2024-2025 Pre-Doctoral Fellows

2024-2025 Pre-Doctoral Fellow Projects by Research Category

Clinical and Translational Sciences (includes pharmacotherapy, experimental therapeutics, PK/PD, modeling and simulation)

Cecilia Barajas, University of Minnesota, AFPE Regional Award

Mentor: Dr. Carolyn Fairbanks

Research Title: Mechanistic Investigation of Agmatine, a Small Molecule in Therapeutic Development for Chronic Pain and Opioid Use Disorder

“Although chronic pain affects a significant fraction of the world population, finding safe and effective treatments remains a challenge. Opioids remain as the gold standard for pain management despite dangerous side effects. Since the early 1970s, several effective pharmacotherapies have been approved by the Food and Drug Administration (FDA) to treat opioid use disorder however, the stigma surrounding opioids perpetuates a hesitancy to classify addiction as a medical disease, limiting the use of these therapies and thus reducing their perceived efficacy. Moreover, the practical restrictions surrounding treatments for opioid addiction, particularly the specialized clinics and in-person daily dosing, further inhibit the use of these therapies. Without an alternative solution to help people suffering from chronic pain, there emerges an urgent need for novel, non-opioid, therapies to address pain and the manifestations of chronic opioid exposure. Recent interest in adeno-associated viruses as gene therapies for chronic pain and opioid use disorder has grown due to their presumed single-dose, long-term effectivity, and their ability to harness endogenous features of the nervous system. We and others have repeatedly demonstrated that the endogenous NMDA receptor antagonist agmatine has high therapeutic potential in preclinical models of pain and addiction. Moreover, our lab has shown that the synthetic upregulation of agmatine through administration of a gene therapy provides long-term reversal of neuropathic pain. Therefore, the goals of this proposal are to pursue the development of a non-stigmatized and effective therapeutic to treat pain and opioid use disorder through the optimization of agmatine as a gene therapy. To achieve this, we will identify the cortical loci and cellular populations necessary for agmatine’s inhibitory action to inform us of the optimally effective installment location.”

 

 

Nam H. K. Nguyen, University of Florida, Second Year Fellow

Mentor: Dr. Jatinder Lamba

Research Title: CRISPR Synthetic Lethality Screen Identifies Genomic Resistant/Sensitive Modulators of Standard Chemotherapy in Pediatric Acute Myeloid Leukemia (pAML)

“Acute myeloid leukemia (AML) has one of the biggest death contributions in all leukemia subtypes in both the pediatric and adult populations. It was estimated that 5 years OS of pediatric is about 70% and adult is only 25%. It is a devastating disease and we need to have better care for our patients. AML is a heterogeneous disease with limited drug treatment options, where cytarabine and daunorubicin also known as 7+3, has been the standard backbone chemotherapy for almost 5 decades despite recently newly approved drugs. These newly approved agents are typically used in combination with 7+3 or in subsequence of this standard chemotherapy once the patient relapse. Because of limited therapy options, chemotherapy resistance is a significant factor that can affect patients’ outcomes. Therefore my research is to understand the genetic modulators associated with response to chemotherapy when treatment are given to AML patients, and to discover novel pathways and targets that can overcome drug resistance. Ultimate goal is to improve patient outcomes My dissertation work broke into two main parts: Firstly, is to use CRISPR technology with a custom library to perform synthetic lethal screen multiple AML cells with common used drug in AML treatment. Herein, our custom library has three components: 1) all AML and leukemia prognostic genes, 2) all PKPD genes of our standard of care treatment and 3)a druggable genome with approved agents. At the CRISPR screen, I will identify a list of drug resistance genes and sensitive genes for chemotherapy then this will be integrate into clinical integration. I hypothesize that drug resistance genes will show better outcome with lower expression and vice versa for drug sensitive genes, where lower expression collated to clinical outcomes. Futher significant genes from CRISPR screen with prognostic potential will be further be investigated mechanistically. At the end of my dissertation work, I hope to identify novel genes and pathway associated that lead to drug resistance. Also, my work will profile a list of genes with the prognostic potential to predict patient outcomes. Hopefully, this will provide insight for drug combination guided by gene expression. Because our custom CRISPR gene contain druggable genome, we hope to use that repurpose approved drug that can be combined with chemotherapy to overcome drug resistance”

