The Staff Assembly will honor her and other award recipients at a ceremony at 5 p.m., Monday, Oct. 4 at the Walter A. Buehler Alumni Center, said Tasha Burr and Danielle Kehler, co-chairs of the Citations of Excellence Committee. McReynolds will receive a $1500 check.
“Our nominee, a 10-year UC Davis employee and longtime scientist with a master's degree in pharmacology and a bachelor's degree in animal science, excels at program management, research administration, and research itself,” wrote nominators Bruce Hammock, forensic entomologist Robert Kimsey and communications specialist Kathy Keatley Garvey.
“She was the lead author of research that may be ‘the missing link' as to why some COVID-19 patients recover and some don't,” they wrote. “Her innovative work on a blood plasma biomarker discovered in hospitalized COVID-19 patients may not only predict the severity of adult respiratory distress syndrome but further research may lead to inhibiting its progression. She initiated the collaborative research to test specialized pro?resolving mediators (SPM) for their therapeutic potential against COVID-19 in a preclinical model at Rutgers University. This ongoing study is expected to provide ‘proof-of-concept' for a novel treatment to COVID-19.”
The trio pointed out that “her expertise includes grants management (applying and budgeting), organizing program outreach, coordinating training grants for trainees funded by a multi-million national grant, and mentoring students, whether in the lab or in the classroom. Our nominee goes above and beyond what is expected of her. Her supervisor says she is ‘the most amazing person I've ever met. For her entire career at UC Davis, she has been a phenomenal asset to the laboratory and campus. In her role in the laboratory, she oversees an accountant who handles the complex budget problems of the federally funded UC Davis Superfund Program Project. This multi-college, multi-principal investigator program has essentially five separate NIH grants, each of which itself is multi-departmental and multi-college supported by three cores.”
In addition, McReynolds also helped establish a community research program on human and environmental health in Northern California with the Yurok Indian Tribe, and a research translation program with several state agencies to identify STEM opportunities between UC Davis and surrounding communities.
Coordinated National Meeting
Hammock, who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center and for nearly four decades has directed the UC Davis Superfund Research Program (funded by the National Institutes of Health's National Institute of Environmental Health Sciences) noted that in 2019-20, McReynolds coordinated the national meeting of the Superfund Programs with multiple state and federal agencies. “She played an integral and critical role in submitting a competing renewal for years 30-35 of the program. This massive effort involved integrating multiple budgets across campus and coordinating with NIH, the campus research office, and multiple colleges.”
“On all of these projects, her knowledge of accounting and grantsmanship, coupled with her personal skills (always congenial and eager to help) proved critical,” Hammock said. “She was involved even to the point of editing specific objectives to make the projects more integrated, which relied on her knowledge as a scientist as well.” This was on top of being office manager for the large Hammock research laboratory involving a team of multiple disciplines.
“During this time, she served as both the lab manager and the accountant/business manager, replacing a retiree,” Hammock noted.
The nominators pointed out that McReynolds is a doctoral candidate (now PhD graduate), wife, mother of two, and a community volunteer. Known for sharing her scientific expertise, she organized a “Science Day” with UC Davis and Davis primary schools; organized speakers for “Meet a Scientist”; judged Davis science fairs; helped struggling high school students with their science projects; and coached the Davis Youth Robotics Team.
“She balances her multiple difficult tasks with skill, efficiency and good humor,” the nominators wrote. “She is always eager to help, even to transporting a colleague's newly eclosed, out-of-season monarch butterfly to an overwintering site in Santa Cruz!”
'Brilliant Researcher and Wonderful Instructor'
Kimsey praised her work in teaching and mentoring students in his animal biology classes. “She has not only made their time and efforts highly productive in the research arena, but provides effective counseling on their career trajectories, how to balance personal life, kids and family with university life,” Kimsey said. “She is not only a brilliant researcher, a wonderful instructor for undergraduates that enter the laboratory, but is a dedicated and caring mentor. Her principal investigator has stated that she is possibly the most amazing person he has ever met. I very certainly concur in all regards.”
McReynolds, who received her doctorate in pharmacology and toxicology in June, initially sought a career as a veterinarian. She received her bachelor's degree in animal science from UC Davis in 1999, and her master's degree in animal science from Washington State University, Pullman, in 2001.
