BRCA2 and Other DDR Genes in Prostate Cancer

BRCA2; DDR; Prostate cancerBRCA2; DDR; Càncer de pròstataBRCA2; DDR; Cáncer de próstataGermline and somatic aberrations in DNA damage repair (DDR) genes are more prevalent in prostate cancer than previously recognized, with BRCA2 as the most commonly altered gene. Germline mutations in BRCA2 have been linked to poor prognosis when patients are managed under the protocols currently approved for prostate cancer. The impact of germline mutations in other DDR genes beyond BRCA2 remain unclear. Importantly, a quarter of prostate cancer patients identified as germline mutation carriers lack a family history of cancer. The clinical implications of somatic DDR defects are yet to be elucidated. Poly ADP-ribose polymerase (PARP) inhibitors and platinum-based chemotherapy have proven to be effective in the treatment of other tumor types linked to BRCA1 and BRCA2 alterations and several trials are currently evaluating their efficacy in prostate cancer. Here, we summarize the available evidence regarding the prevalence of somatic and germline DDR defects in prostate cancer; their association with clinical outcomes; the trials assessing the efficacy of new therapies that exploit DDR defects in prostate cancer and briefly discuss some uncertainties about the most appropriate management for these patients.Supported by grants CM17/00221, PI16/01070, CP15/00090 and PI16/01565 from the Instituto de Salud Carlos III, PC170510P2 from the U.S. Department of Defense, W81XWH-18-1-0193 from the U.S. Department of Defense, RYC-2015-18625 from the Ministerio de Economía y Competitividad and Young Investigator Awards from the Prostate Cancer Foundatio

Value of Early Circulating Tumor Cells Dynamics to Estimate Docetaxel Benefit in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients

Biomarcadores; Células tumorales circulantes; DocetaxelBiomarkers; Circulating tumor cells; DocetaxelBiomarcadors; Cèl·lules tumorals circulants; DocetaxelCirculating tumor cell (CTC) enumeration and changes following treatment have been demonstrated to be superior to PSA response in determining mCRPC outcome in patients receiving AR signaling inhibitors but not taxanes. We carried out a pooled analysis of two prospective studies in mCRPC patients treated with docetaxel. CTCs were measured at baseline and 3–6 weeks post treatment initiation. Cox regression models were constructed to compare 6-month radiographical progression-free survival (rPFS), CTCs and PSA changes predicting outcome. Among the subjects, 80 and 52 patients had evaluable baseline and post-treatment CTC counts, respectively. A significant association of higher baseline CTC count with worse overall survival (OS), PFS and time to PSA progression (TTPP) was observed. While CTC response at 3–6 weeks (CTC conversion (from ≥5 to <5 CTCs), CTC30 (≥30% decline in CTC) or CTC0 (decline to 0 CTC)) and 6-month rPFS were significantly associated with OS (all p < 0.005), the association was not significant for PSA30 or PSA50 response. CTC and PSA response were discordant in over 50% of cases, with outcome driven by CTC response in these patients. The c-index values for OS were superior for early CTC changes compared to PSA response endpoints, and similar to 6-month rPFS. Early CTC declines were good predictors of improved outcomes in mCRPC patients treated with docetaxel in this small study, offering a superior and/or earlier estimation of docetaxel benefit in comparison to PSA or rPFS that merits further confirmation in larger studies.The results reported here were generated as part of two academic studies supported by various grants. The funding sources had no role in study design, data analysis, data interpretation or writing of the report. R.L., D.L. and D.O. had full access to all of the data and had final responsibility for the decision to submit for publication. This project represents independent research supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care

Myocardial injury following transcatheter aortic valve implantation : insights from delayed-enhancement cardiovascular magnetic resonance

Aims: The aim of this study was to evaluate the presence, localisation and extent of myocardial injury as determined by late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) imaging in patients undergoing transcatheter aortic valve implantation (TAVI). Methods and results: A total of 37 patients, who underwent successful TAVI with a balloon-expandable valve (transapical [TA], n=11; non-TA, n=26), were included. Cardiac biomarker (CK-MB and cTnT) lev- els were determined at baseline and following TAVI. CMR was performed within a week before and within 30 days following TAVI. Some increase in cardiac biomarkers was detected in 97% of the patients as deter- mined by a rise in cTnT, and in 49% of the patients as determined by a rise in CK-MB. Following TAVI, no new myocardial necrosis defects were observed with the non-TA approach. Nonetheless, all patients who underwent TAVI through the TA approach had new focal myocardial necrosis in the apex, with a median myo-cardial extent and necrotic mass of 5% [2.0-7.0] and 3.5 g [2.3-4.5], respectively. Conclusions: Although some increase in cardiac biomarkers of myocardial injury was systematically detected following TAVI, new myocardial necrosis as evaluated by CMR was observed only in patients undergoing the procedure through the TA approach, involving ~5% of the myocardium in the apex

METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer

Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N-7-methylguanosine (m(7)G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m(7)G tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5'tRNA fragments. 5'tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m(7)G tRNA methylation in cancer cell translation control and tumour biology

Docetaxel response characterization and identification of predictive biomarkers in metastatic castration resistant prostate cancer

