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Tumor kinase activity in locally advanced rectal cancer: angiogenic signaling and early systemic dissemination.

ABSTRACT: Tumor hypoxia is a common determinant of resistance to cytotoxic therapies and metastatic behavior. In rectal cancer patients receiving preoperative chemoradiotherapy, tyrosine kinase activities in tumors with poor and good treatment responses were found to differ. Given that tyrosine kinase signaling mediates hypoxic tissue adaptation, the present study examined whether tumor kinase activity might also correlate with systemic dissemination of rectal cancer. Immunomagnetic selection of disseminated tumor cells (DTC) from bone marrow aspirates was undertaken in 55 patients with locally advanced rectal cancer. Using peptide arrays with 144 tyrosine kinase substrates, phosphopeptide signatures were generated from patients' baseline tumor biopsies, to study association between DTC and tumor tyrosine kinase activity regulated ex vivo by sunitinib. Disseminated tumor cells were detected in 60% of cases, and these patients had significantly poorer metastasis-free survival than patients without DTC. Phosphorylation of 31 array tyrosine kinase substrates by tumor samples was significantly more strongly inhibited by sunitinib in the DTC-negative patients, with a number of phosphosubstrates representing angiogenic factors. In this cohort of rectal cancer patients, tumor phenotypes defined by a subset of tyrosine kinase activities correlating with weak ex vivo inhibition by sunitinib, was associated with early systemic dissemination.

SUBMITTER: Saelen MG

PROVIDER: S-EPMC3214264 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Tumor phosphatidylinositol-3-kinase signaling and development of metastatic disease in locally advanced rectal cancer.

Project description:BackgroundRecognizing EGFR as key orchestrator of the metastatic process in colorectal cancer, but also the substantial heterogeneity of responses to anti-EGFR therapy, we examined the pattern of composite tumor kinase activities governed by EGFR-mediated signaling that might be implicated in development of metastatic disease.Patients and methodsPoint mutations in KRAS, BRAF, and PIK3CA and ERBB2 amplification were determined in primary tumors from 63 patients with locally advanced rectal cancer scheduled for radical treatment. Using peptide arrays with tyrosine kinase substrates, ex vivo phosphopeptide profiles were generated from the same baseline tumor samples and correlated to metastasis-free survival.ResultsUnsupervised clustering analysis of the resulting phosphorylation of 102 array substrates defined two tumor classes, both consisting of cases with and without KRAS/BRAF mutations. The smaller cluster group of patients, with tumors generating high ex vivo phosphorylation of phosphatidylinositol-3-kinase-related substrates, had a particularly aggressive disease course, with almost a half of patients developing metastatic disease within one year of follow-up.ConclusionHigh phosphatidylinositol-3-kinase-mediated signaling activity of the primary tumor, rather than KRAS/BRAF mutation status, was identified as a hallmark of poor metastasis-free survival in patients with locally advanced rectal cancer undergoing radical treatment of the pelvic cavity.

| S-EPMC3511283 | biostudies-literature

Kinase activity profiling of human locally advanced rectal cancer samples

Project description:Locally advanced rectal cancer characterized by multiplex kinase activity profiling

2010-08-05 | E-TABM-913 | biostudies-arrayexpress

Systemic inflammatory indices predict tumor response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer.

Project description:Systemic inflammatory responses are associated with the prognosis of patients with colorectal cancer. However, the value in predicting tumor responses to neoadjuvant chemoradiotherapy (nCRT) remains to be elucidated. The current study aimed to investigate the association between systemic inflammatory indices and pathological complete response (pCR). The training and validation cohorts included 225 and 96 patients with locally advanced rectal cancer. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio were recorded prior to nCRT and radical surgery. Univariate and multivariate analysis were used to investigate the association between systemic inflammatory indices and pCR. Systemic inflammatory indices prior to or following treatment had no significant association with pCR; however, the percentage change in NLR from pre-nCRT to post-nCRT was associated with a poor response, and a percentage change of >21.5% NLR (P=0.006; OR=0.413; 95% CI=0.22-0.773) was a predictor of poor pCR. Therefore, in rectal cancer, the percentage change in NLR from pre- to post-nCRT was found to be a predictor of poor pCR.

| S-EPMC7400706 | biostudies-literature

Total neoadjuvant therapy in locally advanced rectal cancer: Role of systemic chemotherapy.

