DAta | National Center for Advancing Translational Sciences

ID	Title	Body
467	Small Molecule Combinations for Basic and Translational Studies	Multicomponent/combination drug therapies have found tremendous clinical utility. Coincidentally, the down-regulation of two targets or pathways offers a means to bypass pathway redundancies and/or causes a synergistic cellular response that is greater than either agent can accomplish individually. Conditions ranging from CNS disorders to infectious diseases have utilized drug pairings and the standards-of-care for diseases such as AIDS and cancer, in particular, now rely heavily on drug combinations. The discovery of drug combinations, however, is often the result of clinical speculation or trial-by-error strategies that result in a preponderance of failures. When discovered, however, the synergy of two targeted therapies can yield spectacular results. We have spearheaded the development of an advanced small molecule library containing high-value small molecule tools, chemical biology probes, and approved and candidate drugs for screening in matrix format. Pilot studies have been initiated in several cancer lines, and an experimental flow that defines single agent IC50 values followed by 4X4 matrix assessment of active agents, followed by 10X10 matrix assessment of agent combinations with putative synergy, has yielded a high-throughput strategy for defining novel pharmacological combinations. Lead Collaborator National Cancer Institute Lou Staudt, M.D., Ph.D. Public Health Impact This program offers researchers access to a screening methodology capable of identifying new drug-drug combinations for deciphering overlapping pathways in systems biology and potential clinical examinations. Outcomes In progress.
466	A BODIPY Conjugate of the BCR-ABL Kinase Inhibitor Nilotinib	Tasigna® (AMN107, Nilotinib) is a recently approved BCR-ABL kinase inhibitor for the treatment of drug-resistant chronic myelogenous leukemia (CML). The efflux of tyrosine kinase inhibitors by ATP-binding cassette (ABC) drug transporters, which actively extrude the drugs out of the cells by utilizing ATP as energy source, has been linked to the development of drug resistance in CML patients. In collaboration with the Ambudkar lab (NCI), we designed and characterized a fluorescent derivative of Tasigna to study its interaction with two major ABC transporters, P-glycoprotein (Pgp) and ABCG2, in in vitro and ex vivo assays. The BODIPY® FL Tasigna inhibited the BCR-ABL kinase activity in K562 cells and was also effluxed by Pgp- and ABCG2-expressing cells in both cultured cells and rat brain capillaries expressing Pgp and ABCG2. Further, we propose that BODIPY® FL Tasigna can potentially be used as an in vivo probe to study Tasigna in imaging Pgp and/or ABCG2 expressing cancer cells and other preclinical studies. A similar approach may be used to study whether a given TKI is transported by Pgp or ABCG2. It could also be adapted for use in in vivo imaging studies to assess the accumulation of xenobiotics in the brain that are transported by Pgp or ABCG2. Lead Collaborator National Cancer Institute Suresh Ambudkar, Ph.D. Public Health Impact This study describes a fluorescent conjugate of the drug Tasigna and utilizes this novel agent to demonstrate that this drug is transported by Pgp and ABCG2. Publication Shukla S, Skoumbourdis AP, Walsh MJ, et al. Synthesis and characterization of a BODIPY conjugate of the BCR-ABL kinase inhibitor Tasigna (nilotinib): evidence for transport of Tasigna and its fluorescent derivative by ABC drug transporters. Mol Pharm, 2011;8(4):1292-1302. Outcomes The BCR-ABL inhibitor Tasigna is a substrate for drug transporters.