“After receiving a master's degree in animal science, I quickly realized that I had an interest and passion for understanding the roles of nutrition and environment on disease outcomes in both human and animal health,” McReynolds related. “Instead of continuing my research career in animal science, I left to gain experience in development therapeutics for humans and animals. My work in understanding the role of bioactive lipid mediators began in 2006 when I joined Arete Therapeutics, South San Francisco, as project manager to advance soluble epoxide inhibitors through clinical trials for treating hypertension. After leaving Arete, I joined Dr. Hammock's laboratory as a research administrator where I gained important experience in project management, budgeting and grants administration. Once my children were old enough to accommodate the often-inconsistent schedule of laboratory work, I continued my career goals of becoming a PhD scientist.”
McReynolds traced her interest in scientific research to her “formative years in a small town in western Kentucky, cataloging observations of animals in a notebook.”
Understanding the Roles of Lipid Mediators
McReynolds has studied the biological activity of lipid mediators for the past 12 years. “My current efforts focus on understanding the roles of lipid mediators in inflammation especially relating to pain and degenerative disease,” said McReynolds, who is a member of the American Society for Pharmacology and Experimental Therapeutics and the American Chemical Society. “My research focuses on developing tools for use in in vitro and in vivo knockout studies to understand their role in inflammation with a focus on mechanism of pharmacokinetics.”
McReynolds said her “career aspirations are to lead collaborative research programs that will use science to improve overall health outcomes by developing disruptive treatment or diagnostic capabilities to predict early responders/nonresponders to therapies,” she said, adding that “I approach problems and challenges now, not with a pass/fail approach, but with an understanding of how to address the problem at hand.”
“In my career, I strive to make significant contributions in advancing science to understand disease so that there are better treatment options for everyone; I strive to provide encouragement to women struggling to balance a family and career, to lead by example that it is possible to be a mom and scientist; I strive to motivate others, as I have been motivated by my mentors, that their fears are not too big to prevent them from reaching their goals; I strive to create a positive, collaborative work environment. Ultimately, I strive to share my enthusiasm for science and learning as well as unique background to advance a basic understanding of biology that will benefit global health outcomes for all.”
The Staff Assembly's annual awards program provides recognition for individual staff and staff teams “who have demonstrated outstanding achievement that go above and beyond the requirements outlined in their position descriptions.” Staff Assembly presents Individual awards in the categories of innovation, research, service, supervision and teaching; and team awards for project or program staff, office staff, or other similar groups.
A blood plasma biomarker discovered in hospitalized COVID-19 patients may not only predict the severity of adult respiratory distress syndrome (ARDS) but further research may lead to inhibiting the progression, a team of eight University of California researchers announced today.
The UC researchers, primarily from the laboratory of UC Davis distinguished professor Bruce Hammock, found that four compounds in the blood of COVID-19 patients are highly associated with the disease. Their paper, “Plasma Linoleate Diols Are Potential Biomarkers for Severe COVID-19 Infections,” is published as open access in the current edition of Frontiers in Physiology.
ARDS, characterized by fluid build-up in the lungs, is the second leading cause of death in COVID-19 patients, next to viral pneumonia, according to the National Center for Biotechnology Information.
“Different outcomes from COVID-19 infections are both terrifying from a human health perspective and fascinating from a research perspective,” said UC Davis lead author and doctoral candidate Cindy McReynolds of the Hammock lab. “Our data provide an important clue to help determine what impacts the severity of COVID-19 outcomes. Initially, we focused on the immune response and cytokine profile as important drivers in severity, but considering what we now know from our study and others in the field, lipid mediators may be the missing link to answering questions such as why some people are asymptomatic while others die, or why some disease resolves quickly while others suffer from long-haul COVID.”
The compounds, known as leukotoxins and leukotoxin diols, originate from linoleic acid, the body's most abundant dietary fat, said Hammock, who holds a joint appointment in the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center and directs the National Institute of Environmental Health Sciences (NEIHS) Superfund Research Program at UC Davis. “The leukotoxins (also called EpOMEs) are converted to the leukotoxin diols (also called DiHOMES) by the soluble epoxide hydrolase we work on.”
