ZNF217 confers resistance to the pro-apoptotic signals of paclitaxel and aberrant expression of Aurora-A in breast cancer cells

<p>Abstract</p> <p>Background</p> <p>ZNF217 is a candidate oncogene located at 20q13, a chromosomal region frequently amplified in breast cancers. The precise mechanisms involved in ZNF217 pro-survival function are currently unknown, and utmost importance is given to deciphering the role of ZNF217 in cancer therapy response.</p> <p>Results</p> <p>We provide evidence that stable overexpression of ZNF217 in MDA-MB-231 breast cancer cells conferred resistance to paclitaxel, stimulated cell proliferation <it>in vitro </it>associated with aberrant expression of several cyclins, and increased tumor growth in mouse xenograft models. Conversely, siRNA-mediated silencing of ZNF217 expression in MCF7 breast cancer cells, which possess high endogenous levels of ZNF217, led to decreased cell proliferation and increased sensitivity to paclitaxel. The paclitaxel resistance developed by ZNF217-overexpressing MDA-MB-231 cells was not mediated by the ABCB1/PgP transporter. However, ZNF217 was able to counteract the apoptotic signals mediated by paclitaxel as a consequence of alterations in the intrinsic apoptotic pathway through constitutive deregulation of the balance of Bcl-2 family proteins. Interestingly, ZNF217 expression levels were correlated with the oncogenic kinase Aurora-A expression levels, as ZNF217 overexpression led to increased expression of the Aurora-A protein, whereas ZNF217 silencing was associated with low Aurora-A expression levels. We showed that a potent Aurora-A kinase inhibitor was able to reverse paclitaxel resistance in the ZNF217-overexpressing cells.</p> <p>Conclusion</p> <p>Altogether, these data suggest that ZNF217 might play an important role in breast neoplastic progression and chemoresistance, and that Aurora-A might be involved in ZNF217-mediated effects.</p

hPG\u3csub\u3e80\u3c/sub\u3e (Circulating Progastrin), a Novel Blood-Based Biomarker for Detection of Poorly Differentiated Neuroendocrine Carcinoma and Well Differentiated Neuroendocrine Tumors

Current blood-based biomarkers for neuroendocrine neoplasms (NENs) lack both sensitivity and specificity. Human circulating progastrin (hPG80) is a novel biomarker that can be easily measured in plasma by ELISA. This study is the first to examine hPG80 in NENs. Plasma hPG80 was quantified from 95 stage IV NEN patients, using DxPG80 technology (ECS Progastrin, Switzerland) and compared with hPG80 concentrations in two cohorts of healthy donor controls aged 50–80 (n = 252) and 18–25 (n = 137). Median hPG80 in NENs patients was 5.54 pM compared to 1.5 pM for the 50–80 controls and 0.29 pM the 18–25 cohort (p \u3c 0.0001). Subgroup analysis revealed median hPG80 levels significantly higher than for either control cohort in neuroendocrine carcinoma (NEC; n = 25) and neuroendocrine tumors (NET; n = 70) including the small-cell lung cancer (SCLC) sub-cohort (n = 13). Diagnostic accuracy, estimated by AUCs, was high for NENs, as well as both sub-groups (NEC/NET) when compared to the younger and older control groups. Plasma hPG80 in NENs may be a diagnostic blood biomarker for both low- and high-grade NENs; further study is warranted. A prospective multi-center trial is ongoing in NET to evaluate hPG80 as a means of monitoring disease (NCT04750954)

Repression of PLA2R1 by c-MYC and HIF-2alpha promotes cancer growth

Loss of secreted phospholipase A2 receptor (PLA2R1) has recently been found to render human primary cells more resistant to senescence whereas increased PLA2R1 expression is able to induce cell cycle arrest, cancer cell death or blockage of cancer cell transformation in vitro, suggesting that PLA2R1 displays tumor suppressive activities. Here we report that PLA2R1 expression strongly decreases in samples of human renal cell carcinoma (RCC). Knockdown of PLA2R1 increases renal cancer cell tumorigenicity supporting a role of PLA2R1 loss to promote in vivo RCC growth. Most RCC result from Von Hippel-Lindau (VHL) tumor suppressor loss-of-function and subsequent gain-of-function of the oncogenic HIF-2alpha/c-MYC pathway. Here, by genetically manipulating VHL, HIF-2alpha and c-MYC, we demonstrate that loss of VHL, stabilization of HIF-2alpha and subsequent increased c-MYC activity, binding and transcriptional repression, through induction of PLA2R1 DNA methylation closed to PLA2R1 transcriptional start site, results in decreased PLA2R1 transcription. Our results describe for the first time an oncogenic pathway leading to PLA2R1 transcriptional repression and the importance of this repression for tumor growth

