Browsing Over 138 Presentations
Conclusion and take-away message (ID 95)
- L. Ellis
- L. Ellis
1P - PIWI proteins play oncogenic functions in pancreatic cancer (ID 142)
- W. Li
- W. Li
- J. Martinez Useros
- M. Fernández-Aceñero
- N. García Carbonero
- J. García-Foncillas
Abstract
Background
Human homologues of PIWI proteins identified are PIWIL1, PIWIL2, PIWIL3 and PIWIL4 (Sasaki et al. 2003). Aberrant expression of these proteins has been associated with hallmarks of cancer, and have also a potential prognostic and diagnostic markers for different cancers (Suzuki et al. 2012). However, their functional and clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains unknown. The purpose of this study was to dissect the role of PIWI proteins and their prognostic relevance.
Methods
PIWI proteins expression were analyzed by western blot in human PDAC derived cell lines and one non-transformed pancreatic cell line. Functional experiments were performed with PIWIL3 and/or PIWIL4 downregulated PDAC derived cell lines and one non-transformed cell line. Immunohistochemistry was performed to evaluate expression of PIWI proteins in 124 PDAC samples from Fundacion Jimenez Diaz Hospital, and with 124 validation cohort from TGCA. Then, association between PIWI proteins expression and survival was assessed.
Results
Only PIWIL3 and PIWIL4 showed differential expression in PDAC cell lines. Both wound-healing and transwell assay showed a decrease in migration ratio after PIWIL3 and/or PIWIL4 downregulation (P < 0.05). Furthermore, both PIWIL3 and/or PIWIL4 are necessary for the maintenance of undifferentiated phenotype highlighted by a reduction in size and number of pancreatic spheres after PIWIL3 and/or PIWIL4 downregulation (P < 0.05). On the other hand, PIWIL1 associated with shorter survival (P = 0.056), and this finding was validated in the TGCA cohort (P = 0.021). PIWIL2 associated significantly to shorter survival (P = 0.046) in our training set, and validation set exhibited a high trend toward significance (P = 0.051). Although PIWIL3 and PIWIL4 did not show association with survival in our training set, validation set revealed a statistically significant association of PIWIL4 with shorter overall survival (P = 0.027).
Conclusions
The present study demonstrate that PIWIL3 and PIWIL4 regulates PDAC aggressiveness by inhibiting cell migration and regulate undifferentiated phenotype of cancer cells. Furthermore, PIWIL1, PIWIL2 and PIWIL4 are potential prognostic biomarkers in PDAC.
Legal entity responsible for the study
Fundación Instituto de Investigación Sanitaria - Fundación Jiménez Díaz (G-85874949).
Funding
Spanish Ministry of Economy and Competitiveness.
Disclosure
All authors have declared no conflicts of interest.
Session DOI (ID 218)
PARP and PD-1/PDL1 inhibition (ID 30)
- G. Curigliano
- G. Curigliano
NTRK (ID 54)
- R. Doebele
- R. Doebele
Q&A (ID 209)
- G. Giaccone
- A. Adjei
- G. Giaccone
- A. Adjei
33P - Proteomic analysis of UKF-NB-4 cells reveals a stimulatory activity of MT-3 on cellular senescence and apoptosis (ID 88)
- M. Merlos Rodrigo
- M. Merlos Rodrigo
- H. Buchtelova
- V. Strmiska
- A. Jimenez Jimenez
- I. Casal
- V. Adam
- Z. Heger
Abstract
Background
Metallothioneins (MTs) family is a intracellular and cysteine-rich proteins with a high affinity to metals. MT-3 could play important neuromodulatory and neuroprotective roles. MT-3 has been also found up-regulated in a number of cancers. Neuroblastoma (Nbl) is a cancer is the most common extra-cranial solid tumour of childhood. The main aim was to provide novel insights into the molecular mechanisms of hMT-3 up-regulation and to elucidate the effects beneath the MT-3 up-regulation in Nbl cells.
