Συστηματική ανασκόπηση των κλινικών μελετών για χορήγηση ανοσοθεραπείας σε ορμονοεξαρτώμενο καρκίνο μαστού

Εισαγωγή: Ιστορικά, ο ορμονοευαίσθητος, μη μεταστατικός καρκίνος του μαστού που δεν εκφράζει τον υποδοχέα του ανθρώπινου αυξητικού επιδερμικού παράγοντα HER2 θεωρείται μη ανοσολογικός καρκίνος. Τα θετικά όμως αποτελέσματα της ανοσοθεραπείας σε άλλους τύπους καρκίνου του μαστού, η καλύτερη κατανόηση του ανοσολογικού μικροπεριβάλλοντος και της ετερογένειας του όγκου οδήγησαν στο να διενεργείται σήμερα σημαντικός αριθμός κλινικών μελετών για τη διερεύνηση του ρόλου των αναστολέων σημείων ελέγχου στο συγκεκριμένο τύπο καρκίνου του μαστού. Σκοπός της παρούσας συστηματικής ανασκόπησης είναι να παρουσιαστούν εκτενώς οι κλινικές μελέτες με αναστολείς σημείων ελέγχου καθώς και τα αποτελέσματα ασφάλειας και αποτελεσματικότητας αυτών στον ορμονοευαίσθητο, μη μεταστατικό καρκίνο του μαστού που δεν εκφράζει τον υποδοχέα του ανθρώπινου αυξητικού επιδερμικού παράγοντα HER2. Μεθοδολογία: Πραγματοποιήθηκε συστηματική ανασκόπηση των κλινικών μελετών στην ιστοσελίδα ClinicalTrials.gov μέχρι και τις 30 Ιουνίου 2022, στη βάση δεδομένων PubMed και στις ανακοινώσεις ετήσιων ογκολογικών συνεδρίων και διεθνών συνεδρίων για τον καρκίνο του μαστού με σκοπό την εύρεση κλινικών μελετών που διερευνούν την ασφάλεια και αποτελεσματικότητα της ανοσοθεραπείας με αναστολείς σημείων ελέγχου σε ορμονοευαίσθητο, μη μεταστατικό καρκίνο μαστού που δεν εκφράζει τον υποδοχέα του ανθρώπινου αυξητικού επιδερμικού παράγοντα HER2. Αποτελέσματα: Στη παρούσα συστηματική ανασκόπηση ανακτήθηκαν 39 κλινικές μελέτες που αποτύπωναν την ασφάλεια και αποτελεσματικότητα των αναστολέων σημείου ελέγχου σε συνδυασμό με άλλες θεραπείες όπως η χημειοθεραπεία, οι στοχεύουσες θεραπείες, οι ογκολυτικοί ιοί, οι τοπικές θεραπείες, η ενδοκρινική θεραπεία και αναστολείς νέων σηματοδοτικών μονοπατιών. Η μονοθεραπεία με αναστολείς σημείων ελέγχου δεν αποτέλεσε αντικείμενο καμίας κλινικής μελέτης. Στην πλειοψηφία τους οι κλινικές μελέτες ήταν φάσης 1 και 2 και μόνο 2 μελέτες φάσης 3 ανακτήθηκαν. Οι περισσότερες μελέτες διερευνούσαν τους αναστολείς σημείων ελέγχου ως νεοεπικουρική θεραπεία σε συνδυασμό με τη χημειοθεραπεία. 18 μελέτες έχουν ανακοινώσει αποτελέσματα αλλά μόνο 6 από αυτές δεδομένα αποτελεσματικότητας. Συμπεράσματα: Τα αποτελέσματα των κλινικών μελετών υποδεικνύουν πως οι αναστολείς σημείων ελέγχου σε συνδυασμό με τη χημειοθεραπεία μπορούν να είναι μια υποσχόμενη θεραπευτική επιλογή αλλά το κλινικό όφελος περιορίζεται σε υποομάδα ασθενών με συγκεκριμένα κλινικά και μοριακά χαρακτηριστικά του όγκου. Αναμένονται τα αποτελέσματα των κλινικών μελετών φάσης 3 για να καθορίσουν το ρόλο των αναστολέων σημείων ελέγχου στον θεραπευτικό αλγόριθμο του ορμονοευαίσθητου μη μεταστατικού καρκίνου του μαστούIntroduction: Historically, hormone receptor-positive, human epidermal growth factor negative breast cancer (HR+/HER2- BC) has been considered immunologically silent, thus investigation of immunotherapy in this intrinsic subtype has evolved slower. Promising results in other BC subtypes, a better understanding of tumor immune microenvironment and heterogeneity have reinforced the notion for ICI investigation in HR+/HER2- BC. Thus, the number of early-phase clinical trials in immunotherapy is growing significantly. Aim: This systematic review offers a comprehensive overview of the clinical trials landscape investigating the safety and efficacy of immune checkpoint inhibitors in non-metastatic HR+/HER2- BC. Material and Methods: We systematically searched ClinicalTrials.gov up to June 30, 2022, PubMed, abstracts in key oncological and breast cancer meetings to identify immunotherapy trials with checkpoint inhibitors in non-metastatic HR+/HER2- breast cancer. Results: 39 trials were identified to evaluate combinatorial modalities with ICIs including chemotherapy, targeted therapies, oncolytic viruses, local treatments such as radiotherapy and ablative therapy, endocrine therapy and novel signaling pathway inhibition, mainly in early-phase clinical trials. None of the trials investigate ICI monotherapy and only 2 Phase 3 clinical trials are ongoing. Most trials investigate the use of ICIs in the neoadjuvant setting in combination with neoadjuvant chemotherapy. 18 trials have reported results and 6 of them have reported efficacy results specifically for HR+/HER2- BC. Conclusion: There is growing interest in immunotherapy for HR+/HER2- BC and combinatorial modalities with ICI could be promising therapeutic strategies according to early-phase clinical trial results. However, clinical benefit is restricted only to specific subgroups of patients. Phase 3 trial results are highly anticipated to determine the role of ICI in the HR+/HER2- treatment algorithm

