scholarly journals O47: IKK-ALPHA AS A POTENTIAL NOVEL TARGET FOR TREATMENT OF COLORECTAL CANCER

2021 ◽  
Vol 108 (Supplement_1) ◽  
Author(s):  
M Patel ◽  
JA Quinn ◽  
KAF Pennel ◽  
D Flanagan ◽  
PG Horgan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Viability ◽  
Mouse Models ◽  
Therapeutic Target ◽  
Dependent Manner ◽  
Cancer Specific Survival ◽  
Similar Reduction ◽  
Novel Target ◽  
The Relationship ◽  
Novel Therapeutic

Abstract Introduction There is substantial evidence linking NF-κB and cancer-related processes. The aim of this study was to investigate the role of IKKα, the main catalytic component of non-canonical NF-κB pathway in colorectal cancer (CRC). Method Immunohistochemistry and immunofluorescence was used to examine expression of IKKα in 1030 patients undergoing resection for stage I-III CRC. To assess IKKα inhibition, organoids were prepared from wild type (WT) mouse colon, mouse models of CRC (Apc and Apc.KRAS.pT53.TGFbR2 (AKPT)) and patient derived human organoids. These were treated with an IKKα inhibitor, SU1433 and organoid size and cell viability assessed. Result High cytoplasmic expression of IKKα was associated with increasing T stage (p=0.012), poor tumour differentiation (p=0.010), tumour necrosis (p=0.013) and low proliferation status (p=0.013). High punctate IKKα expression was associated with reduced CSS (HR1.20 95%CI 1.02-1.42, p<0.001). Immunofluorescence showed IKKα was co-located with a Golgi-related structure. SU1433 did not significantly impact on WT (C57/B16) organoid viability up to a concentration of 1uM, however organoid size and cell viability was significantly reduced in a dose-dependent manner in organoids from both Apc and AKPT mouse models. A similar reduction was observed in patient derived human organoids. Conclusion Punctate IKKα expression was associated with poor cancer specific survival in CRC patients. The relationship between IKKα and the Golgi requires further investigation. Inhibition with SU1433, impacted on CRC mouse and patient derived human organoid size and cell viability. These results suggest that IKKα following further investigation could be employed as a novel therapeutic target in CRC. Take-home message IKKα is up-regulated in patients undergoing surgery for CRC, this is associated with poor survival outcome and inhibition of IKKα and has presented itself as a novel therapeutic target. The relationship between IKKα and the Golgi has raised interesting questions regarding the molecular behaviour of IKKα and this warrants further investigation.

IKKα as a potential novel target for treatment of colorectal cancer.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 174-174
Author(s):  
Jean A. Quinn ◽  
Meera Patel ◽  
Kathryn AF Pennel ◽  
Dustin Flanagan ◽  
Paul G. Horgan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Viability ◽  
Mouse Models ◽  
Dependent Manner ◽  
Cancer Specific Survival ◽  
Similar Reduction ◽  
Novel Target ◽  
Dose Dependent ◽  
Tumour Differentiation

174 Background: Colorectal cancer (CRC) is a heterogeneous disease leading to different survival outcomes for patients with the same stage of disease. The non-canonical NF-κB pathway has been shown to have a key role in tumorigenesis, and the aim of this study was to investigate the role of IKKα, the main catalytic component of this pathway in CRC. Methods: A tissue microarray was retrospectively constructed from a patient cohort (1033) with stage I-III CRC who underwent surgery. IHC was utilised to examine cytoplasmic and punctate IKKα expression and determine any association with clincopathological features and cancer specific survival (CSS). To assess IKKα inhibition, organoids were prepared from wild type (WT) mouse colon, mouse models of CRC (Apc and Apc.KRAS.pT53.TGFbR2 (AKPT)) and patient derived human organoids. These were treated with an IKKα inhibitor, SU1433 and organoid size and cell viability assessed. Results: High cytoplasmic expression of IKKα was associated with increasing T stage (p = 0.012), poor tumour differentiation (p = 0.010), tumour necrosis (p = 0.013) and low proliferation status (p = 0.013) but was not associated with CSS. High punctate IKKα expression associated with tumour differentiation (p = 0.001), necrosis (p = 0.004), proliferation (p = 0.044) and MMR competence (p < 0.001) and was also significantly associated with reduced CSS (HR1.20 95%CI 1.02-1.42, p < 0.001). SU1433 did not significantly impact on WT (C57/B16) organoid viability up to a concentration of 1 uM, however organoid size and cell viability was significantly reduced in a dose dependent manner in organoids from both Apc and AKPT mouse models. A similar reduction was observed in patient derived human organoids. Conclusions: Punctate IKKα expression was associated with poor cancer specific survival in CRC patients, and inhibition with SU1433, impacted on CRC mouse and patient derived human organoid size and cell viability. These results suggest that, following further investigation and confirmation, IKKα may be employed as a novel therapeutic target in CRC.

