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Eric Prossnitz, Ph.D. – 2021 Rainforest Innovation Fellow

21-Innovation-FellowThe UNM Rainforest Innovations Board of Directors is honored to present the 2021 Rainforest Innovation Fellow Award to Dr. Eric Prossnitz. This award was created in 2010 to honor annually a University of New Mexico inventor whose body of technologies has generated significant commercialization activities. Based on achievements in new technologies disclosed, patents received, license and option agreements entered into, new companies started and income generated from these technologies, the UNM Rainforest Innovation Fellow Selection Committee evaluates and selects an Innovation Fellow.

Curious by nature, Eric Prossnitz was drawn to a scientific research career which then led him down a path of translating laboratory discoveries into new therapies for patients. With this new goal, backed by an understanding of cellular functions at the molecular level to disease mechanisms at the organismal level, Dr. Prossnitz and his team have identified new drugs that are currently in clinical trials for cancer patients. He also leads an energetic research team of students, fellows, staff and faculty focused on cancer, cardiovascular and metabolic disease with an underlying focus on drug discovery and development. After centering his early studies of chemotactic immune receptor function, Dr. Prossnitz shifted his research focus to understanding the actions of estrogen through a novel receptor, G protein-coupled estrogen receptor. For nearly 18 years, his work has employed pharmacological and genetic approaches to understand this receptor’s roles in health and disease.

As an expert in cell and receptor biology, biochemistry and pharmacology, Dr. Prossnitz has been studying a family of receptors named G protein-coupled receptors (GPCRs) for the past 30 years. GPCRs form a large group (over 800 in humans) of evolutionarily related cell surface proteins that detect molecules outside the cell and activate cellular responses. They represent the largest family of proteins targeted by approved drugs. More than 125 GPCRs are targets for FDA-approved drugs, being the target of about 700 approved drugs. His studies have led to the first clinical trial of a UNM-developed drug, which is led by the UNM Comprehensive Cancer Center.

With continuous NIH funding as a principal investigator since 1994, his work has led to more than $50 million in funding at UNM as PI or Co-PI. He has authored over 220 peer-reviewed articles and reviews, with over 22,000 citations and an h-index of 81. His research has led to the disclosure of 18 technologies at UNM Rainforest Innovations, 8 U.S. issued patents and 3 pending patents.

Dr. Prossnitz received his Ph.D. in biochemistry from the University of California, Berkeley, in 1989, and carried out postdoctoral training at the Scripps Clinic and Research Institute, where he received his first faculty appointment in 1994. In 1997, Dr. Prossnitz was recruited to the faculty of the Department of Cell Biology and Physiology at the University of New Mexico (UNM) Health Sciences Center and in 2015 the Department of Internal Medicine. He has been a program leader at the UNM Comprehensive Cancer Center since 2008, a module lead in the UNM Clinical and Translational Science Center since 2010 and Chief of the Division of Molecular Medicine since 2018. He has also led components of the New Mexico INBRE and Mountain West Clinical & Translational Research Infrastructure Network (MW CTR-IN), serves as the Associate Director of the Autophagy, Inflammation and Metabolism Center (AIM CoBRE), and is the Academic Lead for the ASCEND Accelerator Hub that promotes entrepreneurship and commercialization of university basic and translational science the seven western IDeA states.

An Innovator’s Journey

Growing up in Victoria, B.C. Canada, I was that kid that always took things apart to see how they worked. On rare occasions, I could put my dismantled device back together, with no spare parts left over! In high school I was fortunate to have science teachers and a group of science friends that collectively sparked my interest in the sciences, particularly biology and chemistry. When I started university at the University of Victoria, I was excited to learn there was a field (and degree major) called biochemistry that combined the two areas I was most passionate about. In my first year, I petitioned to take 200 level courses in biochemistry and microbiology, which fascinated me regarding the workings of bacterial cells. My undergraduate senior research project involved HPLC purification and Edman degradation sequencing of ribosomal proteins from archaebacteria, with the goal of understanding their phylogenetic relationship to eubacteria. In my final undergraduate year, one of my professors asked about my plans for graduate school and put me in touch with Giovanna Ferro-Luzzi Ames in the Biochemistry Department at UC Berkeley, where I would go to carry out my PhD investigating bacterial membrane transporters, starting my career of studying membrane proteins. This was an exciting time, having friends in the labs of pioneering researchers such as Randy Schekman, Robert Tjian, Gerry Rubin, Bruce Ames and Howard Schachman, not to mention the fun associated with Department Retreats at Asilomar and class outings to Stinson Beach.

During the last year of my graduate career, I began to think about how to expand my knowledge and skills to study eukaryotic cells, as I hoped that would lead to work more directly applicable to human health. One Saturday morning, I received a totally unexpected call from Dr. Charles (Charlie) Cochrane from Scripps Clinic and Research Foundation. A post-doc from my lab in Berkeley had given him my name after he moved to Scripps. Charlie explained he was starting a molecular biology group with the initial goal of cloning members of the family of neutrophil chemoattractant receptors. At that time only a small number of these G protein-coupled receptors (GPCRs) had been cloned and sequenced. As one of the founders of Scripps in the 1960s, he led a diverse group of researchers that studied various aspects of neutrophil biology. A month later I was visiting Scripps, giving a seminar and meeting the lab heads within this group, including Gary Bokoch, Richard Ulevitch and a biophysicist named Larry Sklar. I joined a nascent molecular biology group led by recent recruit Richard Ye in the fall of 1989 and began to learn about expression cloning approaches. Although we were soon scooped in the cloning of our primary two receptor targets we were attempting to clone, we did subsequently clone other chemoattractant family receptor members. Although cloning might seem like an end, it really represents an enablement of studies for structure-activity relationships at the amino acid level of a protein. This began long term studies of the N-formyl peptide receptor (FPR), and the generation of a large number of site-directed mutants.

