Therapy In Colorectal Cancer Patients Research Articles

Adamalysines as Biomarkers and a Potential Target of Therapy in Colorectal Cancer Patients: Preliminary Results.

Colorectal cancer is one of the most common cancers in the world. Due to its still undetermined pathogenesis, we are searching for signaling pathways that are important in the development of colorectal cancer. In this article, we present results of study on the role of ADAM proteins in colorectal cancer. The study included 85 adult colorectal cancer patients (48 men, 37 women) and 25 patients in the control group (after diagnostic colonoscopy—without cancer). During hospitalization, a serum sample (3 cm3) was collected from the study and control group, anthropometric measurements were conducted and others clinical data were analyzed. In the serum ADAM10, 12, 17, and 28, protein concentrations were determined and, in the next step, examined the relationship between ADAMs concentrations and selected clinical parameters in both groups. The analysis showed that serum levels of ADAM10 and ADAM28 are significantly higher in patients with colorectal cancer and correlate with histopathological grading and with presence of distant metastases. Moreover, noticed the trend to correlate concentrations of adamalysines with higher BMI score. One of the functions of adamalysines is the activation of growth factors involved in cancer, including IGF and TNFα. The increased activity of adamalysines in patients may play a role in the pathogenesis of colorectal cancer. Our study highlights the prevalence of metabolic disorders in the group of patients with diagnosed CRC, and this cancer seems to be a further complication of obesity.

Novel SFRP2 DNA Methylation Profile Following Neoadjuvant Therapy in Colorectal Cancer Patients with Different Grades of BMI.

The relationship between body weight and different cancers is now well-recognized and among such cancers, colorectal cancer (CRC) is reported most frequently. Our group recently published findings, through an epigenome-wide association study, suggesting that body mass index (BMI) could act as a relevant risk factor in the CRC. In addition, aberrant SFRP2 methylation is one of the major mechanisms for Wnt signaling activation in CRC. Conversely, neoadjuvant chemo-radiotherapy appears to alter the rectal cancer epigenome. This study was aimed to evaluate the effect of obesity, measured by BMI, on the methylation of SFRP2 in tumor samples of patients with CRC. Non-treated CRC patients and CRC patients treated with pre-operative neoadjuvant therapy from 2011 to 2013 were included and classified by BMI < 25.0 kg/m2 and BMI > 25.0 kg/m2. SFRP2 DNA methylation in tumor samples was measured by pyrosequencing. Our findings suggest a possible interaction between SFRP2 methylation levels and BMI in CRC tumor samples. The correlation of SFRP2 hypomethylation with an elevated BMI was stronger within the non-treated CRC patient group than within the treated CRC patient group. We have successfully demonstrated that the beneficial association of tumor SFRP2 hypomethylation is dependent on patient BMI in non-treated CRC, suggesting a possible tumor suppressor role for SFRP2 in overweight and obese patients. Additional studies of clinical pathologies would be necessary to strengthen these preliminary results.

Abstract 1703: New genetic variations discovered in KRAS wild-type cetuximab resistant Chinese colorectal cancer patients

