que se publica nueva informaciónes limitar su uso para casos en los cuales proporcionará información valiosa capaz de modificar la estrategia terapéutica.El único método confiable para el diagnóstico de las mutaciones en trombofilia es por medio de la biología molecular, locual incurre en costes elevados para un sistema de salud como el nuestro, motivo por el cual se hace necesario efectuar unanálisis de la literatura acerca de la utilidad real del tamizaje por trombofilia y diseñar una estrategia basada en evidenciapara seleccionar pacientes que van a obtener un beneficio al someterse a este tipo de estudios.

Thromboembolic disorders are one of the leading causes of morbidity and mortality among patients hospitalized aswell as outpatients. There is an active debate about the contribution of genetic causes to thrombotic events such asdeep vein trombosis mainly because of the great variability between gene-gene and gene-environment interactions.Due to growing new evidence, there is a trend toward limiting thrombophilia testing to patients in whom the resultcould influence the treatment strategy. The only reliable method to diagnose mutations in thrombophilia is by means ofmolecular biology tests which incurrs in a high cost to our nacional social security. For this reasons, a revision of currentliterature is necessary to develop a evidence based- approach to patients with these diseases.

Polimorfismos del gen de la enzima convertidora de angiotensina, inserción/delección, y factores de riesgo asociados en pacientes con infarto agudo del mioicardio / Angiotensin converting enzime gene polimorphisms insertion/deletion and cardiovascular risk factors in patients with acute myocardial infarction

Introducción. Los factores clásicos de riesgo cardiovascular están ampliamente estudiados y estrechamente vinculados con el desarrollo de infarto agudo del miocardio, accidente vascular cerebral y enfermedad vascular periférica. Entre los factores genéticos que subyacen a estas condiciones están las mutaciones en el gen de la enzima convertidora de angiotensina. El principal objetivo de este estudio fue establecer la relación entre polimorfismos inserción/delección de la enzima conversora de angiotensina en una grupo de pacientes con cardiopatía isquémica. Métodos: Se realizó un estudio prospectivo de casos y controles en un grupo de pacientes con infarto agudo del miocardio referidos para coronariografía. Se obtuvo información clínica a partir de los expedientes clínicos y la entrevista personal. La obtención de ácido desoxirribunocleico y el análisis de polimorfismo de la enzima convertidora de angiotensina, inserción/delección, se realizaron con técnicas de biología molecular previamente descritas. Resultados: Se incluyeron en el estudio 33 casos y 67 controles. El 87.7 por ciento de los pacientes fueron de sexo masculino y el índice de masa corporal fue mayor en los casos, 35.6 que en los controles, 24.8 En el grupo de casos, el fumado, p mayor 0.001, hipertensión p mayor 0.001 e hiperfibrinogenemia p mayor 0.001 fueron factores significativamente asociados a la presencia de enfermedad cardiovascular, OR: 16.78; OR: 5.63; y OR: 16.8, respectivamente. No se encontró asociación del genotipo DD entre los casos y controles, ni su asociación con la hipertensión arterial en los individuos estudiados; en cambio, sí se encontró asociación entre los niveles del fibrinógeno y del genotipo II, p mayor 0.005. Angiográficamente, la arteria descendente anterior fue el vaso coronario más frecuentemente afectado en este grupoo. conclusión: No se encontró asociación entre el genotipo DD de la enzima convertidora de angitensina y la presencia de enfermedad cardiovascula...