Of the many issues affecting current cancer therapeutics, one of the most problematic is the development of chemo-resistant cancer types-specifically taxane resistance. Taxanes belong to a class of chemotherapeutics which function by stabilizing beta-tubulin within a dividing cell. By stabilizing the tubule, the cell is suspended in metaphase of the mitotic cycle essentially inhibiting the cell's ability to divide. Multiple variations of taxane therapies exist, and are primarily used for the treatment of metastatic cancers such as metastatic pancreatic adenocarcinoma.
Orlistat is an FDA-approved lipase inhibitor generally prescribed as a weight loss drug. As a part of our project though, we were interested in its ability to inhibit the mechanism of fatty acid synthase (FASN), a protein that is over expressed in multiple cancer types. Increased lipid synthesis is associated with more aggressive tumor models making it an attractive target for therapy research.
In order to use Orlistat as a therapy, we initially modified the drug into a nanoparticle formulation aptly named, "Nano-Orlistat". Our discovery showed that not only did the formulation inhibit tumor growth, but it also helped to reverse taxane resistance when nano-orlistat was synergized with other taxanes. By combining the two therapies in the correct ratios, not only was tumor growth inhibited through the FASN mechanism, but also an amplified effect of taxanes in cell lines which had previously shown resistance. In establishing this synergistic chemotherapeutic regimen, there is a promise for improved prognosis among patients with advanced metastatic cancers.
Souchek, J.J., Muraskin, L., Houser, L., Vu, Q., & Mohs, A.M. (2019). Targeting fatty acid synthase to inhibit tumor growth and overcome taxane resistance. Proceedings of the SPIE, 10859(09). https://doi.org/10.1117/12.2512244
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