Abstract The efficacy of Cetuximab therapy in colorectal cancer patients is limited by the development of therapeutic resistance. The currently known oncogenic ‘driver’ mutations do not fully explain the resistance mechanism of Cetuximab. Currently there are no reports of any studies that have explored new driver mutations in Cetuximab resistance by whole exome sequencing (WES). In this study, we performed WES to identify common genetic factors from twenty-two Cetuximab-sensitive and ten Cetuximab-resistant patients, aiming to discover characteristic genes associated with Cetuximab resistance. For Cetuximab-sensitive patients, the mutation frequency of MUC16, FCGBP, DMBT1 was found to be 100%, 90.91% and 86.36%, respectively. MUC16, PDE4DIP and TACC2 were altered in all 10 Cetuximab-resistant samples. We also discovered there are 151 significantly mutated genes (SMGs) in Cetuximab sensitive group and 37 in the resistant group. CYP4A11 was the most frequently mutated gene in Cetuximab-resistant patients. BCAS1, GOLGA6L1 and WNT16 were found to be the second group of frequently mutated genes which found in to occur at a frequency of 60% in resistant patients. After cosine similarity analysis with 30 known signatures, three mutational signatures (signature a, b and c) were found in all CRC tumors, similar to Signature 1, 5 and 6 in COSMIC, respectively. Gene ontology analysis was performed on SMGs and found twelve enriched GO terms. Four genes are enriched in six specific KEGG pathway groups, such as metabolism of xenobiotics by cytochrome P450, Steroid hormone biosynthesis, retinol metabolism and drug metabolism. In conclusion, we show that the establishment of a WES clinical study of Cetuximab resistance CRC with prospective follow-up of patients can help to identify candidate predictive biomarkers of response. Note: This abstract was not presented at the meeting. Citation Format: Changwen Jing, Ting Wang, Rong Ma, Haixia Cao, EnShun Xu, Zhuo Wang, Siwen Liu, Dan Chen, Junying Zhang, Yang Wu, Yuan Zhang, Ping Ding, Michael Y. Sha, Jianzhong Wu, Jifeng Feng. New genetic variations discovered in KRAS wild-type cetuximab resistant Chinese colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1703.

StomieCare : un programme d’intervention psycho-éducationnelle individuelle à composantes cognitivo-comportementales pour des patients opérés d’un cancer du rectum avec stomie temporaire

Notre recherche visait à développer et mettre en place un programme d’intervention psychosociale individuelle à l’attention des personnes opérées d’un cancer du rectum avec stomie temporaire. Cet article présente la structure et le contenu de ce programme d’intervention psycho-éducationnelle qui est une adaptation du programme développé et validé par Dolbeault et al. (2009) auprès de femmes atteintes d’un cancer du sein. Ce programme s’inspire largement des techniques cognitivo-comportementales et comprend des discussions thématiques autour de problèmes communs, d’apport d’informations et d’apprentissage de techniques (résolution de problème, restructuration cognitive). Il cible plus particulièrement les besoins psychosociaux des patients et vise à favoriser l’expression des émotions, à réguler la détresse émotionnelle et à restaurer l’image du corps et la qualité de vie de ces sujets. Ce programme, dont la validité a été mise à l’épreuve et sera présentée dans un article à venir, a suscité un vif intérêt chez les patients qui y ont participé et devrait pouvoir être généralisé à tout sujet volontaire opéré d’un cancer du rectum avec stomie temporaire. Worldwide, colorectal cancer is one of the most commonly diagnosed cancers. For locally advanced rectal cancer, the standard treatment is rectal excision with or without preoperative chemoradiotherapy. Anastomotic leakage is one of the most important early complications and is associated with high morbidity and mortality rates. Temporary/protective stoma is recommended to prevent anastomotic leakage. Despite its clinical benefits, stomas unavoidably affect patients’ physically, psychologically and socially. In the context of cancer care, psychosocial interventions are valuable complements to physical treatments to help minimize stress, improve quality of life and reduce depression. The literature review performed by Hoon et al. (2013) revealed that very few studies (n = 11) focused on psychological interventions for colorectal cancer patients (with or without stoma). Educational interventions and cognitive-behavioral therapy were the two most commonly used psychosocial interventions. Regarding educational interventions, we performed a systematic review of the educational interventions on colorectal cancer patients with stoma. We noted that most interventions and evaluations were focused on stoma self-management and very few on psychosocial skills (Faury et al., 2017). Concerning the cognitive-behavioral therapies for colorectal cancer patients, their primary objectives are to implement lifestyle interventions to modify diet, exercise, smoking and alcohol consumption, to manage symptoms and fatigue, and to adjust weight control behaviors (Hoon et al., 2013). As part of our research project, we have developed an individual psychosocial intervention for people with rectal cancer and temporary stoma during and after their surgical treatment period. The main objective of our research was to study the effects of this type of intervention on variables such as psychological distress, quality of life, and body image through a randomized study comparing a treatment group to a control group. This article describes the structure and the content of this intervention, which is an adaption of the psycho-educational intervention developed by Dolbeault et al. (2009) for French women with breast cancer after the end of their treatment period. Largely based on cognitive-behavioral techniques, it consists of thematic discussions, information and education, and teaching problem solving and cognitive restructuring. It specifically targets emotional needs and body image. The program included three individual sessions with a psychologist (45 to 60 min): the first session was performed during the first hospitalization (rectal excision with temporary stoma); the second during the second hospitalization (stoma reversal operation) and the third, one month after the stoma reversal operation. The topics of these interventions were: the meaning of cancer and its treatments (session 1); the effects of cancer and its treatments on quality of life and self-esteem (session 2); the effects of a reversal stoma operation on patients’ life and uncertainty management (session 3). At the end of each session, a drawing of the person, which is a real clinical tool, was used in order to allow patients to discuss their perception of their body. The purpose of this article is to help other clinicians who want to help patients with rectal cancer and temporary stoma, since patient satisfaction appears to be very high.

