Translational Medical Research Commons^™

Combined Inhibition Of Ddr1 And Cdk4/6 Induces Synergistic Effects In Er-Positive, Her2-Negative Breast Cancer With Pik3ca/Akt1 Mutations, Maryam Shariati, Maryam Shariati

Dissertations & Theses (Open Access)

COMBINED INHIBITION OF DDR1 AND CDK4/6 INDUCES SYNERGISTIC EFFECTS IN ER-POSITIVE, HER2-NEGATIVE BREAST CANCER WITH PIK3CA/AKT1 MUTATIONS

Maryam Shariati, M.S. Advisory Professor: Funda Meric-Bernstam, M.D.

Molecular alterations in the phosphatidylinositol 3‑kinase (PI3K)/ serine/threonine protein kinase B (AKT) signaling pathway occur frequently in estrogen receptor–positive (ER-positive) breast tumors. Patients with ER-positive, human epidermal growth factor receptor 2–negative (HER2-negative) metastatic breast cancer are often treated with cyclin-dependent kinase (CDK4/6) inhibitors such as palbociclib in combination with endocrine therapy. Although this is a very effective regimen, disease progression ultimately occurs in most patients. Further, the modulators of palbociclib sensitivity remain unclear. The purpose …

From Bedside To Bench: Use Of Patient-Derived Xenograft Models To Develop Novel Therapeutic Strategies For Triple-Negative Breast Cancer, Tia H. Turner

Theses and Dissertations

Triple-negative breast cancer (TNBC) is a clinically aggressive disease that is associated with bleak outcomes due to its metastatic propensity, frequent failure to respond to chemotherapy, and lack of alternative treatment options. Despite decades of major translational research efforts, there has been very little success thus far in the development of effective targeted therapies for this disease. It is imperative to develop novel therapeutic strategies to improve patient outcomes, as well as minimize the toxicity associated with standard-of-care chemotherapeutics. Given that metastatic disease accounts for the vast majority of TNBC-related deaths, a better understanding of therapeutic responses within common sites …

Investigating The Mechanisms Of Breast Cancer Metastasis Using Multimodality Molecular Imaging, Katie Parkins

Electronic Thesis and Dissertation Repository

Introduction: Breast cancer recurrence continues to be a significant challenge in the clinic. Despite successful removal and/or treatment of the original tumour, many patients experience relapse in the breast or at distant sites. Furthermore, the diagnosis of metastatic disease often occurs too late for effective treatment. Methods: In this thesis, we combine iron-based cellular MRI and longitudinal BLI to noninvasively track the fate of cancer cells into overt tumours in the mouse brain. We then apply this imaging model to study the effect of a primary breast tumour on the growth of secondary metastases in an immune competent …

Genomic Evolution Of Chemoresistance In Triple-Negative Breast Cancer Delineated By Single Cell Sequencing, Charissa Kim

Dissertations & Theses (Open Access)

Triple-negative breast cancer (TNBC) is an aggressive subtype that displays extensive intratumor heterogeneity and frequently (46%) develops resistance to neoadjuvant chemotherapy (NAC). Currently, the genomic basis of chemoresistance remains poorly understood. An important question is whether resistance to chemotherapy is driven by the selection of rare pre-existing subclones with genomic mutations and transcriptional programs that confer resistance to chemotherapy (adaptive resistance) or by the spontaneous induction of new mutations and expression changes that confer a resistant phenotype (acquired resistance). To investigate this question we applied single cell DNA and RNA sequencing methods and deep-exome sequencing to longitudinal time-point samples collected …

Intraoperative Photoacoustic Imaging Of Breast Cancer, Ivan Kosik

Electronic Thesis and Dissertation Repository

Breast cancer is one of the most common cancers to affect women, presenting a lifetime risk of 1 in 8. Treatment of stage 1 and 2 cancers usually involves breast conserving surgery (BCS). The goal of BCS is to remove the entire tumour with a surrounding envelope of healthy tissue, referred to as a negative margin. Unfortunately, up to 50% of surgeries fail to remove the whole tumour. To minimize the risk of cancer recurrence, a second surgery, must therefore be performed. Currently, there is no widely accepted intraoperative tool to significantly mitigate this problem. Employed systems are usually based …