Les thérapies ciblées contre le cancer (rôle du pharmacien d'officine dans l'optimisation du traitement et dans la gestion des effets indésirables)

Les thérapies ciblées anti-cancéreuses représentent aujourd'hui une avancée majeure dans les traitements anti-cancéreux et le pharmacien d'officine constitue réellement l'un des pivots de la gestion du traitement et des effets indésirables associés à ces thérapies. Dans une première partie, nous rappellerons les processus connus à ce jour mis en, place lors de l'oncogenèse afin de comprendre plus aisément les mécanismes d'action de ces traitements. Nous détaillerons ensuite les différentes classes de thérapies ciblées existantes en explicitant leur fonctionnement. La deuxième partie sera consacrée au rôle que joue le pharmacien d'officine dans la gestion de ces associations thérapeutiques. Il est en effet un acteur majeur de proximité et se doit de prodiguer au patient les meilleurs conseils préventifs et curatifs possibles. Afin d'illustrer concrètement nos propos, nous étudierons deux associations représentatives de thérapies ciblées, le protocole FOLFIRI-AVASTIN et le protocole XELODA-TYVERB. Nous expliquerons d'abord quelles sont les conditions de prise pour optimiser l'efficacité des médicaments, quelles sont les associations à éviter ainsi que les contre-indications à connaître. Ensuite, nous étudierons les effets indésirables de ces deux associations, en les décrivant puis en explicitant, pour chacune d'entre elles, des conseils aux patients afin d'une part de prévenir les effets indésirables et d'autre part de diminuer au maximum leur intensité. Une fiche récapitulative de chaque association sera ensuite proposée, résumant les principales conditions de prise ainsi que les effets indésirables majeurs avec leur prévention et leur prise en charge.LYON1-BU Santé (693882101) / SudocSudocFranceF

Les anticorps monoclonaux conjugués aux principes actifs et leur utilisation en oncologie

Le terme cancer regroupe de nombreuses maladies très hétérogènes ce qui rend le traitement difficile, complexe et lourd. Les thérapies classiques peuvent être à l'origine d'effets indésirables importants et peuvent se heurter à des résistances des cellules malignes. Pour ces raisons les thérapies ciblées et personnalisées sont en essor. Les anticorps conjugués aux anticancéreux en font partie et constituent un domaine très innovateur et dynamique. Il s'agit d'anticorps monoclonaux dirigés contre un antigène spécifique des cellules malignes, conjugués par un linker à des petites molécules anticancéreuses très puissantes et non spécifiques. Les cytotoxiques utilisés ont des origines, des structures et des modes d'action très variés, les classes principales étant les auristatines, les maytansinoïdes et les calichéamycines. La conjugaison est une technique de vectorisation pour augmenter l'efficacité anticancéreuse en limitant l'action des principes actifs au niveau des cellules porteuses de l'antigène, en améliorant les caractéristiques pharmacocinétiques, en évitant certains mécanismes de résistance et permet de plus de réduire la toxicité non-spécifique des cytotoxiques notamment. Il s'agit d'une nouvelle classe de médicaments et d'un domaine très prometteur, mais de nombreux facteurs éventuellement limitants existent. La pharmacologie de ces conjugués est complexe, le marché et l'utilisation de ces traitements chers difficilement prévisible et les connaissances physiopathologiques des cancers restent parfois restreintesLYON1-BU Santé (693882101) / SudocSudocFranceF

Sécurité clinique des médicaments (impact de la pharmacogénomique et de la phamacogénétique)