Rethinking of the conversion therapy in colorectal cancer patients with liver metastasis

The incidence of colorectal cancer liver metastasis (CRLM) has gradually increased in recent years. Surgical resection is the main method to achieve long-term survival for patients with CRLM. However, only 20% of these patients have the chance to undergo surgical resection. If the unresectable metastases can be converted to resectable ones by effective conversion therapy, the 5-year survival rate of patients received liver resection can exceed to 30%, which is significantly better than palliative treatment. Therefore, for patients who are initially unresectable, rationally developing a conversion therapy strategy to convert the initial unresectable CRLM into resectable ones is the key to improve the long-term survival of CRLM patients. However, there are still many controversies in clinical practice. In this article, we discuss three critical issues related to the conversion therapy for CRLM based on previous related researches and our experience, including the applicable population of conversion therapy, how to choose a conversion regime and the recognition and treatment of disappeared lesions after chemotherapy.

NSD2 circular RNA promotes metastasis of colorectal cancer by targeting miR-199b-5p-mediated DDR1 and JAG1 signalling.

Liver metastasis is the main cause of death in patients with colorectal cancer (CRC). Here, we searched for CRC metastasis-associated circular RNA in a mouse model of liver metastasis of CRC by using RNA (transcriptome)-sequencing. We identified a novel and conserved circular RNA, circ-NSD2, functioning as a promoter of CRC metastasis. Circ-NSD2 expression was elevated in CRC tissues and was markedly increased in advanced stages or metastatic tumours of CRC patients. Gain-of-function and loss-of-function experiments demonstrated that circ-NSD2 promoted migration and metastasis of CRC in vitro and in vivo. Mechanistically, circ-NSD2 acted as a sponge for the tumour suppressor miR-199b-5p and activated DDR1 (discoidin domain receptor tyrosine kinase 1) and JAG1 (Jagged 1) genes, which synergistically helped with cell-matrix interaction, migration and metastasis of CRC cells. Taken together, our findings highlight a novel oncogenic function of circ-NSD2 and uncover a key mechanism for the circ-NSD2/miR-199b-5p/DDR1/JAG1 axis in CRC metastasis, which may serve as a prognostic factor and therapeutic target for antimetastatic therapy in CRC patients. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Study on colorectal cancer using air-liquid interface organoid culture method

Colorectal cancer is a disease with high unmet medical needs. An increase in the number of cancer patients who are resistant to anti-cancer drugs is one of factors that increase the number of fatalities. Since there was no suitable experimental model to recapitulate the tumor environment in which various cells in the tissues exist, it was extremely difficult to develop a medicine that overcomes the anti-cancer drug resistance in each colorectal cancer patient. In this review, we describe the current status and problems of drug therapy for colorectal cancer patients, and introduce our study to develop the new targeting drugs using human colon tissue-derived air liquid interface organoid culture method.

