Medicine and Health Sciences Commons^™

Modulation Of Autophagy And Senescence To Enhance The Response To Therapy In Triple Negative Breast Cancer, Liliya Tyutyunyk-Massey

Theses and Dissertations

Abstract

Although great strides have been made over the decades in development and optimization of anti-cancer therapies, even highly effective drugs often fail to completely eliminate tumors. Residual tumor cells can enter into a state of dormancy for prolonged periods of time but eventually are able to regain proliferative capacity and reemerge as chemotherapy-resistant disease. Because recurrent disease is a leading contributor to patient’s mortality, it is paramount to identify strategies for effectively destroying residual tumor cells.

Cytotoxic drugs and ionizing radiation are used as standard therapies in a variety of cancers. These modalities induce apoptosis, autophagy and senescence. Senescence …

Interaction Between Atm Kinase And P53 In Determining Glioma Radiosensitivity, Syed F. Ahmad

Theses and Dissertations

Glioblastoma multiforme (GBM) is the most common primary brain tumor. Studies have shown that targeting the DNA damage response can sensitize cancer cells to DNA damaging agents. Ataxia telangiectasia mutated (ATM) is involved in signaling DNA double strand breaks. Our group has previously shown that ATM inhibitors (ATMi) sensitize GBM cells and tumors to ionizing radiation. This effect is greater when the tumor suppressor p53 is mutated.

The goals of this work include validation of a new ATM inhibitor, AZ32, and elucidation of how ATMi and p53 status interact to promote cell death after radiation. We propose that ATMi and …

Cytoprotective Versus Non-Protective Autophagy Induced By Radiation In Head And Neck Cancer Cells, Duaa Bakhshwin

Theses and Dissertations

The primary treatment options for head and neck cancer are radiation therapy or surgery, or both combined; chemotherapy is often used as an additional, or adjuvant, treatment. Patients treated with radiotherapy are exposed to a high cumulative dose of radiation over a period of time and there is a 17-33% chance of recurrence. High cumulative doses of radiation, a long time course of treatment, side effects and the possibility of recurrence provide the rationale for developing approaches for radiation sensitization, which could be helpful to patients in decreasing the dose, duration of radiation, side effects, or the chance of recurrence. …

Combined Antiproliferative Effects Of The Aminoalkylindole Win55,212-2 And Radiation In Breast Cancer Cells, Sean Emery

Theses and Dissertations

The potential antitumor activity of mixed CB1/CB2 cannabinoid receptor agonists, such as the aminoalkylindole WIN55,212-2 (WIN2), has been extensively studied, but little information is available as to their potential interaction with conventional cancer therapies, such as ionizing radiation (IR). In the present work, we investigated the effects of WIN2 on the antiproliferative effects of radiation in human (MCF-7 and MDA-MB-231) and murine (4T1) breast cancer cells, as well as an immortalized human breast epithelial cell line (MCF-10A). WIN2 or radiation alone inhibited breast tumor growth, while the combination of WIN2 and radiation was more effective than either agent alone in …

Mda-9/Syntenin: From Glioblastoma Pathogenesis To Targeted Therapy, Timothy P. Kegelman

Theses and Dissertations

The most common malignant glioma, glioblastoma multiforme (GBM), remains an intractable tumor despite advances in therapy. Its proclivity to infiltrate surrounding brain tissue contributes greatly to its treatment failure and the grim prognosis of patients. Radiation is a staple in modern therapeutic regimens, though cells surviving radiation become more aggressive and invasive. Consequently, it is imperative to define further the cellular mechanisms that control GBM invasion and identify promising novel therapeutic targets. Melanoma differentiation associated gene-9 (MDA-9/Syntenin) is a highly conserved PDZ domain-containing scaffolding protein that promotes invasion and metastasis in human melanoma models. We show that MDA-9/Syntenin is robustly …

Radiation Sensitization Of Breast Cancer Cells By Vitamin D Through The Promotion Of Autophagic Cell Death, Eden Wilson

Theses and Dissertations

Radiation therapy is a widely used tool in cancer therapy and is frequently offered as the first line of treatment for cancers of the breast. While radiotherapy is often initially effective in killing tumor cells or suppressing their growth, there are factors that confer tumor cell resistance to irradiation. Development of resistance may lead to disease recurrence despite the use of surgery, chemotherapy and radiation therapy. A primary goal of the studies in Dr. Gewirtz’s laboratory is to develop strategies to overcome resistance to radiation (and chemotherapy) in breast cancer, with the ultimate goal of preventing or attenuating disease recurrence. …

Role Of Autophagy In Radiosensitization Of Breast Tumor Cells, Molly L. Bristol

Theses and Dissertations

In MCF-7 breast tumor cells, ionizing radiation promoted autophagy that was cytoprotective; pharmacological or genetic interference with autophagy induced by radiation resulted in growth suppression and/or cell killing (primarily by apoptosis). The hormonally active form of vitamin D, 1,25D3, also promoted autophagy in irradiated MCF-7 cells, sensitized the cells to radiation and suppressed the proliferative recovery that occurs after radiation alone. 1,25D3 also enhanced radiosensitivity and promoted autophagy in MCF7 cells that overexpress Her-2/neu as well as in p53 mutant Hs578t breast tumor cells. In contrast, 1,25D3 failed to alter radiosensitivity or promote autophagy in the BT474 breast tumor cell …

Nonhomologous End-Joining: Tdp1-Mediated Processing, Atm-Mediated Signaling, Amy Hawkins

Theses and Dissertations

This thesis investigates two separate features of nonhomologous end-joining (NHEJ) DNA repair: end processing, and DNA repair kinase signaling. DNA end processing was investigated in a mouse model of hereditary spinocerebellar ataxia with axonal neuropathy (SCAN1), a congenital neurodegenerative disease. SCAN1 is caused by a homozygous H493R mutation in the active site of tyrosyl-DNA phosphodiesterase (TDP1). To address how the H493R mutation elicits the specific pathologies of SCAN1 and to further elucidate the role of TDP1 in processing DNA end modifications, we generated a Tdp1 knockout mouse and characterized their behavior and specific repair deficiencies in extracts of embryonic fibroblasts …