Koda-Kimble Seed Award fuels eight original research projects

The UCSF School of Pharmacy 2018 Mary Anne Koda-Kimble Seed Award for Innovation marked its fourth year of funding with the February 26 announcement by Dean B. Joseph Guglielmo, PharmD, of eight research award recipients. Awardees are from across the School and range from full faculty members to PharmD and PhD students.

“The School’s drive to seek and apply new knowledge is once again fueled by the Koda-Kimble Seed Award for Innovation,” said Guglielmo. “The breadth of the projects funded this year is true to the intent of the award.”

The award was established in 2012 to fund innovative projects that have the potential to move forward the mission of the UCSF School of Pharmacy in new ways. Applicants are encouraged to submit their boldest, riskiest, and most blue-sky ideas—those for which there is no ready or traditional source of funding. Projects may be large or small in scope.

Faculty members, staff, and students from within the School; UCSF faculty members outside the School who teach the School's doctor of pharmacy (PharmD) students; UCSF PharmD residents; and postdoctoral scholars working with School faculty members were all encouraged to apply.

Mary Anne Koda-Kimble, PharmD, served as the School’s dean from 1998 to 2012 and represented a leadership style of relentless support for new directions in science, education, and patient care. The Seed Award for Innovation honors her legacy.

The eight projects described briefly below were chosen to receive 2018 Seed Awards, and will share nearly $100,000 in total funding.

Identification of proteostasis drug combination targets for treatment of castration-resistant prostate cancer

Principal applicant: Arielle Shkedi, student, Pharmaceutical Sciences and Pharmacogenomics PhD degree program

Award funding: $8,448

The challenge: Prostate cancer is the third leading cause of cancer death among men. In prostate cancer, tumor growth is driven by the androgen receptor (AR). The AR normally acts as a transcription factor, but in prostate cancer aberrant AR signaling leads to tumor growth. Targeting AR signaling is therefore a major strategy for treating prostate cancer.

Advanced prostate cancer is treated with androgen deprivation therapy (ADT), which blocks androgen signaling. However, following ADT, a majority of patients develop resistance, and their disease progresses to castration-resistant prostate cancer (CRPC).

The project: Because the AR depends on molecular chaperones for its proper function and activation, the investigator hypothesizes that there are molecular chaperones and proteostasis inhibitor combinations that can be targeted for treatment of CRPC. The goal of this project is to identify synergistic proteostasis inhibitor combinations that can be used to treat castration resistant prostate cancer.

Modeling spatio-temporal antimicrobial pharmacodynamics on pseudomonas aeruginosa biofilms using microfluidic flow-cell technology and advanced microscopy

Principal applicant: Katherine Yang, PharmD, MPH, faculty member, Department of Clinical Pharmacy

Award funding: $21,718.27

The challenge: Biofilms are three-dimensional structured bacterial communities surrounded by a self-produced matrix and exhibit increased antibiotic resistance compared to free-swimming (planktonic) bacteria. Biofilms make up over 70% of all human infections, including endocarditis, orthopedic implant infections, and cystic fibrosis, and they are near impossible to eradicate with antibiotics alone. Current clinical antibiotic susceptibility testing and pharmacodynamic (PD) studies informing antibiotic dosing are limited to planktonic bacteria and have little relevance to biofilms. Within the 3-D biofilm, microcolonies of bacteria exhibit variation in antibiotic susceptibility.

Researchers have previously developed in-vitro pharmacodynamic simulators capable of replicating the pharmacokinetic profiles of human antibiotic dosing regimens on biofilms grown in flow-cells. PK (pharmacokinetics)/PD simulators are the first of their kind, allowing simultaneous visualization and quantification of the effect of dynamic antibiotic drug concentrations while keeping external factors affecting biofilm growth and metabolism constant.

The project: While prototypic PK/PD simulators are easy to construct and operate, the current design has limitations. Investigators have been partnering with the Chan Zuckerberg Biohub to develop an improved PK/PD biofilm platform using microfluidics. The goal of this proposal is to construct an integrate, in-vitro biofilm PK/PD microfluidic simulator with automated drug delivery, imaging, and drug/biofilm sampling.

