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 …

Preclinical Studies Of A Novel Idh1 Inhibitor In Acute Myeloid Leukemia (Aml), Vivian Salama

Dissertations & Theses (Open Access)

LY3410738, a novel covalent Isocitrate Dehydrogenase 1 (IDH1) inhibitor in Acute Myeloid Leukemia, it is more effective than Ivosidenib (AG120) and has a potent anti-leukemic effect against IDH1 mutant acute myeloid leukemia in combination with Venetoclax (ABT-199).

Acute myeloid Leukemia (AML) is an aggressive neoplastic blood disorder characterized by proliferation of poorly differentiated cells of myeloid lineage. IDH1 is a cytoplasmic enzyme that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) in the citric acid cycle. Somatic gain-of-function mutations in IDH1 occur in ~10% of the newly diagnosed AML patients. The neo-enzymatic activity of mutant IDH1 results in accumulation …

Anaplastic Thyroid Cancer: Identification Of Candidate Therapeutics And Mechanisms Of Disease Progression, Nicole Pinto

Electronic Thesis and Dissertation Repository

Malignancies derived from follicular cells of the thyroid can be divided into well-differentiated thyroid cancer (WDTC), poorly differentiated thyroid cancer and anaplastic (undifferentiated) thyroid cancer (ATC). While the majority of thyroid cancers are well-differentiated in nature and have an excellent prognosis, ATC is rare, nonresponsive to conventional therapies, and is nearly universally fatal. In this study, I employed high-throughput screening of kinase inhibitors to identify candidate drugs to control ATC and expanded these studies to include a focus on studying the underlying progression from WDTC to ATC. Two compounds, lestaurtinib (JAK2 inhibitor) and flavopiridol (pan-CDK inhibitor) were selected from the …

High Throughput Screening For Drug Discovery In Head And Neck Squamous Cell Carcinoma, Morgan D. Black

Electronic Thesis and Dissertation Repository

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and despite advancements in traditional therapies, the survival rate of ~40% remains unchanged, thus highlighting the need for novel treatments in HNSCC. High throughput robotic screening of a panel of HNSCC cell lines was carried out against 1,505 compounds, where drug activity was measured using metabolic agent alamarBlue and quantified by percent activity. Initial screening found that the majority of active compounds could be grouped based upon their cellular target(s) and/or function including: cell cycle regulation, cytoskeleton disruption, and DNA topoisomerase function. Potency was confirmed with …

Targeting Autophagy In Multiple Myeloma, Yun Dai

Theses and Dissertations

Apoptosis (Type I) and autophagy (Type II) represent two major forms of programmed cell death. Numerous anticancer agents employed in standard chemotherapy or novel targeted therapy induce both apoptosis and autophagy. Of note, a cytoprotective autophagic response often counteracts apoptosis triggered by such agents, potentially contributing to drug-resistance. Mechanistically, autophagy and apoptosis share molecular regulatory mechanisms primarily governed by the Bcl-2 family proteins. However, since autophagy acts as the double-edge sword in cancer, whether autophagy should be inhibited or activated in cancer treatment remains the subject of debate. Here we report a) a novel autophagy-targeted strategy that targeting the adaptor …