“So the leukotoxins and leukotoxin diols,” Hammock said, “are indicators of respiratory problems in COVID-19 patients as plasma biomarkers. They also present a pathway for reducing ARDS in COVID-19 if we could inhibit the soluble epoxide hydrolase, a key regulatory enzyme involved in the metabolism of immune resolving fatty acids.”
Professor John Imig, director and eminent scholar of the Medical College of Wisconsin's Drug Discovery Center, who was not involved in the study, said: “The COVID-19 pandemic has demonstrated that coronaviruses can have deadly consequences. Lung distress is a major reason for death in COVID-19 patients infected with the coronavirus (SARS-CoV-2). The findings of McReynolds et al. identified lipids called leukotoxin diols in the blood of COVID-19 patients that could act as a biomarker for lung distress. In addition, leukotoxin diols could be responsible for lung distress in COVID-19 patients. Excitingly, this suggest that therapies to lower leukotoxin diols could treat lung distress and prevent death in COVID-19 patients.”
“The findings presented in this paper bring important attention to a role for oxylipin metabolites in COVID-19 infections,” said Professor A. Daniel Jones of Michigan State University's Department of Biochemistry and Molecular Biology and director of the university's Research Technology Facility's Mass Spectrometry and Metabolomics Core. “Most notably, metabolites known as DiHOMEs which have been previously implicated in lung inflammation show promise for their potential to predict outcomes in COVID patients and guide therapeutic, and perhaps dietary interventions beneficial to human populations.” Jones, who was not involved in the study, serves as secretary of the Metabolomics Association of North America.
The UC Davis scientists used clinical data collected from six patients with laboratory-confirmed SARS-CoV-2 infection and admitted to the UC Davis Medical Center, Sacramento, and 44 healthy samples carefully chosen from the healthy control arm of a recently completed clinical study.
The Hammock lab's 50-year research on soluble epoxide hydrolase (sEH) and its inhibitors led the professor to found and direct EicOsis Human Health, a Davis-based company that is developing a potent soluble epoxide hydrolase inhibitor for pain relief. Epoxy fatty acids control blood pressure, fibrosis, immunity, tissue growth, depression, pain, inflammation and other processes.
But more recently, the Hammock lab has turned its attention to using sEH as a means to resolve inflammation associated with COVID-19 and the fibrosis that can follow.
Lipid metabolism researcher Ameer Taha of the UC Davis Department of Food Science and Technology pointed out that linoleic acid is an essential fatty acid present in only small amounts in our evolutionary diets. “In addition to nutritional and structural roles of linoleate, minor linoleate metabolites including the leukotoxin diols (also known as DiHOMEs) regulate a number functions including body temperature, cardiac health and vascular permeability. This study cautions that now with dietary linoleate levels at an all-time high, in periods of high stress as with COVID-19, these regulatory functions may become detrimental.”
The paper is the work of Hammock, McReynolds and Jun Yang of the Department of Entomology and Nematology and EicOsis Human Health; Irene Cortes-Puch of the Department of Entomology and Nematology, EicOsis Human Health, and the Department of Internal Medicine's Division of Pulmonary Critical Care and Sleep Medicine; Resmi Ravindran and Imran Khan of the Department of Pathology and Laboratory Medicine; Bruce G. Hammock of UC Davis Department of Veterinary Medicine, Aquatic Health; and Pei-an Betty Shih of the UC San Diego Department of Psychiatry.
“This study resulted from an exciting collaboration with Imran Khan and Angela Haczku of the UC Davis School of Medicine to identify potential biomarkers for differentiating the severity of COVID-19 diseases,” said Yang, the corresponding author.
The research drew financial support from several National Institutes of Health agencies: National Institute of Environmental Health Sciences (NIEHS) Superfund Research Program and R35 grant, National Institute of General Medical Sciences (NIGMS),and the National Institute of Mental Health (NIMH).
- EicOsis: Developing a New Approach to Treat Pain
- Bruce Hammock: Lifetime Achievement Award from the Chancellor
- Cindy McReynolds Receives Major NIH Training Grant
- Cancer Team's Research Paper Named Journal of Clinical Investigation's Editor's Pick (Includes Bruce Hammock and Jun Yang)
- Bruce Hammock at firstname.lastname@example.org
- Cindy McReynolds at email@example.com or firstname.lastname@example.org
- Jun Yang at email@example.com
“The fast-track process is designed to facilitate the development and expedite the review of new therapies to treat an unmet medical need in the treatment of a serious condition,” said EicOsis founder and CEO Hammock, who holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
“This designation will enable us to have early and frequent communication with the FDA throughout the drug development and review process,” Hammock said, “and this often leads to faster drug approval and patient access.”
The drug candidate, known as EC5026, targets a novel pathway to block the underlying cause of certain types of pain. Described by EicOsis, a Davis-based company, as a “novel, non-opioid and oral therapy for neuropathic and inflammatory pain,” it inhibits the soluble epoxide hydrolase (sEH) enzyme, a key regulatory enzyme involved in the metabolism of fatty acids. UC Davis recently licensed certain patents supporting the underlying technology exclusively to EicOsis.
The FDA granted EC5026, an investigational new drug (IND) clearance in October 2019. It is currently the subject of a Phase 1a clinical trial in healthy human volunteers. Phase 1b clinical trials are scheduled to begin this fall.
Earlier studies showed that the EicOsis-developed inhibitors reduce inflammatory and neuropathic pain in rodents, horses, dogs and cats, and without the addictive effects associated with opioids or multiple side effects of nonsteroidal anti-inflammatory drugs (NSAIDS).
Hammock said the successful fast-track application is the work of three EicOsis team members: clinical scientist Irene Cortés-Puch, a critical care medicine physician and researcher; project manager Cindy McReynolds, a UC Davis doctoral student in pharmacology and toxicology; and vice president of clinical development William Schmidt, who has focused his entire professional career on developing novel pain medicines.
“Without them, we would not have had the fast track,” Hammock said. “They did a superb job.”
“Listening to patient stories and working with pain management specialists has given me an understanding of the urgent need for new pain medications,” said McReynolds. “It's inspiring to work with such an amazing team in addressing this critical problem and the Fast Track status will allow us to advance this potential treatment as quickly as possible.”
Said Schmidt: “FDA's decision to grant the fast track designation to EC5026 is an important milestone in our ongoing efforts to develop a safe and effective new approach for pain management. We look forward to working closely with the FDA to optimize the development of this novel, non-opioid drug candidate for neuropathic pain.”
Dr. Scott Fishman, vice chair of the UC Davis School of Medicine's Department of Anesthesiology and Pain Medicine, who is not involved with EicOsis, commented: “It is not a coincidence that this FDA fast-track designation comes as the United States is addressing the enormous problem of opioid abuse and is seeking safer and more effective treatment for pain. This FDA designation reflects the substantial promise of this new and novel analgesic drug.”
Nearly 16 million Americans suffer from neuropathic pain, according to the National Institutes of Health (NIH). Physicians often prescribe opioids, which can lead to misuse, addiction and intolerance. Alternatively, the EicOsis drug is an effective, non-addictive drug for pain management, Hammock said.
Every day more than 130 Americans die from opioid overdose, according to the National Institute of Drug Abuse. The total economic burden of prescription opioid misuse alone in the United States is estimated at $78.5 billion a year. That includes the costs of health care, lost productivity, addiction treatment, and criminal justice involvement.
“I know my patient is suffering and sadly I know I've gone through everything available to help,” said rheumatologist Laura Carbone, professor and division chief of rheumatology in the Department of Medicine, Medical College of Georgia, Augusta University. “I struggle, we both struggle, to find a way to make today better as we both hope for something better to come that will really help. That is the daily reality of pain.” She is not involved with EicOsis.
NIH has financially supported the discovery and development of EC5026 and its advancement into clinical trials through the Blueprint Neurotherapeutics Network (BPN) of the NIH Blueprint for Neuroscience Research and the NIH's Helping to End Addiction Long-term (HEAL) Initiative.
Hammock, a member of the UC Davis faculty since 1980, received his doctorate in entomology and toxicology from UC Berkeley. Nationally recognized for his achievements, he is a fellow of the National Academy of Inventors, which honors academic invention and encourages translations of inventions to benefit society. He is a member of the U.S. National Academy of Sciences, a fellow of the Entomological Society of America, and the recipient of scores of awards, including the first McGiff Memorial Awardee in Lipid Biochemistry; and the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics.
