O11: MYOFERLIN: A NOVEL BIOMARKER OF RADIOSENSITIVITY IN LOCALLY ADVANCED RECTAL CANCER

Abstract Introduction Our proteomic data has validated that high levels of the protein myoferlin confers poorer response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Myoferlin plays a role in membrane repair and VEGF signal transduction, and is associated with worse prognosis in numerous other epithelial cancers. We aim to assess the impact of myoferlin on the radiosensitivity of rectal cancer. Method Clonogenic assays were performed using immortalised colorectal cancer cells (HCT116,HT29,LIM,MDST8) to assess survival at escalating radiation doses following knockdown with myoferlin siRNA or a small molecular inhibitor(WJ460). 3D models (spheroids) were used to examine the effect of WJ460 on tumour growth. Result Quantification of myoferlin using immunoblotting demonstrated that MDST8 and LIM were higher expressors than HCT116 and HT29. Higher levels correlated with increasing radio-resistance as calculated by colony formation efficiency (CFE). Using clonogenic assays, cells treated with myoferlin siRNA or WJ460 demonstrated increased radiosensitivity compared to controls across all radiation doses, most significantly at 4Gy. Treatment of spheroids with WJ460 significantly reduced growth compared to controls at all radiation doses (p<0.05), with WJ460 limiting growth considerably more than treatment with the current gold standard 5-FU. HCT116 spheroid volume day 15; WJ460 4.96um3,5-FU 6.74um3,DMSO 24.9um3. Conclusion Inhibition of myoferlin is associated with increased radiosensitivity of colorectal cancer cells, and treatment with a small molecular inhibitor significantly reduces growth in spheroid models. Further work is required further validate its potential use as a biomarker in locally advanced rectal cancer. Take-home message We have found that myoferlin is a protein associated with poor response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Manipulation of this protein sensitises the cancer cells to radiotherapy.

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The predictive value of baseline volumetric PET/CT parameters on treatment response and prognosis in locally-advanced rectal cancer treated with neoadjuvant chemoradiotherapy

10.21203/rs.3.rs-212603/v1 ◽

2021 ◽

Author(s):

Abdullah SAKİN ◽

Suleyman Sahin ◽

Sevda Saglampınar Karyagar ◽

Savas Karyagar ◽

Muhammed Mustafa atci ◽

...

Keyword(s):

Rectal Cancer ◽

Cancer Cells ◽

Treatment Response ◽

Locally Advanced ◽

Neoadjuvant Chemoradiotherapy ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Group I ◽

Pet Ct ◽

Group Ii

Abstract Purpose:To investigate the prognostic effects of baseline volumetric PET/CT parameters including the maximum standard uptake value(SUVmax), metabolic tumor volume(MTV), and tumor lesion glycolysis(TLG) on treatment response and prognosis in locally-advanced rectal cancer(LARC) treated with neoadjuvant chemoradiotherapy(NACRT).Methods:Between 2015 and 2018, 51 patients with LARC treated with NACRT followed by surgery were included in this retrospective study. Patients were divided into 2 groups by tumor regression grade(TRG) as follows;Group I=TRG 1(No detectable cancer cells)+TRG 2(single cells and/or small groups of cancer cells) and Group II=TRG3(residual tumor outgrown by fibrosis)+TRG 4(remarkable fibrosis outgrown by tumor cells)+TRG 5(No fibrosis with extensive residual cancer).Results:Of the 51 patients, 34(66.7%) were male. The median age was 55(range,37-78) years. According to TRG status, 14(27.4%) patients were in group I and 37(72.6%) patients were in group II. The area under the curve(95% CI) was 0.749(0.593-0.905) in the ROC curve plotted for MTV. The cut of value for MTV was 12, with 70% sensitivity and 65% specificity. MTV was≥12 in 32(62.8%) patients. MTV and TLG values were significantly different between Group I and II, whereas there was no significant difference between the groups in terms of SUVmax values (p=0.006, p=0.033, and p=0.673, respectively). The disease-free survival was not reached in patients with MTV<12 vs. 20 months in those with MTV≥12 (p=0.323). In multivariate analysis, MTV(OR, 95% Cl, 5.00[1.17-21.383]) was found to be the factor that affected pathological complete response.Conclusion:In LARC treated with NACRT, MTV prior to treatment can help predict the response to treatment.

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Screening of MicroRNA Related to Irradiation Response and the Regulation Mechanism of miRNA-96-5p in Rectal Cancer Cells

Frontiers in Oncology ◽

10.3389/fonc.2021.699475 ◽

2021 ◽

Vol 11 ◽

Author(s):

Fengpeng Wu ◽

Bingyue Wu ◽

Xiaoxiao Zhang ◽

Congrong Yang ◽

Chaoxi Zhou ◽

...

Keyword(s):

Rectal Cancer ◽

Cancer Cells ◽

Locally Advanced ◽

Neoadjuvant Chemoradiotherapy ◽

Signal Transduction Pathway ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Regulation Mechanism ◽

Canonical Wnt ◽

Irradiation Resistance

Neoadjuvant chemoradiotherapy has been widely used in the treatment of locally advanced rectal cancer due to the excellent advantages of irradiation in cancer therapy. Unfortunately, not every patient can benefit from this treatment, therefore, it is of great significance to explore biomarkers that can predict irradiation sensitivity. In this study, we screened microRNAs (miRNAs) which were positively correlated with irradiation resistance and found that miRNA-552 and miRNA-183 families were positively correlated with the irradiation resistance of rectal cancer, and found that high expression of miRNA-96-5p enhanced the irradiation resistance of rectal cancer cells through direct regulation of the GPC3 gene and abnormal activation of the canonical Wnt signal transduction pathway. Based on the radioreactivity results of patient-derived xenograft models, this is the first screening report for radio-resistant biomarkers in rectal cancer. Our results suggest that miRNA-96-5p expression is an important factor affecting the radiation response of colorectal cancer cells.