scholarly journals The Relationship Between Tumor Budding, Tumor Microenvironment, and Survival in Patients with Primary Operable Colorectal Cancer

2019 ◽  
Vol 26 (13) ◽  
pp. 4397-4404 ◽  
Author(s):  
Hester C. van Wyk ◽  
Antonia Roseweir ◽  
Peter Alexander ◽  
James H. Park ◽  
Paul G. Horgan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Evaluation Method ◽  
Venous Invasion ◽  
Staging System ◽  
Consensus Conference ◽  
Tumor Budding ◽  
Inflammatory Cell Infiltrate ◽  
Cancer Specific Survival ◽  
The Relationship

Abstract Background Tumor budding is an independent prognostic factor in colorectal cancer (CRC) and has recently been well-defined by the International Tumour Budding Consensus Conference (ITBCC). Objective The aim of the present study was to use the ITBCC budding evaluation method to examine the relationship between tumor budding, tumor factors, tumor microenvironment, and survival in patients with primary operable CRC. Methods Hematoxylin and eosin-stained slides of 952 CRC patients diagnosed between 1997 and 2007 were evaluated for tumor budding according to the ITBCC criteria. The tumor microenvironment was evaluated using tumor stroma percentage (TSP) and Klintrup–Makinen (KM) grade to assess the tumor inflammatory cell infiltrate. Results High budding (n = 268, 28%) was significantly associated with TNM stage (p < 0.001), competent mismatch repair (MMR; p < 0.05), venous invasion (p < 0.001), weak KM grade (p < 0.001), high TSP (p < 0.001), and reduced cancer-specific survival (CSS) (hazard ratio 8.68, 95% confidence interval 6.30–11.97; p < 0.001). Tumor budding effectively stratifies CSS stage T1 through to T4 (all p < 0.05) independent of associated factors. Conclusions Tumor budding effectively stratifies patients’ survival in primary operable CRC independent of other phenotypic features. In particular, the combination of T stage and budding should form the basis of a new staging system for primary operable CRC.

scholarly journals MicroRNA-518-3p suppresses cell proliferation, invasiveness, and migration in colorectal cancer via targeting TRIP4

2020 ◽  
Vol 98 (5) ◽  
pp. 575-582
Author(s):  
Heng Yang ◽  
Jia Ren ◽  
Yu Bai ◽  
Jielin Jiang ◽  
Shiyao Xiao
Keyword(s):  
Colorectal Cancer ◽  
Cell Viability ◽  
Colony Formation ◽  
Thyroid Hormone Receptor ◽  
Formation Rate ◽  
Negative Control ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Closure Rate ◽  
Normal Tissues

MicroRNA (miR)-518-3p has been shown to function as a tumor suppressor. This study was conducted to investigate the effects of miR-518-3p in colorectal cancer (CRC). The miR-518-3p mimic, mimic negative control (NC), miR-518-3p inhibitor, inhibitor-NC, ShRNA-TRIP4, and ShRNA-NC vectors were transfected into SW480 cells using Lipofectamine 2000. Cell viability was detected using CCK-8. Colony formation, cell invasiveness, and cell migration were assessed by plate colony formation, Transwell assays, and wound healing assays, respectively. Relative mRNA and protein levels were detected using RT–qPCR and Western blot, respectively. The target gene thyroid hormone receptor interactor 4 (TRIP4) of miR-518-3p was identified and further verified using dual-luciferase reporter assay. Compared with normal tissues, levels of miR-518-3p were decreased and TRIP4 was significantly increased in the tissues from patients with CRC. Following transfection with a miR-518-3p mimic or ShRNA-TRIP4, cell viability decreased in a time-dependent manner, and colony formation rate, wound closure rate, and the number of invasive cells were much lower for the transfected cells than in the corresponding NC and control groups. miR-518-3p overexpression or silencing of TRIP4 significantly down-regulated the expression of MMP-2 and MMP-9. Knockdown of miR-518-3p had the opposite effects, and TRIP4 was identified as a target of miR-518-3p. The inhibitory effects of miR-518-3p on the progressions of CRC are associated with TRIP4.

