Selective PARP-2 targeted therapy as a new strategy in pancreatic cancer: Beyond personalized medicine

Trabajo presentado en el 2nd Annual Congress of Conexión Cáncer, celebrado en Benidorm (España), del 23 al 25 de enero de 2023Pancreatic ductal adenocarcinoma (PDA) has been predicted to soon become the second leading cause of cancer related deaths. Although poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have emerged as promising anti-cancer drugs for BRCA mutated tumors, in pancreatic cancer, phase III clinical results have failed. Major limitations of PARPi are due to their lack of selectivity. In this regard, we have recently demonstrated that Parp-2, but not Parp-1, plays a specific role in replicative stress, which is a known PDA hallmark. Therefore, we hypothesized that Parp-2 may represent a new potential target to fight against PDA. Importantly, Parp-2 genetic deletion in Ela-myc transgenic mice resulted in a 43% increase in animal survival. Tumor histopathological characterization showed that Parp-2 inhibition hampers acinar-to- ductal metaplasia, a key event in pancreatic cancer initiation. Parp-2 loss in vitro significantly decreased tumoroid generation capacity and induced DNA damage accumulation, increasing replicative stress and apoptosis. Molecular analysis of Ela-myc:Parp-2-/- vs Ela-myc Parp- 2+/+ pancreatic tumors in preneoplastic lesions, indicated that Parp-2 inhibition resulted in a less immune-evasive environment. Moreover, GSEA at late tumor stages shows p53 pathway enrichment in Ela-myc Parp-2+/+ vs Ela-myc:Parp-2-/-. Indeed, p53 inactivation was found in primary cell lines established from late stage Ela-myc:Parp-2-/- tumors, suggesting that loss of function of this pathway is required for tumor progression in the absence of Parp-2. Altogether our data highlight that Parp-2 is a novel target in pancreatic cancer and open new avenues for therapeutic intervention against this aggressive tumor by using specific Parp-2 pharmacological inhibitors

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Impact of DNA damage response-targeted therapies on the immune response to tumours

The DNA damage response (DDR) maintains the stability of a genome faced with genotoxic insults (exogenous or endogenous), and aberrations of the DDR are a hallmark of cancer cells. These cancer-specific DDR defects present new therapeutic opportunities, and different compounds that inhibit key components of DDR have been approved for clinical use or are in various stages of clinical trials. Although the therapeutic rationale of these DDR-targeted agents initially focused on their action against tumour cells themselves, these agents might also impact the crosstalk between tumour cells and the immune system, which can facilitate or impede tumour progression. In this review, we summarise recent data on how DDR-targeted agents can affect the interactions between tumour cells and the components of the immune system, both by acting directly on the immune cells themselves and by altering the expression of different molecules and pathways in tumour cells that are critical for their relationship with the immune system. Obtaining an in-depth understanding of the mechanisms behind how DDR-targeted therapies affect the immune system, and their crosstalk with tumour cells, may provide invaluable clues for the rational development of new therapeutic strategies in cancer

Understanding the specific functions of PARP-1 and PARP-2 in c-Myc-driven tumors

Trabajo presentado en el Cold Spring Harbor meeting: The PARP Family & ADP-ribosylation, celebrado online, del 30 de marzo al 2 de abril de 2022Dysregulated expression of oncogenes, as c-Myc, is a key source of replicati on stress and a major driver of genomicinstability leading to tumor development. Replicati on stress is signalled and suppressed by a signalling cascade,termed the DNA-damage response (DDR). ATR kinase acti vati on initi ates the replicati on stress response throughphosphorylati on of many substrates. Besides phosphorylati on, PARylati on of specifi c proteins by the two ADP-ribosyltransferases PARP1 and PARP2 has emerged as a criti cal mediator of the DDR. Accordingly, PARP inhibitors havebecome established cancer therapeuti cs. However, the inhibitors available for clinical use are not able to discriminatebetween individual ADP-ribosyltransferases, despite increasing evidence suggesti ng that PARP1 and PARP2 havedisti nct biological roles. For instance, PARP-2, but not PARP-1, has been involved in processes related with highproliferati ve cell rate. These diff erences have also been noted in other mouse models with a compromise response toreplicati on stress. We have examined how specifi c PARP1-defi ciency or PARP2-defi ciency impacts in c-Myc-driventumor development in two diff erent mouse models. In one of these models, the c-Myc oncogene is driven by theimmunoglobulin heavy enhancer giving rise to B-cell lymphomas. Interesti ngly, PARP2 defi ciency prevented c-Myc¿driven B-cell lymphoma in mice, whereas PARP1 defi ciency accelerated tumor progression. At cellular level, PARP2limited replicati on stress of c-Myc¿overexpressing B cells, whereas PARP1 aff ects the cross-talk between tumor cellsand the immune system. In our second model, c-Myc is driven by the pancreas-specifi c elastase promoter giving riseto pancreati c tumors. In this model, PARP2-defi ciency delays tumor progression and signifi cantly increases micesurvival while PARP1 defi ciency has no impact on tumour-free survival. Our results provide crucial informati on thatmay impact for the development of PARP-centred therapies