 

Drug Delivery, Bioengineering (includes nanomedicine, devices, biotechnology, protein delivery and characterization, and biopharmaceuticals)

 

Namir Khalasawi, University of Michigan, Dr. Paul B. Myrdal Memorial Fund for Pharmaceutical Education

Mentor: Dr. Peter Tessier

Research Title: Engineered antibodies for therapeutic immune modulation

“Multiple sclerosis (MS) is a chronic autoimmune disease that involves immune cell infiltration into the brain and spinal cord, inflammation, and neurodegeneration. Over time, this leads to slowing of nerve impulses and eventually loss of function. In MS, the production of anti-inflammatory cytokines is suppressed, and thus delivering these cytokines to the central nervous system (CNS) represents an attractive strategy for reducing inflammation and preventing further nerve damage. Therefore, the goal of my project is to develop a therapeutic agent that can deliver anti-inflammatory cytokines to the CNS to attenuate the pro-inflammatory environment associated with MS. This agent, termed a bispecific immunocytokine, consists of i) a shuttling antibody to facilitate passage into the CNS; ii) a targeting antibody to localize the agent to areas of neurodegeneration; and iii) an anti-inflammatory cytokine to mediate sustained therapeutic activity. Importantly, I aim to optimize this bispecific immunocytokine for predictable behavior in vivo such that researchers could easily modify it by using a different cell-specific target and/or a different cytokine payload. This would allow the delivery of potentially any cytokine to the CNS to treat a variety of diseases, including cancer, autoimmunity, and infection.”

 

 

Jonathan Perri, University of Buffalo, The State University of New York

Mentor: Dr. Robert Straubinger

Research Title: Nanoparticle-Based Approaches to Generate Integrated Immune Responses in Immune Deficient Solid Tumors

The ultimate goal of my project is to improve the effectiveness of immune-based anti-cancer therapy in solid cancers. To achieve this, I propose that ligand-targeted nanoparticle drug carriers loaded with immune-stimulatory drugs can promote the invasion of cytotoxic immune cells into solid tumors while also engaging anti-cancer activity directly through nanoparticle targeting ligand binding. Many solid tumors present immense treatment challenges due to their location in the body near vital organs or critical blood vessels, preventing surgical removal. Traditional chemotherapy may offer limited effectiveness due to treatment-induced resistance and subsequent tumor regrowth. Immune-based therapy harnesses a patient’s native immune system to eliminate cancer cells and has shown great promise in blood cancers, but limited efficacy in the immune-suppressed interior of solid cancers. Immune stimulators like the drug ‘AMD3100’ have shown promise in reinvigorating the immune system in immune-deficient solid tumors, but its circulation in the blood is short-lived, and as a result ‘AMD3100’ requires long infusions which can be toxic to some patients. Long-circulating drug nanocarriers can overcome these limitations by carrying large concentrations of ‘AMD3100’ to the tumor site, thus avoiding off-target toxicity while enhancing immune-stimulatory effects of ‘AMD3100’. Further, drug-loaded nanoparticles will be surface-activated with antibodies targeting both tumor cells and immune cells, creating immuno-nanoparticles that bring immune cells in closer proximity to cancer cells and directly stimulate anti-cancer activity of patient immune cells. Together, this targeted drug delivery platform functions as an all-in-one therapeutic that can overcome tumor immune deficiency and adapt contemporary immune-based therapeutic strategies to solid cancers.”