Evaluation of the clinical impact of concomitant acid suppression therapy in colorectal cancer patients treated with capecitabine monotherapy.

Capecitabine is an oral chemotherapeutic agent used in colorectal cancer. Two prior studies found a negative impact with the concomitant use of proton pump inhibitor agents during treatment with capecitabine in patients with early colorectal and gastroesophageal cancers. To determine if there is a clinical impact of the concomitant use of capecitabine and acid suppression therapy in patients with local and metastatic colorectal cancer. This was a single-center retrospective cohort study of adult patients with colorectal cancer on capecitabine monotherapy between 2011 and 2017. Progression-free survival (PFS) and overall survival were compared between patients on acid suppression therapy and those not on acid suppression therapy. A total of 70 patients were included. Patients on acid suppression therapy at capecitabine initiation (21%) had decreased progression-free survival versus those not on acid suppression therapy (HR 2.24, 95% CI 1.06-4.41, p = 0.035), after adjusting for disease severity and age. Acid suppression therapy use was associated with a numerical decrease in overall survival (HR 1.86, 95% CI 0.81-3.91, p = 0.14). In patients on any concomitant acid suppression therapy (25%), there was a decreased rate of progression-free survival (HR 6.21, 95% CI 2.56-14.32, p = 0.0001) but not overall survival (HR 1.64, 95% CI 0.68-3.54, p = 0.25) versus those without concomitant acid suppression therapy, after adjusting for age and disease severity. Concurrent use of acid suppression therapy and capecitabine was associated with decreased progression-free survival, and there was a trend towards decreased overall survival. Due to the demonstrated potential of decreased efficacy, concurrent use of proton pump inhibitors or histamine 2 receptor antagonists should be avoided in colorectal cancer patients on treatment with capecitabine monotherapy.

Biomarkers in colorectal cancer: Current clinical utility and future perspectives.

Colorectal cancer (CRC) is a major cause of cancer death worldwide. CRC has poor prognosis and there is a crucial need for new diagnostic and prognostic biomarkers to avoid CRC-related deaths. CRC can be considered a sporadic disease in most cases (75%-80%), but it has been suggested that crosstalk between gene mutations (i.e., mutations of BRAF, KRAS, and p53 as well as microsatellite instability) and epigenetic alterations (i.e., DNA methylation of CpG island promoter regions) could play a pivotal role in cancer development. A number of studies have focused on molecular testing to guide targeted and conventional treatments for patients with CRC, sometimes with contrasting results. Some of the most useful innovations in the management of CRC include the possibility to detect the absence of KRAS, BRAF, NRAS and PIK3CA gene mutations with the subsequent choice to administer targeted adjuvant therapy with anti-epidermal growth factor receptor antibodies. Moreover, CRC patients can benefit from tests for microsatellite instability and for the detection of loss of heterozygosity of chromosome 18q that can be helpful in guiding therapeutic decisions as regards the administration of 5-FU. The aim of this review was to summarize the most recent evidence on the possible use of genetic or epigenetic biomarkers for diagnosis, prognosis and response to therapy in CRC patients.

Telephone-based reminiscence therapy for colorectal cancer patients undergoing postoperative chemotherapy complicated with depression: a three-arm randomised controlled trial.