Project description:For the past several decades, disease-related outcomes, particularly local recurrence rate, in patients with locally advanced rectal cancer have significantly improved as a result of advancement of surgical technique and implementation of neoadjuvant chemoradiation. However, distant metastasis remains unresolved, being a significant cause of cancer death. To focus on micrometastases early in the course of multimodal treatment, delivering systemic chemotherapy in the neoadjuvant setting is emerging. Also, driven by patient demand and interest in preserving quality of life, upfront chemotherapy prior to surgery serves as a strategy for organ preservation in the management of rectal cancer. Herein, currently available literature on different methods and strategies of the multimodal approach is critically appraised.

| S-EPMC6635691 | biostudies-literature

Systemic inflammation score in locally advanced rectal cancer patients following total mesorectal excision.

Project description:ObjectiveThe objective of the study was to evaluate whether any association exists between systemic inflammation score (SIS) and adverse events (AEs) and survival of locally advanced rectal cancer patients treated with total mesorectal excision (TME) followed by adjuvant chemoradiotherapy.Patients and methodsAll of the 109 rectal cancer patients recruited between May 2008 and June 2015 were treated with TME followed by adjuvant chemoradiotherapy. The prognostic ability of SIS for overall survival (OS) was calculated by the receiver operating characteristic (ROC) curves.ResultsAccording to the classification of the SIS, 22 (20.2%), 59 (54.1%) and 28 (25.7%) patients were classified as a score of 2, 1 and 0, respectively. With an area under the curve (AUC) of 0.616, the SIS score of 1 was defined as the optimal cut-off value. Therefore, we divided the patients into the SIS-low group (SIS score of 1 or 0, n=87) and SIS-high group (SIS score of 2, n=22). Multivariate analysis indicated that SIS was associated with OS (HR 0.390, 95% CI 0.186-0.817, P=0.012). The 5-year OS rate in patients without adjuvant chemotherapy was lower than the patients with adjuvant chemotherapy (53.3% vs 75.8%, P=0.010). Multivariate analysis showed that adjuvant chemotherapy was associated with OS (HR 0.217, 95% CI 0.089-0.529, P=0.001). A marginal statistically significant difference was observed in terms of leukopenia during adjuvant chemoradiotherapy between the SIS-low group and the SIS-high group (P=0.05).ConclusionThese results suggest that SIS might serve as an independent biomarker for predicting AEs and prognosis in locally advanced rectal cancer treated with TME followed by adjuvant chemoradiotherapy. Strengthening treatment may be administered to locally advanced rectal cancer with high SIS score obtained before adjuvant chemoradiotherapy.

| S-EPMC6707432 | biostudies-literature

The Prognostic Value of Tyrosine Kinase SRC Expression in Locally Advanced Rectal Cancer.

Project description:The cellular sarcoma gene (SRC) is a proto-oncogene encoding for a tyrosine kinase. SRC expression was determined in locally advanced rectal adenocarcinoma tissue from pretreatment biopsies and resection specimens. The expression level was correlated with clinicopathological parameters to evaluate the predictive and prognostic capacity. For this monocentric analysis 186 patients with locally advanced rectal cancer (median: 63.7 years; 130 men (69.9%), 56 women (30.1%)) were included. Patients with a carcinoma of the upper third of the rectum were treated with primary tumor resection (n=27; 14.5%). All other patients received a preoperative chemoradiotherapy (CRT) with 50.4 Gy and concomitant 5-fluorouracil (5-FU) or 5-FU+oxaliplatin followed by postoperative chemotherapy with 5-FU or 5-FU+oxaliplatin. SRC expression was determined with immunohistochemical staining from pretreatment biopsies (n=152) and residual tumor tissue from the resection specimens (n=163). The results were correlated with clinicopathological parameters and long-term follow-up. The expression of SRC was determined in pretherapeutic biopsies (mean H-Score: 229) and resection specimens (mean H-Score: 254). High SRC expression in pretherapeutic tumor samples significantly correlated with a negative postoperative nodal status (p=0.005). Furthermore an increased protein expression in residual tumor tissue was associated with fewer distant metastases (p=0.04). The overexpression of SRC in pretreatment tumor biopsies showed also a trend for a longer cancer-specific survival (CSS; p=0.05) and fewer local relapses (p=0.06) during long-term follow-up. High SRC expression in rectal cancer seems to be associated with a better long-term outcome. This finding could help in the future to stratify patients for a recurrence risk adapted postoperative treatment.

| S-EPMC5463438 | biostudies-literature

B cells are the predominant mediators of early systemic viral dissemination during rectal LCMV infection.