 

Drug discovery/medicinal chemistry

Brian Anderson, University of North Carolina at Chapel Hill

Mentor: Dr. David Drewry

Research Title: Development of a chemical toolbox for the interrogation of the NEK family of kinases

“Most genes within the human genome are still understudied. This means there is a lack of scientific understanding of the role the gene plays in normal physiology, as well as disease. My project hopes to illuminate the normal biological functions and roles in disease for a family of understudied kinases. Kinases are enzymes which are necessary for many of the biological processes which occur daily within humans. Some of these kinases are known to play a role in serious human illnesses, such as cancers and neurological diseases. The kinases which currently have drugs available to prevent them from causing disease when they are mutated, or in some other way compromised, are typically from a subset of the around 500 human kinases which have been very well studied. Knowing how a kinase functions normally, and what it does when it is not functioning properly, allows for researchers to understand how best to target them to remedy any adverse effects caused when they are compromised. I am focusing on a family of understudied kinases which have been implicated in multiple diseases but still remain understudied. It is my hope that by using medicinal chemistry and chemical biology, I will be able to provide an open-source set of tools which will help us understand how these kinases are functioning and how their unwanted changes are causing illnesses.”

 

Nicole Benson, Ohio State University

Mentor: Dr. James Fuchs

Research Title: Medicinal Chemistry; Organic Synthesis; Natural Products; Translation Inhibitor

“Cancer is one of the leading causes of death world-wide and it is projected by the National Cancer Institute (NCI) that by 2040 there will be 16.4 million deaths yearly due to cancer. While we have a broad range of therapies available for the treatment of cancer, it is imperative that we continue to discover new drugs in hopes of finding ones that can overcome the limitations of currently available treatments, such as drug-resistance and severe side effects. Molecules found in nature have traditionally been used to help design drugs for a variety of diseases, including cancer. My project involves using organic chemistry to synthesize a molecule isolated from nature, known as (−)-didesmethylrocaglamide (DDR), that has shown promise with regard to treating cancers that are refractory and resistant to currently available therapies. Cancerous cells can be similar to the body’s normal cells in some ways; this can make them difficult for drugs to target and results in the side effects people often experience when undergoing cancer chemotherapy. However, one way that cancerous cells differ from normal cells is that they upregulate or overexpress certain proteins that are required to achieve a high level of unregulated cellular growth and it is thought that DDR inhibits one of these proteins (eukaryotic initiation factor 4A or eIF4A). This inhibition results in a decrease of cellular growth and signals the onset of programmed cellular death, known as apoptosis. While DDR has advantages over other similar anticancer molecules, there are certain aspects that need to be improved in order for it to be used as a drug in the clinic. For example, in order for most drugs to be effective they must be soluble in water to a certain degree. The aqueous solubility (solubility in water) is a physicochemical property of DDR that we seek to improve while still allowing it to effectively inhibit cancerous cells. In addition to synthesizing DDR, the long-term goal of my research is to chemically modify this molecule in order to make it an overall better drug that could one day be used to treat patients with cancers that would otherwise be untreatable.”

 

Henry Dieckhaus, University of North Carolina at Chapel Hill

Mentor: Dr. Brian Kuhlman

Research Title: Stabilizing Protein-Based Therapeutics Using Deep Learning

“My project aims to develop computational models of protein stability to help pharmaceutical scientists make protein-based drugs safer and more effective. Proteins are linear chains of amino acids that tend to adopt a specific 3D structure (or “fold”) when at equilibrium. This structure determines what a particular protein can do, such as catalyze a chemical reaction, bind a neurotransmitter in the brain, or recognize an antigen in a cancer cell. However, the chemical forces that hold this structure together are limited, and proteins can denature (or “unfold”) at higher temperatures or under other energetic stresses. Since unfolded proteins are no longer capable of carrying out their jobs and are typically rapidly degraded in the body, the stability of a particular protein is an important property. As protein-based therapeutics have become more commonly used in drug discovery, pharmaceutical scientists have had to contend with protein stability as an important ADME (absorption, distribution, metabolism, and excretion) property that must be optimized during drug development. Unfortunately, it is difficult to predict what changes (i.e., mutations) are likely to result in improved protein stability, so exhaustive experimental screening is frequently used. My project aims to streamline this process by providing computational models that can nominate a small number of mutations to be experimentally validated, saving time and development costs. I plan to do this by training a deep learning model to recognize patterns in protein structures and use these patterns to determine what mutations are most likely to be successful. This platform can then be applied to protein-based drugs aimed at treating virtually any disease, making it a widely useful and potentially transformative pharmaceutical research tool.”

