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- Title
- TARGETING CELLULAR SIGNALING PATHWAYS IN ESTROGEN RECEPTOR POSITIVE BREAST CANCER
- Creator
- Gentile, Sonia Kumar
- Date
- 2018
- Collection
- Electronic Theses & Dissertations
- Description
-
Estrogen receptor positive (ER+) breast cancer is the most common type of breast cancer diagnosed in women. While usually initially responsive to combinations of chemotherapy with hormonal therapies, resistance to current clinically used treatments is becoming more and more frequent. It is vital to continue to study the mechanisms of resistance to endocrine therapies and discover methods for combating this drug resistance to improve patient survival. The mixed lineage kinase (MLK) inhibitor,...
Show moreEstrogen receptor positive (ER+) breast cancer is the most common type of breast cancer diagnosed in women. While usually initially responsive to combinations of chemotherapy with hormonal therapies, resistance to current clinically used treatments is becoming more and more frequent. It is vital to continue to study the mechanisms of resistance to endocrine therapies and discover methods for combating this drug resistance to improve patient survival. The mixed lineage kinase (MLK) inhibitor, CEP-1347, was studied in culture and in pre-clinical models to evaluate its efficacy, alone and in combination with the clinically available selective estrogen receptor downregulator ICI 182,780, in treating endocrine sensitive and resistant ER+ breast cancers. Using cell lines models, its effects on cell viability, cell death, and cell cycle progression were analyzed, and nuclear and cellular morphology throughout mitosis were examined. Studies were expanded to animals to determine the efficacy of CEP-1347 against tumor growth in a pre-clinical setting. Tumor cell growth and death were studied, as well as the potential for tumor regrowth after the cessation of treatment. Investigation into drug efficacy were expanded into patient derived xenograft (PDX) lines and effects on cell cycle progression were analyzed.The data demonstrate that CEP-1347, especially in combination with ICI 182,780 has the potential to treat endocrine resistant disease through causing a cell cycle arrest which leads to a combination of decreasing proliferation and inducing apoptosis of tumor cells. Furthermore, inhibition of regrowth after cessation of treatment in endocrine sensitive cells suggests that perhaps if used as an earlier line therapy, CEP-1347 in combination with ICI 182,780 may slow or prevent the development of resistance.
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- Title
- SULFATED AND SIALYLATED N-ACETYL-LACTOSAMINE AS BIOMARKER OF SUBPOPULATIONS OF PANCREATIC DUCTAL ADENOCARCINOMAS
- Creator
- Hsueh, Peter Yiping
- Date
- 2019
- Collection
- Electronic Theses & Dissertations
- Description
-
The sialyl Lewis A (sLeA) glycan forms the basis of the CA19-9 blood test and is the current biomarker for pancreatic ductal adenocarcinoma (PDAC). However, it is not elevated in approximately 25% of PDAC patients and it also has difficulties in diagnosing early-stage PDAC. My overarching goal was focusing on improving precision of overall PDAC diagnostics. I hypothesized that other glycans within the Lewis blood group family besides sLeA are aberrantly increased in the subpopulation of PDAC...
Show moreThe sialyl Lewis A (sLeA) glycan forms the basis of the CA19-9 blood test and is the current biomarker for pancreatic ductal adenocarcinoma (PDAC). However, it is not elevated in approximately 25% of PDAC patients and it also has difficulties in diagnosing early-stage PDAC. My overarching goal was focusing on improving precision of overall PDAC diagnostics. I hypothesized that other glycans within the Lewis blood group family besides sLeA are aberrantly increased in the subpopulation of PDAC patients who do not secret sLeA into their blood. To test the hypothesis, two specific approaches were implemented in this study: 1) Profile an isomer of sLeA, named sialyl-Lewis X (sLeX), and glycans with fucosylated motifs in the plasma of sLeA-low PDAC patients using antibody and lectin microarray method; and 2) Test the sulfated and sialylated glycans derived from type 2 N-acetyl-lactosamine precursor in subpopulations of PDACs using a novel on-chip analysis method.In the first approach, I profiled the levels of multiple glycans and glycosylated mucins in plasma from two cohorts of 200 and 116 test subjects with PDACs and non-malignant disease patients. From these screens, I found significant increases in two categories of glycans: sialyl Lewis X variants, presented both in sulfated and non-sulfated forms, and the sialylated type 1 N-acetyl-lactosamine. These glycans are increased in distinct groups of PDAC patients and contribute to the improved accuracy of a biomarker panel.Thus, I concluded that detecting other glycans within the Lewis blood-group besides sLeA has the potential to improve diagnoses of PDAC patients.To further elucidate the structural nuances of sialyl Lewis X variants from initial screen, I developed a new assay called On-chip Glycan Modification and Probing and a complementary computational algorithm to accurately analyze novel sulfated and sialylated glycans from plasma of pancreatic cancer patients. In detailed structural information, I observed strong evidences of sulfated and sialylated type 2 N-acetyl-lactosamine glycans overexpressed in plasma of PDAC patients and pancreatic cancer cell lines, but not in the plasma of healthy people. In addition, the sulfated and sialylated type 2 N-acetyl-lactosamine glycans presented on a specific mucin, MUC5AC, was statistically associated (p < 0.001) with short time-to-progression of PDAC patients, but CA19-9 test was not. I concluded sulfated and sialylated type 2 N-acetyl-lactosamine glycans presented on MUC5AC were new serological biomarkers that could improve precision of current practices for diagnosis and prognosis of PDACs patients.
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