It was at this time that I met Voula Gerolimatos, who worked as a technician for Gary Bokoch in the bay next to me along with three new post-docs. The five of us joined an intramural volleyball team, sailed on Mission Bay, experimented in cooking at weekly dinners and camped at Joshua Tree. Voula and I were married less than a year later in 1990! That same year in fact, not that long after I arrived at Scripps, I learned that one of the group leads, Larry Sklar, was relocating to New Mexico (what seemed at the time a perplexing choice). In the early 1990s, as I was creating collections of FPR mutants, to take advantage of fluorescent methods that Larry had developed to study FPR function, I travelled to UNM to characterize my mutants, my first exposure to the Land of Enchantment. Having been supported by a post-doctoral fellowship from the Human Frontiers Science Program, in 1993 I applied for my first NIH funding as a PI through the R29 mechanism. I received the best percentile score I have ever received and thought “Well, that wasn’t so difficult”. A couple years later (1996), our first son was born and Voula and I started thinking about where we wanted to raise a family as I thought about the type of institution at which I wanted to be a faculty member. As I was applying for positions, Larry Sklar told me that UNM was building a new cancer research building and hiring a cadre of new faculty supported by an HHMI Medical School Development Grant (written by Cheryl Willman). In December 1997, we (Voula, our sons Alex and Michael (in utero), a dog, a cat and I) drove to Albuquerque to start a new phase of our lives.

As I began to set up my lab in the brand-new Cancer Research Facility in 1998, battling alternating artic and sauna temperatures, Larry Sklar was organizing a Bioengineering Research Partnership Grant Application to develop high throughput cytometry, in which I participated, along with Bruce Edwards and Gabriel Lopez from the School of Engineering. During the course of this grant, Tudor Oprea and Cristian Bologa joined UNM, bringing their expertise in cheminformatics. Then, at an Endometrial SPORE grant planning meeting in 2002, Kim Leslie, a recent recruit to OB/GYN, presented a paper that suggested estrogen could mediate rapid cell responses (as opposed to the traditional regulation of gene expression) in cells transfected to express an orphan GPCR (a cloned and sequenced receptor with no known ligand or function), named GPR30. Chetana Revankar, a post-doc in my lab, began to work with this receptor as a side project. We were used to working with fluorescent peptide ligands to measure and track receptors and found the lack of a fluorescent estrogen derivative challenging. Larry then mentioned he had recently met a synthetic organic chemist from New Mexico State University, Jeffrey Arterburn, who provided us with the ideal precursor to make fluorescent estrogens. These would be essential for both demonstrating ligand binding and setting up a screening assay as there were no compounds at that time that selectively bound GPR30. By 2003, Tudor had acquired a library of 10,000 compounds that we contemplated screening. Unfortunately, despite the ongoing development of high throughput screening, our binding assay was not suitable for scaling up to 10,000 compounds.  To help narrow things down, Cristian performed a virtual in silico (i.e., computer-based) screen to rank the 10,000 compounds by their similarity to estrogen. So Chetana started with the first 100 compounds, finding seven in the first screen that moderately reduced binding. The best of these was reproducible and would become G-1 (named for being the first GPR30-binding compound). G-1 turned out to be an agonist (activator) of GPR30, and it was highly selective for GPER, not binding the classical estrogen receptor ER. At this time, very little was yet known about what GPR30 did in vivo, and we needed to study mice with the gene for GPR30 was deleted. Unfortunately, these mice did not exist but Helen Hathaway, with her experience in mouse models, stepped up to the plate.

Over the next years, we would team up with many to explore the roles of GPR30 (renamed GPER in 2007) in normal physiology and disease. Some of these include: Harriet Smith (UNM OB/GYN) to examine GPER expression in endometrial and ovarian cancer, Matthias Barton (University of Zurich) to explore cardiovascular function, Pamela Hall (UNM College of Pharmacy) to examine bacterial infections, Ellen Beswick (UNM Molecular Genetics and Microbiology) to evaluate GPER’s role in colon cancer, Thomas Howdieshell (UNM Surgery) to examine wound healing, all the while continuing to work with Helen Hathaway (UNM Cell Biology and Physiology) in breast cancer and with Jeff Arterburn (NMSU) in compound development. A large number of lab members over the years were critical to these studies, particularly Geetanjali Sharma, who began and now continues metabolic studies, and Matthias Meyer, who was instrumental in cardiovascular studies.

Our original application for a composition of matter patent for G-1 and analogs in 2006 was issued five years later but attempts to translate/commercialize these compounds were hampered by the lack of knowledge regarding the biology of the receptor in vivo. Around 2015, this began to change with our description of the metabolic effects of G-1 and Todd Ridky’s finding at UPenn of the effects of G-1 in melanin production in melanocytes, leading to the unexpected finding of synergistic effects of G-1 with immune checkpoint inhibition in melanoma. The latter resulted in the formation of the company Linnaeus Therapeutics, which has brought G-1 to Phase I clinical trials, while the former has led to the creation of GPER G-1 Development Group, focused on bringing G-1 to the clinic for metabolic disorders, particularly diabetes and obesity. With the initiation of the Phase I clinical trial of G-1 at UNM Cancer Center in October 2019 under the guidance of Carolyn Muller (UNM OB/GYN), this represented the first UNM-discovered compound to progress all the way to first-in-human clinical trials.

As should be more than evident, my personal journey leading to the 2021 Rainforest Innovation Fellow Award would not have been possible without the support, collegiality and hard work of my family, colleagues and collaborators, post-docs, graduate students and staff, UNM leadership, and the leadership and staff at UNM Rainforest Innovations and CoSud Intellectual Property Solutions.