Dissertations, Theses, and Capstone Projects

Date of Degree

9-2023

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Maria Contel

Committee Members

Karen Hubbard

Frida Kleiman

Annie Castonguay

Kristy Brown

Subject Categories

Cancer Biology

Keywords

cancer, breast cancer, drug development

Abstract

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that represents roughly 15% of all diagnosed breast cancers. TNBC is defined by the absence of expression of progesterone, estrogen, and human epidermal growth factor 2 receptors, and has a higher incidence rate in pre-menopausal women and women of African and of Hispanic ancestry. Due to the inability to target a receptor, treatment is limited to nonspecific chemotherapy or immunotherapy. Only one FDA approved therapy is available specifically to treat TNBC, which is antibody drug conjugate Sacitzumab-govitecan, given to patients who have already gone through two rounds of more traditional chemotherapeutic treatment. Given the high mortality rate and target demographic of TNBC, enhanced treatment options are necessary to ameliorate this deadly disease.

A potential water-soluble ruthenium-based chemotherapeutic agent (Ru-IM) has been developed, with preclinical evaluation of this complex showing significant anti-angiogenic, anti-invasive, and anti-migratory properties in both European and African-derived TNBC cell lines in vitro. Further testing revealed a caspase-dependent, apoptotic mechanism of cell death and slight G2/M cell cycle arrest. Ru-IM shows high cellular uptake and considerable subcellular accumulation in the mitochondria. Treatment of TNBC with Ru-IM produces increased mitochondrial ROS generation along with mitochondrial membrane depolarization. Interestingly targeted proteomic and epigenetic analysis has implicated the inhibition of PI3K/AKT/mTOR pathway of high relevance in TNBC, as a potential target of this drug, with decreased protein expression levels observed for key markers along the pathway (PI3K, AKT3, mTOR, PDK1).

Additionally, this ruthenium-based complex has been tested in a comparative in vivo study with PARP inhibitor Olaparib in combination and monotherapies. Nod.SCID mice xenografted with TNBC MDA-MB-231 cell lines (with treatment amounts of 5mg/kg Ru-IM and 50mg/kg Olaparib, and 5mg/kg Ru-IM with 50mg/kg Olaparib for the combination provided every 48 h) displayed a 40% tumor reduction with Olaparib, a 59% tumor reduction with Ru-IM, and a 64% tumor reduction with a combination of both over a 28-day study with every other day dosing. Histopathology results showed no test-related toxicity with the ruthenium treatment and completed CBC panels revealed signs of inflammation and metastasis only in non-treated control mice. Further mechanistic studies in tumors obtained from Ru-IM treated mice, also demonstrate relevant cell proliferation inhibition, and decrease of markers along the PI3K/AKT/mTOR pathway.

Taken altogether, this compound displays an extremely potent anti-cancer activity both in vitro and in vivo for TNBC (with the highest tumor shrinkage, preferential tumor accumulation in a mouse model of any metal-based compound described to date). Its water solubility, long shelf-life, facile and low-cost synthesis are also attractive properties that warrant further advanced pre-clinical studies (formulation, studies on syngeneic, and patient-derived orthoptic mice models as well as dose-escalation studies). The availability of more targeted and cost-effective treatments for TNBC are integral in the fight against this deadly disease, and further evaluation may prove the potential future clinical success of Ru-IM.

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