The UC Davis professor traces the history of his enzyme research to 1969 during his graduate student days in the John Casida laboratory, UC Berkeley. Hammock was researching insect developmental biology and green insecticides when he and colleague Sarjeet Gill, now a distinguished professor at UC Riverside, discovered the target enzyme in mammals that regulates epoxy fatty acids.
“My research led to the discovery that many regulatory molecules are controlled as much by degradation and biosynthesis,” Hammock said. “The epoxy fatty acids control blood pressure, fibrosis, immunity, tissue growth, depression, pain and inflammation to name a few processes.”
The drug candidate, known as EC5026, targets a novel pathway to block the underlying cause of certain types of pain. Described by EicOsis as a “novel, non-opioid and oral therapy for neuropathic and inflammatory pain,” it is an inhibitor to the soluble epoxide hydrolase (sEH) enzyme, a key regulatory enzyme involved in the metabolism of fatty acids. UC Davis recently licensed certain patents supporting the underlying technology exclusively to EicOsis.
Clinical trials are expected to begin this summer. “The clinical trials would be the world's first clinical evaluation of sEH for pain,” said William Schmidt, EicOsis vice president of clinical development, who has focused his entire professional career on developing novel pain medicines. “I am thrilled that we have a drug candidate lacking the side effects of both opioids and non-steroidal anti-inflammatory drugs that can potentially produce lead to an entirely new way to treat chronic pain.”
“Chronic pain is an enormous emotional and economic burden for more than 100 million people in the United States alone,” said Hammock, a UC Davis a distinguished professor who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. He co-founded EicOsis in December 2011 to alleviate pain in humans and companion animals. “The extreme and poorly treated pain that I observed as a medical officer working in a burn clinic in the Army, is a major driver for me to translate my research to help patients with severe pain.”
National statistics show that as many as eight out of every 10 American adults suffer from chronic pain; three out of four patients consider their therapies for pain ineffective; and as many as a third of the opioid-prescribed patients misuse them.
Every day, more than 130 people in the United States die from opioid overdose, according to the National Institute of Drug Abuse. The Centers for Disease Control and Prevention estimates that the total economic burden of prescription opioid misuse alone in the United States is $78.5 billion a year. That includes the costs of health care, lost productivity, addiction treatment, and criminal justice involvement.
“This completes the fundraising for Phase 1 of the clinical development program of this novel pain therapeutic,” said Hammock. “We are particularly pleased that the support came from Open Philanthropy with its history of both financially successful and socially important investments.”
Dushyant Pathak, UC Davis associate vice chancellor for Research and executive director of Venture Catalyst, lauded the achievement. “We are very pleased to see the achievement of this important business milestone by EicOsis,” Pathak said. “It's especially heartening to see the entrepreneurial persistence of Bruce Hammock being recognized by Open Philanthropy.”
Open Philanthropy identifies outstanding investment opportunities and makes grants based on importance, need, and tractability, according to the organization's scientific advisors Chris Somerville and Heather Youngs. They said Open Philanthropy selected the Davis project because the EicOsis drug “may reduce suffering from chronic pain conditions which are severe in both developed and developing nations.”
On its website, http://www.eicosis.com, EicOsis depicts itself as “a privately held company developing a first-in-class therapy of a once daily, oral treatment for neuropathic and inflammatory pain in humans and companion animals.”
“Our orally active compounds stabilize natural regulatory mediators in the body that reduce endoplasmic reticulum stress, which, in turn, appears to cause a variety of chronic diseases,” said EicOsis neurobiologist Karen Wagner. “The EicOsis compounds represent a new mechanism of action that both resolves inflammation and reduces pain.”
EicOsis (pronounced eye-cosis), derives its name from eicosanoid, “the major backbone of chemical mediators in the arachidonate cascade,” said Cindy McReynolds, an EicOsis project manager and a doctoral student in pharmacology and toxicology at UC Davis. “It symbolizes the epoxide group in chemistry, which is key to the anti-inflammatory chemical mediators and where the biochemical target called soluble epoxide hydrolase works.”