465	CTI Frequently Asked Questions	What is the collaboration between NIH and Pfizer? How will the CTI model work at NIH? When will NIH intramural investigators have the opportunity to submit CTI pre-proposals? What types of CTI projects are of interest for further development? Are Pfizer scientists going to work at NIH? Under what mechanism will NIH intramural investigators work with CTI? Who will own the intellectual property (IP) discovered through this project? If Pfizer commercializes a compound produced through this collaboration, how will NIH receive compensation? Who do I contact if I want to submit a pre-proposal? What is the collaboration between NIH and Pfizer? NCATS has entered into a research collaboration under a cooperative research and development agreement (CRADA) with Pfizer’s Centers for Therapeutic Innovation (CTI) to involve intramural research programs at the National Institutes of Health (NIH). Pfizer is bringing its drug development expertise to complement NIH’s research. The program is managed by Pfizer and NCATS via a joint steering committee. CTI is part of Pfizer’s Worldwide Research & Development division. CTI partners at academic medical centers, disease foundations and NIH aim to translate promising science into clinical candidates more quickly. CTI was founded on a collaborative model, with shared decision making and aligned incentives. The CTI model features the first NIH-wide biologics initiative that NCATS will coordinate on behalf of all NIH intramural researchers. The goal is to identify biologic compounds with a pathway or target of interest to NIH and to Pfizer, then attempt to move these compounds into the clinic rapidly to establish proof-of-mechanism. This agreement does not preclude NIH researchers from working with other biopharmaceutical partners. How will the CTI model work at NIH? Through this collaboration, NIH’s intramural scientists will have the opportunity to respond to CTI calls for proposals two times each year. A joint steering committee composed of members from NIH and Pfizer will review submissions. If selected, the NIH intramural investigator will receive access to Pfizer’s drug development expertise and publishing rights — as well as a dedicated project team to help investigate the target or pathway. The call for proposals is part of CTI’s established process to identify research projects. NIH investigators are invited to participate in CTI calls for proposals alongside academic medical centers within CTI’s network of partners. NIH investigators can submit their first pre-proposals under this partnership for targets that are tractable with biologics (i.e., surface proteins, secreted proteins). The steering committee will make decisions based on ability to demonstrate a strong link from targeted pathway to disease, ability to address unmet medical needs, and ability to show a path to proof-of-mechanism in humans. If selected, a team of scientists from CTI and NIH will work together to submit a full proposal and project plan to advance the research. The number of projects will depend on the merit of the individual research proposals submitted, as evaluated by the steering committee, and the resources available. When will NIH intramural investigators have the opportunity to submit CTI pre-proposals? Pfizer’s CTI program has two calls for proposals each year. Learn more about the CTI call for proposals. What types of CTI projects are of interest for further development? Each call for proposals may contain different areas of therapeutic focus. Review the call for proposals to explore the types of projects appropriate for CTI. Are Pfizer scientists going to work at NIH? The agreement allows the flexibility for scientists from both organizations to work at each other’s facilities. Under what mechanism will NIH intramural investigators work with CTI? In coordination with the NIH Office of Technology Transfer and the Office of the General Counsel, NCATS has negotiated a NIH-wide “umbrella” cooperative research and development agreement (CRADA) for approved NIH CTI projects. Coordinate with your Institute or Center’s technology transfer office and technology development coordinators to learn more about the terms and conditions of the NIH-Pfizer CTI CRADA. Who will own the intellectual property (IP) discovered through this project? If Pfizer commercializes a compound produced through this collaboration, how will NIH receive compensation? Pfizer has the first right of refusal to exclusively license clinical probes and other IP developed under the NIH-Pfizer CTI CRADA. However, if Pfizer decides not to license a jointly developed clinical probe, NIH has the option of licensing that probe to another company. Research rights are not compromised by this collaboration. Should Pfizer decide not to move forward with a project, NIH still owns all the background IP that it brought to the partnership, and the investigator may continue his or her research independently from CTI. Who do I contact if I want to submit a pre-proposal? NIH investigators should contact their NIH Institute or Center’s technology transfer office (TTO) to submit a pre-proposal. If TTO staff have any questions about the process, they can contact NCATS or Manjula Donepudi, Ph.D., at Pfizer CTI for more information.
464	Robert I. Tepper, M.D. (February 2017)	Robert I. Tepper, co-founder of Third Rock Ventures, focuses on the formation, development and scientific strategy of Third Rock’s portfolio companies as well as actively identifies and evaluates new investments. Dr. Tepper also assumes active leadership roles in Third Rock’s portfolio companies, functioning as chief scientific officer through the first 12–18 months post launch. Prior to joining Third Rock, Tepper was president of research and development at Millennium Pharmaceuticals and was vital in its expansion from a drug discovery company to a fully integrated biopharmaceutical company. Prior to joining Millennium, Tepper co-founded Cell Genesys/Abgenix. Currently, Tepper serves as an adjunct faculty member at Harvard Medical School and Massachusetts General Hospital and is an advisory board member of several leading health care institutions, including the Partners HealthCare Center for Personalized Genetic Medicine, Harvard Medical School and Tufts Medical School. Tepper earned his medical degree from Harvard Medical School.
