Personalized treatment for colorectal cancer: novel developments and putative therapeutic strategies

Akkad, Jamil; Bochum, Sylvia; Martens, Uwe M.

doi:10.1007/s00423-015-1276-0

Cited by 16 publications

(19 citation statements)

References 136 publications

(150 reference statements)

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“…Tumor proteins such as P53, KRAS, and others have been associated with colorectal cancer progression and prognosis. However, tumor heterogeneity suggests the need for new markers of CRC [4, 6]. …”

Section: Introductionmentioning

confidence: 99%

Overexpression of LARP1 predicts poor prognosis of colorectal cancer and is expected to be a potential therapeutic target

Lin

et al. 2016

Tumor Biol.

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This study investigated the significance of La-related protein 1 (LARP1) in the development and progression of colorectal cancer (CRC). Quantitative real-time polymerase chain reaction and Western blot analyses were carried out to determine the mRNA and protein expression of LARP1 in CRC tumor tissues and paired adjacent normal mucosa. The expression of LARP1 was upregulated in CRC. Immunohistochemical analysis using tissue microarray was performed. A positive correlation between LARP1 and proliferating cell nuclear antigen (PCNA) in the area of proliferation was observed using the Spearman’s correlation coefficient test (r = 0.332, P < 0.01). The elevated expression of LARP1 significantly correlated with T stage (P = 0.02), N stage (P = 0.006), M stage (P < 0.001), American Joint Committee on Cancer (AJCC) stage (P = 0.04), differentiation rank (P < 0.001), and PCNA level (P < 0.001). In addition, the inhibitory effect of LARP1 knockdown on CRC cell proliferation was demonstrated using Cell Counting Kit-8 (CCK8) and colony-forming cell (CFC) assays. Multivariate analysis showed that LARP1 was an independent prognostic factor for overall survival (OS; hazard rate (HR) = 0.244; 95 % confidence interval (CI), 0.078–0.769; P = 0.016) and disease-free survival (DFS; HR = 0.281; 95 % CI, 0.086–0.917; P = 0.035) in CRC patients. LARP1 plays an important role in the proliferation of colorectal cancer and represents a new prognostic indicator.

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Section: Introductionmentioning

confidence: 99%

Overexpression of LARP1 predicts poor prognosis of colorectal cancer and is expected to be a potential therapeutic target

Lin

et al. 2016

Tumor Biol.

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“…No predictive biomarkers for anti-angiogenic treatment have been identified [16]. Gene expression profiling is indispensable for molecular subtyping of CRC but no established genomic signature has been found useful in clinical practice [27]. Gene expression signatures have been proposed for early detection based on blood samples [28,29]; for prognosis [30]; for estimating the risk of cancer occurrence [31]; for predicting response to chemotherapy in metastatic CRC [32] etc.…”

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confidence: 99%

Novel insights into transcriptional dysregulation in colorectal cancer

Feodorova

Tashkova

Koev

et al. 2018

neo

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Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Although CRC has been comprehensively characterized at the molecular level, the tumor heterogeneity hinders the identification of reliable diagnostic, prognostic and predictive biomarkers. Molecular stratification of CRC is based on prevalent gene mutations and transcription profiles but its significance for clinical practice remains obscure. Indeed, activating mutations in the genes KRAS, NRAS and BRAF are the only predictive biomarkers for anti-EGFR antibody therapy routinely tested the clinic for advanced stages of CRC. Gene expression signatures are important for clarifying the molecular mechanisms of CRC development and progression, but only two such tests for predicting recurrence risk are commercially available. The aim of our study was to propose a diagnostic approach based on mutation and gene expression analysis that can be routinely applied in the clinic for defining the most appropriate treatment strategy for each patient. We used qPCR to determine the presence of KRAS mutations and measure the transcription levels of a panel of 26 genes in 24 CRC patients. Statistical analyses were applied to check for associations between clinico-pathological and molecular parameters. Our results reveal novel data concerning CRC carcinogenesis: almost universal downregulation of EGFR; differential role of the pro-inflammatory cytokines TNF-α and IL-6; overexpression of the vitamin B12 transporter transcobalamin 1; tumor-suppressor function of SETD2, CA7 and GUCA2B. The practical application of these findings has yet to be clarified.

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“…Importantly, the 5-year survival of metastatic colorectal cancer patients is only about 10% (French National Cancer Institute, 2010 Report). Although liver metastases can be resected surgically, the treatment of metastatic disease is based mainly on chemotherapy and, more rarely, on targeted therapies (17).…”

Section: Introductionmentioning

confidence: 99%

Functional Analysis of Somatic Mutations Affecting Receptor Tyrosine Kinase Family in Metastatic Colorectal Cancer

Duplaquet

Figeac

Leprêtre

et al. 2019

Molecular Cancer Therapeutics

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Besides the detection of somatic receptor tyrosine kinases (RTK) mutations in tumor samples, the current challenge is to interpret their biological relevance to give patients effective targeted treatment. By high-throughput sequencing of the 58 RTK exons of healthy tissues, colorectal tumors, and hepatic metastases from 30 patients, 38 different somatic mutations in RTKs were identified. The mutations in the kinase domains and present in both tumors and metastases were reconstituted to perform an unbiased functional study. Among eight variants found in seven RTKs (EPHA4-Met726Ile, EPHB2-Val621Ile, ERBB4-Thr731Met, FGFR4-Ala585Thr, VEGFR3-Leu1014Phe, KIT-Pro875Leu, TRKB-Leu584Val, and NTRK2-Lys618Thr), none displayed significantly increased tyrosine kinase activity. Consistently, none of them induced transformation of NIH3T3 fibroblasts. On the contrary, two RTK variants (FGFR4-Ala585Thr and FLT4-Leu1014Phe) caused drastic inhibition of their kinase activity. These findings indicate that these RTK variants are not suitable targets and highlight the importance of functional studies to validate RTK mutations as potential therapeutic targets.

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Personalized treatment for colorectal cancer: novel developments and putative therapeutic strategies

Cited by 16 publications

References 136 publications

Overexpression of LARP1 predicts poor prognosis of colorectal cancer and is expected to be a potential therapeutic target

Overexpression of LARP1 predicts poor prognosis of colorectal cancer and is expected to be a potential therapeutic target

Novel insights into transcriptional dysregulation in colorectal cancer

Functional Analysis of Somatic Mutations Affecting Receptor Tyrosine Kinase Family in Metastatic Colorectal Cancer

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