Selective PARP 2 inhibition hampers pancreatic cancer tumorigenesis and progression

Trabajo presentado en el 18th ASEICA International Congress, celebrado en Santiago de Compostela (España), del 16 al 18 de noviembre de 202

Selective PARP-2 targeted therapy as anew strategy in pancreatic cancer

Trabajo presentado en el Defence is the Best Attack: Immuno-Oncology Breakthroughs. EACR Conference, celebrada en Barcelona (España), del 9 al 11 de mayo de 2023Pancreatic ductal adenocarcinoma (PDA) has been predicted to soon becomethe second leading cause of cancer related deaths. Although poly (ADPribose)polymerase (PARP) inhibitors (PARPi) have emerged as promising anticancerdrugs for BRCA mutated tumors, in pancreatic cancer, phase III clinical resultshave failed. Major limitations of PARPi are due to their lack of selectivity. In thisregard, we have recently demonstrated that Parp-2, but not Parp-1, plays aspecific role in replicative stress, which is a known PDA hallmark. Therefore, wehypothesized that Parp-2 may represent a new potential target to fight againstPDA. Importantly, Parp-2 genetic deletion in Ela-myc transgenic mice resulted in a43% increase in animal survival. Tumor histopathological characterizationshowed that Parp-2 inhibition hampers acinarto-ductal metaplasia, a key eventin pancreatic cancer initiation. Parp-2 loss in vitro significantly decreasedtumoroid generation capacity and induced DNA damage accumulation,increasing replicative stress and apoptosis. Molecular analysis of Ela-myc:Parp-2-/- vs Ela-myc Parp-2+/+ pancreatic tumors in preneoplastic lesions, indicatedthat Parp-2 inhibition resulted in a less immune-evasive environment. Moreover,GSEA at late tumor stages shows p53 pathway enrichment in Ela-myc Parp-2+/+vs Ela-myc:Parp-2-/-. Indeed, p53 inactivation was found in primary cell linesestablished from late stage Ela-myc:Parp-2-/- tumors, suggesting that loss offunction of this pathway is required for tumor progression in the absence ofParp-2. Altogether our data highlight that Parp-2 is a novel target in pancreaticcancer and open new avenues for therapeutic intervention against thisaggressive tumor by using specific Parp-2 pharmacological inhibitors

Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice.