Multiplexed single-cell surface profiling by sequencing for tumor biomarker discovery

Principal applicant: Cyrille L. Delley, PhD, postdoctoral scholar, Department of Bioengineering and Therapeutic Sciences

Award funding: $3,250

The challenge: The human immune system is excellently adapted at discriminating between invading pathogens and body tissue. However, cancerous malignancies and some pathogens evolved mechanisms to exploit self-tolerance and to fool the immune system. Many of the resulting diseases pose a considerable challenge to treatment.

Especially for some cancers, it was demonstrated that when given the appropriate support, the immune system can be used very effectively to eliminate malignant cells. The appropriate support can be provided by employing antibodies to target surface proteins which are overexpressed on cancerous tissue.

The project: To find cell-specific surface reads, it is necessary to know the cell-type for each cell, its phenotype composition and the phenotype compositions of all other cells. A microfluidic approach is ideal for this type of problem. Antibodies have a long tradition as probes for cellular phenotypes. The goal of this project is to use a library of randomized antibodies to directly profile a heterogeneous cell sample, like phage in display, but applied to not one but an unknown number of target proteins.

Discovering novel anxiolytics though manipulation of the endocannabinoid system

Principal applicant: Adam Melgoza, student, Pharmaceutical Sciences and Pharmacogenomics PhD degree program

Award funding: $5,208

The challenge: Anxiety disorders are debilitating, often co-morbid with neurological and cardiovascular illnesses, affect people of all ages, and consume a large amount of health care resources. While there are a variety of treatment options, they are expensive, have many unwanted side effects, and are not effective in all populations. The Endocannabinoid System (eCBs) is known to play a crucial role in anxiety, stress, and fear responses. It is a highly conserved pathway amongst vertebrates, and is made up of cannabinoid receptors CB1 and CB2, endogenous ligands known as endocannabinoids, and enzymes that synthesize and degrade these ligands.

Drugs that activate CB1, such as the compound THC in marijuana, reduce anxiety at low doses but have unwanted psychotropic effects, making CB1 agonists a poor choice as novel anxiolytics. Though it is clear that CB1 is playing a role in anxiety, it is less clear how other proteins involved in the eCBs may be also be modulating anxiety. Likewise, the neural circuitry underlying these changes in behavior caused by the eCBs is poorly understood. Understanding how each component of the eCBs affects anxiety as well as the underlying neural circuitry will pave the way for novel therapeutics for anxiety disorders.

The project: The goal of this project is to screen a comprehensive library of compounds that alter the various components of the eCBsin search of novel drugs/targets that reduce anxiety-like behaviors. Hits can then be further studied by examining neuron activity, providing insight on the neural circuitry by which the eCBs attenuates or enhances anxiety.

Exploring drug binding using molecular dynamics and virtual reality

Principal applicant: Thomas Goddard, research specialist, Department of Pharmaceutical Chemistry

Award funding: $17,127

The challenge: Antibiotic and antiviral drug resistance can be conferred by mutations in the drug binding site, by either single residue changes or post-translational modifications, such as methylation. The effects on drug binding of such mutations can be understood using molecular dynamics simulations. Consumer virtual reality headsets of ligand and neighboring receptor side-chains scaled to room-size allows a central vantage point that significantly improves perception of the stereochemistry of the binding site. The consequences of receptor and ligand modifications can be probed to understand the biophysical constraints of the binding site. Interactive molecular dynamics and virtual reality can be used as an exploratory hypothesis testing tool to inform the design of computationally intensive searches for tighter binding ligands and analyses of specificity or drug resistance.

The project: The goal of this project is to combine interactive molecular dynamics with virtual reality visualization to explore the effects of binding site modifications such as point mutations, methylation and ligand modifications, interactively making and testing the effects of many modifications in a short session. Investigators will develop, validate on well-understood systems with structurally similar ligands, and distribute this easy-to-use capability within the UCSF ChimeraX software package, for researchers and UCSF PhD and PharmD students. This will be a first working use of virtual reality for biomolecular research.

