The molecular therapy of colorectal cancer

Waldner, Maximilian J.; Neurath, Markus F.

doi:10.1016/j.mam.2010.02.005

Cited by 56 publications

(47 citation statements)

References 79 publications

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“…This implies that HIPK1 directly phophorylates p53, even if it cannot be excluded that another factor or a multiprotein complex is required for this event to occur. 10,12,13 This interaction with p53 is also shared by two is specifically activated in pre-malignant CRC lesions, of which some are particularly prone to genetic instability, 43 in order to delay cell division. We show here that, like ATM, HIPK1 is suddenly overexpressed during the initial phases of cancer development and is able to phosphorylate p53 serine 15.…”

Section: Discussionmentioning

confidence: 99%

HIPK1 drives p53 activation to limit colorectal cancer cell growth

et al. 2013

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Section: Discussionmentioning

confidence: 99%

HIPK1 drives p53 activation to limit colorectal cancer cell growth

et al. 2013

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“…In fact, the main obstacle to successful treatment of this disease, as in the other solid tumors, is presented by drug resistance. Looking at the mechanisms underlying this phenomenon, several reports have described the close relationship between genetic stability of the tumor and the selective pressure of the tumor microenvironment (2). This explains why many biomarkers capable of predicting the response to chemotherapy are linked to pathways of cell survival that are activated as adaptive response in stressing microenvironments (3).…”

Section: Introductionmentioning

confidence: 99%

Gender Influences the Class III and V β-Tubulin Ability to Predict Poor Outcome in Colorectal Cancer

Mariani

Zannoni

Sioletic

et al. 2012

Clinical Cancer Research

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Purpose: Colorectal cancer is one of the deadliest diseases in Western countries. To predict the outcome of therapy, we assessed the role of class III (TUBB3) and class V b-tubulin (TUBB6) as predictive biomarkers.Experimental Design: Using immunohistochemistry and nanofluidics, the expression of TUBB3 and TUBB6 was assessed in two cohorts of 180 and 134 patients, respectively. The CYP17A1 RS743572 was genotyped to identify GG carriers with enhanced androgen levels. TUBB3 and TUBB6 were investigated in 22 colorectal cancer cell lines in basal conditions and after serum starvation, the latter serving as activator of this prosurvival pathway. To ascertain the role of androgen receptor (AR) in such regulation, we silenced AR and checked TUBB3 and TUBB6 expression and sensitivity to chemotherapy.Results: There was a link between poor survival, the expression of TUBB3/TUBB6, and AR only in females. Conversely, only in males carriers of the GG phenotype exhibited the worst outcome. Importantly, male cell lines were resistant to serum starvation and exhibited higher levels of TUBB6, thereby suggesting that the pathway is activated by androgens. In female cells this phenomenon was absent. In both genders, AR was the main driver of TUBB3/TUBB6 expression, as constitutive silencing of AR was associated with downregulation of TUBB3/TUBB6 expression and increased sensitivity to oxaliplatin and SN-38.Conclusions: The involvement of androgens in the TUBB3 pathway opens the way for clinical trials to assess the efficacy of antiandrogens for increasing the efficacy of chemotherapy in male colorectal cancer patients.

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“…[4][5][6] Based on the good clinical compliance and the findings of several research groups that revealed K-ras mutations in stools consistent with the K-ras status in matching Chip-based detection of stool K-ras mutation H Zhang et al tumor tissues, [28][29][30] mutated DNA in stools has become the latest target of several detection methods. [8][9][10] Although stoolbased DNA detection could report CRC tissue K-ras genotypes faithfully, severe difficulties because of complicated procedures and low sensitivity have hampered further progress in using stool samples to detect K-ras mutations and preventatively screen for CRC.…”

Section: Discussionmentioning

confidence: 99%

“…Constitutively activating mutations in K-ras, particularly at 'limited hot spot' codons 12 and 13, may lead to uncontrolled cell proliferation and may render tumor cells independent of EGFR signaling and thereby resistant to EGFR-targeted therapies. [4][5][6] An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) has addressed the utility of K-ras gene mutation testing in patients with metastatic CRC to predict the response to anti-EGFR therapy with cetuximab or panitumumab. 7 Therefore, it is of the utmost importance to screen and assess these patients for K-ras status to guide personalized medicine and to avoid the application of costly drugs that would only cause toxic side effects.…”

mentioning

confidence: 99%

Rapid detection of low-abundance K-ras mutation in stools of colorectal cancer patients using chip-based temperature gradient capillary electrophoresis

Zhang

Wang

et al. 2011

Laboratory Investigation

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Mutant K-ras provides an independent negative predictive marker for epidermal growth factor receptor (EGFR)-targeted therapy in colorectal cancers (CRCs). Rapid, sensitive, and cost-effective screening for K-ras status will overarch rational personalized medicine. Stool-based DNA testing offers unique advantages for CRC screening such as noninvasiveness, high specificity, and patient compliance, whereas complicated procedures and the low sensitivity of the present approaches have hampered its application on a wide scale. In this study, a chip-based temperature gradient capillary electrophoresis (TGCE) technique was applied to detect low-abundance K-ras mutations under a pooled experiment and analyze K-ras mutations in 30 paired stool samples and cancer tissues of CRC patients and 15 stool samples of healthy volunteers. The chip-based TGCE results showed that the successful analysis of K-ras status could be achieved within 6 min with an extremely low sample consumption of 14 nl. Detection is sensitive enough to reliably report 0.2% mutant CRC cells in a wild-type background, and 0.5 ng of template DNA was sufficient for chip-based TGCE. Of the 30 stool samples of CRC patients analyzed, 17 (57%) harbored K-ras mutations, and the lowest percentage of the detectable mutant K-ras in stool samples was 2%. The coincidence rate for K-ras mutations between stools and tissues obtained by the chip-based method reached 97% (29/30). One of the 15 stool samples of normal controls carried K-ras mutations, producing a specificity of 93%. Clone sequencing data entirely confirmed the results obtained by chip-based TGCE. The study demonstrates that chip-based TGCE is capable of rapidly screening low-abundance K-ras mutations with high sensitivity, reproducibility, simplicity, and significant savings of time and sample. Application of this method to genotype the K-ras gene in stools would provide a potential means for predicting the effectiveness of EGFR-targeted therapy in CRC patients using noninvasive approaches.

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The molecular therapy of colorectal cancer

Cited by 56 publications

References 79 publications

HIPK1 drives p53 activation to limit colorectal cancer cell growth

HIPK1 drives p53 activation to limit colorectal cancer cell growth

Gender Influences the Class III and V β-Tubulin Ability to Predict Poor Outcome in Colorectal Cancer

Rapid detection of low-abundance K-ras mutation in stools of colorectal cancer patients using chip-based temperature gradient capillary electrophoresis

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