Item Details

abstract

Breast cancer is the most commonly diagnosed cancer among women in the US. Despite improvements in early detection and the development of different therapies, about 30% of patients will relapse with distant metastases. Metastatic breast cancer remains the leading cause of death among breast cancer patients making breast cancer the second leading cause of cancer-related deaths in women. Although there have been improvements in the management of metastatic breast cancer, the development of effective targeted treatments against primary tumors and their progression into distant metastases remains challenging. Our laboratory identified the FDA-approved anti-fungal, ketoconazole, to selectively target a tumor-specific transcription factor, truncated glioma-associated oncogene homolog 1 (tGLI1), known to promote breast cancer brain metastasis. In an effort to further develop novel tGLI1 inhibitors, the chemical structure of ketoconazole was used to synthesize several derivatives of the compound. Our work led to the identification of WF-268A that appeared efficacious towards breast cancer cells regardless of tGLI1 expression both in vitro and in vivo while lacking effects on non-cancerous human mammary epithelial cells. WF-268A also showed increased potency against the breast cancer stem cells (CSCs) population through the downregulation of stemness markers CD44, Nanog, Sox2, and OCT4. Additional studies indicated that WF-268A targets breast cancer cells and tumors through the inhibition of proliferation and the induction of apoptosis in vitro and in vivo. Overall, our results show that WF-268A is an effective treatment of breast cancer in vitro and in vivo without normal cell toxicity, and the efficacy is attributed to inhibition of CSC and cell proliferation, as well as induction of apoptosis. These observations support further development of WF-268 for breast cancer therapy.

subject

Apoptosis

Breast Cancer

Cancer

Ketoconazole

Proliferation

Stemness markers

Lo, Hui-Wen (advisor)

contributor

Najjar, Mariana Kamal (author)

Smalley, Terrence (committee member)

Lo, Hui-Wen (committee member)

Said, Neveen (committee member)

date

2023-01-24T09:35:42Z (accessioned)

2023 (issued)

degree

Biomedical Science – MS (discipline)

2025-01-23 (liftdate)

embargo

2025-01-23 (terms)

identifier

http://hdl.handle.net/10339/101772 (uri)

language

en (iso)

publisher

Wake Forest University

title

IDENTIFICATION OF A KETOCONAZOLE DERIVATIVE WF-268A THAT DEMONSTRATES EFFICACY AGAINST BREAST CANCER

type

Thesis