Colorectal cancer patients undergoing postoperative chemotherapy often exhibit symptoms of depression that in turn may negatively affect outcome. The aim of this study was to assess the efficacy of telephone-based reminiscence therapy on the depression, anxiety, subjective well-being, and social support of colorectal cancer patients undergoing postoperative chemotherapy complicated with depression. Patients were divided randomly into a control group (CON, n = 45), telephone support group (TS, n = 45), and telephone-based reminiscence therapy group (TBR, n = 45). Patients in TS and TBR groups received six 20-40-min telephone intervention sessions conducted weekly. Patients were assessed at baseline and at 6weeks. The primary outcomes were changes on the Self-Rating Depression Scale (SDS) and Hamilton Depression Scale (HAMD), which were used to evaluate depression symptoms. Secondary outcomes were changes in Self-Rating Anxiety Scale (SAS), Hamilton Anxiety Scale (HAMA), Memorial University of Newfoundland Scale of Happiness (MUNSH), and Perceived Social Support Scale (PSSS) scores, which were used to evaluate anxiety symptoms, subjective well-being, and social support, respectively. After 6weeks, SDS and HAMD scores were significantly lower than pre-intervention baseline in the TBR group but not in the CON and TS groups (P <0.05). Both SAS and HAMA scores were significantly reduced in TBR and TS groups but not the CON group (P < 0.05) following intervention; however, there was no significant difference in post-intervention scores between TS and TBR groups (P > 0.05). Neither telephone support nor telephone-based reminiscence therapy improved subjective well-being or social support (P >0.05). These findings suggest that telephone-based reminiscence therapy can reduce depression symptoms in colorectal cancer patients undergoing postoperative chemotherapy. Telephone-based reminiscence therapy may also improve anxiety, but no better than telephone support. Alternatively, telephone-based reminiscence therapy did not improve subjective well-being or social support. We suggest that clinicians provide appropriate telephone-based reminiscence therapy in long-term care institutions based on patient mental health status.

DJ-1 promotes colorectal cancer progression through activating PLAGL2/Wnt/BMP4 axis

Metastasis remains a big barrier for the clinical treatment of colorectal cancer (CRC). Our previous proteomics analysis identified DJ-1 as a potential metastasis biomarker of CRC. In this study, we found that DJ-1 was upregulated in CRC. The levels of DJ-1 were closely correlated with the depths of invasion and predicted patient outcome. Enforced expression of DJ-1 could enhance CRC proliferation and metastasis in vitro and in vivo by stimulating Wnt-β-catenin signaling. Specifically, DJ-1-induced β-catenin nuclear translocation stimulated TCF transcription activity, which promoted BMP4 expression for CRC cell migration and invasion, and elevated CCND1 expression for CRC cell proliferation, respectively. Furthermore, DJ-1-induced Wnt signaling activation was dependent on PLAGL2 expression. In conclusion, our study demonstrates that DJ-1 can promote CRC metastasis by activating PLAGL2–Wnt–BMP4 axis, suggesting novel therapeutic opportunities for postoperative adjuvant therapy in CRC patients.

Current understanding and clinical utility of miRNAs regulation of colon cancer stem cells.

Cancer stem cells (CSCs) in colorectal tumorigenesis are suggested to be responsible for initiation, development and propagation of colorectal cancer (CRC) and have been extensively characterized by the expression of phenotypic determinants, such as surface or intracellular proteins. The generation of CSCs is likely due to a dysregulation of the signaling pathways that principally control self-renewal and pluripotency in normal intestinal stem cells (ISCs) through different (epi)genetic changes that define cell fate, identity, and phenotype of CSCs. These aspects are currently under intense investigation. In the framework of the oncogenic signaling pathways controlled by microRNAs (miRNAs) during CRC development, a plethora of data suggests that miRNAs can play a key role in several regulatory pathways involving CSCs biology, epithelial-mesenchymal transition (EMT), angiogenesis, metastatization, and pharmacoresistance. This review examines the most relevant evidences about the role of miRNAs in the etiology of CRC, through the regulation of colon CSCs and the principal differences between colorectal CSCs and benign stem cells. In this perspective, the utility of the principal CSCs-related miRNAs changes is explored, emphasizing their use as potential biomarkers to aid in diagnosis, prognosis and predicting response to therapy in CRC patients, but also as promising targets for more effective and personalized anti-CRC treatments.