Methods
To increase the expression of MT-3 Nbl (UKF-NB-4) cells were transiently transfected with a plasmid containing MT-3 gene (pcDNA3.1-GFP-hMT-3-TOPO). Separations of tryptic digests were carried out on an Easy-nLC 1000 nano system. MS analysis was performed using a Q-Exactive MS. The mass spectrum *.raw file was searched against the human SwissProt 57.15 database using MASCOT search engine (version 2.3, Matrix Science).
Results
The efficiency of transfection analysed through a fluorescence of GFP tag expressed at the C-terminus of MT-3 showed more 70% transfection efficiency for both constructed plasmids (mock and MT-3). From the total of common proteins in dataset (hMT-3 vs. mock), 176, 20 and 1244 proteins were quantitatively identified with up-regulation, down-regulation, and no significant differences between hMT-3 and mock treatments. Noteworthy, the bioinformatical analyses revealed the exclusive expression (induced by MT-3) and up-regulation proteins of a number of proteins affecting biological pathways related to mitotic cell cycle, cellular responses to stress, positive regulation of proteolysis, negative regulation of cell cycle and programmed cell death.
Conclusions
Our proteomic data shed some light on the proteins involved in inducing senescence and apoptosis in tested Nbl cells with up-regulated MT-3. Organisms with renewable tissues had to evolve mechanisms to prevent the development of cancer. Cellular senescence and apoptosis are among those mechanisms. Further experiments will be performed to functionally verify these data to provide novel insights into the Nbl biology. These might be useful to develop novel therapeutic protocols utilizing MT-3 as prognostic biomarker or therapeutic target.
Legal entity responsible for the study
Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, CZ.
Funding
European Research Council (ERC) under the European Uniońs Horizon 2020 Research and Innovation Programme (grant agreement No. 759585).
Disclosure
All authors have declared no conflicts of interest.
Application of CRISPR screen to guide therapy for lymphoma (ID 21)
- H. Wendel
- H. Wendel
Replication stress and DNA repair inhibitors (ID 44)
- G. Shapiro
- G. Shapiro
2O - A phase Ib/II study of APG-115 in combination with pembrolizumab in patients with unresectable or metastatic melanomas or advanced solid tumors (ID 173)
- A. Tolcher
- A. Tolcher
- D. Fang
- Y. Li
- Y. Tang
- J. Ji
- H. Wang
- R. Karim
- C. Rosas
- Y. Huang
- Y. Zhai
Abstract
Background
Emerging evidence suggests that p53 participates in the regulation of tumor immunity. TP53 activation in the myeloid linage suppresses alternative (M2) macrophage polarization and attenuates tumor development and invasion. Retrospective clinical analyses suggested that MDM2 amplification is associated with hyper-progression. Targeting MDM2-p53 pathway may represent a novel strategy for reversing immunosuppression and enhancing antitumor immunity of PD-1/PD-L1 blockade. APG-115 is a potent and orally active small-molecule MDM2 protein inhibitor. Binding to MDM2 protein, APG-115 restores p53 expression, activates p53 - mediated apoptosis in tumor cells retaining wild-type p53. Preclinical studies demonstrated that APG-115 promoted the production of proinflammatory cytokines in T cells, enhanced CD4+ T cell activation, and increased PD-L1 expression on tumor cells. Enhanced antitumor activity was demonstrated in syngeneic tumor models after APG-115 combined with PD-1 blockade.
Methods
APG-115 has been evaluated as a single agent in a Phase I study in US (NCT02935907). In this study, total six dose levels (10 mg, 20 mg, 50 mg, 100 mg, 200 mg and 300 mg) have been tested. The preliminary results suggested a favorable safety and tolerability profile. APG-115 exhibited an approximately dose proportional increase in exposure in PK analyses. A Phase Ib/II study of APG-115 in combination with pembrolizumab for treatment of patients with metastatic solid tumor is ongoing. Pembrolizumab is administrated as a fixed dose of 200mg IV on d1 of a 21-d cycle. Safety, tolerability, and determination of the MTD and RP2D are primary objectives of phase Ib.
