Medicine and Health Sciences Commons^™

Mathematical Modeling Reveals That G2/M Checkpoint Override Creates A Therapeutic Vulnerability In Tsc2-Null Tumors, Hui Ju Hsieh

Dissertations & Theses (Open Access)

Cell cycle checkpoints determine whether cells meet requirements to progress through the next stage. In response to DNA damage, how cells activate checkpoints have been well studied, but little is known about checkpoint deactivation (recovery), which directly impacts on cell fate. In tumor cells, the signaling network has been rewired due to epigenetic and genetic alterations, which result in resistance to the cell cycle control, and thus resistance to chemotherapy or radiation therapy. Therefore, it is critical to identify molecules required for checkpoint recovery or adaptation after DNA damage.

To achieve this goal, we performed a multidisciplinary study combining reverse …

Mathematical Modeling Reveals That G2/M Checkpoint Override, Hui Ju Hsieh

Dissertations & Theses (Open Access)

Cell cycle checkpoints determine whether cells meet requirements to progress through the next stage. In response to DNA damage, how cells activate checkpoints have been well studied, but little is known about checkpoint deactivation (recovery), which directly impacts on cell fate. In tumor cells, the signaling network has been rewired due to epigenetic and genetic alterations, which result in resistance to the cell cycle control, and thus resistance to chemotherapy or radiation therapy. Therefore, it is critical to identify molecules required for checkpoint recovery or adaptation after DNA damage.

To achieve this goal, we performed a multidisciplinary study combining reverse …

Mathematical Modeling Reveals That G2/M Checkpoint Override Creates A Therapeutic Vulnerability In Tsc2-Null Tumors, Hui-Ju Hsieh

Dissertations & Theses (Open Access)

Cell cycle checkpoints determine whether cells meet requirements to progress through the next stage. In response to DNA damage, how cells activate checkpoints have been well studied, but little is known about checkpoint deactivation (recovery), which directly impacts on cell fate. In tumor cells, the signaling network has been rewired due to epigenetic and genetic alterations, which result in resistance to the cell cycle control, and thus resistance to chemotherapy or radiation therapy. Therefore, it is critical to identify molecules required for checkpoint recovery or adaptation after DNA damage.

To achieve this goal, we performed a multidisciplinary study combining reverse …

Concomitant Targeting Of The Mtor/Mapk Pathways: Novel Therapeutic Strategy In Subsets Of Non-Small Cell Lung Cancer, Dennis Ruder

Dissertations & Theses (Open Access)

Over the last decade, a paradigm-shift in lung cancer therapy has evolved into targeted-driven medicinal approaches. However, patients frequently relapse and develop resistance to available therapies. Herein, we utilized genomic mutation data from advanced chemorefractory non-small cell lung cancer (NSCLC) patients enrolled in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE-2) clinical trial to characterize novel actionable genomic alterations potentially of clinical relevance. We identified RICTOR alterations (mutations, amplifications) in 17% of lung adenocarcinomas and found RICTOR expression correlates to worse overall survival. There was enrichment of MAPK pathway genetic aberrations in key oncogenes (e.g. KRAS, BRAF, …

A Phase I Dose-Escalation Study Of The Braf Inhibitor Vemurafenib In Combination With The Mtor Inhibitor Everolimus In Subjects With Advanced Cancer, Javier Munoz

Dissertations & Theses (Open Access)

Vemurafenib has been approved in the United States for the treatment of relapsed or refractory BRAF mutation positive malignant melanoma and is being investigated in various other malignancies. The RAS/RAF/MEK/ERK (MAPK) pathway is critical to cell proliferation in many human cancers. The mTOR inhibitors are well known to exert profound anticancer effects across malignancies through inhibition of the PTEN/PI3K/AKT/mTOR (mTOR) pathway. We hypothesize that the toxicity profile of the combination of vemurafenib and everolimus will be well tolerated. The primary objective is to find the maximum tolerated dose (MTD) and the toxicity of the combination of vemurafenib and everolimus following …

Ankyrin-B And Mtor Complex 1 In The Regulation Of Electrical Activities In The Heart, Henry C. Wu, Henry C. Wu

Dissertations & Theses (Open Access)

The mammalian target of rapamycin complex 1 (mTORC1) activity is paramount in the regulation of electrical activities in the brain and the heart. In the brain, the tumor suppressor gene TSC2 encodes the protein product tuberin that interacts with hamartin to form a heterodimer Tuberous Sclerosis Complex (TSC) that regulates mTORC1. When TSC2 is disrupted, mTORC1 activity becomes dysregulated resulting in abnormal electrical activities in the brain manifesting in the form of epileptic seizures. In the heart, mTORC1 activity is triggered by a sustained increase in hemodynamic pressure causing the heart to electrically remodel. A likely candidate serving as the …