Long noncoding RNA LINC01510 promotes the growth of colorectal cancer cells by modulating MET expression

BackgroundAbnormal expression of long non-coding RNA (lncRNAs) often facilitates unrestricted growth of cancer cells. Long intergenic non-protein coding RNA 1510, an enhancer lncRNA (LINC01510), a lncRNA enhancer is upregulated in colorectal cancer (CRC), and its expression might relate to MET as revealed by lncRNA microarray data. However, the potential biological role of LINC01510 and its regulatory mechanism in CRC remain unclear. Therefore, we investigated the involvement of LINC01510 in the proliferation of CRC cells.MethodsMicroarray analysis, In situ hybridization, colony formation assay, MTT assay, Western blotting, quantitative RT-PCR and flow cytometry were applied. The two-tailed Student’s t test and analysis of variance or general linear model of single factor variable was used for statistical analyse.ResultsIn the present study, we found that LINC01510 was significantly upregulated in CRC tissues and cell lines. The LINC01510 expression level were associated with the clinicopathological grade and stage. Meanwhile, gain- and loss-of-function assays demonstrated that LINC01510 overexpression increased CRC cell proliferation, and promoted cell cycle progression from the G1 phase to the S phase. Further study indicated that LINC01510 was positively correlated with the expression of MET, and its effects were most likely at the transcriptional level.ConclusionsTaken together, our findings suggested that upregulation of LINC01510 contributes to the proliferation of CRC cells, at least in part, through the regulation of MET protein. LINC01510 could be a candidate prognostic biomarker and a target for new therapies in CRC patients.

C-MET Overexpression in Colorectal Cancer: A Poor Prognostic Factor for Survival

IntroductionIncreased mesenchymal-epithelial transition factor gene (c-MET) expression in several human malignancies is related to increased tumor progression and is a new potential drug target for several types of cancers. In the present study, we investigated the incidence of c-MET overexpression and its prognostic significance in patients with colorectal cancer (CRC). Patients and MethodsWe retrospectively reviewed the data from 255 stage IV CRC patients who had results from a c-MET immunohistochemical test at Samsung Medical Center. We explored the relationships between c-MET overexpression and clinicopathological features and survival. ResultsPrimary tumor sites were 67 right-sided colon, 98 left-sided colon, and 90 rectum. Forty-two patients (16.7%) had poorly differentiated or mucinous carcinoma. Among the 255 patients, 39 (15.3%) exhibited c-MET overexpression. There was no significant difference in the prevalence of c-MET overexpression according to primary site, histologic differentiation, molecular markers, or metastatic sites. In a comparison of the tumor response to first-line chemotherapy according to the level of c-MET expression, we found no significant difference in either partial response or disease control rate. In the survival analysis, patients with c-MET overexpression had significantly shorter overall survival (39 vs. 27 months; P = .018) and progression-free survival (PFS) during bevacizumab treatment (10 vs. 7 months; P = .024). Conclusionc-MET overexpression, which was detected in 39 CRC patients (15.3%) irrespective of primary sites or molecular markers, indicated a poor survival prognosis and predicted shorter PFS during bevacizumab treatment in patients with CRC. Further studies are warranted to elucidate the value of c–MET-targeted therapy in CRC patients.

