The Advisory Committee to the Director, National Cancer Institute (ACD), met on Sunday, March 1, 1998, at 7:00 p.m. at the Bethesda Hyatt Hotel, Bethesda, Maryland.

Advisory Committee Members present:
Richard D. Klausner, M.D., Director, National Cancer Institute (Chairman)
Joan Brugge, Ph.D., Harvard Medical School (Board of Scientific Advisors)
Waun Ki Hong, M.D., M.D. Anderson Cancer Center (Board of Scientific Advisors)
Amy S. Langer, M.B.A., National Alliance of Breast Cancer Organizations (Board of Scientific Advisors - Consumer Representative) David M. Livingston, M.D., Dana-Farber Cancer Institute (Board of Scientific Advisors)
Matthew D. Scharff, M.D., Albert Einstein College of Medicine (Board of Scientific Counselors)

Advisory Committee Members absent:
Martin D. Abeloff, M.D., The Johns Hopkins Oncology Center (Board of Scientific Counselors)
Michael Bishop, M.D., University of California, San Francisco (National Cancer Advisory Board)

Ex Officio Members present:
Marvin Kalt, Ph.D., Director, Division of Extramural Activities, National Cancer Institute
Alan Rabson, M.D., Deputy Director, National Cancer Institute
Robert Wittes, M.D., Deputy Director for Extramural Science, National Cancer Institute

Executive Secretary:
Susan J. Waldrop, Office of Science Policy, National Cancer Institute

Other Participants:
Alan Bernstein, Ph.D., National Cancer Institute Board of Scientific Counselors
Norma Carroll, National Cancer Institute
Ted Colton, Sc.D., National Cancer Institute Board of Scientific Counselors
Paulette Gray, Ph.D., National Cancer Institute
Robert Hammond, Ph.D., National Cancer Institute
Douglas Hanahan, Ph.D., University of California, San Francisco (Co-chair, Preclinical Models for Human Cancers Working Group [by telephone])
Jean McKay, National Cancer Institute
Luis Parada, Ph.D., National Cancer Institute Board of Scientific Counselors
Robert Reddick, M.D., National Cancer Institute Board of Scientific Counselors
Anna Skalka, Ph.D., National Cancer Institute Board of Scientific Counselors
Robert Strausberg, Ph.D., National Cancer Institute
The ACD approved the minutes of the January 12, 1998 conference call as submitted.

The purpose of the March 1 meeting was to provide the ACD with an update on the activities of the Working Groups and the Progress Review Groups, and to discuss the recommendation from the Preclinical Models for Human Cancers Working Group for a set of single nucleotide polymorphisms (SNPs) for the mouse genome.

Ms. Waldrop noted that Dr. Bishop has been appointed as the Chair of the National Cancer Institute National Cancer Advisory Board, which makes him a member of the ACD. Ms. Waldrop reported that there were no conflicts of interest with respect to the items for discussion at the March 1 meeting.

Update - Cancer Genome Anatomy Project (CGAP)

Dr. Klausner began his update of the CGAP by recognizing the efforts of Dr. Robert Strausberg, who oversees the activities of the project. CGAP is becoming a widely-used infrastructure for many exciting projects at the National Cancer Institute (NCI) as well as other NIH Institutes. The CGAP website is the primary mechanism by which the research community can access the project's resources.

The rate of gene discovery via CGAP has not changed (estimated at about 1.5% - 2%) and there is no evidence of saturation. Sixty to seventy percent of the new genes currently being discovered using public databases are from CGAP. Efforts are underway to provide full-insert sequencing of at least 10,000 clones, which will facilitate the use of vectors for gene expression. Issues to be addressed include high-throughput analysis and library quality control. Summary information on the prostate from the CGAP website was presented as an illustration of results to date.

Both the Cancer Genetics Working Group and the Developmental Diagnostics Working Group have identified a need for ways to identify single nucleotide polymorphisms (SNPs). Therefore, the NCI, building on CGAP, has begun to develop collaborations between its intramural and extramural programs, as well as with the National Center for Biotechnology Information to develop technological modules for different approaches to SNP identification. Dr. Klausner distinguished the technology assessment phase of the genetic annotation project from the SNP discovery phase. The technology assessment phase will rely on the already consented CEPH families in order to establish transmission as part of SNP technology validation. The SNP discovery phase will utilize DNA from diverse populations, and common and standard DNA sets as they become available.

Ms. Langer suggested the development of a lay language update of CGAP activities that would include information about progress and funding. Dr. Klausner agreed that public progress reports, in understandable language, would be useful.

Working Groups

Implementation Process - Dr. Wittes is responsible for developing an overall strategy by which the NCI responds to the recommendations resulting from the various planning activities, including the Working Groups, the Progress Review Groups, and the Program Review Groups. The overall approach developed by Dr. Wittes recognizes the inherent trans-Divisional nature of the recommendations emerging from the various groups, as well as the variety of forms in which recommendations are made. The result is a series of implementation steps that are modified as the process unfolds. The NCI utilized interdivisional task forces to address recommendations from the Working Groups. This approach was further refined to include external and internal members to respond to reports from Program Review Groups. In response to a question from Ms. Langer, Dr. Wittes noted that the external members are usually not from the original Program Review Group, but some overlap does occur. Dr. Klausner remarked that it was hoped that this approach will allow those problems identified, but unresolved, by the original review group to be solved or further delineated by another group. It was anticipated that the report of the Developmental Therapeutics Review Group (a program review group) would be available by Fall 1998.

