Undergraduate Honors Theses

Thesis Defended

Spring 2018

Document Type

Thesis

Type of Thesis

Departmental Honors

Department

Molecular, Cellular, & Developmental Biology

First Advisor

Tin Tin Su

Abstract

Translation is a cellular process frequently dysregulated in cancer (SIlvera et al., 2010). There are translation inhibitors currently in the clinic, homoharringtonine (omacetaxine mepesuccinate), or in clinical trials, MNK1/2 inhibitors, however, translation remains an underutilized target for oncology. Here, I report the study of a proprietary translation inhibitor SVC112 in colorectal carcinoma (CRC) and acute myeloid leukemia (AML). These cancers were selected because of their dependence on short half-life proteins such as proto-oncoprotein c-Myc or anti-apoptotic protein Mcl-1, which are predicted to be sensitive to inhibition of translation. I found that CRC cells as a group are more resistant to SVC112 than AML cells as a group; the median IC50 for 3-day growth assays for CRC cell lines was 482 nM but 95 nM for AML cell lines. Within each cancer type, cell lines showed IC50s that differed by 1000-fold. Therefore, I set out to understand the basis for differential sensitivities of cancer cell lines to SVC112. I identified gene expression signatures in CRC cells that correlate with sensitivity/resistance to SVC112. In addition, I found that reduction of protein synthesis of c-Myc, p53 and survivin after drug treatment correlates with sensitivity to SVC112. In AML cells, I found that basal, pre-treatment level of anti-apoptotic protein BCL-xL correlates with resistance to SVC112. These findings could be useful in optimizing clinical strategies and developing biomarkers for SVC112.

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