LYON1-BU Santé (693882101) / SudocSudocFranceF

Immunotoxicité des anticorps monoclonaux et sécurité clinique (application aux anticorps anti-cytokines)

LYON1-BU Santé (693882101) / SudocSudocFranceF

Plasma hPG80 (Circulating Progastrin) as a Novel Prognostic Biomarker for early-stage breast cancer in a breast cancer cohort

Abstract Background Recurrence and metastases are still frequent outcomes after initial tumour control in women diagnosed with breast cancer. Although therapies are selected based on tumour characteristics measured at baseline, prognostic biomarkers can identify those at risk of poor outcomes. Circulating progastrin or hPG80 was found to be associated with survival outcomes in renal and hepatocellular carcinomas and was a plausible prognostic biomarker for breast cancer. Methods Women with incident breast cancers from Calgary, Alberta, Canada enrolled in the Breast to Bone (B2B) study between 2010 to 2016 and provided blood samples prior to any treatment initiation. Plasma from these baseline samples were analysed for circulating progastrin or hPG80. Participant characteristics as well as tumour ones were evaluated for their association with hPG80 and survival outcomes (time to recurrence, recurrence – free survival, breast cancer specific survival and overall survival) in Cox proportional hazards regression models. Results The 464 participants with measurable hPG80 in this study had an average age of 57.03 years (standard deviation of 11.17 years) and were predominantly diagnosed with Stage I (52.2%) and Stage II (40.1%) disease. A total of 50 recurrences and 50 deaths were recorded as of June 2022. In Cox PH regression models adjusted for chemotherapy, radiation therapy, cancer stage and age at diagnosis, log hPG80 (pmol/L) significantly increased the risks for recurrence (Hazard Ratio (HR) = 1.330, 95% Confidence Interval (CI) = (0.995 – 1.777, p = 0.054)), recurrence-free survival (HR = 1.399, 95% CI = (1.106 – 1.770), p = 0.005) and overall survival (HR = 1.385, 95% CI = (1.046 – 1.834), = 0.023) but not for breast cancer specific survival (HR = 1.015, 95% CI = (0.684 – 1.505), p = 0.942). Conclusions hPG80 levels measured at diagnosis were significantly associated with the risk of recurrence or death from any cause in women with breast cancer. Since the recurrence rates of breast cancer are still relatively high amongst women diagnosed at an early stage, identifying women at high risk of recurrence at their time of diagnosis is important. hPG80 is a promising new prognostic biomarker that could improve the identification of women at higher risk of poor outcomes

Direct Comparative Analysis of a Pharmacogenomics Panel with PacBio Hifi® Long-Read and Illumina Short-Read Sequencing

International audienceBackground: Pharmacogenetics (PGx) aims to determine genetic signatures that can be used in clinical settings to individualize treatment for each patient, including anti-cancer drugs, anti-psychotics, and painkillers. Taken together, a better understanding of the impacts of genetic variants on the corresponding protein function or expression permits the prediction of the pharmacological response: responders, non-responders, and those with adverse drug reactions (ADRs). Objective: This work provides a comparison between innovative long-read sequencing (LRS) and short-read sequencing (SRS) techniques. Methods and Materials: The gene panel captured using PacBio HiFi® sequencing was tested on thirteen clinical samples on GENTYANE’s platform. SRS, using a comprehensive pharmacogenetics panel, was performed in routine settings at the Civil Hospitals of Lyon. We focused on complex regions analysis, including copy number variations (CNVs), structural variants, repeated regions, and phasing-haplotyping for three key pharmacogenes: CYP2D6, UGT1A1, and NAT2. Results: Variants and the corresponding expected star (*) alleles were reported. Although only 38.4% concordance was found for haplotype determination and 61.5% for diplotype, this did not affect the metabolism scoring. A better accuracy of LRS was obtained for the detection of the CYP2D6*5 haplotype in the presence of the duplicated wild-type CYP2D6*2 form. A total concordance was performed for UGT1A1 TA repeat detection. Direct phasing using the LRS approach allowed us to correct certain NAT2 profiles. Conclusions: Combining an optimized variant-calling pipeline and with direct phasing analysis, LRS is a robust technique for PGx analysis that can minimize the risk of mis-haplotyping