Destiny Durante, University of Illinois at Chapel Hill

Mentor: Dr. Terry Moore

Research Title: N-substituted Heterocycles as Pan-filoviral Entry Inhibitors

“The goal of my project is to design and synthesize novel small molecule therapeutics for Ebola virus. Like many other viruses, there are several variants of Ebola virus that are human-infectious and disease inducing. My goal is to develop effective treatments against diverse filoviral species to provide infected patients with wider protection against these pathogenic viruses.”

 

Luke Harding, University of Illinois at Chapel Hill

Mentor: Dr. Pavel Petukhov

Research Title: Novel, potent, and selective inhibitors of SmHDAC8 with schistosomicidal activity and meclonazepam target identification in Schistosoma mansoni

“Schistosomiasis is a major neglected tropical disease caused by the parasitic helminths of the Schistosoma spp. Current reports estimate 200 million cases yet over the past 40 years there has been no improvement in treatment. The overarching goal of this project is to advance schistosomiasis chemotherapy by inventing small molecule inhibitors of S. mansoni histone deacetylase 8 (SmHDAC8) with schistosomicidal activity and by identifying the target of meclonazepam in S. mansoni. SmHDAC8 has been shown to be a druggable protein that is essential for worm development while the benzodiazepine meclonazepam is highly therapeutic, but the source of its pharmaceutical effect is unknown. Novel drugs that work through mechanisms distinct to the current standard of care with the anthelmintic praziquantel will address the current limitations of praziquantel monotherapy. SmHDAC8 Inhibitors will be identified using iterative rounds of computer-aided molecular dynamics, medicinal chemistry, and available X-ray crystallographic structures. Synthesized SmHDAC8 inhibitors will be evaluated for their in vitro potency and selectivity between parasitic and human HDAC8 orthologs. The best performing inhibitors will be evaluated for their schistosomicidal activity in worms and against toxicity in human cells in vitro. The target of meclonazepam will be identified by synthesizing meclonazepam-based photoreactive probes for photoaffinity labeling experiments in S. mansoni. Successive generations of probes will be synthesized with improved potency and solubility to corroborate the results from previous experiments. The most promising targets will be verified by synergistic experiments by treating worms with meclonazepam and ligands associated with the target or other targets in the same pathway identified through the ChEMBL database.”

 

Kelsey Holdaway, University of Minnesota, Second Year Fellow

Mentor: Dr. Gunda Georg

Research Title: Development of Selective, Allosteric Inhibitors of Cyclin-Dependent Kinase 2 for the Therapeutic Treatment of Cancer

“In diseases such as ovarian, breast, and colorectal cancers a particular enzyme termed CDK2 is overactivated, which leads to cancer cell growth. One approach toward the treatment of these types of cancers is to inhibit CDK2 and thus inhibit cancer cell growth. A main challenge in this approach is how to selectively target CDK2 over other similar enzymes, which if also inhibited will cause negative side effects. One such strategy to overcome this challenge is to design inhibitors that bind to a location on CDK2 that is unique and less conserved amongst other similar enzymes, which would result in improved selectivity and fewer or no undesirable side effects. Our lab has identified two such unique locations on CDK2 that are suitable for selective binding of an allosteric inhibitor. For the first site, our lab has already developed inhibitors capable of binding, however, they exhibit a problem with being outcompeted for binding by a small protein that activates CDK2. In order to improve the ability of our inhibitor to preferentially bind at this site, we propose to develop inhibitors capable of permanently binding. As the other protein binds in such a manner as it attaches and detaches cyclically, a permanently binding inhibitor could overcome the issue of being outcompeted. For the second site, computational analysis will be performed to help identify an inhibitor that would be compatible with binding at this location and inhibit the enzyme selectively. The outcome of this analysis is expected to identify an inhibitor that is compatible with binding to CDK2 at the specific location. With this knowledge, a variety of inhibitors can be synthesized and subsequently tested for their ability to selectively bind at this location and inhibit CDK2. Upon synthesis of inhibitors capable of selectively binding at either of these locations, the goal will be to test for inhibition activity against CDK2 and test the analogs for anticancer activity in several ovarian cancer cell lines. From this, it can be deduced how effective the inhibitors are at inhibiting CDK2 activity and thus inhibiting cancer cell growth. Ultimate goals are to test these inhibitors in animal models of cancer and then in clinical studies.”

