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Angela Wandinger-Ness, Ph.D. – 2019 STC.UNM Innovation Fellow

Innovation Fellow Wandinger-NessPassionate about science and education, Dr. Wandinger-Ness is motivated by sleuthing out disease mechanisms and translating discoveries into better or new therapies.  In the cancer arena, she and her team have identified new uses for known drugs and are evaluating the benefits for ovarian cancer in patient trials. She leads a vibrant research team that includes students and fellows focused on ovarian cancer and kidney disease. In the area of kidney disease she has elucidated the mechanisms underlying autosomal dominant polycystic kidney disease and relationships to oral-cranio-facial disease. Her current work includes developing strategies for kidney regeneration through the use of stem cells and decellularized scaffolds.

Dr. Wandinger-Ness received her Ph.D. in biochemistry at the University of California, Los Angeles, and completed postdoctoral training at the European Molecular Biology Laboratory in Heidelberg, Germany. Her first faculty appointment was at Northwestern University. Since 1999, Dr. Wandinger-Ness has been on the faculty in the Department of Pathology at the UNMHSC and a member of the UNM Comprehensive Cancer Center.

She holds awards for teaching and research; has authored over 90 peer-reviewed articles and reviews; and has disclosed 19 technologies, received six U.S. issued patents and has six pending patents while at UNM. Her laboratory has been extramurally funded since 1993 through NIH, NSF (including a prestigious CAREER award) and a variety of private foundations totaling 39 grants as PI and $23 million dollars in direct costs. Dr. Wandinger-Ness is an elected fellow of the American Association for the Advancement of Science, served as a visiting professor at the Max-Planck Institute for Molecular Physiology in Dortmund, Germany, and a research ambassador for the German Academic Exchange Program. She is the recipient of a Women in Technology Award and is a five-time STC Innovation Awardee.

An expert in cell biology and protein biochemistry, Dr. Wandinger-Ness has been studying enzymes called GTPases for nearly 30 years.  GTPases are molecular switches that control cell behavior, regulating how cells break down, organize, move around and attach to one another.

GTPases have long been recognized as important targets for developing new drugs.  Ras proteins are the key targets in cancer therapeutics development, since mutations in Ras proteins have implications in more than 30% of human cancers. In addition, other small GTPases in the Ras superfamily, such as Rac and Rho subfamilies, play a role in cancer progression and metastasis. Rac1 is a signaling protein and is classified as an oncoprotein because it mutates and dysregulates in many cancers. Rac1 is associated with poor prognosis and drug resistance in ovarian, breast, colon, and other cancers.  In ovarian cancer, Rac1 is overexpressed in more than 50% of patients.  It is a key but unexploited therapeutic target for cancer.

Dr. Wandinger-Ness and her team discovered that a component of the drug Ketorolac (marketed as Toradol®) acts on GTPases in ovarian cancer cells to keep the cells from growing and spreading.  Ketorolac has been used to relieve pain after surgery since the FDA approved it in the 1970s.  Dr. Wandinger-Ness found that the drug had a huge survival benefit for ovarian cancer patients who were given ketorolac for pain after surgery.

The drug has two components:  one component of the drug, S-ketorolac, is the pain reliever; the other component, R-ketorolac, wasn’t known to have any activity, that is, until the UNM team discovered its true potential as an anti-cancer drug.  Dr. Wandinger-Ness established R-ketorolac as a Rac1 and Cdc42 (a Rho GTPase) inhibitor and showed their therapeutic benefits for ovarian cancer patients.

The STC.UNM Board of Directors is honored to present the 2019 STC.UNM Innovation Fellow Award to Dr. Angela Wandinger-Ness.  Below, in her own words, Dr. Wandinger-Ness recalls her career accomplishments and collaborations.

