Current Fellow Spotlight
AFPE Pre-Doctoral Fellow, Larry Rodriguez, is a student at the University of Southern California. Alongside his mentor, Dr. Daryl Davies, Larry Rodriguez is researching “The Role of P2X4 Receptors within the Mesolimbic Pathway in Dopamine Signaling and Disease.” In the video below, Rodriguez explains his research in greater detail.Larry Rodriguez – Suppressing receptor function in the brain ex vivo using CRISPR/CAS from USC School of Pharmacy on Vimeo.
Emily Plyler, a graduate student at Northeast Ohio Medical University is researching “Identifying Novel Targets to Ameliorate Amyloid-Induced Neuroinflammation in the Retinal Projection” with her mentor, Dr. Samuel Crish.
Historically, amyloid-beta (Aβ) has been associated with Alzheimer’s disease (AD), but recently has been linked to chronic neurodegenerations of the visual system, including glaucoma, age-related macular degeneration, and diabetic retinopathy. Intriguingly, Aβ deposits are detected in the retina in AD patients prior to detection in the brain, making it an attractive target for early detection and therapeutic intervention. However, the mechanisms by which Aβ accumulates, spreads, and promotes cellular degeneration remain unclear, preventing the development of much-needed therapies.
In all of these disorders, neuroinflammation plays an important role in initiating and exacerbating pathology. Microglia, the primary immune cells of the central nervous system (CNS), interact with Aβ through a number of membrane receptors, especially scavenger receptor cluster of differentiation 36 (CD36). Activation of this receptor induces an intracellular signaling cascade that promotes secretion of pro-inflammatory cytokines and production of reactive oxygen species that damage neural tissue. Thus, CD36-mediated microglial activation may be the mechanism by which Aβ exerts its destructive effects throughout the retinal projection and elsewhere in the CNS.
My research focuses on determining whether intervening in the Aβ-CD36 interaction can slow or prevent degradation of the visual system in common neurodegenerations. Specifically, I am testing the therapeutic potential of CD36 inhibitors as neuroprotective treatments in a mouse model of retinal amyloidosis, with the goal of identifying compounds or mechanisms that may be used to treat AD, glaucoma, and related disorders.
AFPE Pre-Doctoral Fellow, Lauren Fontana, is currently a doctoral candidate in her final year at the University of Connecticut, advised by Dr. Robin Bogner. For her dissertation research, she is developing a Raman spectroscopic method to detect structural changes, which are important to drug potency, in dry proteins formulations. The goal is to develop a rapid screening method to support drug development in the biopharmaceutical sector.
FDA approvals of protein drugs has risen dramatically. Most of these drugs require sterile liquid injections. However, protein drugs are often not stable in liquid form, meaning that they are more likely to degrade during storage before reaching the patient. Approximately 30% of these drugs are freeze dried to improve storage stability. Freeze drying is the process of water removal under vacuum to remove the ice from a frozen sample, which transforms the liquid drug to a dry solid product that is stable during storage. However, protein structural changes during the freeze-drying process itself may negatively impact drug potency. Currently no routine method is able to predict the loss in potency during storage. A simple analysis of the freeze-dried protein immediately after processing that predicts stability would be ideal.
Raman light scattering shows promise as a powerful routine tool to determine protein structural changes in dry formulations that are expected to predict long-term protein product stability. Using this method as a screening tool would ideally enable companies to make improved drug products in a shorter amount of time — ensuring the patient receives higher quality medications at a lower cost.
Lauren received pre-doctoral fellowships from both AFPE and PhRMA to support her research goals. “The fellowships allow me to focus on my research goals, allowing latitude in defining my research direction” said Fontana. “In addition, networking with previous pre-doctoral fellows have enhanced my career trajectory.”
Upon graduation, Lauren’s goal is to contribute to the development and transfer of new pharmaceutical products from concept to manufacturing. Using her previous 15 years of experience, Lauren looks forward to leading a team of scientists. Her goal is to have a career that is interesting, challenging and enables her to contribute to the greater good with improved medicines for patients.
