Line of Research

Prostate cancer (PCa) is the second leading cause of cancer death in men in the United States. Incidence increases with patient age and represents the most important risk factor. Localized PCa can be cured in most cases, but when the disease escapes the confines of the gland, the prospects for cure decrease drastically. Androgen ablation is the most effective way of halting PCa progression, but given sufficient time, growth of the cancer resumes in most cases, and the disease becomes “castration resistant”. Bone is the most common and frequently the only site of PCa progression, and men with PCa display characteristically osteoblastic bone metastases, which are the main cause of morbidity and mortality of the disease. No therapy is curative for patients with castrate resistant PCa (CRPC). This resistance requires consecutive modifications in treatment; each new change may not be the best suitable option and may even favor the further development of drug resistance. Thus, there is a critical need for a reliable system to select the best possible and prompt therapy target for each patient (individualized patient therapy).
Currently our view of cancer has evolved to include, in addition to the transformed cells that have re-arranged oncogenic signaling pathways, a deregulation in metabolism. The acquired metabolic signature is an essential determinant of the characteristics of the tumor progression, contributing to the failure of MAB therapy. Mass spectrometry (MS) has expanded from a tool for the identification and characterization of isolated proteins to an interrogating platform for complex proteomes, and moreover, coupled to a liquid chromatograph to define metabolomes by matching spectra to sequence databases10. Hence metabolomics is developing at an exponential rate with the improvement of technology, including the acceleration of metabolites enrichment methods, MS instrumentation, bioinformatics software, and high-throughput affinity assays for screening large sample sets. It is therefore imperative to identify new molecules/mechanisms that boost the cancer cell and bypass tumor-induced immune tolerance, especially critical in advanced prostate cancer.

Mammalian cells use two main pathways to generate energy in the form of adenosine triphosphate (ATP) from glucose: oxidative phosphorylation in the mitochondria, with CO2 and H2O as final products, and glycolysis in the cytoplasm, yielding lactate. Glycolysis is usually inhibited in the presence of oxygen. However, in some circumstances such as highly proliferating cells or neoplastic transformation, glucose will be metabolized to lactate even in the presence of oxygen, which is known as the Warburg effect12. The impaired function of the TCA cycle envisions that the normal energetic status of this gland is highly glycolytic. Although not fully explained, the metabolic pathways of greatest relevance in PCa seem to be fatty acid (FA) and glutamine metabolism. The enormous complexity of energy metabolism pathways, the notion that by identifying signaling molecules that control glycolytic genes we are only scratching the surface of this process, and the awareness that most molecular data supporting this model derive from cell culture studies, underline the existence of extensive gaps in our understanding of this phenotype, with an obvious negative impact on our ability to harness it for clinical purposes.

The discovery of effective prognostic and diagnostic biomarkers and future PCa drug development in the era of personalized medicine, would greatly benefit from the field of metabolomics. Allowing the characterization of the information flow through protein pathways that interconnect the metabolic pathways with the control of gene transcription is the ultimate goal of metabolomics to achieve a patient-tailored therapy. Hence, the application of metabolomics to query prostate tissue specimens yields novel prostate cancer biomarkers. Therefore, we employ a metabolomic based approach for the identification of predictive PCa biomarker candidates characterizing the metabolic signature mediated by heme oxygenase-1 (HO-1).

The main goal of the projects is identify a biomarker that improves the diagnosis and prognosis of prostate cancer and acute leukemia.

The specific aims include:

– To study the role of the glucocorticoid receptor in prostate cancer progression and metastasis.

– To study the molecular mechanisms involved in the development of castration-resistant prostate cancer.

– To study markers of oxidative stress as an additional tool for prostate cancer diagnosis.

– To study the pharmacogenetics of acute lymphoblastic leukemia. This is multicenter and multinational protocol of the BFM study group.

Considering that HO-1 has a role beyond heme degradation in Prostate cancer, we seek to identify molecular partners by which HO-1 could impair the cellular processes that promote tumorigenesis. These molecular partners could potentially be tested as biomarkers and be selected to define a subtype of PCa patients who require an alternative therapeutic option.

We propose the following specific aims:

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To identify HO-1 interactome through a proteomic approach and the use of bioinformatics tools.

– To identify the potentiality of the HO-1 interactome as prognostic/diagnostic biomarkers of PCa with tissue microarray technology.

– To validate the biological significance and functionality of HO-1 interactome through in vitro assays and PCa xenografts.

Caracterización de la firma metabólica de cáncer de próstata mediada por HO-1:

El cáncer de próstata (PCa) constituye el tipo de cáncer más comúnmente diagnosticado en el hombre con más de 1 millón de casos nuevos por año. A pesar que el advenimiento de la detección del antígeno prostático específico (PSA) ha facilitado el diagnóstico de nuevos casos para su intervención temprana, este hecho no parece disminuír su mortalidad y algunos pacientes todavía experimentan progresión de la enfermedad luego de recibir tratamiento primario. Actualmente, el tratamiento sistémico estándar para el PCa avanzado está basado en la deprivación de andrógenos a los cuales los tumores responden inicialmente pero eventualmente se vuelven resistentes a la castración (CRPC). Para los pacientes con CRPC, ninguna terapia es curativa, de esta manera surge la necesidad de identificar nuevos blancos y diseñar combinaciones terapéuticas novedosas para controlar la progresión del PCa.

El diagnóstico y la clasificación apropiados de los cánceres es vital para la clínica. La categorización de los mismos se ha sustentado en signos clínicos o histológicos y en los perfiles de expresión génicos. Las alteraciones del metabolismo energético constituyen un punto clave en la enfermedad neoplásica y la importancia de la reprogramación metabólica ha resurgido al hacerse evidente las numerosas conexiones entre las vías de señalización que incluyen oncoproteínas y las enzimas claves en el metabolismo energético. La variación en un solo gen podría orquestar el cambio de una ruta metabólica y así conferir una ventaja adaptativa. Es por eso, que el análisis metabolómico provee información de suma relevancia que no es accesible mediante un estudio de genómica o proteómica, ya que un cambio en la regulación de un gen se puede manifestar amplificado en los procesos metabólicos. Dado el rol anti-tumoral de HO-1 en el PCa previamente reportado en nuestro laboratorio, nuestra hipótesis se basa en que HO-1 y sus interactores pueden reprogramar a la célula del PCa alterando su metabolismo, favoreciendo así el establecimiento de un fenotipo menos agresivo.

En el marco de un abordaje metabolómico para el desarrollo de nuevos blancos para la síntesis de drogas, biomarcadores para el diagnóstico temprano o candidatos para nuevas terapias, utilizamos técnicas para definir la firma metabólica en líneas de PCa (sensibles e insensibles a andrógenos) bajo modulación génica y farmacológica de HO-1. El análisis de los metabolomas en células de PCa permite identificar metabolitos y vías enzimáticas que se producen y expresan de manera diferencial y en forma dinámica, en respuesta a la modulación de HO-1, manifestando la importancia de la regulación de esta proteína en el PCa. Asímismo utilizamos un abordaje proteómico para identificar interactores mitocondriales de HO-1 y su potencial como biomarcadores predictivos de la carcinogénesis prostática.