Two‐pore Domain Potassium Channel Genes and Breast Cancer in The Cancer Genome Atlas

The overarching goal of this dissertation was to systematically evaluate molecular markers (DNA methylation, gene expression, and copy number changes) of K2P channel genes in relation to breast cancer subtype, clinical covariates and prognosis, using a landscape approach in TCGA breast cancer data. Findings show that overexpression of KCNK5, KCNK9, KCNK10 and KCNK12, and underexpression of KCNK6 and KCNK15, are significantly associated with our primary outcome of TN subtype. Similar patterns of association were also evident for most of the related secondary subtype outcomes. We found CG loci to be associated with nH black race: 4 loci in the promoter region of KCNK15, and 3 more loci near KCNK4, and 2 near KCNK5. CG loci on KCNK2, KCNK5 and KCNK9 were significantly associated with negative expression across all hormone-receptor negative related subtype outcomes. Another locus near KCNK12 also had consistent correlations with positive gene expression across most hormone receptor related negative subtypes. In addition, copy number loss in KCNK10, KCNK13, KCNK16 and KCNK18, and gain in KCNK3, KCNK4, KCNK5, KCNK6, KCNK7, KCNK9, KCNK12, KCNK16, KCNK17 and KCNK18, were common associations across hormone receptor negative subtypes. We found K2P markers together accounted for, or mediated, a substantial proportion of the observed subtype disparity (i.e. increased risk of ER/PR-negative/TN disease) in black women, and gene methylation accounted for the largest proportion mediated. K2P gene markers together also mediated a substantial part of the molecular ER/PR-negative/TN subtype disparity observed with p53 expression. Finally, KCNK4 and KCNK9 may be associated with worse survival. Our study findings are however considered preliminary and need to be validated in additional studies

The value of regional intra-arterial therapy with novel sustained-release ethiodol based preparations for hepatic-neoplastic disease

We continue to search for effective therapies for hepatic-metastatic disease. Loco-regional therapy is attractive because it allows for tumour directed dose intensification without associated increase in systemic toxicity, which may lead to improved efficacy. In addition, the use of sustained-release or depot preparations may obviate the need for continuous infusion via expensive implantable pumps, and may also allow treatment of patients who are unfit for surgery, or who have more advanced disease. The iodinated poppyseed oil, Ethiodol, is selectively retained in liver tumours for weeks to months after hepatic intra-arterial infusion (HAI), and demonstrates ideal properties as a vehicle for development of depot or sustained-release HAI therapies of lipophillic or oil-soluble novel anticancer agents. This project demonstrated the value of Ethiodol for this purpose. A reproducible experimental animal hepatic-metastatic model using Fisher rats and syngenic MADB106 breast adenocarcinoma cells was established, and allowed evaluation of Ethiodol based HAI preparations. Several novel anticancer agents were soluble in Ethiodol and exhibited sustained-release characteristics. These preparations included (a) the topoisomerase-1 inhibitor 9-aminocamptothecin (9AC), (b) the cytokine human recombinant interleukin-2 (Hril2), and (c) several nitric oxide (NO) donors NOR1, NOR2, NOR3, SNAP and sodium nitroprusside. These compounds were effective antitumour agents both in vitro and in vivo, and inhibited tumour engraftment after subcutaneous inoculation with admixed tumour cells. They were well tolerated and eradicated hepatic-metastatic disease when administered as loco-regional HAI therapy, with decreased toxicity compared to equivalent systemic therapy. Investigation of mechanisms of antitimour activity revealed that macrophages appeared to be important for hRIL2 activity, and that NO and cyanide ion production appeared to both contribute to the effects of sodium nitroprusside. Results suggest that clinical studies of these compounds are feasible and warrant further investigation