Tyler Ackley, a 4th-year Pharmacy student at the University of Connecticut, and a 2018-2019 Gateway Scholar is focusing on the changes in cellular signaling that occur during Rheumatoid Arthritis (RA) disease progression. RA is a chronic, inflammatory disease characterized by immune cell induction and subsequent degradation of joint tissues. This autoimmune attack of the joint space leads to irreparable damage, lifelong pain, and diminished mobility. Like many other autoimmune diseases, RA is thought to be due to the multifactorial effects of underlying genetics, environmental triggers, and various regulatory genes.
Recent research has implicated the Epidermal Growth Factor Receptor (EGFR) in RA disease. Activation of EGFR induces cellular behaviors like proliferation, survival, and migration. Given these characteristics, EGFR is traditionally associated with cancer biology and is upregulated in many malignancies such as breast and non-small cell lung cancer. A soluble isoform of EGFR (sEGFR), has been found to modulate and reduce EGFR signaling. Ackley is working to characterize the biological role of sEGFR in RA, as well as determine its use as a potential biomarker and therapeutic target.
Following Ackley’s Pharm.D. graduation in spring 2019, he plans to continue his education in a Ph.D. program in the pharmaceutical sciences with a focus in biochemistry or toxicology. Using his undergraduate and Pharm.D. laboratory experience as a backbone, he hopes to further his understanding of biology as well as the underlying mechanisms of disease. Ultimately, he hopes to return to a pharmacy school and establish a role in academia.
“The AFPE Gateway to Research scholarship provides the means to further develop this project, allowing me to take on more intricate and thorough experiments. The information gained therein will provide a more holistic understanding of EGFR signaling in RA. Further, we can begin to explore clinical avenues for the project and begin to look at patient data directly,” said Ackley.
2017 AFPE Fellow, Ashley Cole, MPH, is researching the “Comparative Effectiveness and Safety of First-Line Chemotherapeutic Regimens for Unresectable Pancreatic Cancer”
Cole is completing this research project with Dr. Stacie Dusetzina at the University of North Carolina, Chapel Hill. Her project is explained below:
Pancreatic cancer ranks third among the deadliest cancers, with less than 8% of patients surviving 5 years or more. Due to a lack of clinical signs and symptoms, patients often present at an advanced stage. Consequently, over 80% of patients are diagnosed with tumors that cannot be removed with surgery, making chemotherapy a critically important treatment option.
Over the past 30 years, the prognosis for pancreatic cancer has shown the least improvement of any cancer site, in part due to lack of advances in treatment. However, in the past 5 years, 2 first-line chemotherapy regimens have emerged for the treatment of unresectable pancreatic cancer: oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) and gemcitabine and nab-paclitaxel. Both regimens have demonstrated superior overall survival to treatment with gemcitabine alone, but no clinical trials have directly compared the effectiveness or safety of these 2 options head-to-head.
The proposed study will use administrative claims data to investigate the comparative effectiveness and safety of gemcitabine/nab-paclitaxel versus FOLFIRINOX as first-line chemotherapy for unresectable pancreatic cancer. We will address the following specific aims:
Aim 1 Describe predictors of treatment for unresectable pancreatic cancer between 2013 and 2017.
Descriptive statistics will be used to characterize current practice patterns in first-line treatment of unresectable pancreatic cancer. The probability of treatment with either FOLFIRINOX or gemcitabine/nab-paclitaxel will be investigated using modified Poisson regression.
Aim 2 Compare the effectiveness of first-line treatment with gemcitabine/nab-paclitaxel versus FOLFIRINOX for unresectable pancreatic cancer.
Using predictors of treatment identified from Aim 1, overall survival will be compared between propensity-score weighted patients who receive first-line gemcitabine/nab-paclitaxel versus first-line FOLFIRINOX using Cox proportional hazards models.
Aim 3 Compare the safety of first-line treatment with gemcitabine/nab-paclitaxel versus FOLFIRINOX among for unresectable pancreatic cancer.
The incidence of adverse events will be compared between propensity-score weighted patients who receive first-line gemcitabine/nab-paclitaxel versus first-line FOLFIRINOX using Cox proportional hazards models, to account for censoring in the follow-up period.
This is the first study to directly compare the effectiveness and safety of gemcitabine/nab-paclitaxel versus FOLFIRINOX as first-line chemotherapy for patients with unresectable pancreatic cancer. Findings will directly inform treatment decisions for over 80% of patients diagnosed with this devastating disease.
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