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ARRA Investments in Cancer Drug Development

Public Health Burden
Cancer is the second leading cause of death in the United States after heart disease. In 2009, it is estimated that nearly 1.5 million new cases of invasive cancer will be diagnosed in this country and more than 560,000 people will die of the disease.

Cancer Drug Development Overview
The improvements in cancer survival seen over the last few decades are, in large part, a result of new and improved treatments, especially drug treatments. Researchers are continuing to develop new drugs, both through “traditional” approaches, in which vast libraries of chemical compounds are tested to find those that have anticancer activity, and through newer approaches, in which drugs are developed that have activity against targets identified by genetic and molecular studies of tumors. Both approaches require the ability to scale up the production of test compounds, as well as intensive preclinical studies to determine the effects of the compounds on the growth of human tumor cells in culture and implanted in animals. A series of ARRA-funded initiatives will accelerate the production and testing of promising compounds.

New Therapeutic Molecules
The goal of this initiative is to improve efficiencies in the production and evaluation of new drug candidates at the Frederick campus to ensure patients in clinical studies will have adequate supplies of test drugs, including biologic agents, natural products, and synthetic compounds:
  • Biologic agents: Difficulties in expanding the production of biologic agents, such as monoclonal antibodies, can limit the availability of these agents to larger populations of patients. Delays in expanding production are often due to the processes necessary to qualify facilities and for producing the agents at additional sites. ARRA funding will allow the Frederick Federally Funded Research and Development Center (FFRDC)1 to expand its production capacity for biologic agents produced originally at Frederick so larger sets of patients can be treated before commercial facilities are approved by the FDA. This expansion of production capacity is particularly important when there is no commercial source for the agents.
  • Natural products: Natural products—substances produced naturally by plants or other organisms—were once the dominant source of new drugs. The commercial sector has de-emphasized the use of natural products, and NIH, therefore, has a unique role in investigating new therapies from these sources. ARRA funding will allow, through contracts,2 the identification of 100 natural product extracts that show sufficient activity to warrant further development toward possible clinical use.
  • Synthetic compounds: The Developmental Therapeutics Program (DTP) has a backlog of approximately 100 synthetic compounds that have shown anticancer activity and are ready for further testing in animal tumor models. Through the same contracts used for natural products development, ARRA funds will reduce the delay in moving these compounds to further testing from 1 year to just 2 months.
In Vitro Screening of Combinations of Chemotherapy Drugs
The DTP supports applied drug development through a program that includes both in vitro and in vivo screening of potential therapeutic compounds. The in vitro screening program initially uses a panel of 60 human cancer cell lines to screen compounds for their ability to reduce cancer cell growth. Typically, the compounds are tested singly in such screens, even though, in clinical practice, drugs are generally used in combination. To integrate this clinical approach earlier in the drug development process, ARRA-funded contracts3 will expand and accelerate in vitro screening of combinations of compounds by establishing a network of collaborative screening laboratories. Another goal is to investigate the molecular basis of intracellular responses to compound-induced perturbations, which should enable the design of combinatorial pharmacologic regimens that independently modulate key signaling pathways, cooperatively block redundancy loops, and/or concurrently target specific types of cancer cells. This work should increase the number of potential cancer drug combinations moved forward from in vitro cell-culture screening to in vivo laboratory animal efficacy and toxicology testing.

In Vivo Screening of Combinations of Chemotherapy Drugs
In the in vivo screening component of DTP’s drug development program, potential therapeutic compounds are tested in mice that bear tumors derived from human cancer cell lines to assess the effects of the compounds on tumor growth and to analyze their toxic effects. This step in drug development is technically demanding and labor intensive, and the establishment of a network of collaborative in vivo screening laboratories (through the same ARRA-funded contracts used in the companion in vitro screening program) will expand access to drug development expertise. As in the case of the in vitro studies, compounds will be tested in a combinatorial fashion to better capture the way they are used in the clinic. The most tangible outcome will be an increase in the number of potential dugs and combinations that can be moved forward into clinical testing.

Information Technology Program for Facilitating Drug Discovery and Development
The use of new software for data acquisition, storage, and evaluation will greatly facilitate the discovery and development of new drugs. ARRA funding will allow the FFRDC4 to accelerate integration of this software.

  1. HHSN261200800001EN01CO-2008-00001, SAIC-Frederick (MD)
  2. N01CM42202, ITTRIResearchInstitute(IL);N01CM42203, andN01CM52201, SRIInternational(CA);N01CM42204, BridgePharmaceuticalCorp.(MD);N01CM52202, UniversityofPittsburgh(PA);N01CM5220, UniversityofTexas(TX);N01CM52205, OhioStateUniversity(OH);N01CM52207, University of Alabama (AL)
  3. N01CM42202ITTRIResearchInstitute(IL);N01CM42203andN01CM52201, SRIInternational(CA);N01CM42204, BridgePharmaceuticalCorp.(MD);N01CM52202, University of Pittsburgh (PA); N01CM52204, University of Texas (TX); N01CM52205, Ohio State University (OH): N01CM52207, University of Alabama (AL)
  4. HHSN261200800001EN01CO-2008-00001, SAIC-Frederick (MD)

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