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Novel therapeutic targets in colon cancer
Publication . Simões, André Gonçalo do Espírito Santo, 1988-; Rodrigues, Cecília M. P., 1968-; Borralho, Pedro Miguel Martinho, 1979-
Colon cancer is a major health problem worldwide, representing the third most commonly diagnosed non-cutaneous cancer in men and the second most common in women. Interestingly, colon cancer-related deaths have decreased over the last decades. This is largely attributed to improvement in screening methods and shift in risk behavior. Only in 12% of the cases is mortality decline attributed to improved therapeutics. In addition, despite the accomplishments in colon cancer management, the metastatic form of the disease is the most commonly diagnosed and remains almost incurable. The implementation of new cytotoxic or targeted systemic agents, however, greatly improved current treatment options. Further, the belief is that the best therapeutic choice would be an appropriate combination therapy. Therefore, the discovery of new druggable targets is in high demand to improve colon cancer therapy, and multiple efforts have been undertaken to produce novel agents and to design novel combination therapies. The studies presented in this thesis were driven by the need to provide novel druggable targets, as well as suitable targeted delivery strategies for efficient and specific treatment of colon cancer. We explored the potential of cetuximab as a specific targeting agent to direct antibody-protamine conjugated and solid lipid nanoparticle systems, thoroughly designed to deliver microRNAs (miRNAs), to colon cancer cells. The results confirmed that cetuximab represents a successful specific targeting agent adequately supporting the development of the delivery tools. More importantly, our data demonstrated that the delivery systems are stable enough to reach target cells and be efficiently internalized. Further method development efforts resulted in a novel, simple and effective protocol that allows protein recovery from biological samples previously treated with TRIzolR and TRIzolRLS for RNA and/or DNA collection, thus surpassing the manufacturer’s limitations and improving extraction performance. In addition, this improvement greatly increases the amount of information extracted from a single sample. Finally, we hypothesized that ERK5 signaling represents a relevant protein and putative therapeutic target in colon cancer. ERK5 has recently been reported overexpressed in top-leading diagnosed cancers, and several lines of evidence suggest its potential deregulation in colon cancer. MiRNA-143, whose main target is ERK5 messenger RNA, is typically downregulated in colon cancer. Moreover, we have previously demonstrated that induced expression of miRNA-143, with concomitant repression of ERK5, contributes to reduced colon tumor growth and sensitization to 5-FU treatment. Remarkably, our results showed that ERK5 is aberrantly expressed in colon adenomas and adenocarcinomas, regardless of DNA mismatch repair system status, and that ERK5 overexpression correlates with more advanced and aggressive colon cancer. In addition, we demonstrated that ERK5 activation accelerates cell cycle progression and increases tumor cell migration via NF-κB activation, increasing its relevance as a potential druggable target. Further, in a mouse model, lymph node metastasis was exclusively seen in orthotopically implanted tumors with overactivated MEK5/ERK5 signaling, and not in tumors with inhibited MEK5/ERK5. In conclusion, the results presented in this thesis suggest two potential delivery strategies of small non-coding RNAs that are expected to unravel new therapeutic options for colon cancer; provide a protocol suitable for simultaneous isolation of proteins coupled to nucleic acid isolation; and unveil the role of ERK5 signaling as a novel relevant therapeutic target in colon cancer.
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Fundação para a Ciência e a Tecnologia
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SFRH
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SFRH