Fendrr synergizes with Wnt signalling to regulate fibrosis related genes during lung development via its RNA:dsDNA triplex element

Long non-coding RNAs are a very versatile class of molecules that can have important roles in regulating a cells function, including regulating other genes on the transcriptional level. One of these mechanisms is that RNA can directly interact with DNA thereby recruiting additional components such as proteins to these sites via an RNA:dsDNA triplex formation. We genetically deleted the triplex forming sequence (FendrrBox) from the lncRNA Fendrr in mice and found that this FendrrBox is partially required for Fendrr function in vivo. We found that the loss of the triplex forming site in developing lungs causes a dysregulation of gene programs associated with lung fibrosis. A set of these genes contain a triplex site directly at their promoter and are expressed in lung fibroblasts. We biophysically confirmed the formation of an RNA:dsDNA triplex with target promoters in vitro. We found that Fendrr with the Wnt signalling pathway regulates these genes, implicating that Fendrr synergizes with Wnt signalling in lung fibrosis

The lncRNA Sweetheart regulates compensatory cardiac hypertrophy after myocardial injury in murine males

Abstract After myocardial infarction in the adult heart the remaining, non-infarcted tissue adapts to compensate the loss of functional tissue. This adaptation requires changes in gene expression networks, which are mostly controlled by transcription regulating proteins. Long non-coding transcripts (lncRNAs) are taking part in fine-tuning such gene programs. We describe and characterize the cardiomyocyte specific lncRNA Sweetheart RNA (Swhtr), an approximately 10 kb long transcript divergently expressed from the cardiac core transcription factor coding gene Nkx2-5. We show that Swhtr is dispensable for normal heart development and function but becomes essential for the tissue adaptation process after myocardial infarction in murine males. Re-expressing Swhtr from an exogenous locus rescues the Swhtr null phenotype. Genes that depend on Swhtr after cardiac stress are significantly occupied and therefore most likely regulated by NKX2-5. The Swhtr transcript interacts with NKX2-5 and disperses upon hypoxic stress in cardiomyocytes, indicating an auxiliary role of Swhtr for NKX2-5 function in tissue adaptation after myocardial injury

Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia

Introduction: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development. Methods: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal. Results: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants. Conclusion: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF

Human exome and mouse embryonic expression data implicateZFHX3,TRPS1, andCHD7in human esophageal atresia

Introduction Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutationalde novoevents in genes involved in foregut development. Methods To identify mutationalde novoevents in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmedde novovariants were prioritized usingin silicoprediction tools. To investigate the embryonic role of genes harboring prioritizedde novovariants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal. Results In total we prioritized 14 novelde novovariants in 14 different genes (APOL2,EEF1D,CHD7,FANCB,GGT6,KIAA0556,NFX1,NPR2,PIGC,SLC5A2,TANC2,TRPS1,UBA3, andZFHX3) and eight rarede novovariants in eight additional genes (CELSR1,CLP1,GPR133,HPS3,MTA3,PLEC,STAB1, andPPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rarede novovariant inZFHX3.In silicoprediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritizedCHD7,TRPS1, andZFHX3as EA/TEF candidate genes. Re-sequencing ofZFHX3in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants. Conclusion Our study suggests that rare mutationalde novoevents in genes involved in foregut development contribute to the development of EA/TEF

First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 x 10(-8); odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10-5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 x 10(-10); OR = 1.47; 95% CI, 1.38-1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 x 10(-16); OR = 1.75; 95% CI, 1.64-1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% +/- 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes