Access Type

Open Access Dissertation

Date of Award

January 2015

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Cancer Biology

First Advisor

Larry H. Matherly

Abstract

Ovarian Cancer is the fifth leading cause of cancer-related death of women in the United States. Epithelial Ovarian Cancer (EOC) constitutes 85-90% of malignancies within the ovary, with an alarming majority of these cases diagnosed at advanced stage. While most patients are initially highly responsive to the current treatment standard, there is a very high probability that they will recur with a drug resistant fatal disease. Currently there is no validated comprehensive model of disease progression for ovarian cancer, although tremendous progress has been made in understanding the origin of this disease and a putative precursor lesion has been identified via molecular profiling. This progress has led to the identification of molecular signatures that not only distinguish high grade from low grade tumors, but it also highlights mutations that are unique to each histological type. Even though we are armed with this information and are well within the age of molecular targeting, the treatment of ovarian cancer has remained the same for over 40 years, when the use of platinum-based therapies and taxanes were introduced.

Approximately 90 percent of EOC are folate receptor alpha (FRα) positive with the extent of receptor over-expression corresponding with stage and grade of disease. FRα based therapies are a subject of increasing interest warranted by a growing number malignancies, from various tissue types, showing FRα expression. Due to this increase of receptor expression in advance disease in EOC, designing FRα-targeted agents will enhance the therapeutic window in a population of patients where most treatments fail. The clinically approved antifolates, MTX and PMX, have greatly improved treatment outcomes in a number of malignancies, however they have been implicated in dose-limiting toxicities that are thought to arise from uptake mediated by the ubiquitously express protein, the reduced folate carrier (RFC). This encourages the development of novel antifolates that utilize other available folate transport mechanisms over RFC.

In this study we explored the impact of the addition of various structural components on a pyrrolo[2,3-d]pyrimidine scaffold and demonstrated: (1) the significance of a 5 vs 6 position substitution on the scaffold and how it impacts the pharmacology of the compound; (2) that novel 6-substituted pyrrolo[2,3-d]pyrimidines show remarkable potencies that are mediated via FRα membrane transport; and (3) the impact of purine salvage on the efficacy of novel antifolates.

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