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MicroRNA-199b Downregulation Confers Resistance to 5-Fluorouracil Treatment and Predicts Poor Outcome and Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Patients

Cancers ◽

10.3390/cancers12061655 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1655 ◽

Cited By ~ 2

Author(s):

Ion Cristóbal ◽

Jaime Rubio ◽

Andrea Santos ◽

Blanca Torrejón ◽

Cristina Caramés ◽

...

Keyword(s):

Colorectal Cancer ◽

Rectal Cancer ◽

Locally Advanced ◽

Neoadjuvant Chemoradiotherapy ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Preoperative Treatment ◽

Dependent Manner ◽

Current Standard ◽

Poor Outcome

Neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy followed by mesorectal excision is the current standard treatment in locally advanced rectal cancer (LARC) and the lack of complete response represents a major problem that compromises long-term patient survival. However, there is a lack of robust established markers predictive of response to this preoperative treatment available in the clinical routine. The tumor suppressor microRNA (miR)-199b directly targets the PP2A inhibitor SET, which has been involved in 5-FU resistance, and its downregulation has been found to correlate with poor outcome in metastatic colorectal cancer. Here, we studied the functional effects of miR-199b on 5-FU sensitivity after its ectopic modulation, and its expression was quantified by real-time-PCR in a cohort of 110 LARC patients to evaluate its potential clinical significance. Interestingly, our findings demonstrate that miR-199b enhances the sensitivity of colorectal cancer cells to 5-FU in a SET-dependent manner, and that both miR-199b overexpression and SET inhibition are able to overcome resistance to this drug using an acquired 5-FU-resistant model. MiR-199b was found downregulated in 26.4% of cases and was associated with positive lymph node levels after chemoradiotherapy (CRT, p = 0.007) and high pathological stage (p = 0.029). Moreover, miR-199b downregulation determined shorter overall (p = 0.003) and event-free survival (p = 0.005), and was an independent predictor of poor response to preoperative CRT (p = 0.004). In conclusion, our findings highlight the clinical impact of miR-199b downregulation predicting poor outcome and pathological response in LARC, and suggest the miR-199b/SET signaling axis as a novel molecular target to prevent the development of resistance to 5-FU treatment.

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Long-term outcomes of locally advanced rectal cancer after neoadjuvant chemoradiotherapy: A bi-national colorectal cancer audit study

World Journal of Colorectal Surgery ◽

10.4103/wjcs.wjcs_16_19 ◽

2019 ◽

Vol 8 (3) ◽

pp. 74

Author(s):

JosephC Kong ◽

GlenR Guerra ◽

Angus Lee ◽

SatishK Warrier ◽

ACraig Lynch ◽

...

Keyword(s):

Colorectal Cancer ◽

Rectal Cancer ◽

Locally Advanced ◽

Neoadjuvant Chemoradiotherapy ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Long Term Outcomes

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Molecular and Dynamic Evaluation of Proteins Related to Resistance to Neoadjuvant Treatment with Chemoradiotherapy in Circulating Tumor Cells of Patients with Locally Advanced Rectal Cancer

Cells ◽

10.3390/cells10061539 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1539

Author(s):

Virgílio Souza e Silva ◽

Emne Ali Abdallah ◽

Bianca de Cássia Troncarelli Flores ◽

Alexcia Camila Braun ◽

Daniela de Jesus Ferreira Costa ◽

...

Keyword(s):

Rectal Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Transforming Growth Factor ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Neoadjuvant Chemoradiotherapy ◽

Disease Free Survival ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer

The heterogeneity of response to neoadjuvant chemoradiotherapy (NCRT) is still a challenge in locally advanced rectal cancer (LARC). The evaluation of thymidylate synthase (TYMS) and RAD23 homolog B (RAD23B) expression in circulating tumor cells (CTCs) provides complementary clinical information. CTCs were prospectively evaluated in 166 blood samples (63 patients) with LARC undergoing NCRT. The primary objective was to verify if the absence of RAD23B/TYMS in CTCs would correlate with pathological complete response (pCR). Secondary objectives were to correlate CTC kinetics before (C1)/after NCRT (C2), in addition to the expression of transforming growth factor-β receptor I (TGF-βRI) with survival rates. CTCs were isolated by ISET and evaluated by immunocytochemistry (protein expression). At C1, RAD23B was detected in 54.1% of patients with no pCR and its absence in 91.7% of patients with pCR (p = 0.014); TYMS− was observed in 90% of patients with pCR and TYMS+ in 51.7% without pCR (p = 0.057). Patients with CTC2 > CTC1 had worse disease-free survival (DFS) (p = 0.00025) and overall survival (OS) (p = 0.0036) compared with those with CTC2 ≤ CTC1. TGF-βRI expression in any time correlated with worse DFS (p = 0.059). To conclude, RAD23B/TYMS and CTC kinetics may facilitate the personalized treatment of LARC.

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