375 MER as a novel therapeutic target in colorectal cancer

2014 ◽  
Vol 50 ◽  
pp. 120-121
Author(s):  
K. Wong ◽  
A.C. Tan ◽  
T. Pitts ◽  
P. Klauck ◽  
S. Earp ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Therapeutic Target ◽  
Novel Therapeutic

The relationship between tumor and host factors and survival in patients undergoing adjuvant chemotherapy for colorectal cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 525-525
Author(s):  
James Hugh Park ◽  
Colin H. Richards ◽  
Donald C. Mcmillan ◽  
Paul G. Horgan ◽  
Campbell S. D. Roxburgh
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Chemotherapy ◽  
Tumor Microenvironment ◽  
Inflammatory Responses ◽  
Prognostic Score ◽  
Glasgow Prognostic Score ◽  
Cancer Specific Survival ◽  
Local Inflammatory Response ◽  
Invasive Margin ◽  
The Relationship

525 Background: The tumor microenvironment and host inflammatory responses are important determinants of outcome in colorectal cancer (CRC), however their impact on survival in patients receiving adjuvant chemotherapy remains unclear. The aim of the present study was to examine the relationship between these factors, clinicopathological characteristics and survival in patients receiving adjuvant chemotherapy for CRC. Methods: 365 patients who had undergone CRC resection at a single institution between 1997-2008 were included; 88 patients subsequently received chemotherapy. Tumor stroma percentage (TSP) and necrosis were assessed on H and E sections and graded as low or high. Local inflammatory response was assessed using the Klintrup-Mäkinen (K-M), Galon and revised Immunoscore (CD45RO+ /CD8+, and CD3+/CD8+at the invasive margin and tumor center, respectively). Systemic inflammation was assessed using modified Glasgow Prognostic Score (mGPS). Results: Patients receiving adjuvant chemotherapy were younger with a lower ASA (both P<0.05), had advanced T- and N-stage (P<0.05 and P<0.001, respectively), poor tumor differentiation (P<0.05), venous invasion (VI) (P<0.01), margin involvement, infiltrative invasive margin (both P<0.05) and high TSP (P<0.01). In those patients who received adjuvant chemotherapy, on multivariate analysis of clinicopathological factors, VI (HR 3.00, 95%CI 1.22-7.37, P=0.017), TSP (HR 3.00, 95%CI 1.26-7.12, P=0.013), K-M score (HR 5.24, 95%CI 1.21-22.68, P=0.027) and mGPS (HR 3.10 95%CI 1.47-6.55, P=0.003) were independently associated with cancer-specific survival. When the interrelationships between factors independently associated with cancer survival were examined, VI, mGPS, K-M score and TSP were independent of each other (all P>0.05). Conclusions: Compared to standard CRC pathological staging, the present results suggest that assessment of both tumor microenvironment and host inflammatory responses may have superior prognostic value compared with TNM in patients receiving adjuvant chemotherapy.

The relationship between the non-canonical NF-κB pathway, tumour microenvironment, systemic inflammation and survival in patients undergoing surgery for colorectal caner.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 631-631
Author(s):  
Meera Patel ◽  
Lindsay Bennett ◽  
Jean A Quinn ◽  
Hester Catharina van Wyk ◽  
Paul G. Horgan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Responses ◽  
Venous Invasion ◽  
Tumour Microenvironment ◽  
Braf V600e ◽  
High Expression ◽  
Inflammatory Cell Infiltrate ◽  
Cancer Specific Survival ◽  
Local Inflammatory Response ◽  
The Relationship

