Novel drug discovery opportunities for colorectal cancer

Curtin, Joshua C.

doi:10.1517/17460441.2013.807249

Cited by 19 publications

(12 citation statements)

References 104 publications

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“…Indeed, Wnt/β-catenin pathway activation not only is involved in colorectal cancer development but also seems to be a common event to IBD and early stages of colon carcinogenesis [22], and deregulation or constitutive activation of this pathway could represent the connection between colonic chronic inflammation and increased risk of developing SCC. Thus, drugs targeting this pathway could be also useful for developing chemopreventive strategies against CRC [17, 19, 20, 27, 28]. …”

Section: Discussionmentioning

confidence: 99%

“…We obtained evidence that this multiparametric analysis, when combined with the histology, not only might allow a more accurate diagnosis, by discriminating between early and late phase within each stage, but could also predict response to Wnt-targeting chemotherapy (Figure 7). The main therapeutic approaches that are currently explored in this field, some of which are under Phase 1/2 clinical investigation (Supplementary Table S3) [33], imply the use of drugs targeting molecules participating to upstream events, such as Wnt ligands [34], Fzd receptors [35], LPR co-receptors [36, 37], Dishevelled [38] and others [27], or drugs targeting downstream events such as β-catenin/TCF or β-catenin/CBP interactions [39, 40]. As schematized in Figure 7, our multiparametric approach suggests that: i) drugs targeting upstream events could be useful for chemopreventive strategies and for treatment of patients suffering for IBD, low and high dysplasia as well as non-invasive carcinoma; ii) drugs targeting downstream events could be more effective when used for treatment of late HD and IS; iii) the advanced carcinoma could be not responsive to drugs targeting upstream events and poor responsive to drugs targeting downstream events.…”

Section: Discussionmentioning

confidence: 99%

“…Even if the biomarkers included in this study should be validated with a larger number of samples to increase the statistical significance, our results provide the basis for the development of a multiparametric platform that might be used to design “specific maps” for CRC early diagnosis and staging, and that would represent an useful tool for determining the responsiveness to new drugs targeting the Wnt signaling. Even if clinically useful agents that specifically inhibit Wnt signaling cascade are not currently available, several therapeutic strategies in this sense are in currently developing and need to be validate [27, 34-39]. In this context, the model of DMH-induced carcinogenesis in rats, that mimics the molecular events of Wnt signaling during IBD and SCC carcinogenesis in humans, may be a useful preclinical model for evaluating the chemopreventive or therapeutic efficacy of these drugs.…”

Section: Discussionmentioning

confidence: 99%

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WNT-pathway components as predictive markers useful for diagnosis, prevention and therapy in inflammatory bowel disease and sporadic colorectal cancer

et al. 2014

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The key role of the Wnt/β-catenin signaling in colorectal cancer (CRC) insurgence and progression is now recognized and several therapeutic strategies targeting this pathway are currently in developing. Wnt/β-catenin signaling not only dominates the early stages of sporadic colorectal cancer (SCC), but could also represent the connection between inflammatory bowel diseases (IBD) and increased risk of developing SCC. The knowledge on the sequential molecular events of Wnt-signaling cascade in IBD and during colorectal carcinogenesis, might provide new diagnostic/prognostic markers and could be helpful for optimizing the treatment protocols, thus improving the efficacy of Wnt-targeting therapies. We performed a comparative evaluation of the expression of some crucial molecules participating to Wnt signaling in an animal model of chemically-induced CRC and in human tissues obtained from patients suffering from IBD or at sequential stages of SCC. Specifically, we analyzed upstream events of Wnt signaling including β-catenin nuclear translocation and loss of E-cadherin and APC functions, and downstream events including c-Myc and Cyclin-D1 expression. We demonstrated that these crucial components of the Wnt/β-catenin pathway, when evaluated by immunohistochemistry using a multiparametric approach that includes the analyses of both expression and localization, could be potent markers for diagnosis, prevention and therapy in IBD and SCC, also possessing a predictive value for responsiveness to Wnt-targeting therapies. Furthermore, we showed that the animal model of chemically-induced CRC mimics the molecular events of Wnt signaling during IBD and SCC development in humans and may therefore be suitable for testing chemopreventive or therapeutic drugs targeting this pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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WNT-pathway components as predictive markers useful for diagnosis, prevention and therapy in inflammatory bowel disease and sporadic colorectal cancer

