Targeting Organic Anion Transporting Polypeptides in Cancer to Improve Diagnostics and Therapy

Abstract

Organic Anion Transporting Polypeptides (OATPs) are multispecific transport proteins that mediate the uptake of numerous endogenous and exogenous compounds into cells. Recently, OATPs have been shown to have altered expression in cancer tissue compared to their normal expression profiles. It has been proposed that OATPs can be targeted to improve cancer therapeutics. Therefore, I tested the hypothesis that expression of OATPs in cancer combined with their ability to transport cytotoxic anticancer drugs makes them potential targets for improving cancer diagnosis and therapy. The hypothesis was tested via the following specific aims: 1) to identify and characterize OATP expression in cancer, 2) to identify novel anticancer drug substrates of OATPs, and 3) to identify novel cytotoxic compounds from plant extracts that are substrates of OATPs and can be developed into anticancer drugs that target OATP-expressing cancers. In the first specific aim, OATPs expressed in pancreatic cancer were identified by immunohistochemical staining of pancreatic cancer tissue specimens. Completion of this specific aim identified four major OATPs expressed in pancreatic adenocarcinomas. Additionally, OATP1B3 expression was observed to be highest in low stage adenocarcinoma and absent in metastatic tissue. These results demonstrate that OATP1B3 may serve as a diagnostic marker and/or therapeutic target in early stage adenocarcinomas. In specific aim two, novel anticancer drug substrates of OATP1B3 were identified by screening the NCI/DTP oncology drug set containing all of the FDA approved chemotherapy drugs. In this study, I determined the effect of the anticancer drugs on transport and cell viability of OATP1B3-expressing cells. Finally, I demonstrated that the anticancer drugs etoposide, oxaliplatin and plicamycin are substrates of OATP1B3. These results suggest that the mentioned cytotoxic anticancer drugs could potentially be used to treat OATP1B3-expressing cancers. In the last specific aim, Kansas plant extracts were screened using bioassay guided fractionation and cell viability assays to isolate novel cytotoxic compounds that are substrates of OATP1B3. Given that these novel plant compounds are cytotoxic and are also transported by OATP1B3 suggests that they can be used for lead optimization studies to develop new anticancer drug entities. This dissertation demonstrates that OATP1B3 is a potential target for mechanisms of OATP-mediated anticancer therapy. Ultimately, this knowledge can be used to utilize OATP1B3 expression in cancer as a diagnostic marker, as well as a target for cytotoxic anticancer drug therapies.