Sandra Begay
Chair
STC.UNM Board of Directors

An Innovator’s Journey

Science was always a first love for me. Inspired by my father, Lothar Wandinger, who received his PhD in physics at the University of Munich and my mother, Hella Wandinger, who worked in a medical laboratory, I conducted early science fair projects under their guidance.  I still remember the wonder of how different blood cells stained with hematoxylin and eosin could be distinguished under the microscope. Spurred on by an intensive biology class at Long Branch Junior High School in New Jersey, I continued to pursue my curiosity and passion for science and, in high school, was the recipient of a Bausch and Lomb Honorary Science Award. Growing up in an enclave of German physicists and their families, who had been recruited to the US by the Department of Defense in the late 1950s/early 1960s, I also grew up bilingual and added languages to my repertoire along the way.

As a freshman at the University of Massachusetts, Amherst, I first elected a major in biology with a focus on zoology.  By my sophomore year, however, I was captivated by a new undergraduate major being offered in biochemistry. Membrane biology was a hot topic at the time with the 1972 groundbreaking study on the fluid-mosaic model to describe the structure of cell membranes published by Singer and Nicholson. I was, therefore, ecstatic about the opportunity to work in the laboratory of Dr. Bruce Jacobson whose love of science was infectious and who welcomed undergraduates. My interests quickly turned to studies of membrane biology, particularly how membranes became notably more fluid in cancer cells and could be purified using polylysine-coated beads. Reflecting back on these early experiences makes me smile to think how they may have influenced my life and scientific journey coast-to-coast, across five US states and many European countries, ultimately leading me in 1999 to the “Land of Enchantment” with a faculty appointment in the Department of Pathology at the University of New Mexico.

Fatigued with formal coursework after graduating with a Bachelor of Science and wanting a more immersive science experience, I took a year off from school. I moved from Massachusetts to the University of Maryland, Baltimore County, which had just recently opened its doors to many students and new faculty. I joined the Laboratory for Chemical Dynamics, led by Dr. Donald J. Creighton, and, after a year in the lab, experienced the thrill of publishing my first research article in FEBS Letters. Under Creighton’s patient tutelage, I gained expertise in enzymology and in techniques to measure enzymes precisely to determine the mechanisms of their action. Dr. Creighton, a California native, had received his PhD in the Department of Chemistry and Biochemistry at UCLA before moving eastward. “California Dreamin’” provoked me to pursue my own graduate studies in the very same department as my former mentor.

It was a joyous time to be in science, extending unlimited opportunities, it seemed, to grow and learn and discover. The 1980 entering graduate class became fast friends, working and playing hard. Intramural and beach volleyball, inner-tube water polo, barbeques on the beach, trips to Hawaii, and road trips to explore the Canadian Rockies and ski the mountains of California and Utah are among many fond memories. However, the fondest memory of all is meeting a California boy and the love of my life, Scott Ness, PhD. From our meeting as first-year graduate students through our exchange of wedding vows in 1984 to today, Scott has been my steadfast and biggest champion through the years.

Electing to join the UCLA laboratory of Dr. Richard L. Weiss, Scott and I teamed up to dissect the enzymes involved in the biosynthesis of arginine in the bread mold, Neurospora crassa. My interest in protein biochemistry and Scott’s interest in the emerging field of molecular biology were complementary. With PhDs in hand, we pursued postdoctoral fellowship appointments at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany. Supported by F32 National Research Service Awards from the National Institutes of Health (NIH), Scott embarked on his 30+ year devotion to unveiling the secretive functions of the Myb oncogene in hematologic to colorectal to adenoid cystic carcinoma. I stayed true to my protein biochemistry roots and expanded my expertise to cell biology.

Working as a fellow at the EMBL with Dr. Kai Simons and other giants in cell biology, along with many ambitious postdoctoral fellows drawn from all corners of the world was another truly pivotal time. At the EMBL, if you could dream it, you could do it. Many scientific and personal relationships forged there have lasted a lifetime. One of the first confocal microscopes was built by physicists collaborating with biologists on site; this collaboration yielded unprecedented 3-D views of kidney epithelia by my longstanding friend and colleague Dr. Robert Bacallao. At the EMBL, I developed, along with fellow scientist Dr. Mark Bennett, a perforated cell system that, with the aid of specially coated magnetic beads, allowed the purification of microscopic cell vesicles carrying cargo to the cell membrane. The studies demonstrated for the first time that proteins destined for the surface of cells that line all body surfaces (epithelia) were packaged into distinct carriers inside the cell and directly delivered to distinct apical and basolateral cell membrane domains. The relevance of the finding relates to how epithelia maintain their barrier function between the outside world and protect the inner body from environmental exposures. Disruption of this normal architecture underlies many diseases including cancer. The work hearkened back to the early days of isolating membranes with polylysine beads and inspired similar breakthroughs in studies of yeast cell biology. The importance of the many ongoing studies into cell membrane transport at the time (1986-1991) is underscored by Nobel Prizes awarded in 1999 and 2013 to cell biology leaders for the zip codes and machinery regulating vesicle transport.

