© 2000 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 28, 55-57,
2000
© 2000 Oxford University Press
Role of the National Cancer Institute in Acquired Immunodeficiency Syndrome-Related Drug Discovery
Presented at the Third National AIDS Malignancy Conference.
Affiliation of authors: E. A. Sausville, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD; R. H. Shoemaker, Screening Technologies Branch, Developmental Therapeutics Program, National Cancer Institute-Frederick, Frederick, MD.
Correspondence to: Robert H. Shoemaker, Ph.D., Screening Technologies Branch, Bldg. 440, National Cancer Institute-Frederick, Frederick, MD 21702-1201 (e-mail: shoemaker{at}dtpax2.ncifcrf.gov).
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INTRODUCTION |
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 Top Introduction Program ReviewsCurrent Resources for Drug...Future DirectionsNew Initiatives in Drug...References |
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The primary role of the Developmental Therapeutics Program of the National Cancer Institute (NCI) is to facilitate drug discovery by the extramural cancer and acquired immunodeficiency syndrome (AIDS) research communities. This role is accomplished in a variety of ways through grants programs, web-based informatics, pro vision of chemicals and natural product extracts, and screening services that will be described briefly in this article. Recently, the NCI has begun efforts to bring together molecular-targeted, high-throughput screening and extramural sites with chemical libraries of interest. This new initiative is designed to match emerging molecular targets and high-throughput assay technology with novel sources of chemical diversity in the extramural community.
Shortly after recognition of the AIDS epidemic, the Developmental Therapeutics Program (DTP) of the NCI was charged with developing a drug-screening program that might give rise to the discovery of novel therapeutics for the treatment of human immunodeficiency virus (HIV) disease. Beginning in 1987 and continuing through 1997, a functional screen for primary antiviral treatments with the use of a cell-based assay system was in place. Details of the colorimetric-assay methodology and screening strategy have been published (1g,2). This screening program supported discovery of numerous lead compounds, from both natural and synthetic sources, many of which were subsequently demonstrated to be nucleoside and non-nucleoside reverse transcriptase inhibitors. A substantial number of novel natural product agents with anti-HIV activity have been isolated, including cyanovirin, a novel gp120-binding protein derived from a cultured blue-green alga (3). Detailed information on these molecules may be found on the DTP web site (http://dtp.nci.nih. gov), which is described below in detail.
Several novel molecules identified by the screen, or derivatives of screening leads, have been developed to the point of clinical trials. The nucleoside analog 3TC was submitted to the screen as a racemic mixture by IAF Biochem International, Inc. (Ville de Laval, Quebec), a Canadian pharmaceutical company, and subsequently licensed to Glaxo-Wellcome (Research Triangle Park, NC) for clinical development. This drug and Ziagen, a prodrug form of carbovir (4) also licensed by Glaxo-Wellcome, have been approved by the U.S. Food and Drug Administration for use in the treatment of HIV disease.
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PROGRAM REVIEWS |
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In 1995, the National Institutes of Health (NIH) Office of AIDS Research (OAR) initiated a wide-ranging review of research activities that pertain to HIV at the National Institutes of Health. This review resulted in a number of recommendations pertinent to NCI. Prominent recommendations were that there should no longer be a focus on the mechanistically unselective cell-based screen for discovery of new AIDS-directed therapeutics and that there should be a review of the management structure and the directions that the program would be taking in the future. The full text of this review is available at the OAR web site (http://www.nih.gov/od/oar/).
After receiving that report, NCI discontinued large-scale screening of synthetic compounds and natural product extracts with the cell-based assay. Information derived from this screening effort has been cataloged and made available on the DTP web site. Data for approximately 32 000 compounds are available and may be searched by biologic activity, as well as by chemical class.
