Mapping of Genomic Vulnerabilities in the Post-Translational Ubiquitination, SUMOylation and Neddylation Machinery in Breast Cancer

© 2021 by the authors.The dysregulation of post-translational modifications (PTM) transversally impacts cancer hallmarks and constitutes an appealing vulnerability for drug development. In breast cancer there is growing preclinical evidence of the role of ubiquitin and ubiquitin-like SUMO and Nedd8 peptide conjugation to the proteome in tumorigenesis and drug resistance, particularly through their interplay with estrogen receptor signaling and DNA repair. Herein we explored genomic alterations in these processes using RNA-seq and mutation data from TCGA and METABRIC datasets, and analyzed them using a bioinformatic pipeline in search of those with prognostic and predictive capability which could qualify as subjects of drug research. Amplification of UBE2T, UBE2C, and BIRC5 conferred a worse prognosis in luminal A/B and basal-like tumors, luminal A/B tumors, and luminal A tumors, respectively. Higher UBE2T expression levels were predictive of a lower rate of pathological complete response in triple negative breast cancer patients following neoadjuvant chemotherapy, whereas UBE2C and BIRC5 expression was higher in luminal A patients with tumor relapse within 5 years of endocrine therapy or chemotherapy. The transcriptomic signatures of USP9X and USP7 gene mutations also conferred worse prognosis in luminal A, HER2-enriched, and basal-like tumors, and in luminal A tumors, respectively. In conclusion, we identified and characterized the clinical value of a group of genomic alterations in ubiquitination, SUMOylation, and neddylation enzymes, with potential for drug development in breast cancer.Work in Alberto Ocaña’s lab is supported by the Instituto de Salud Carlos III (ISCIII, PI19/00808); ACEPAIN; Diputación de Albacete; and the CRIS Cancer Foundation. Work in Atanasio Pandiella’s lab is supported by the Ministry of Economy and Competitiveness of Spain (BFU2015- 71371-R, the Junta de Castilla y León (CSI146P20), and the CRIS Foundation. Balázs Györffy is financed by the 2018-2.1.17-TET-KR-00001 grant and by the Higher Education Institutional Excellence Programme of the Ministry for Innovation and Technology (MIT) in Hungary, within the framework of the Bionic thematic programme of the Semmelweis University

Somos diversidad. Actividades para la formación de profesionales de la educación formal y no formal en diversidad sexual, familiar, corporal y de expresión e identidad de género

Este manual se presenta como una “caja de herramientas” donde acudir en busca de recursos y actividades didácticas para elaborar formaciones en diversidad sexual, familiar, corporal y de expresión e identidad de género, dirigidas a profesionales que trabajan con jóvenes. En este sentido, son materiales que se pueden adaptar a las necesidades de cada formación y a distintos niveles de conocimiento, tanto de los grupos participantes, como de la persona que dinamice las actividades y que son lo suficientemente flexibles para que puedan ser moldeados y utilizados según los recursos temporales y espaciales que presente cada propuestaformativa. “Somos diversidad” ofrece un total de 44 actividades articuladas en 5 módulos temáticos. Abrazar la diversidad como una oportunidad educativa Transformarse para transformar: afectividad, diferencia y diversidad Sexualidades Corporalidades, identidades y expresiones de género Diversidad familiar Cada módulo ofrece un índice inicial, una breve bienvenida donde se reflejan la justificación y objetivos del módulo, una serie de actividades y un apartado de bibliografía citada y consultada. En cada actividad se detalla su duración estimada, los objetivos propuestos, los recursos necesarios, las indicaciones para su desarrollo, y se aportan finalmente los materiales específicos necesarios para realizarlas. Este manual es el resultado de la actividad “Juventud y LGTBI+: abrazar la diversidad en la educación no formal y formal” dentro del Plan de Actividades Transnacionales (TCA) del programa Erasmus+: Juventud en Acción, organizada por el Injuve y el Grupo de Investigación “Antropología, Diversidad y Convivencia” de la Universidad Complutense de Madrid

sj-jpg-1-tam-10.1177_17588359211072621 – Supplemental material for Prognostic value of the immune target CEACAM6 in cancer: a meta-analysis [Dataset]

Supplemental material, sj-jpg-1-tam-10.1177_17588359211072621 for Prognostic value of the immune target CEACAM6 in cancer: a meta-analysis by Miguel Burgos, Iván Cavero-Redondo, Celia Álvarez-Bueno, Eva María Galán-Moya, Atanasio Pandiella, Eitan Amir and Alberto Ocaña in Therapeutic Advances in Medical OncologyInstituto de Salud Carlos IIIPeer reviewe

sj-docx-2-tam-10.1177_17588359211072621 – Supplemental material for Prognostic value of the immune target CEACAM6 in cancer a meta-analysis [Dataset]

Supplemental material, sj-docx-2-tam-10.1177_17588359211072621 for Prognostic value of the immune target CEACAM6 in cancer: a meta-analysis by Miguel Burgos, Iván Cavero-Redondo, Celia Álvarez-Bueno, Eva María Galán-Moya, Atanasio Pandiella, Eitan Amir and Alberto Ocaña in Therapeutic Advances in Medical OncologyInstituto de Salud Carlos IIIPeer reviewe

sj-jpg-2-tam-10.1177_17588359211072621 – Supplemental material for Prognostic value of the immune target CEACAM6 in cancer: a meta-analysis [Dataset]

Supplemental material, sj-jpg-2-tam-10.1177_17588359211072621 for Prognostic value of the immune target CEACAM6 in cancer: a meta-analysis by Miguel Burgos, Iván Cavero-Redondo, Celia Álvarez-Bueno, Eva María Galán-Moya, Atanasio Pandiella, Eitan Amir and Alberto Ocaña in Therapeutic Advances in Medical OncologyInstituto de Salud Carlos IIIPeer reviewe

sj-docx-1-tam-10.1177_17588359211072621 – Supplemental material for Prognostic value of the immune target CEACAM6 in cancer: a meta-analysis [Dataset]

Supplemental material, sj-docx-1-tam-10.1177_17588359211072621 for Prognostic value of the immune target CEACAM6 in cancer: a meta-analysis by Miguel Burgos, Iván Cavero-Redondo, Celia Álvarez-Bueno, Eva María Galán-Moya, Atanasio Pandiella, Eitan Amir and Alberto Ocaña in Therapeutic Advances in Medical OncologyInstituto de Salud Carlos IIIPeer reviewe

MZ1 co-operates with trastuzumab in HER2 positive breast cancer

© The Author(s).[Background]: Although the anti-HER2 antibody trastuzumab augments patient survival in HER2+ breast cancer, a relevant number of patients progress to this treatment. In this context, novel drug combinations are needed to increase its antitumor activity. In this work, we have evaluated the efficacy of proteolysis targeting chimera (PROTAC) compounds based on BET inhibitors (BETi) to augment the activity of trastuzumab in HER2+ breast cancer models.[Methods]: BT474 and SKBR3 HER2+ breast cancer cell lines were used. The effects of trastuzumab and the BET-PROTAC MZ1 either alone or in combination, were evaluated using MTT proliferation assays, three-dimensional invasion and adhesion cultures, flow cytometry, qPCR and Western blot. In vivo studies were carried out in a xenografted model in mice. Finally, a Clariom_S_Human transcriptomic array was applied to identify deregulated genes after treatments.[Results]: MZ1 induced a higher antiproliferative effect compared to the BETi JQ1. The combination of MZ1 and -trastuzumab significantly decreased cell proliferation, the formation of three-dimensional structures and cellular invasion compared to either of the drugs alone. Evaluation of apoptosis resulted in an increase of cell death following treatment with the combination, and biochemical studies displayed modifications of apoptosis and DNA damage components. In vivo administration of agents alone or combined, to tumors orthotopically xenografted in mice, resulted in a decrease of the tumor volume only after MZ1-Trastuzumab combination treatment. Results from a transcriptomic array indicated a series of newly described transcription factors including HOXB7, MEIS2, TCERG1, and DNAJC2, that were associated to poor outcome in HER2+ breast cancer subtype and downregulated by the MZ1-trastuzumab combination.[Conclusions]: We describe an active novel combination that includes the BET-PROTAC MZ1 and trastuzumab, in HER2+ tumors. Further studies should be performed to confirm these findings and pave the way for their future clinical development.This work has been supported by Instituto de Salud Carlos III (PI19/00808), ACEPAIN, Diputación de Albacete, CIBERONC and CRIS Cancer Foundation (to A. Ocaña), Ministry of Economy and Competitiveness of Spain (BFU2015–71371-R), the Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD12/0036/0003) and CIBERONC, the scientific foundation of the AECC and the CRIS Foundation (to A. Pandiella). The work carried out in our laboratories receive support from the European Community through the regional development funding program (FEDER). MdM. Noblejas-López was supported by Spanish Ministry of Education (FPU grant; Ref.: FPU18/01319). E.M. Galan-Moya is funded by the implementation research program of the UCLM (UCLM resolution date: 31/07/2014), with a contract for accessing the Spanish System of Science, Technology and Innovation-SECTI (co-funded by the European Commission/FSE funds). This work has been supported by Junta de Comunidades de Castilla-La Mancha (SBPLY/19/180501/000173) (to E.M. Galan-Moya and A.Ocana). D. Tébar-García is funded by a contract from Junta de Comunidades de Castilla-La Mancha (SBPLY/19/180501/000173). J.C. Montero is funded by the Instituto de Salud Carlos III through a Miguel Servet program (CPII17/00015) and receives research support from the same institution (PI15/00684 and PI18/00796 M). M. Burgos is funded by Castilla-La Mancha support grant for Biomedicine and Health Science Research ref.: II-2018_11

Prognostic value of the immune target CEACAM6 in cancer: a meta-analysis

[Background]: Identification of membrane proteins differentially expressed on tumor cells is a key step in drug development. The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is a cell adhesion protein belonging to the immunoglobulin superfamily. Here, we explore the prognostic role CEACAM6 expression on patient outcome in cancer. [Methods]: A systematic search for studies evaluating the association between tumor expression of CEACAM6 and overall survival (OS) and disease-free survival (DFS) was performed. Hazard ratios (HR) were pooled in a meta-analysis using generic inverse variance and random effect modeling. Subgroup analyses were conducted based on tumor type and method of HR extraction. [Results]: Sixteen studies met the inclusion criteria. CEACAM6 expression was associated with worse OS [HR = 1.96, 95% confidence interval (CI) = 1.51–2.53], and DFS (HR = 2.49, 95% CI = 2.01–3.07) with subgroup analysis showing no significant differences between disease site subgroups. [Conclusions]: High expression of CEACAM6 is associated with worse OS and DFS in different malignancies. CEACAM6 is a target for the future development of novel therapeutics.This work has been supported by Instituto de Salud Carlos III (PI19/00808), ACEPAIN, Diputación de Albacete, CIBERONC and CRIS Cancer Foundation (to AO). MB is funded by University of Castilla-La Mancha (UCLM). EMGM holds a Distinguished Researcher contract from the UCLM. This work has been supported by Junta de Comunidades de Castilla-La Mancha (SBPLY/19/180501/ 000173) (to EMGM and AO)

Impact of availability of companion diagnostics on the clinical development of anticancer drugs

[Background]: Companion diagnostics permit the selection of patients likely to respond to targeted anticancer drugs; however, it is unclear if the drug development process differs between drugs developed with or without companion diagnostics. Identification of differences in study design could help future clinical development. [Patients and Methods]: Anticancer drugs approved for use in solid tumors between 28 September 2000 and 4 January 2014 were identified using a search of the US FDA website. Phase III trials supporting registration were extracted from the drug label. Each published study was reviewed to obtain information about the phase I and II trials used for the development of the respective drug. [Results]: We identified 35 drugs and 59 phase III randomized trials supporting regulatory approval. Fifty-three phase I trials and 47 phase II trials were cited in the studies and were used to support the design of these phase III trials. The approval of drugs using a companion diagnostic has increased over time (p for trend 0.01). Expansion cohorts were more frequently observed with drugs developed with a companion diagnostic (62 vs. 20%; p = 0.005). No differences between drugs developed with or without a companion diagnostic were observed for the design of phase I and II studies. [Conclusions]: The approval of drugs developed with a companion diagnostic has increased over time. The availability of a companion diagnostic was associated with more frequent use of phase I expansion cohorts comprising patients selected by the companion diagnostic.Instituto de Salud Carlos III (PI16/01121), ACEPAIN; Diputación de Albacete and CRIS Cancer Foundation (to AO); Beca Ampliación de Estudios (BAE) to AO for his stay at Yale University; Ministry of Economy and Competitiveness of Spain (BFU2012–39151 and BFU2015-71371-R), the Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD12/0036/0003) and the CIBERONC, the scientific foundation of the Asociación Española Contra el Cáncer (AECC) and the CRIS Foundation (to AP). The work carried out in the Spanish laboratories receives support from the European Community through the regional development funding program (FEDER).Peer reviewe

Genomic correlates of dna damage in breast cancer subtypes

© 2021 by the authors.Among the described druggable vulnerabilities, acting on the DNA repair mechanism has gained momentum, with the approval of PARP inhibitors in several indications, including breast cancer. However, beyond the mere presence of BRCA1/BRCA2 mutations, the identification of additional biomarkers that would help to select tumors with an extreme dependence on DNA repair machinery would help to stratify therapeutic decisions. Gene set enrichment analyses (GSEA) using public datasets evaluating expression values between normal breast tissue and breast cancer identified a set of upregulated genes. Genes included in different pathways, such as ATM/ATR, BARD1, and Fanconi Anemia, which are involved in the DNA damage response, were selected and confirmed using molecular alterations data contained at cBioportal. Nineteen genes from these gene sets were identified to be amplified and upregulated in breast cancer but only five of them NBN, PRKDC, RFWD2, UBE2T, and YWHAZ meet criteria in all breast cancer molecular subtypes. Correlation of the selected genes with prognosis (relapse free survival, RFS, and overall survival, OS) was performed using the KM Plotter Online Tool. In last place, we selected the best signature of genes within this process whose upregulation can be indicative of a more aggressive phenotype and linked with worse outcome. In summary, we identify genomic correlates within DNA damage pathway associated with prognosis in breast cancer.We would like to thank our funding institutions, Instituto de Salud Carlos III, Diputación de Albacete, AECC Foundation, Ministry of Economy and Competitiveness of Spain, the Spanish Cancer Centers Network Program, and the European Commission as the FEDER funding program responsible institution. We would like to especially thank our supporting foundations, such as the “Asociación Costuras en la Piel en Apoyo a la investigación de cáncer en Albacete” (ACEPAIN) and the Cris Cancer Foundation for their continuous efforts to support our work