Targeted Inhibition Of Pi3k, Mtor, And Igf1r For The Treatment Of Undifferentiated Pleomorphic Sarcoma, Caitlin Denise May

Dissertations & Theses (Open Access)

Undifferentiated pleomorphic sarcoma (UPS) is an aggressive mesenchymal malignancy largely devoid of indicators for its originating tissue. Surgery remains the standard of care, as radiation therapy and systemic chemotherapy have limited efficacy in UPS patients with localized and metastatic disease, respectively. Therefore, it is imperative to identify and evaluate novel therapeutic targets in UPS in order to provide more efficacious treatment options for patients. Previous studies have revealed that members of the phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathway can be used to predict patient outcome in cohorts containing patients with various subtypes of soft tissue sarcoma. Furthermore, we have …

Pi3k- And Mtor-Dependent Mechanisms Of Lapatinib Resistance And Resulting Therapeutic Opportunities, Samuel Brady

Dissertations & Theses (Open Access)

Breast cancers with HER2 amplification represent 20-25% of breast cancer cases and are frequently responsive to the HER2 kinase inhibitor lapatinib, but generally for only short duration. We aimed to understand how breast cancers with HER2 amplification become resistant to lapatinib, in order to identify potential therapies that can overcome lapatinib resistance. To establish lapatinib resistance models we treated three HER2+ breast cancer cell lines with lapatinib for several months until they became lapatinib-resistant. We then compared lapatinib-sensitive (parental) cells with their lapatinib-resistant (LapR) counterparts to identify changes conferring lapatinib resistance. We found that activation of PI3K, specifically the p110α …

Strategies To Sensitize Bladder Cancer Cells To Small Molecule Inhibitors Targeting The Pi3k Pathway, Giovanni Nitti

Dissertations & Theses (Open Access)

After many years of cancer research, it is well accepted by the scientific community that the future cure for this disease lies in a personalized therapeutic approach. Anticipating therapeutic outcome based on the genetic signature of a tumor has become the new paradigm. The PI3K pathway represents an ideal target for bladder cancer, as many of the key proteins of this pathway are altered or mutated in this particular type of cancer. Several small molecule inhibitors have been developed to target this pathway, but their efficacy has been shown to be heterogeneous among different cell lines and mostly cytostatic but …

Differential Regulation Of Iress In The Aurora A Mrna By Bfgf Through The Mtor Complex Torc2 Modulates Aurora A Kinase Expression, Roy L. Voice Iii

Dissertations & Theses (Open Access)

Identifying the mechanisms that contribute to tumorigenesis is a major area of focus in our fight against cancer. Epithelial malignant tumors, such as breast, colon, ovarian and pancreatic cancers have been shown to overexpress proteins that control cell mitosis, growth, and proliferation. One of those proteins is the Aurora A kinase. Aurora A kinase is a member of a small family of kinases that contribute to mitotic events such as centrosome duplication, separation, and maturation. Aurora A overexpression leads to genomic instability, which can contribute to tumorigenesis, on the other hand, inhibiting Aurora A expression leads to apoptosis, making it …

Metabolic Regulation Of Mtor Activation And Endoplasmic Reticulum Stress In The Heart, Shiraj Sen

Dissertations & Theses (Open Access)

When subjected to increased workload, the heart responds metabolically by increasing its reliance on glucose and structurally by increasing the size of myocytes. Whether changes in metabolism regulate the structural remodeling process is unknown. A likely candidate for a link between metabolism and growth in the heart is the mammalian target of rapamycin (mTOR), which couples energy and nutrient metabolism to cell growth. Recently, sustained mTOR activation has also been implicated in the development of endoplasmic reticulum (ER) stress. We explored possible mechanisms by which acute metabolic changes in the hemodynamically stressed heart regulate mTOR activation, ER stress and cardiac …

Atm Signaling To Tsc2: Mechanisms And Implications For Cancer Therapy, Angela Alexander

Dissertations & Theses (Open Access)

Ataxia telangiectasia mutated (ATM) is a critical component of the cellular response to DNA damage, where it acts as a damage sensor, and signals to a large network of proteins which execute the important tasks involved in responding to the damage, namely inducing cell cycle checkpoints, inducing DNA repair, modulating transcriptional responses, and regulating cell death pathways if the damage cannot be repaired faithfully. We have now discovered that an additional novel component of this ATM-dependent damage response involves induction of autophagy in response to oxidative stress. In contrast to DNA damage-induced ATM activation however, oxidative stress induced ATM, occurs …