Returning stateside with two babes in arms in 1991, the Wandinger-Ness and Ness duo set up our own laboratories at Northwestern University in the Biochemistry, Molecular Biology, and Cell Biology Department (now Northwestern’s Department of Molecular Biosciences). Here I embarked on new studies of GTPase enzymes and began my 30-year odyssey of pursuing basic and translational science with disease relevance. Working with pathologist Dr. Frank Carrone and nephrologist Dr. Robert Bacallao at the Northwestern University Feinberg School of Medicine, I began teasing out the cell and molecular pathways that go awry and give rise to autosomal dominant polycystic kidney disease. After a successful start with eager undergraduate and graduate students joining the lab, publications, and grant awards from the National Science Foundation (NSF) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), I was again captured by the allure of the West. Persuaded by UNM Pathology Chair, Dr. Mary Lipscomb, and prospective colleagues Drs. Janet Oliver, Cheryl Willman, Bridget Wilson and Laurie Hudson, the Wandinger-Ness/Ness family moved to New Mexico in 1999 to accept Howard Hughes Medical Institute-supported faculty appointments at the UNM School of Medicine.

Twenty years at the University of New Mexico have brought many new opportunities. Especially cherished are the many collaborations that have advanced the success of young scientists and led to strategies for kidney repair/regeneration and the development of new therapeutic interventions for ovarian cancer. The ovarian cancer interventions center on blocking enzymes known as GTPases. GTPases act as switches that control all aspects of cell physiology from cell growth to cell adherence to cell death pathways. Targeting GTPases with drugs and other small molecules affords a unique opportunity to modify cell behaviors and, for example, block tumor growth and metastasis.

Transdisciplinary collaborations among physician scientists Sarah Adams, Carolyn Muller, and Teresa Rutledge; pharmacologist Laurie Hudson; epidemiologist Linda S. Cook; biophysicists and flow cytometry experts Tione Buranda and Larry A. Sklar; chemists Jeffery B. Arterburn, Jennifer Golden and Jeffrey Aubé; and computational experts Tudor I. Oprea and Oleg Ursu led to approximately 44 issued patents and 14 pending patent applications that are UNM-related. All patents and submissions were facilitated by the dedicated support of staff at STC and legal counsel Cosud Intellectual Property Solutions. The patents arising from these collaborations center on new technology for high throughput screening for GTPase targeted drugs, rapid measurement of GTPase activity, and new classes of molecules with applications for treating cancer and other diseases.

A small clinical trial in ovarian cancer patients was supported by the UNM Comprehensive Cancer Center, a grant from the Department of Defense Congressionally Directed Medical Research Programs (DOD CDRMP), and gap funding from STC. The outcomes demonstrated a repurposed drug that was first identified through unbiased screening had efficacy in neutralizing the targeted GTPases. Furthermore, a retrospective analysis of patients who received the drug for its clinically indicated use showed a profound survival benefit.  A licensing agreement with Revere Pharmaceuticals, led by UNM chemistry alumnus, Robert Silverman PhD, JD, is forging a pathway to further drug development and translation to the clinic. Finally, and most important to the success of this work, are the many emerging scientists who were part of the team and named on patents while en route to their own independent careers.

These achievements and my receiving the 2019 STC.UNM Innovation Fellow Award would not have been possible without an entrepreneurial spirit and the support of my dear family, faculty colleagues, staff and trainees.