Targeting Autophagy To Improve Efficacy Of Cdk4/6 Inhibition In Breast Cancer, Smruthi Vijayaraghavan

Dissertations & Theses (Open Access)

Deregulation of the cell cycle machinery is a hallmark of cancer, leading to aberrant proliferation and tumorigenesis. The crucial role of the CDK4/6-Cyclin D pathway has led to the development and FDA approval (palbociclib, ribociclib) of CDK4/6 inhibitors for the treatment of advanced estrogen receptor positive breast cancer. However, three major clinical challenges remain: i) adverse events leading to discontinuation of therapy and ii) lack of reliable biomarkers to identify responsive patients and iii) acquired resistance to CDK4/6 inhibitors. Previous in vitro studies have shown that palbociclib mediated CDK4/6 inhibition induces G1 arrest and senescence in ER+ breast cancer cells, …

Prophylactic Cranial Irradiation Reduces The Incidence Of Brain Metastasis In A Mouse Model Of Metastatic Breast Cancer, Daniel L. Smith

Dissertations & Theses (Open Access)

Prophylactic cranial irradiation (PCI) is a preventative whole-brain irradiation technique used to reduce the incidence of brain metastasis and improve overall survival in select patients with small cell lung cancer and acute lymphoblastic leukemia. A population of breast cancer patients – stage IV, HER2+ or triple-negative – has emerged as having a high risk of developing brain metastases. Because only 10-20% of breast cancer patients diagnosed with brain metastases survive longer than one year, in this high-risk population the benefit of PCI – potential for reduced incidence of brain metastasis and improved overall survival – may outweigh the risks – …

Targeting Cox-2 And Rank In Aggressive Breast Cancers: Inflammatory Breast Cancer And Triple-Negative Breast Cancer, Monica E. Reyes

Dissertations & Theses (Open Access)

Inflammatory breast cancer (IBC) and triple-negative breast cancer (TNBC) are two highly aggressive breast cancer subtypes associated with a poor outcome. Despite sensitivity to current treatment, these breast cancers subtypes have a high recurrence rate and proclivity to metastasize early. The aggressiveness of IBC and TNBC have been linked to CSCs and epithelial to mesenchymal transition (EMT), which are critical features of breast cancer progression and metastasis. The clinical challenge faced in the treatment of IBC and TNBC is finding a treatment strategy to target the cancer stem-like (CSC) population to block metastasis. Cyclooxygenase-2 (COX-2) and receptor activator of nuclear …

Sildenafil And Celecoxib Interact To Kill Breast Cancer Cells, Brittany Binion

Theses and Dissertations

Breast cancer is the second most commonly diagnosed cancer among American women and is responsible for the second highest number of cancer-related deaths. Targeted therapeutic agents sildenafil, a phosphodiesterase type 5 inhibitor, and celecoxib, a cyclooxygenase-2 inhibitor, have been used individually in conjunction with other chemotherapeutic agents to enhance cell killing in a variety of cancers. Sildenafil when combined with traditional chemotherapeutic drugs, such as the taxanes and anthracyclines, or celecoxib combined with traditional hormone therapies have been used to increase cytotoxicity and cell killing. The data presented here demonstrates that the novel combination of sildenafil and celecoxib work together …

Stay Beautiful -- Stay Alive: Assessing The Receptivity Of African American Beauty Salon Owners To The Integration Of Breast Cancer Intervention Programs Into Salon Operations, Funmi Apantaku-Onayemi

Ed.D. Dissertations

The lower incidence rate of breast cancer in African American women is dwarfed by the excessive number of deaths due to late diagnosis and treatment. Lack of screening, socioeconomic factors, fatalistic beliefs and inequality of care are major contributing factors. Studies have suggested that those who had more knowledge about breast cancer are more likely to have reduced fatalistic attitudes and engage in screening behaviors. This study investigated beauty salons as sustainable and viable venues to reach women with health intervention programs because they fit the prescriptions of the principles of adult learning. In a mixed-method, descriptive study involving 115 …