Mechanistic Evaluation of Macrocyclic Diterpenoids with Selective Triple Negative Breast Cancer Activity - PROJECT SUMMARY
Triple-negative breast cancer (TNBC) is a highly heterogeneous disease largely devoid of targeted therapy due
to the absence of estrogen, progesterone, and HER2 receptors. Due to this, conventional chemotherapy is the
only systemic pharmacological option used to treat TNBC patients. However many women do not have a
lasting response to this treatment alone particularly in the later stages of the disease. Therefore, the
identification of agents that can selectively target molecularly defined subtypes of TNBC would be beneficial.
To this end, we have pioneered the screening of natural product extracts for TNBC subtype-selective
constituent, resulting in the identification of the macrocyclic diterpenoid yuanhuacine. This proposal thus
focuses on elucidating the molecular mechanisms by which yuanhuacine mediates TNBC subtype-selective
cytotoxicity and which pharmacophores in the structure modulate such activity. This work will test the central
hypothesis that the epoxide on carbon 6,7 of ring B on the macrocyclic diterpene ester skeleton is pivotal in
mediating potent and selective cytotoxicity against the basal-like 2 (BL2) subtype of TNBC through a protein
kinase C (PKC) dependent pathway. Preliminary studies suggest that the PKC βII isozyme of PKC may
mediate the sensitivity of BL2 TNBC cells towards yuanhuacine. In Specific Aim 1, we will determine whether
PKC βII isozyme expression is both necessary and sufficient for these activities, and how the compound alters
PKC kinase activity in both sensitive and resistant cells. Previous studies comparing the potency of
macrocyclic diterpenoids that lack the epoxide group on carbons 6 and 7 to those that do, demonstrate a
significant loss in cytotoxicity potency when compared to the epoxidated derivatives. In Specific Aim 2, we will
define additional structural pharmacophores that are critical to mediating the potent and selective cytotoxicity
against the BL2 TNBC cells and further establish the importance of the epoxide group by comparing the
activity of a series of established and newly synthesized derivatives representatives of the distinct subclasses
of macrocyclic diterpenoids. Successful completion of the proposed studies will provide insights into an
unanticipated druggable oncogenic pathway and a companion drug to advance the development of targeted
therapies against TNBC. Additionally, the integrative approaches proposed here will serve as a platform for me
to obtain new mentored career training and pave the way to establishing a sustainable research program at a
primarily undergraduate institution (PUI) conducive to excellence in biomedical research.