 

Brandon Lowe, University of Maryland, Baltimore, ASHP-AFPE Pre-Doctoral Fellowship

Mentor: Dr. Steven Fletcher

Research Title: Design, Synthesis, and Biological Evaluation of Non-Hydroxamate-based, Selective Histone Deacetylase 8 (HDAC8) Inhibitors

“The primary goal of my project is to design and chemically synthesize novel compounds that block the action of a protein called histone deacetylase 8 (HDAC8). This protein is present in all of our healthy cells and it helps to regulate the synthesis of many other proteins from our genes. Specifically, HDAC8 turns off this process thus leaving the cells without proteins crucial for healthy cell function. Cancer cells from various cancers have been found to synthesize larger than normal amounts of HDAC8. This prevents these cancer cells from synthesizing proteins that program them for cell death, allowing the cancer cells to stay alive and divide. In short, by synthesizing chemical compounds that block HDAC8 action, we hope to prevent these cancer cells from staying alive long enough to rapidly divide.”

 

Steven McKay, State University of New York at Binghamton

Mentor: Dr. Tracy Brooks

Research Title: Design, synthesis, and evaluation of MYC pathway targeting degraders for the treatment of pancreatic cancer

“Proteolysis targeting chimeras (PROTACs) are a new class of therapeutics that has shown promise in treating various cancers. This class of compounds typically contains three parts: a ligand to target a protein of interest, a ligand to target an E3 ligase, and a linker between these two. My idea is to utilize the ubiquitin pathway system already within the body to degrade a protein of interest via forced proximity due to the PROTAC. In the context of cancer, there have been many proteins identified that are both upregulated and facilitate tumor growth and maintenance. One such example is MYC, which is dysregulated in a majority of cancers. When MYC is suppressed, a potent anti-cancer effect is seen, including in pancreatic cancer. JQ1 is a small-molecule inhibitor of bromodomain-containing protein 4 (BRD4), which is an upstream regulator of MYC. JQ1 has been shown to reduce MYC transcription, albeit transiently due to its short half-life and reversible nature. I have been synthesizing PROTACs containing JQ1 as the protein-targeting moiety linked to pomalidomide, which is an E3 ligase-targeting moiety that binds to cereblon. Notably cereblon is moderately expressed in pancreatic cancer, providing a potential selective index for treatment. Thus far, my work has focused on optimizing the linker that connects the two. Once a panel of PROTACs has been synthesized, I will perform cell-based functional tests assessing their cytotoxic and target degradation effects, as compared to a JQ1-based PROTAC reported in literature, ARV-771. The top 2 or 3 performing PROTACs within the in vitro studies will then be tested in mice assessing the reduction in tumor burden and correlating target degradation. Ultimately, my goal is to contribute to the development of more effective and targeted cancer treatments for pancreatic malignancies.”

 

Howard J Phang, University of California, San Diego, Second  Year Fellow

Mentor: Dr. Anthony Molina

Research Title: Using Human Cell Models of Aging to Identify Modulators of Mitochondrial Function

“A growing body of research indicates that your cells’ ability to generate energy via mitochondria plays an important role in healthy aging and preventing age-related illness. The goal of my project is to develop a platform to accelerate the discovery of substances with the ability to make mitochondria work better or more efficiently. This will be done through laboratory techniques that will use human skin cells to test and measure individual chemicals’ ability to affect mitochondrial function.”