463	Scott J. Weir, Pharm.D., Ph.D. (February 2017)	Scott J. Weir is director of the Institute for Advancing Medical Innovation (IAMI) at the University of Kansas. IAMI conducts product development-focused translational research on products with clear paths to market and assists the university and the region in advancing medical innovations technologies through product development and commercialization-focused decision points, to create and enhance product value proposition. IAMI is establishing and executing projects through high-performance collaborations with industry, academia, government and disease philanthropy organizations. Weir co-leads one of four cancer research programs within the University of Kansas Cancer Center and also serves as associate director of translational research. Weir’s specific areas of expertise are in clinical pharmacology, pharmacokinetics, biopharmaceutics, and developing innovative approaches to lead optimization and early drug development. He has built a reputation of being innovative in bridging the "Valley of Death" through high-performance public-private partnerships as well as repurposing approved drugs and rescuing abandoned drugs. Weir received his doctorate in pharmacokinetics and biopharmaceutics from the University of Nebraska Medical Center and his Doctor of Pharmacy from the University of Nebraska College of Pharmacy.
462	Robert J. Beall, Ph.D. (February 2017)	Robert J. Beall, has been with the Cystic Fibrosis (CF) Foundation for more than 30 years and currently serves as president and CEO. Beall began his tenure as executive vice president for medical affairs, and for the past 18 years, he has served as president and CEO. Prior to joining the CF Foundation, Beall was on the medical school faculty of Case Western Reserve University in Cleveland, Ohio, and at NIH, where he managed a large portion of the agency’s cystic fibrosis program. Under Beall’s leadership, the CF Foundation has become one of the most respected voluntary health organizations in the country and is recognized for its innovative approaches to bringing new therapies to patients with the disease. The creation of an innovative research centers program in the 1980s (the Research Development Program) attracted many leading institutions and first-rate scientists to the CF research effort. This collaborative network contributed to the identification of the CF gene in 1989. Since that time, the focus has been on translating knowledge about the gene and the basic defect into the development of novel CF treatments. In 1998, the CF Foundation launched its ground-breaking Therapeutics Development Program, a unique coalition between industry, academia and the CF Foundation that is directed at the discovery and development of additional approaches to CF drug discovery and development. As a result of the pioneering business model of the CF Foundation, there are currently nearly 30 potential CF therapeutic products in the development pipeline, and the prospects for a cure and control for cystic fibrosis have never been higher. Beall received his doctorate in biochemistry from the State University of New York at Buffalo.
460	Victoria G. Hale, Ph.D. (2015)	Victoria G. Hale is the founder and CEO of Medicines360, a hybrid nonprofit/for-profit pharmaceutical company that combines a nonprofit mission with a financially sustainable business model, enabling cross-subsidization of medicines for the underserved. In addition to Medicines360, Hale also founded and served as CEO of OneWorld Health, the first nonprofit pharmaceutical company in the United States, where she currently serves as chair emeritus. Under her leadership, the organization developed a new cure for visceral leishmaniasis, developed a platform technology to reduce the cost of malaria drugs by more than 10-fold and is developing an anti-secretory drug to use with oral rehydration therapy for cholera. Hale has served as an advisor to numerous national and global health organizations and to various professional committees. Her honors include receiving the President’s Award of Distinction from the American Association of Pharmaceutical Scientists and The Economist’s Social and Economic Innovation Award. She is recognized internationally as a social entrepreneur by the Skoll and Schwab Foundations as well as Ashoka. Hale is a member of the Institute of Medicine and a MacArthur fellow. She earned her doctorate from the University of California, San Francisco, where she maintains an adjunct associate professorship in biomedical engineering and therapeutic sciences.