DNA damage in blood cells in relation to chemotherapy and nutritional status in colorectal cancer patients—A pilot study

DNA damage can be considered as a biomarker for toxicity and response to chemotherapy. It is not known whether the chemotherapy-induced genotoxicity is associated with malnutrition. In this pilot study, we assess genotoxicity by means of DNA damage in patients with lymph-node positive colorectal cancer (CRC) and explore associations with chemotherapy treatment and nutritional status. DNA damage was compared between patients receiving chemotherapy (n = 24) and those not receiving chemotherapy (n = 20). DNA damage was measured in frozen whole blood by the comet assay. Associations between DNA damage and various indicators of malnutrition were also explored, including Patient-Generated Subjective Global Assessment (PG-SGA), bioelectrical impedance analysis (BIA) and anthropometric measurements, using multiple linear regression models. Patients on chemotherapy have higher levels of DNA damage in blood cells than patients not receiving chemotherapy (median of 16.9 and 7.9% tail DNA respectively, p = 0.001). The moderately malnourished patients (PG-SGA category B), representing 41% of the patients, have higher levels of cellular DNA damage than patients with good nutritional status (mean difference of 7.5% tail DNA, p = 0.033). In conclusion, adjuvant chemotherapy and malnutrition are both associated with increased levels of DNA damage in blood cells of CRC patients. Carefully controlled longitudinal studies or randomized controlled trials should be performed to determine whether good nutritional status may protect against chemotherapy-induced genotoxicity and enhance compliance to therapy in CRC patients.

Targeting the PI3K Signalling as a Therapeutic Strategy in Colorectal Cancer.

Colorectal cancer (CRC) remains one of the leading causes of cancer mortality worldwide. Regarded as a heterogeneous disease, a number of biomarkers have been proposed to help in the stratification of CRC patients and to enable the selection of the best therapy for each patient towards personalized therapy. However, although the molecular mechanisms underlying the development of CRC have been elucidated, the therapeutic strategies available for these patients are still quite limited. Thus, over the last few years, a multitude of novel targets and therapeutic strategies have emerged focusing on deregulated molecules and pathways that are implicated in cell growth and survival. Particularly relevant in CRC are the activating mutations in the oncogene PIK3CA that frequently occur in concomitancy with KRAS and BRAF mutations and that lead to deregulation of the major signalling pathways PI3K and MAPK, downstream of EGFR. This review focus on the importance of the PI3K signalling in CRC development, on the current knowledge of PI3K inhibition as a therapeutic approach in CRC and on the implications PI3K signalling molecules may have as potential biomarkers and as new targets for directed therapies in CRC patients.

Potentiating Effect of Oxymatrine and 5-fluorouracil on Cell Survival and Inhibition of Cancer Metastasis in SW-620 Colorectal Cancer Cells

Colorectal cancer (CRC) is the most common cancer in the world, beginning in the cell lining of the colon and rectum. 5-fluorouracil (5-FU) is a first-line therapy for colorectal cancer patients. However, the response rate of 5-FU in advanced colorectal cancer patients is only 10 - 15 %, and can fail due to drug resistance. Therefore, the development of a new anticancer compound for improving the response rate or for reversing resistance to 5-FU is urgently needed. Oxymatrine is a major component of Sophora flavescens. Recently, many pharmacological effects have been exhibited. The objectives of the present study were to investigate the anticancer activity of oxymatrine, as well as to potentiate the effect of oxymatrine with 5-FU on cell viability, colony-forming, cell migration, cell invasion, and determined MMP-9 protein expression in SW-620 colorectal cancer cells. The results demonstrated that oxymatrine significantly inhibited the cell viability of SW-620 cells after 24, 48, and 72 h treatments. Oxymatrine and 5-FU interaction was synergistically greater in inhibiting the cell survival of SW-620 cells than 5-FU was alone. Oxymatrine also decreased colony formation, cell migration, and cell invasion through reducing the level of MMP-9 protein in SW-620 cells. These first findings elucidated an efficacious anticancer agent, which is derived from natural sources, which could be used to overcome 5-FU resistance in colorectal cancer, and may be beneficial for patients with colorectal cancer who are treated with 5-FU.

Homeobox B9 Mediates Resistance to Anti-VEGF Therapy in Colorectal Cancer Patients.