 

Pharmaceutical Technology (includes formulation sciences, dosage form design, materials science, physical pharmacy)

 

 

Pharmacology, Toxicology (includes cell biology, chemical biology, and pharmacognosy)

 

Sohpia Bonar, Oregon State University

Mentor: Dr. Jane Ishmael

Research Title: Preclinical Evaluation of the Cyclic Depsipeptide Marine Natural Product Odoamide

“This project aims to identify the mechanism of death, protein target, and in vivo efficacy of a new marine natural product compound that has been previously shown by our lab to induce a complete loss of viability in wild type and drug resistant ovarian cancer cells. We aim to understand the mechanism of death to determine if treatment may cause any damage to surrounding tissue or activate an immune response. We plan to identify the binding target(s) of this compound to help determine how it is able to overcome drug resistance in ovarian cancer and to anticipate any off-target toxicity. Finally, an in vivo study with a library of structural analogs will allow us to determine if this compound, or any of those in the library, has a future as a drug candidate for the treatment of ovarian cancer.”

 

 

Alexander Meyer, University of Michigan

Mentor: Dr. Wei Cheng

Research Title: The Identification of Key Signals for the Induction of Durable Humoral Immunity

“Vaccines are often considered one of the greatest public health interventions ever developed, with examples of impactful vaccines including those against smallpox, polio, and COVID-19. Despite these successes, the duration of antibody responses induced by vaccination remains inconsistent. For example, although the smallpox vaccine produces antibodies which last for decades, the mRNA COVID-19 vaccines produce antibody responses which decrease rapidly in the first several months after vaccination. To improve upon this inconsistency, my project focuses on identifying which signals are needed to induce long-lasting antibody protection using a novel liposomal viral mimic developed by our lab, which we call synthetic virus-like structures (SVLS). SVLS mimic the basic structural and biochemical features of a virus, allowing us to determine how the immune system detects and responds to different viral features alone and cooperatively when generating an immune response. I am using these structures to determine the role of several potential signals on the magnitude and durability of antibody responses in mice and nonhuman primates. The long-term goal of this research is to identify which immune signals are critical for inducing long-lasting antibody responses so that we can develop new vaccines more efficiently and effectively. Additionally, I am developing a new assay for the isolation and quantitation of serum antibodies which improves upon traditional techniques, such as ELISA. This will allow us to more accurately determine the concentration and affinity of antibodies produced in an immune response, which is necessary for the understanding of immune responses and the development of vaccines.”

 

Social and Administrative Sciences

Amna Rizvi-Toner, University of Michigan, Second Year Fellow

Mentor: Dr. Karen Farris

Research Title: Oral Anticancer Agents: Symptom Self-Management and Healthcare Utilization

“The primary goal of my project is to understand the role patient self-efficacy plays in their ability to self-manage symptoms arising from oral anticancer agents (OAA), as well as their use of healthcare services. Additionally, my project seeks to understand the patient experience while taking OAA, which includes their quality of life, OAA adherence, self-efficacy levels over time, symptoms that result from the OAA, symptom severity, and behaviors to self-manage symptoms. Lastly, my project also aims to understand the cancer care clinicians’ perspectives on supporting patients with managing OAA symptoms. Cancer care clinicians will include the following members of the patients’ cancer care team: physicians, pharmacists, advanced practice providers (e.g. nurse practitioners and physician assistants), and nurses.”

 

Rana Zalmai, University of Texas at Austin, Pre-Doctoral Fellowship in Health Outcomes Disparities

Mentor: Dr. Carolyn Brown

Research Title: Social Determinants of Health and Medications for Opioid Use Disorder

“Parkinson’s disease (PD) is one of the world’s fastest-growing nervous disorders. It affects nearly one million people in the United States. However, there are no effective treatments for PD. Because type 2 diabetes (T2D) and PD are both age-related diseases, they shared similar pathways including insulin signaling. Thus, newer glucose-lowering drugs (GLDs) may be potential treatments for PD. In this study, I will use the Medicare administrative data to evaluate the association between newer GLDs and the risk of PD in people with T2D by estimating the average treatment effects among the overall population and identifying which subgroups could get the most benefits.”