Title

Development Of Novel Breast Cancer Chemotherapeutics Directed Towards The Attenuation Of Metastatic And Chemo-Resistant Breast Cancer

Date of Award

January 2017

Degree Type

Closed Access Thesis

Degree Name

Master of Science (MS)

Department

Biological Sciences

First Advisor

Lindsay E. Calderon

Second Advisor

Margaret W. Ndinguri

Third Advisor

Tanea T. Reed

Abstract

Cancer has always plagued humans and animals alike. Throughout history, it has been called many names, been the center of myths and legends, and has been ritualistically studied in hopes of finding a cure. Did it arise from sin, or perhaps a curse, or did it simply happen at random? Cancer's underlying cause has, until recently, been eluding doctors and scientists for decades, leaving in its wake the vital need to dismantle the shroud of secrecy surrounding it. But what exactly is cancer, and more importantly, why is there such urgency in deciphering its genetic anomaly? Cancer is, at its basic definition, the rapid and uncontrollable proliferation of cells. These cells eventually become a mass, feeding off nutrients from other organs, eventually invading other organ systems and overtaking the body. Once cancer has reached this stage, surgical intervention is no longer effective, leaving other methods necessary to eliminate cellular growth. Although chemotherapy has had a relatively short history, it has led to a diverse and complex field of treatment options that holds the potential to attenuate aggressive cancers. Older generations of chemotherapy target specific phases of the cell cycle, to arrest development, or they target the DNA itself. New generations of chemotherapeutics looked to overcome problems that the first had left: improved selectivity, reduced side effects, increased potency, and the ability to target cancer cells more precisely. As such, the first phase in this project aimed to attenuate the proliferation and spread of cancer by targeting enzymes crucial for cell division and migration, (iPLA2β and MMP-9), with a suicide inhibitor Bromoenol Lactone (BEL). Although this approach did result in significant attenuation of tumor growth and migration, it lacked the ability to be highly selective and the therapeutic index left something to be desired. With that in mind, the second phase of this project aimed to circumvent the problems with the previous chemotherapeutic, as well as traditional agents, by targeting a receptor that is vastly overexpressed on the surface of cancer cells. It has been previously found that Luteinizing Hormone Releasing Hormone (LHRH) receptors are overexpressed in many different cancer types, thus giving a new target to deliver higher concentrations of drug while sparing normal tissues. By linking a molecule of this peptide with traditional platinum based chemotherapy, Cisplatin, cancer cells were easily targeted and selectively attacked. Results from preliminary pre-clinical trials with this newly synthesized drug, named Pt-Mal-LHRH, showed a significant decrease in cancer cell viability, greater cellular uptake of the drug compared to others, significant tumor volume reduction, and the ability to spare normal cells. With such promising results, this Pt-Mal-LHRH leaves the hope for a new type of targeted and selective drug that can destroy cancer cells while sparring healthy tissue. Future directions of this project include continuing with pre-clinical trials and expanding on the pharmacological index of this drug in hopes of a potential move into clinical testing.

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