The DTP AIDS program has recently undergone an additional review that was chaired by Dr. Jack Edwards of the University of California at Los Angeles and included experts from academia, industry, and the community with expertise in virology, chemistry, biology, pharmaceutical development, and clinical trials. The recommendations from this group will help shape the form of future NCI efforts in the area of HIV and AIDS-associated malignancies. This additional review follows a comprehensive review of DTP's cancer program that was initiated in 1997. The recommendations of that group, which was chaired by Dr. Susan Horwitz of Albert Einstein College of Medicine, have led to wide-ranging changes, including an emphasis on molecular targets for drug discovery and on increased interaction with the extramural drug discovery and development community. The full text of the committee's report is available on request.
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CURRENT RESOURCES FOR DRUG DISCOVERY |
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Resources currently available from DTP to support drug discovery are summarized in Table 1
. Grant support is available in the form of traditional investigator-initiated grants as well as special programs, such as the National Cooperative Drug Discovery Grants. New initiatives designed to exploit molecular targets will be discussed below. DTP maintains a web site (http://dtp.nci.nih.gov) that provides a wealth of information about NCI programs, chemical compounds that have been acquired and screened in anticancer and anti-HIV assays, as well as access to screening results. Tools are available on the web site to facilitate use of the information. Chemical analogue searching is possible, as is use of the COMPARE algorithm (5) for pattern recognition analysis of the anticancer drug screening database. The COMPARE program performs a correlation analysis with the use of patterns of relative in vitro sensitivity of 60 tumor cell lines and has been shown to be useful in helping to define the mechanism of cytotoxicity of compounds tested in the screen. The web site supports the interactive use of this program and also provides information on the chemical and natural product extract libraries maintained by NCI. More than 100 000 crude natural product extracts derived from a wide variety of natural sources, including terrestrial plants, cultured fungi, marine organisms, and other microorganisms, are described. Two- and three-dimensional structures for more than 200 000 synthetic compounds are accessible as well as information on how to obtain samples from the repositories. A limited capacity for anti-HIV testing in the cell-based assay has been maintained and is available primarily to support research by NIH grantees.
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FUTURE DIRECTIONS |
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During the next few years, the focus of screening and discovery activities will shift away from primarily intramurally based programs to a focus on extramurally driven activities. NCI will work toward partnering extramural principal investigators with molecular targets and sources of screening expertise with investigators developing chemical libraries. It is hoped that this partnering will occur in concert with new grant programs that DTP expects to be announced and phased in within the next year. These new grant programs will establish centers of excellence in chemical diversity as well as centers of excellence in molecular targets. They can begin to define the effects of these molecules on in vitro systems and then utilize NCI resources for the later stage preclinical studies that lead ultimately to clinical trial.
NCI anticipates the need to operate selected high-throughput, molecular-targeted screens at the Frederick Cancer Research and Development Center or through other contract mechanisms, either as service functions to the extramural community or in collaboration with extramural investigators with unique molecular targets. The Collaborative Research and Development Agreement (CRADA) provides a formal mechanism for defining a research plan agreeable to both NCI and a university- or industry-based investigator. The type of resources that DTP would bring to these areas would include screening expertise, a diverse repository of chemical compounds, natural products repository, expertise in bioassay-directed isolation, and characterization of leads obtained from natural products, as well as medicinal chemistry, molecular modeling, and bioinformatics resources. The resources the CRADA partner would bring to NCI would be access to state-of-the-art molecular targets and an in-depth knowledge of the biology pertinent to these systems.
As described above, the prior focus had been on HIV as a primary screening target in a cell-based assay. In the future, NCI anticipates focusing on selected molecular targets presented by HIV and extending efforts in the area of AIDS-related malignancies. These targets, associated with particular diseases, for example, angiogenesis and Kaposi's sarcoma, could also extend to aspects of immunity implicated in the expression or in the occurrence of malignancies as well as targets intrinsic to viruses associated with particular malignancies.
Presentations at this conference have alluded to potential molecular targets related to human herpesvirus 8 (HHV8) and Kaposi's sarcoma, Epstein–Barr virus and associated lymphomas, and human papillomavirus as related to the occurrence of cervical and anogenital tumors.