459	Louis J. DeGennaro, Ph.D. (February 2017)	Louis J. DeGennaro is president and chief executive officer of the Leukemia & Lymphoma Society (LLS). DeGennaro has served as interim president and CEO of LLS since February 2014 and leads the operations of this $300 million cancer patient advocacy agency with headquarters in White Plains, New York. A critical member of the LLS executive leadership team, he joined LLS in 2005 and was named chief mission officer in 2009, with responsibility for leadership of LLS's mission functions of research, patient access, education, public policy and advocacy. DeGennaro is recognized as the key architect of LLS's cures and access agenda to help save lives of blood cancer patients and the LLS Therapy Acceleration Program® - a venture philanthropy endeavor that defined the role of nonprofit organizations in supporting drug discovery and development with the biotechnology industry. DeGennaro has more than 25 years of research, drug development and executive management experience in academic and private-sector settings. He received his doctorate in biochemistry from the University of California, San Francisco, and conducted his postdoctoral research at Yale University School of Medicine. His previous academic appointments include research group leader at the Max Planck Institute in Munich, Germany, where his laboratory was among the first to clone genes expressed exclusively in the nervous system, and associate professor of neurology and cell biology at the University of Massachusetts Medical School. DeGennaro’s private-sector positions include senior director of molecular genetics at Wyeth Pharmaceuticals in Princeton, N.J., where his department contributed to the development of pantoprazole (Protonix®) to treat acid reflux disease, Effexor (Venlafaxine®) for anxiety and depression, and Mylotarg® for leukemia; executive vice president for research and development at SynX Pharma, Inc., in Toronto, Canada, where he was responsible for the development of a point-of-care diagnostic test for congestive heart failure; and research manager at Streck, Inc., in Omaha, Nebraska, where he helped develop a diagnostic test for HIV/AIDS approved by the Food and Drug Administration.
458	Margaret A. Anderson, M.A. (February 2017)	Margaret A. Anderson is executive director of FasterCures/The Center for Accelerating Medical Solutions, an "action tank" working to improve the medical research system — to speed up the time it takes to get important new medicines from discovery to patients. She defines the organization's strategic priorities and positions on key issues, develops its programmatic portfolio, and manages its operations. In her role, she helps bring sectors together to facilitate collaboration and ensures policies are in place to promote medical progress. In 2011, the Clinical Research Forum recognized Anderson with an award for leadership in public advocacy, a testament to the positive impact of her leadership and FasterCures' vital role in improving the medical research system. Anderson is president of the Alliance for a Stronger Food and Drug Administration, and she co-chairs the eHealth Initiative's Council on Data and Research. She served as a board member of the Council for American Medical Innovation and the Coalition for the Advancement of Medical Research, she currently is a board member of the Prostate Cancer Foundation Government Affairs Committee and the Institute of Medicine's Forum on Drug Discovery, Development and Translation. She joined FasterCures after five years at the Academy for Educational Development, where she was the deputy director and a team leader in the Center on AIDS & Community Health. Prior to that, Anderson was program director for the Society for Women’s Health Research, health science analyst at the American Public Health Association, and an analyst and project director at the Congressional Office of Technology Assessment. Anderson holds a bachelor's degree from the University of Maryland and a master's degree in science, technology and public policy from George Washington University's Elliott School of International Affairs.
457	Mary L. Disis, M.D. (2015)	Mary L. (Nora) Disis is a professor of medicine and adjunct professor of pathology and obstetrics and gynecology at the University of Washington (UW) and a member of the Fred Hutchinson Cancer Research Center (FHCRC). She is the associate dean for translational science in the UW School of Medicine. Disis received her medical degree from the University of Nebraska Medical School and completed a residency and chief residency in internal medicine at the University of Illinois at Chicago. She completed her fellowship in oncology at UW/FHCRC. Disis is an expert in breast and ovarian cancer immunology and translational research. She is one of the pioneering investigators who discovered that HER-2/neu is a tumor antigen. Her work has led to several clinical trials that evaluate boosting immunity to HER-2/neu with cancer vaccines. Disis is a member of Alpha Omega Alpha and the American Society of Clinical Investigation. She is the deputy editor for translational oncology for the Journal of Clinical Oncology and is a member of several committees and task forces for the American Society of Clinical Oncology and the American Association for Cancer Research. She also is the director of the Institute of Translational Health Sciences and of the Center of Translational Medicine in Women’s Health at UW. Her multifaceted research program within the Tumor Vaccine Group includes the discovery of new antigens for breast and ovarian cancer and the development of vaccine and cellular therapy targeting those antigens.

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