Selectively Targeting PI3K in Breast Cancer Cells with RIDR-PI-103, a Reactive Oxygen-Activated Prodrug

Abstract

By Aaron White, Biology

Advisor: Joan Garrett

Presentation ID: AM_D20

Abstract: Over 60% of breast cancers have abnormal phosphatidylinositol 3-kinase (PI3K) pathway signaling, and as such PI3K is a prime target for drug development. Numerous clinical trials targeting PI3K have failed due to dose-limiting toxicity which stems from the critical role PI3K plays in normal cellular function throughout the body. Reactive Oxygen Species (ROS) levels are elevated in breast cancer cells due to their increased energy requirements. Utilizing ROS-activated prodrugs could improve the selectivity of drugs targeting PI3K, limiting the toxicity to non-malignant cells. We hypothesize that RIDR-PI-103, a prodrug converted to the PI3K inhibitor PI-103 upon exposure to ROS, will demonstrate reduced toxicity and improved selectivity with maintenance of tumor inhibition over PI3K inhibition alone in breast tumors. We propose targeting tumors in vivo with RIDR-PI-103 in combination with a chemotherapeutic agent to increase efficacy synergistically. In addition to this, we propose evaluating RIDR-PI-103 in vivo in chemotherapeutic resistant cell phenotypes. These studies have implications for the 60% of breast cancer patients exhibiting abnormal PI3K signaling with the long-term goal of clinical trials of PI3K inhibiting prodrugs in breast cancer patients, potentially resulting in reduced mortality within this patient population.