631 Background: In patients with colorectal cancer (CRC) the local and systemic inflammatory responses (LIR and SIR) are important determinants of disease progression. The present study examines the association of transcription factor RelB, a key member of the non-canonical NF-κB pathway and its association with LIR and SIR in patients undergoing resection of CRC. Methods: Patients with stage I-III CRC who underwent curative resection in a single institution and were in a previously constructed tissue microarray were studied. IHC was utilised to examine cytoplasmic and nuclear RelB expression. The relationship between RelB, clinicopathological characteristics, LIR (Klintrup-Mäkinen (KM) grade, CD3+ and CD8+T-cell density), SIR and cancer-specific survival (CSS) was examined. Results: 208 patients were included in the analysis. Cytoplasmic RelB (cyto-RelB) was associated with nuclear RelB ( p=0.006). High expression of cyto-RelB was associated with MMR competence ( p=0.010) but not with TNM stage ( p=0.468), venous invasion ( p=0.973), tumour budding ( p=0.068), tumour necrosis ( p=0.786), tumour cell proliferation ( p=0.907), BRAF V600E mutation ( p=0.585) or administration of adjuvant chemotherapy ( p=0.853). High cyto-RelB was inversely associated with mGPS (mGPS >1: low cyto-RelB – 19% vs. high cyto-RelB – 8%, p=0.017). Also, cyto-RelB was inversely associated with tumour inflammatory cell infiltrate at the margin, Klintrup-Mäkinen grade ( p=0.059), (CD3+ p=0.010, CD8+ p=0.007) and in the tumour (CD3+ p=0.002) and a trend with tumour stroma percentage ( p=0.079). High expression of cyto-RelB was not significantly associated with CSS ( p=0.052). Conclusions: In patients undergoing CRC resection, high expression of cyto-RelB was associated with an adverse host local inflammatory response. Up-regulation of the non-canonical NF- κB pathway may be an important mechanism whereby the tumour deregulates local inflammatory responses and evades host immunosurveillance. Further investigation of inflammation based signal transduction pathways in patients with colorectal cancer is warranted.

KIFC1 as a novel therapeutic target for p53 mutant colorectal cancer.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e15585-e15585
Author(s):  
Karuna Mittal ◽  
Guanhao Wei ◽  
Jaspreet Kaur ◽  
Da Hoon Choi ◽  
Michelle D. Reid ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Therapeutic Target ◽  
Novel Therapeutic

Chemotherapy dose reductions in obese patients undergoing adjuvant chemotherapy for colorectal cancer: secondary analyses of trial data and the Greater Manchester and Cheshire Cancer Network Audit.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 763-763
Author(s):  
Prakhar Srivastava ◽  
Lee Malcolmson ◽  
Mark P. Saunders ◽  
Andrew Renehan
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Adjuvant Chemotherapy ◽  
Stage Iv ◽  
Obese Patients ◽  
Cancer Specific Survival ◽  
Stage Iv Cancer ◽  
Cancer Network ◽  
The Relationship ◽  
Dose Reductions

763 Background: In patients with stage II/III colorectal cancer receiving adjuvant chemotherapy, doses are calculated using body surface area (BSA) but often capped at BSA > 2.0. Dose capping might be a mechanism of reported poorer survival in obese patients. We aimed to investigate the different dosing schedules across BMI categories, using trial and ‘real world’ audit datasets, and determine its impact upon overall survival. Methods: Data was accessed for 1122 patients from the control arm of the MOSAIC trial (accessed via the Data Project Sphere) and 327 patients from the Greater Manchester and Cheshire Cancer Network (GMCCN) audit. Pearson’s χ2 and correlation coefficient were used to assess the relationship between BMI (expressed as normal, overweight and obese: and as continuous, respectively) and dose reductions. A multiple logistic regression model was constructed to compare the odds of receiving dose reductions in each BMI category. 4-year overall survival was calculated for each BMI category and dose status. Results: In MOSAIC, there were increasing dose reductions by BMI category: normal, 3%; overweight, 5%; and obese, 11%, with similar patterns in the GMCCN OxMdG group. Obese patients in MOSAIC and the GMCCN OxMdG group had 3- and 12-fold higher odds (OR = 3.4 and 12.5, CI = 1.6-7.0 and 2.0-78.1), respectively, of receiving dose reductions. However, these differences did not translate to differences in overall survival by BMI category or dose status. Conclusions: In our investigated datasets, there appears to be a relationship between increasing BMI and dose reductions, though it is modest and does not manifest as a detrimental influence on overall survival. Our findings agreed with other studies performed using stage IV cancer patients, although the relationship between increasing BMI and dose reductions is more prominent in patients with metastatic disease. Investigating other outcome measures such as cancer-specific survival and chemotherapy related toxicity is required for clarity.

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