Results
The second cohort (APG 115 at 100 mg) has enrolled, no DLT was observed, and evidence of antitumor activity has been observed. Biomarker studies are ongoing to identify potential selection criteria. Updated clinical data will be presented.
Conclusions
This represents one of the first clinical trials to evaluate MDM2-mediated resistance to immunotherapy.
Clinical trial identification
NCT03611868.
Legal entity responsible for the study
Ascentage Pharma Group Corp Limited.
Funding
Ascentage Pharma Group Corp Limited.
Disclosure
A.W. Tolcher: Research funding: AbbVie, ADC Therapeutics, Adagene, Aminex, Acentage, Asana, Birdie, C Stone, Arrys, GlaxoSmithKline, Inhibrx, Innate, Kiromic, NatureWise, NextCure, Nitto BioPharma, Pfizer, Pieris, Deciphera, Syndax, Symphogen, Tizona, Mersana, Zymeworks; Consultancy (includes travel funding): AbbVie, Adagene, ADC Therapeutics, Agenus, Ascentage, AxImmune, Bayer, Bioinvent, Birdie, Boston Biomedical (Syneos), EMD Serono, Forbius (Formerly Formation Biologics), Gilde Healthcare Partners, HBM Partners, Ignyta, Immunome, ImmunoMet, Innate, Jazz Pharmaceuticals, Mekanistic, Nanobiotix, NBE Therapeutics, Nuvalent, Pelican, Pierre Fabre, Ridgeway, Scitemex, Sesen (formerly EBIO), Seattle Genetics, Symphogen, Syneos. D.D. Fang, Y. Li, Y. Tang, J. Ji, H. Wang, Y. Huang, Y. Zhai: Employee of Affiliates of Ascentage Pharma Group Corp Limited (“Ascentage Pharma”); Stock ownership: Ascentage Pharma. All other authors have declared no conflicts of interest.
21P - Evaluation of magnetic nanoparticle of irinotecan for personalized treatment of colorectal cancer (ID 198)
- A. Singh
- A. Singh
Abstract
Background
Cancer, a heterogeneous disease is caused by genetic and epigenetic mutation. Irinotecan was indicated for treatment of colorectal cancer either alone or in combination with other chemotherapeutic drug. Due to associated toxicity, irinotecan was less explored in cancer therapy research. In recent years, magnetic nanoparticles (MNPs) were well explored for different biomedical applications including targeted drug delivery.
Methods
We hypothesized that the anticancer activity of irinotecan would improve when attached to the surface of MNPs. Magnetic nanoparticles were developed using in house developed method. Fourier transform infrared (FT-IR) spectra and scanning electron microscopy (SEM) were recorded to characterize the irinotecan MNPs. In Vitro and in vivo evaluations were perfomed to assess the feasibility of this novel formulation using colon cancer cell lines.
Results
Irinotecan MNPs were successfully developed with an average diameter of the magnetic core of 22 ± 5 nm and the thickness of the shell is around 7 ± 4 nm. Using colon cancer culture (HT-29 cells), we evaluated the effects of MNPs on cancer cell viability and apoptosis. Treatment of cancer cells with the irinotecan MNPs caused a greater decrease in cell viability and a higher rate of apoptosis compared with treatment using free irinotecan.
Conclusions
Although further clinical study is needed, the targeted uptake of irinotecan MNPs by colon cancer cells associated with their ability to eliminate and prevent further cancer cell growth indicates its potential for targeted and personalized cancer therapy with lower toxicity in patients with colon cancer.
Editorial acknowledgement
Not Applicable
Legal entity responsible for the study
Akhilesh Vikram Singh.
Funding
Has not received any funding.
Disclosure
The author has declared no conflicts of interest.
DNA polymerase Theta (POLθ) as an anticancer target (ID 12)
- G. Higgins
- G. Higgins