Purpose: The identification of predictive biomarkers for antiangiogenic therapies remains an unmeet need. We hypothesized that the transcription factor Homeobox B9 (HOXB9) could be responsible for the tumor resistance to the anti-VEGF agent bevacizumab.Experimental Design: HOXB9 expression and activation were measured in eight models of colorectal and pancreatic cancer with different resistance to bevacizumab. Serum levels of Angiopoietin-like Protein (Angptl)2, CXC receptor ligand (CXCL)1, IL8, and TGFβ1 in tumor-bearing mice were measured by multiplex xMAP technology. HOXB9 expression was measured by immunohistochemical analysis in 81 pretreatment specimens from metastatic colorectal cancer patients. Differences in progression-free survival (PFS) were determined using a log-rank test.Results: HOXB9-positive tumors were resistant to bevacizumab, whereas mice bearing HOXB9-negative tumors were cured by this agent. Silencing HOXB9 in bevacizumab-resistant models significantly (P < 0.05) reduced Angptl2, CXCL1, IL8, and TGFβ1 levels, reverted their mesenchymal phenotype, reduced CD11b+ cells infiltration, and restored, in turn, sensitivity to bevacizumab. HOXB9 had no prognostic value in patients treated with a first-line chemotherapeutic regimen noncontaining bevacizumab. However, patients affected by an HOXB9-negative tumor had a significantly longer PFS compared with those with an HOXB9-positive tumor if treated with a first-line regimen containing bevacizumab (18.0 months vs. 10.4 months; HR 2.037; 95% confidence interval, 1.006-4.125; P = 0.048).Conclusions: These findings integrate the complexity of numerous mechanisms of anti-VEGF resistance into the single transcription factor HOXB9. Silencing HOXB9 could be a promising approach to modulate this resistance. Our results candidate HOXB9 as predictive biomarker for selecting colorectal cancer patients for antiangiogenic therapy. Clin Cancer Res; 23(15); 4312-22. ©2017 AACR.

Immune therapy in colorectal cancer

The evidence that the immune system, when rightly stimulated, can eradicate cancer cells, combined with the latest knowledge about antitumor immunity, has led to recent progress in cancer immunotherapy. While infiltration of tumors with immune cells is described in advanced stage colorectal cancer (CRC), the first data concerning the clinical efficacy of immune-targeted therapies in CRC patients were disappointing. The evidence of tumor responses in CRC patients with microsatellite instability treated with immune checkpoint blockers has renewed the interest for research in the field of CRC immunotherapy. In this article, we briefly review the role of T lymphocytes infiltrating CRC tumors in order to introduce a brief history of CRC immunotherapy and then current trials involving immune-based strategies and particularly immune checkpoint blockers.

Methods of selecting combination therapy for colorectal cancer patients: a patent evaluation of US20160025730A1

ABSTRACTIntroduction: Colorectal cancer (CRC) is the fourth most common cancer worldwide. Targeted therapy drugs (TTDs) are a valid treatment, epithelial growth factor receptor (EGFR) inhibitors being one of the most commonly used for CRC patients. However, this treatment is only useful for patients with wild-type KRAS (wtKRAS) and is effective only on about 40 to 60% of this subset due to the high plasticity of ErbB network.Areas covered: The invention proposes the use of ErbB protein levels and ErbB receptor dimer formation as biomarkers for selecting, predicting and monitoring CRC patients showing sensitivity to the action of EGFR inhibitors to benefit from the combination therapy of EGFR and HER2 inhibitors. The in vitro data on Lim1215 cells suggest the over-activation of HER3 signaling pathway in response to the use of EGFR inhibitors on monotherapy; the use of HER2 or HER3 or MEK inhibitors in combination with EGFR inhibitors reversed this activation.Expert opinion: To assess the clinical applicability of this invention, further studies are needed since the conclusions are derived solely based on the data obtained from only one CRC cell line (Lim1215). Furthermore, other biofactors/mutations should be considered to assure the potential benefits of the combination therapies proposed.