Dysregulation of the c-Myc oncogene occurs in a wide variety of hematologic malignancies, and its overexpression has been linked with aggressive tumor progression. Here, we show that poly (ADP-ribose) polymerase 1 (PARP-1) and PARP-2 exert opposing influences on progression of c-Myc-driven B-cell lymphoma. PARP-1 and PARP-2 catalyze the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA strand breaks, playing a central role in the response to DNA damage. Accordingly, PARP inhibitors have emerged as promising new cancer therapeutics. However, the inhibitors currently available for clinical use are not able to discriminate between individual PARP proteins. We found that genetic deletion of PARP-2 prevents c-Myc-driven B-cell lymphoma, whereas PARP-1 deficiency accelerates lymphomagenesis in the Eμ-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in preleukemic Eμ-Myc B cells, resulting in accumulation of DNA damage and concomitant cell death that restricts the c-Myc-driven expansion of B cells, thereby providing protection against B-cell lymphoma. In contrast, PARP-1 deficiency induces a proinflammatory response and an increase in regulatory T cells, likely contributing to immune escape of B-cell lymphoma, resulting in an acceleration of lymphomagenesis. These findings pinpoint specific functions for PARP-1 and PARP-2 in c-Myc-driven lymphomagenesis with antagonistic consequences that may help inform the design of new PARP-centered therapeutic strategies, with selective PARP-2 inhibition potentially representing a new therapeutic approach for the treatment of c-Myc-driven tumors.The authors thank Raul Gomez-Riera for assistance with microscopic analysis, Mar?a Luisa Toribio for providing the HRSIN-ICN1 plasmid, Jessica Gonzalez for technical assistance, and the Flow CytometryUnit and the Genomics Unit at the Centre for Genomic Regulation for assistance with Aseq at the Barcelona Biomedical Research Park. The J.Y. laboratory is funded by the Spanish Ministerio de Econom?a, Industria y Competitividad (grant SAF2017-83565-R) , Spanish Minis-terio de Ciencia e Innovaci?on (grant PID2020-112526RB-I00) , and Fundaci?on Cient?fica de la Asociaci?on Espan~ola Contra el Ca?ncer (grant PROYEI6018Y?ELA) . Work in the J.E.S. laboratory is supported by a core grant to the Laboratory of Molecular Biology from the Med-ical Research Council U105178808) . The F.D. laboratory is supported by a Laboratory of Excellence grant (ANR-10-LABX-0034_Medalis) to Strasbourg University, Centre National de la Recherche Scientifique. The P.N. laboratory is supported by grants from the Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (FEDER; PI17/00199 and PI20/00625) and the Generalitat de Catalunya (2017-SGR-225) . The P.M. labora-tory acknowledges support from Centres de Recerca de Catalunya/Generalitat de Catalunya and Fundaci?o Josep Carreras-Obra Social la Caixa for core support, the Spanish Ministry of Economy and Com-petitiveness (grant SAF-2019-108160-R) , the Fundaci?on Uno entre Cienmil, the Obra Social La Caixa (grant LCF/PR/HR19/52160011) , and the German Josep Carreras Leukamie Stiftung. Work at the G.R. and P.M. laboratories are cofinanced by the European Regional Development Fund through the Interreg V-A Spain-France-Andorra Program (project PROTEOblood; grant EFA360/19) . The O.F.-C. labo-ratory is funded by grants from the Spanish Ministry of Science, Inno-vation and Universities (RTI2018-102204-B-I00; cofinanced with European FEDER funds) and the European Research Council (ERC-617840) . T.V.-H. was supported by a Marie Sklodowska Curie fellow-ship (GA792923) . The A.B. laboratory is supported by the Spanish Ministry of Economy and Competitiveness (grant PID2019-104695RB-I00) .S

Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice

Fundació CarrerasThe J.Y. laboratory is funded by the Spanish Ministerio de Economía, Industria y Competitividad (grant SAF2017-83565-R), Spanish Ministerio de Ciencia e Innovación (grant PID2020-112526RB-I00), and Fundación Científica de la Asociación Española Contra el Cáncer (grant PROYEI6018YÉLA). Work in the J.E.S. laboratory is supported by a core grant to the Laboratory of Molecular Biology from the Medical Research Council (U105178808). The F.D. laboratory is supported by a Laboratory of Excellence grant (ANR-10-LABX-0034_Medalis) to Strasbourg University, Centre National de la Recherche Scientifique. The P.N. laboratory is supported by grants from the Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (FEDER; PI17/00199 and PI20/00625) and the Generalitat de Catalunya (2017-SGR-225). The P.M. laboratory acknowledges support from Centres de Recerca de Catalunya/Generalitat de Catalunya and Fundació Josep Carreras-Obra Social la Caixa for core support, the Spanish Ministry of Economy and Competitiveness (grant SAF-2019-108160-R), the Fundación Uno entre Cienmil, the Obra Social La Caixa (grant LCF/PR/HR19/52160011), and the German Josep Carreras Leukamie Stiftung. Work at the G.R. and P.M. laboratories are cofinanced by the European Regional Development Fund through the Interreg V-A Spain-France-Andorra Program (project PROTEOblood; grant EFA360/19). The O.F.-C. laboratory is funded by grants from the Spanish Ministry of Science, Innovation and Universities (RTI2018-102204-B-I00; cofinanced with European FEDER funds) and the European Research Council (ERC-617840). T.V.-H. was supported by a Marie Sklodowska Curie fellowship (GA792923). The A.B. laboratory is supported by the Spanish Ministry of Economy and Competitiveness (grant PID2019-104695RB-I00).The authors thank Raul Gomez-Riera for assistance with microscopic analysis, Mar?a Luisa Toribio for providing the HRSIN-ICN1 plasmid, Jessica Gonzalez for technical assistance, and the Flow Cytometry Unit and the Genomics Unit at the Centre for Genomic Regulation for assistance with Aseq at the Barcelona Biomedical Research Park. The J.Y. laboratory is funded by the Spanish Ministerio de Econom?a, Industria y Competitividad (grant SAF2017-83565-R), Spanish Ministerio de Ciencia e Innovaci?n (grant PID2020-112526RB-I00), and Fundaci?n Cient?fica de la Asociaci?n Espa?ola Contra el C?ncer (grant PROYEI6018Y?LA). Work in the J.E.S. laboratory is supported by a core grant to the Laboratory of Molecular Biology from the Medical Research Council (U105178808). The F.D. laboratory is supported by a Laboratory of Excellence grant (ANR-10-LABX-0034_Medalis) to Strasbourg University, Centre National de la Recherche Scientifique. The P.N. laboratory is supported by grants from the Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III?Fondo Europeo de Desarrollo Regional (FEDER; PI17/00199 and PI20/00625) and the Generalitat de Catalunya (2017-SGR-225). The P.M. laboratory acknowledges support from Centres de Recerca de Catalunya/Generalitat de Catalunya and Fundaci? Josep Carreras-Obra Social la Caixa for core support, the Spanish Ministry of Economy and Competitiveness (grant SAF-2019-108160-R), the Fundaci?n Uno entre Cienmil, the Obra Social La Caixa (grant LCF/PR/HR19/52160011), and the German Josep Carreras Leukamie Stiftung. Work at the G.R. and P.M. laboratories are cofinanced by the European Regional Development Fund through the Interreg V-A Spain-France-Andorra Program (project PROTEOblood; grant EFA360/19). The O.F.-C. laboratory is funded by grants from the Spanish Ministry of Science, Innovation and Universities (RTI2018-102204-B-I00; cofinanced with European FEDER funds) and the European Research Council (ERC-617840). T.V.-H. was supported by a Marie Sklodowska Curie fellowship (GA792923). The A.B. laboratory is supported by the Spanish Ministry of Economy and Competitiveness (grant PID2019-104695RB-I00).Dysregulation of the c-Myc oncogene occurs in a wide variety of hematologic malignancies, and its overexpression has been linked with aggressive tumor progression. Here, we show that poly (ADP-ribose) polymerase 1 (PARP-1) and PARP-2 exert opposing influences on progression of c-Myc-driven B-cell lymphoma. PARP-1 and PARP-2 catalyze the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA strand breaks, playing a central role in the response to DNA damage. Accordingly, PARP inhibitors have emerged as promising new cancer therapeutics. However, the inhibitors currently available for clinical use are not able to discriminate between individual PARP proteins. We found that genetic deletion of PARP-2 prevents c-Myc-driven B-cell lymphoma, whereas PARP-1 deficiency accelerates lymphomagenesis in the Eμ-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in preleukemic Eμ-Myc B cells, resulting in accumulation of DNA damage and concomitant cell death that restricts the c-Myc-driven expansion of B cells, thereby providing protection against B-cell lymphoma. In contrast, PARP-1 deficiency induces a proinflammatory response and an increase in regulatory T cells, likely contributing to immune escape of B-cell lymphoma, resulting in an acceleration of lymphomagenesis. These findings pinpoint specific functions for PARP-1 and PARP-2 in c-Myc-driven lymphomagenesis with antagonistic consequences that may help inform the design of new PARP-centered therapeutic strategies, with selective PARP-2 inhibition potentially representing a new therapeutic approach for the treatment of c-Myc-driven tumors