Developing bright and economic super resolution microscopy using chemical labeling

Principal applicant: Xiaoyu Shi, PhD, postdoctoral scholar, Department of Pharmaceutical Chemistry

Award funding: $17,245

The challenge: Understanding the molecular mechanisms of cellular processes is the foundation of drug development and gene therapy. Cellular processes are orchestrated by a large number of biomolecules in a spatially and temporally coordinated manner within a tiny volume. Super resolution fluorescence microscopy makes it possible to uncover the underlying organizational principles and their functional relevance at the molecular level. However, these optics-based super resolution technologies require advanced microscopes and special staining protocol to achieve higher than 100 nm resolution. A more economic approach to the super resolution is Expansion Microscopy (ExM). Rather than optically increasing the resolving power, ExM is a sample preparation tool that expands the fluorophore-labeled biological samples using a polymer system.

In principle, ExM could increase the resolution of any microscopy method at least by a factor of 4. Among other benefits, ExM allows those small structures to be imaged with a wider range of microscopy techniques, including conventional fluorescence microscopy and confocal microscopy.

The project: What seriously limits the application of expansion microscopy is the huge fluorescence loss during polymerization. More than 40% of the organic dye or fluorescent tags is quenched or destroyed by the polymerization reaction. The goal of this project is to introduce a polymer network into cellular or tissue samples, and then physically expand that polymer network to increase the size of the biological structures.

Investigation of water-soluble vitamin analogs as treatment for bacterial, parasitic diseases, and cancer

Principal applicant: Clifford Bryant, MS, research specialist, Department of Pharmaceutical Chemistry

Award funding: $25,000

The challenge:

Water soluble vitamins are universal and well understood in living systems. Many vitamins and their biosynthetic intermediates are involved in several different pathways. By making slight modifications in vitamin structure, changes in mechanism as well as pathway flux may be achieved. The resulting compounds would be added to the Small Molecule Discovery Center (SMDC) screening library and tested routinely against examples of the three cell types and others in a plate-based assay.

SMDC screens allow notation of large numbers of phenotypic changes (things like color, shape, texture, morphology, anatomical and behavioral differences) in the same well. With observed changes, investigators have a preliminary hint about what pathways might be involved. Also, given the similarity to vitamins, solubility, pharmacokinetic and bioavailability concerns are addressed, so development of drug or tool compounds is eased.

The project: The SMDC will make a library of compounds that are close analogs of water soluble vitamins such as B1 (thiamine), B3 (niacin-like), B5 (pantothenic acid) B6 (pyridoxine-like), C (ascorbic acid) and carnitine.

Quantitative analysis of absolute neutrophil count to develop new reference intervals based on genetic ancestry

Principal applicant: Richard Ta, student, PharmD degree program

Award funding: $2,000

The challenge: Benign Ethnic Neutropenia (BEN) is a condition where lower than normal neutrophil counts are observed in otherwise healthy individuals from certain populations. Globally, it is estimated that 25% to 50% of persons of African descent and some ethnic groups in the Middle East have BEN. BEN is observed in various ethnic groups, while current ANC reference values are primarily based on Caucasian study populations.

Current reference intervals (RI) for Absolute Neutrophil Count (ANC) are not based on ethnicity. ANC results may prompt health care providers to select alternative therapies, delay administration of myelosuppressants, postpone elective surgeries, or prevent recruitment into clinical trials. Therefore, it is important to recognize the impact genetic ancestry and BEN may have on medical decision-making.

Aggregation of genetic ancestry data is increasing the precision of racial and ethnic definitions. UCSF School of Pharmacy Class of 2020 received 23andMe kits and contributed ancestry data to a previous study. The class’ sample population is primarily of Asian descent. This presents a unique opportunity to analyze this racial background for ANC reference values as a pilot study.

The project: The goal of this pilot study is to serve as precedence in developing ANC RIs based on ancestral backgrounds. By capitalizing on previously collected UCSF School of Pharmacy Class of 2020 and anticipated Class of 2021P 23andMe genetic ancestry data, investigators predict to see a difference in ANC values indicative of BEN within this primarily Asian study population.

More

Mary Anne Koda-Kimble Seed Award for Innovation