et al. 2014

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“…Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide, with over 1.2 million new cases and more than 600,000 mortalities every year (1). In China, the incidence has increased rapidly since the 1980s (2,3).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of cell proliferation and tumor growth of colorectal cancer by inhibitors of Wnt and Notch signaling pathways

et al. 2016

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Understanding the role and mechanism of signaling pathways including Notch and Wnt in colorectal carcinogenesis is critical to the development of novel therapeutics. In the present study, we analyzed the cell proliferation, migration, G2/M percentage and the expression of molecules of signaling pathways in HCT-116 cells through the inhibition of Wnt and Notch pathways, and also investigated the effect of inhibitors of Wnt and Notch pathways on tumor growth in a transplantation tumor model. We observed that rDDK-1 (an inhibitor of the Wnt signaling pathway) and LY374973 (an inhibitor of the Notch signaling pathway) synergistically inhibited the proliferation, migration and G2/M percentage of HCT-116 cell lines, and could further synergistically inhibit the tumor volume and weight in the transplantation tumor model. In the cell line and the transplantation tumor model, rDDK-1 and LY374973 further synergistically inhibited the expression level of all detected Wnt and Notch pathway genes. Our results may pave the way for using inhibitors of Wnt and Notch signaling pathways together to treat colorectal cancer.

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“…Col orectal cancer (CRC) is the third most commonly diagnosed malignancy and the fourth leading cause of cancer-related deaths worldwide (1,2). More than 20% of patients are diagnosed with advanced metastatic disease, with a 5-y survival of less than 10%.…”

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confidence: 99%

Significant Therapeutic Efficacy with Combined Radioimmunotherapy and Cetuximab in Preclinical Models of Colorectal Cancer

et al. 2015

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Despite extensive efforts to improve the clinical management of patients with colorectal cancer, approved treatments for advanced disease offer limited survival benefit. Therefore, the identification of novel treatment strategies is essential. We evaluated the preclinical efficacy of combination radioimmunotherapy, using a humanized 131 Ilabeled anti-carcinoembryonic antigen antibody ( 131 I-huA5B7), with cetuximab in colorectal cancer (CRC). Methods: Three human CRC cell lines-SW1222, LoVo, and LS174T-were used to generate subcutaneous xenografts, and stably luciferase-transfected SW1222 cells were used to establish a model of hepatic metastases in immunocompromised mice. Imaging and biodistribution studies were conducted to confirm the selective tumor localization of 131 I-huA5B7. Efficacy was evaluated on the basis of tumor growth delay and survival, along with markers of DNA damage response, cell cycle, proliferation, and apoptosis. Results: Selective tumor targeting was achieved with 131 IhuA5B7 alone or in combination with cetuximab without observable toxicity. Compared with monotherapy, combining cetuximab with radioimmunotherapy significantly and synergistically reduced tumor growth and prolonged survival of mice in 2 of the subcutaneous and in the metastatic tumor model. Evidence of DNA damage, G2/M arrest, significantly decreased proliferation, and increased apoptosis were observed with radioimmunotherapy and the combination therapy. However, a significant decrease in DNA-protein kinase expression with the combination regimen suggests that the addition of cetuximab suppressed DNA repair. Conclusion: Our results demonstrate enhanced therapeutic efficacy with the combination of cetuximab and radioimmunotherapy in CRC, which could potentially translate into successful clinical outcomes. This strategy could improve the treatment of residual disease postoperatively and ultimately prevent or delay recurrence. Furthermore, other carcinoembryonic antigen-expressing malignancies could also benefit from this approach.

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Novel drug discovery opportunities for colorectal cancer

Cited by 19 publications

References 104 publications

WNT-pathway components as predictive markers useful for diagnosis, prevention and therapy in inflammatory bowel disease and sporadic colorectal cancer

WNT-pathway components as predictive markers useful for diagnosis, prevention and therapy in inflammatory bowel disease and sporadic colorectal cancer

Inhibition of cell proliferation and tumor growth of colorectal cancer by inhibitors of Wnt and Notch signaling pathways

Significant Therapeutic Efficacy with Combined Radioimmunotherapy and Cetuximab in Preclinical Models of Colorectal Cancer

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