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 03-09-2019Esta tesis tiene embargado el acceso al texto completo hasta el 03-03-2021Prostate cancer is the most common malignancy in men and the cause of highest mortality in developed countries. Although radical prostatectomy and radiotherapy are the established treatments for localized disease, androgen deprivation therapy represents the mainstay for the treatment of locally advanced, recurrent or metastatic prostate cancer. Chemical castration is temporarily effective in these patients, but eventually 30% of them progress and develop resistance to castration (CRPC) that can lead to the emergence of new metastases. The first line Docetaxel treatment has shown a survival benefit in patients with mCRPC, but unfortunately, part of them end up developing resistance to treatment. The search for new response biomarkers for treatment with DOC is one of the main objectives of this doctoral thesis, using circulating tumor cells (CTCs) as a surrogate marker of the prostate tumor. In our case, we detected in CTCs the presence of two markers, related to the activity of the DOC, to define its correlation with the response: a mitosis arrest biomarker, phospho-histone-H3 (pHH3), and apoptosis biomarker, cytokeratin M30 (CK-M30). Preclinical models generated from metastatic prostate cancer, by orthotopic injection of human tumor cells in NOD Scid Gamma mice, have faithfully reproduced the clinical progression of patients with mCRPC and have been key to identifying and validating biomarkers in CTCs, as well as to understand the biology of prostate cancer. On the other hand, the detection and counting of CTCs has been shown to be a sensitive marker to control the disease status during the response to treatment with DOC. In addition, we have shown that patients who are more likely to obtain a clinical benefit from DOC treatment can be pre-selected by detecting an increase in CTC pHH3 + in the first treatment cyclesEl cáncer de próstata es el tipo de tumor más común en hombres y el causante de la mayor tasa de mortalidad en países desarrollados. Aunque la prostatectomía radical y la radioterapia son los tratamientos establecidos para enfermedad localizada, la terapia de privación de andrógenos representa el pilar para el manejo del cáncer de próstata localmente avanzado, recurrente o metastásico. A pesar de que la castración química es temporalmente eficaz en estos pacientes, eventualmente un 30% de ellos progresan y desarrollar resistencia a la castración (CRPC) que puede derivar en la aparición de nuevas metástasis. El tratamiento con Docetaxel (DOC) en primera línea ha demostrado un beneficio en la supervivencia de los pacientes con mCRPC, pero desafortunadamente, parte de ellos acaban desarrollando resistencia al tratamiento. La búsqueda de nuevos biomarcadores de respuesta para el tratamiento con DOC es uno de los principales objetivos de esta tesis doctoral, utilizando para ello las células tumorales circulantes (CTCs) como marcador subrogado del tumor de próstata. En nuestro caso, hemos detectado en CTCs la presencia de dos marcadores relacionados con la actividad del DOC para definir su correlación con la respuesta: un marcador de arresto en mitosis, fosfo-histona-H3 (pHH3), y un marcador de apoptosis citoqueratina M30 (CK-M30). Los modelos preclínicos de cáncer de próstata metastásico generados mediante inyección ortotópica células tumorales humanas en ratones NOD Scid Gamma, han reproducido fidedignamente la progresión clínica de los pacientes con mCRPC y han sido claves en para identificar y validar en CTCs biomarcadores, así como para entender la biología de cáncer de próstata. Por otro lado, la detección y recuento de CTCs ha demostrado ser un marcador sensible en la monitorización del estado de la enfermedad durante la respuesta al tratamiento con DOC. Además, hemos demostrado que los pacientes con mayor probabilidad de obtener un beneficio clínico del tratamiento con DOC pueden preseleccionarse detectando un aumento de CTC pHH3 + en los primeros ciclos de tratamient

The role of m6A, m5C and Ψ RNA modifications in cancer: Novel therapeutic opportunities

© The Author(s).RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programmes. Significant advances have been made in understanding the functional role of RNA modifications in regulating coding and non-coding RNA processing and function, which in turn thoroughly shape distinct gene expression programmes. They affect diverse biological processes, and the correct deposition of many of these modifications is required for normal development. Alterations of their deposition are implicated in several diseases, including cancer. In this Review, we focus on the occurrence of N6-methyladenosine (m6A), 5-methylcytosine (m5C) and pseudouridine (Ψ) in coding and non-coding RNAs and describe their physiopathological role in cancer. We will highlight the latest insights into the mechanisms of how these posttranscriptional modifications influence tumour development, maintenance, and progression. Finally, we will summarize the latest advances on the development of small molecule inhibitors that target specific writers or erasers to rewind the epitranscriptome of a cancer cell and their therapeutic potential.This work was supported by Spanish Ministry of Economy and Innovation (MINECO), Ministry of Science and Innovation and Agencia Estatal de Investigación (AEI) and co-financed by the European Development Regional Fund (FEDER) under grant no. SAF2016–78667-R (AEI/FEDER, UE) and PID2019-111692RB-I00. In addition we acknowledge funding from The Scientific Foundation AECC under grant no. LABAE19040BLAN. BML was supported by Junta de Castilla y León-Fondo Social Europeo (ESF) predoctoral fellowship. AUTHOR’s institution is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia co-financed by the Castilla–León autonomous government and the European Regional Development Fund (CLC–2017–01)Peer reviewe

Identification of RNA modifications relevant for Docetaxel resistance in prostate cancer

Trabajo presentado en el 2nd ASPIC ASEICA International Meeting, celebrado en modalidad virtual del 14 al 15 de octubre de 2021

Identification of critical 6-methyladenosine regulators as malignant prognosis factors in prostate adenocarcinoma

Trabajo presentado en el II ASPIC-ASEICA International Meeting, celebrado en modalidad virtual el 14 de octubre de 2021

Identification of critical 6-methyladenosine regulators as malignant prognosis factors in prostate adenocarcinoma

Trabajo presentado en el 3rd Educacional symposium ASEICA, celebrado en modalidad virtual del 23 al 25 de noviembre de 2021