Project description:Determining the magnitude of local immune response during mucosal exposure to viral pathogens is critical to understanding the mechanism of viral pathogenesis. We previously showed that vaginal inoculation of lymphocytic choriomeningitis virus (LCMV) fails to induce a robust innate immune response in the lower female reproductive tract (FRT), allowing high titer viral replication and a delay in T-cell-mediated viral control. Despite this immunological delay, LCMV replication remained confined mainly to the FRT and the draining iliac lymph node. Here, we show that rectal infection with LCMV triggers type I/III interferon responses, followed by innate immune activation and lymphocyte recruitment to the colon. In contrast to vaginal exposure, innate immunity controls LCMV replication in the colon, but virus rapidly disseminates systemically. Virus-induced inflammation promotes the recruitment of LCMV target cells to the colon followed by splenic viral dissemination by infected B cells, and to a lesser extent by CD8 T cells. These findings demonstrate major immunological differences between vaginal and rectal exposure to the same viral pathogen, highlighting unique risks associated with each of these common routes of sexual viral transmission.

| S-EPMC6030459 | biostudies-literature

MRI-Based Radiomics Predicts Tumor Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

Project description:Background: Conventional methods for predicting treatment response to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC) are limited. Methods: This study retrospectively recruited 134 LARC patients who underwent standard nCRT followed by total mesorectal excision surgery in our institution. Based on pre-operative axial T2-weighted images, machine learning radiomics was performed. A receiver operating characteristic (ROC) curve was performed to test the efficiencies of the predictive model. Results: Among the 134 patients, 32 (23.9%) achieved pathological complete response (pCR), 69 (51.5%) achieved a good response, and 91 (67.9%) achieved down-staging. For prediction of pCR, good-response, and down-staging, the predictive model demonstrated high classification efficiencies, with an AUC value of 0.91 (95% CI: 0.83-0.98), 0.90 (95% CI: 0.83-0.97), and 0.93 (95% CI: 0.87-0.98), respectively. Conclusion: Our machine learning radiomics model showed promise for predicting response to nCRT in patients with LARC. Our predictive model based on the commonly used T2-weighted images on pelvic Magnetic Resonance Imaging (MRI) scans has the potential to be adapted in clinical practice. Novelty and Impact Statements: Methods for predicting the response of the locally advanced rectal cancer (LARC, T3-4, or N+) to neoadjuvant chemoradiotherapy (nCRT) is lacking. In the present study, we developed a new machine learning radiomics method based on T2-weighted images. As a non-invasive tool, this method facilitates prediction performance effectively. It achieves a satisfactory overall diagnostic accuracy for predicting of pCR, good response, and down-staging show an AUC of 0.908, 0.902, and 0.930 in LARC patients, respectively.

| S-EPMC6606732 | biostudies-literature

Locally Advanced Rectal Cancer - Radiation Response Prediction Study - Serum Proteins

Project description:The study objective was to find new biomarkers of treatment response and adverse events in patients receiving neoadjuvant therapy for locally advanced rectal cancer. Patients received neoadjuvant chemotherapy (NACT) followed by chemoradiotherapy (CRT) and underwent treatment evaluation four weeks after CRT completion. Radical pelvic surgery was planned 2-4 weeks later. Patients were scored for treatment adverse events, according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, throughout the neoadjuvant treatment course, including at NACT and CRT completion. Treatment response was assessed by histologic ypTN staging and tumor regression grade (TRG) scoring, as well as progression-free survival (time from Inclusion date to Date of local relapse or Date of metastatic disease, whichever came first) recorded for five years after surgery.

2016-04-21 | GSE65622 | GEO

Novelties in treatment of locally advanced rectal cancer.

Project description:Treatment of locally advanced rectal cancer is evolving through surgical innovation and paradigm shifts in neoadjuvant treatment. Whereas local recurrence was a significant concern before the systematic implementation of neoadjuvant chemoradiation therapy and surgery according to total mesorectal excision principles, distant relapse remains a major drawback. Hence, efforts in recent years have focused on delivering preoperative chemotherapy regimens to overcome compliance issues with adjuvant administration. In parallel, new surgical techniques, including transanal video-assisted total mesorectal excision and robot-assisted surgery, emerged to face the challenge to navigate in the deep and narrow spaces of the pelvis. Furthermore, patients experiencing a complete response after neoadjuvant treatment might even escape surgery within a close surveillance strategy. This novel "watch and wait" concept has gained interest to improve quality of life in highly selected patients. This review summarizes recent evidence and controversies and provides an overview on timely and innovative aspects in the treatment of locally advanced rectal cancer.

| S-EPMC6281002 | biostudies-literature

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