Because of the prevalence of Kaposi's sarcoma in AIDS patients, its clear linkage with HHV8, and the availability of complete genomic sequence information, DTP has focused on HHV8 for the first initiatives in the area of AIDS-associated malignancies. As reported elsewhere at this conference, DTP has developed and begun to characterize a cell-based assay for testing potential anti-HHV8 agents. This assay is intended for use in conjunction with high-throughput, molecular-targeted screens.
In collaboration with Dr. Robert Ricciardi of the University of Pennsylvania (Philadelphia, PA), DTP has begun development of methods for screening for selective inhibitors of the HHV8 DNA polymerase and processivity factor. Dr. Ricciardi's group has recently cloned and characterized these genes (6), which have no counterpart in uninfected human cells and thus represent a target with potential for development of highly selective therapeutic agents. This collaboration has been structured as a CRADA in which NCI will scale-up recombinant protein expression and purification and then screen the natural product and synthetic compound repositories to identify lead structures that affect the polymerase and processivity factor. Then, in collaboration with Dr. Ricciardi's group, DTP will characterize the leads biologically in appropriate biochemical and in vivo models. Qualified leads may then be licensed to industry for optimization and for development to clinical trials. This collaboration illustrates one of several ways in which NCI may interact with extramural investigators who have unique molecular targets, screening technologies, or sources of chemical diversity for screening. This and other potential types of interactions are shown schematically in Fig. 1.
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In addition to interaction with the extramural community, DTP anticipates continuing the association with the National Institute of Allergy and Infectious Diseases for drug discovery and development initiatives related to topical microbicides, antimicrobial leads, as well as interactions with intramural NCI laboratories engaged in research directed against relevant molecular targets, such as integrase.
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NEW INITIATIVES IN DRUG DEVELOPMENT |
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In the area of preclinical drug development, NCI has recently launched a new program to facilitate entry of novel therapies into the clinic. The Rapid Access to Intervention Development (RAID) program provides extramural academic investigators access to the same DTP contract resources used for development of compounds through the traditional NCI Decision Network process. Among the activities that can be supported by RAID are bulk production of drugs that would be suitable for clinical use, development of clinical formulations, or conduct of pharmacology and toxicology studies to support investigational new drug filing. For this program, NCI does not hold the investigational new drug. The intent is to remove preclinical barriers to clinical research. Additional details on the RAID program may be found on the DTP web site (http://dtp.nci.nih.gov).
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REFERENCES |
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1
Weislow OS, Kiser R, Fine DL, Bader J, Shoemaker RH, Boyd MR. New soluble-formazan assay for HIV-1 cytopathic effects: application to high-flux screening of synthetic and natural products for AIDS-antiviral activity. J Natl Cancer Inst 1989;81:577–86.
2 Boyd MR. Strategies for the identification of new agents for the treatment of AIDS: a national program to facilitate the discovery and preclinical development of new drug candidates for clinical evaluation. In: DeVita VT, Hellman S, Rosenberg SA, editors. AIDS, etiology, diagnosis, treatment and prevention. Philadelphia (PA), Lippincott; 1988, p. 305–19.
3 Boyd MR, Gustafson KR, McMahon JB, Shoemaker RH, O'Keefe BR, Mori T, et al. Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelope glycoprotein gp120: potential applications to microbicide development. Antimicrob Agents Chemother 1997;41:1521–30.[Abstract]
4 Vince R, Hua M, Brownell J, Daluge S, Lee F, Shannon WM, et al. Potent and selective activity of a new carbocyclic nucleoside (carbovir: NSC 614846) against human immunodeficiency virus in vitro. Biochem Biophys Res Commun 1988;156:1046–53.[CrossRef][ISI][Medline]
5
Paull KD, Shoemaker RH, Hodes L, Monks A, Scudiero DA, Rubinstein L, et al. Display and analysis of patterns of differential activity of drugs against human tumor cell lines: development of mean graph and COMPARE algorithm. J Natl Cancer Inst 1989;81:1088–92.
6
Lin K, Dai CY, Ricciardi RP. Cloning and functional analysis of Kaposi's sarcoma-associated herpesvirus DNA polymerase and its processivity factor. J Virol 1998;72:6228–32.
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