The National Institutes of Health (NIH) Blueprint for Neuroscience Research (Blueprint) awarded EicOsis a $4 million grant to advance compounds through Phase 1 clinical trials for diabetic neuropathic pain. A goal of the Blueprint Neurotherapeutics Network is to discover, develop and generate novel compounds that will ultimately be commercialized and benefit humankind.
In addition, EicOsis received support from the NIH's National Institute of Neurological Disorders and Stroke (NINDS), and the support of two small business programs affiliated with the National Institute of Environmental Sciences: the Small Business Innovation Research (SBIR) and the Small Business Technology Transfer (STTR).
“We are fortunate to receive all this support in the development of our oral medication for pain treatment through human Phase 1a trials, and now Open Philanthropy through human Phase 1b trials and beyond,” said Alan Buckpitt, a UC Davis retired professor of veterinary pharmacology and toxicology, and a principal investigator on the grants.
Nationally recognized for his achievements, Hammock is a fellow of the National Academy of Inventors, which honors academic invention and encourages translations of inventions to benefit society. He is a member of the U.S. National Academy of Sciences, a fellow of the Entomological Society of America, and the recipient of scores of awards, including the first McGiff Memorial Awardee in Lipid Biochemistry; and the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics.
Hammock, a member of the UC Davis faculty since 1980, received his doctorate in entomology and toxicology from UC Berkeley. He traces the history of his enzyme research to 1969 during his graduate student days in the John Casida laboratory. Hammock was researching insect developmental biology and green insecticides when he and colleague Sarjeet Gill, now a distinguished professor at UC Riverside, discovered the target enzyme in mammals that regulates epoxy fatty acids.
“My research led to the discovery that many regulatory molecules are controlled as much by degradation and biosynthesis,” Hammock said. “The epoxy fatty acids control blood pressure, fibrosis, immunity, tissue growth, depression, pain and inflammation to name a few processes.”
“Basically, I began by trying to figure out how a key enzyme, epoxide hydrolase, degrades a caterpillar's juvenile hormone, leading to metamorphosis from the larval stage to the adult insect,” Hammock. He asked himself these questions: “Does the enzyme occur in plants? Does it occur in mammals?" It does, and particularly as a soluble epoxide hydrolase in mammals.
"It is always important to realize that the most significant translational science we do in the university is fundamental science,” said Hammock, marveling that “this all began by asking how caterpillars turn into butterflies.”
CBP supports students engaged in pre-doctoral training at the chemistry-biology interface, preparing them for careers in the biomedical workforce. McReynolds is one of four students selected for the 2017-18 CBP training grant program.
“We are very proud of her,” said Hammock, distinguished professor of entomology, UC Davis Department of Entomology and Nematology, who holds a joint appointment with the UC Davis Comprehensive Cancer Center.
A member of the Pharmacology and Toxicology Graduate Group, McReynolds focuses her research on “developing chemical tools to elucidate the biological relevance of chemical compounds (dihydroxy diols) in biological systems.”
Hammock is her major professor. "Cindy has more than 12 years of experience in research and project management, extensive research experience and advanced knowledge of drug development,” Hammock said.
Prior to enrolling in the doctoral program, McReynolds served as the program administrator of UC Davis/National Institute of Environmental Health Sciences Superfund Research Program, directed by Hammock. She is the project manager of EicOsis, a Davis-based company founded by Hammock to develop a small molecule inhibitor to treat pain in humans and animals.
A native of Louisville, KY, McReynolds received her bachelor of science degree in animal science from UC Davis in 1999, and her master's degree in animal science in 2001 from Washington State University, Pullman, Wash., where she was named Outstanding Graduate Student, Teaching Assistant of the Year and recipient of the Dr. Ralph Erb Outstanding Graduate Student Award. Her master's thesis involved how dietary carotenoids inhibit tumor growth.
McReynolds then joined a project development team at Celera Corporation--an Alameda-based company involved in genetic sequencing and related technologies--that led to the selection of Vorinostat, a cancer treatment. She served as a team leader of the Tumor Development Team at Celera, tasked with developing new models of drug-resistant cancer and analyzing newly generated data from the Human Genome Project to identify new cancer therapies.