For additional information about the activities of the Working Groups, Ms Waldrop referred the ACD to information contained in the meeting materials.

Preclinical Models for Human Cancers Working Group

• Recommendation: Identify a set of single nucleotide polymorphisms (SNPs) that span the mouse genome at high resolution (ca. 1 per 50-100,000 bp), building a platform upon which to implement efficient, array-based genome scanning methods for identifying genes that influence cancer phenotypes.

  Dr. Hanahan gave a brief overview of the recommendation, and noted the three components: 1) development of a "SNP detector;" 2) development of a SNP map that spans the mouse genome; and 3) development of arrays and other formats that would incorporate the mouse SNP map to expedite the discovery of cancer genes. The Mouse Genomics and Genetics Subgroup, which developed the recommendation and of which Dr. Hanahan is a co-chair, agreed that the availability of a SNP resource would enable many more laboratories to take advantage of existing and new mouse models to study tumors altered in cancer on different genetic backgrounds. In response to a question about whether the SNP map should have priority over the BAC map, Dr. Hanahan recognized these "conflicting priorities." However, he stated that a SNP map would likely benefit a broader group of mouse model users and developers. Dr. Klausner noted that the NIH was holding a meeting on March 19-21 to provide guidance to the NIH on priorities for mouse genomics and genetics resources. It was anticipated that the development of a SNP resource would be discussed further at this meeting. Dr. Klausner noted that the NCI has developed a proposal for a new funding mechanism to support the systematic development and validation of mouse models. This proposal would be presented to the Board of Scientific Advisors at their March 2-3 meeting.

  The ACD was supportive of the mouse SNP recommendation. Dr. Klausner recognized the efforts of Dr. Hanahan, and the Preclinical Models for Human Cancers Working Group and its Subgroups.

• Mouse Cancer Genome Anatomy Project (m-CGAP)

  Dr. Robert Strausberg gave an overview of the implementation of the m-CGAP. A m-CGAP, similar to the human CGAP, was among the recommendations discussed by the ACD during the September 18, 1997 conference call. The overall goals of the m-CGAP are :

  • a comparative assessment of mouse cancer stages with those of cognate human cancers, both to validate the mouse models and to promote crossfeeding in the identification of genes that characterize those cancers;
    
  • the discovery of new genes and gene pathways involved in the stages of carcinogenesis.

  There are plans to establish a Steering Committee to identify models and to solicit proposals from the research community for models that would complement the ongoing human CGAP efforts. The Steering Committee would oversee the operation of m-CAP by:

  • establishing specifications for the libraries;
    
  • determining the number of libraries produced from a given type/stage/pathway, and the extent of sequence analysis based on the initial screen and on other knowledge;
    
  • evaluating the merit of further refinements (e.g., normalization, full length, microdissected).

  There was a brief discussion about the kinds of models (e.g., transgenic, knock-outs) that the m-CGAP would use as sources of tissues and libraries. The ACD is interested in hearing further updates as the m-CGAP gets underway.

Developmental Diagnostics Working Group, Cancer Genetics Working Group, and the Imaging Sciences Working Groups

Information about the activities of these Working Groups, in addition to the Preclinical Models for Human Cancers Working Group, was provided to the ACD in their meeting materials. Dr. Klausner commented on the recent meeting of the In Vivo Molecular Imaging Subgroup, stating that this was one of the most exciting meetings of the Working Groups. The Subgroup drew upon experts in molecular and cell biology, chemistry, clinical oncology, and the imaging sciences to consider the relationships between traditional imaging and the concepts of the molecular basis of cancer, including the detection of subtle genomic and molecular changes. In response to a question from Dr. Scharff, Dr. Klausner noted that the Subgroup was also considering in vivo functional imaging of mice.

Progress Review Groups

Organized around specific cancer sites, the Progress Review Groups (PRGs) are charged with developing a site-specific national research agenda that will allow the NCI to move the research in these areas forward. As one step in this process, the PRGs analyze and summarize the NCI research portfolio for the cancer site. The portfolio analyses for breast and prostate cancers have been completed. The next step is to use the information to help establish priorities for cancer research in these areas. The ACD members expressed interest in learning the schedule for presentation of the PRG reports and recommendations, and the process that will be used for setting priorities for addressing other cancer sites.

The NCI plans to assess the usefulness of the PRG process before applying this approach to another cancer site. An important issue to be addressed is the best way to code basic science, which moves quickly, so that it is possible to appropriately describe its relevance to cancer research on a particular site. The current portfolio analyses do not include this information. However, the portfolio analysis approach has been extremely useful for assessing prevention research activities. Many of the participants in the PRGs were interested in pursuing this process for lung cancer. The National Heart, Lung, and Blood Institute has also expressed interest in collaborating with the NCI on a lung cancer PRG.

Director's Consumer Liaison Group (DCLG)

The DCLG had their first meeting on December 17-18, 1997. At this meeting, the group discussed informed consent, access to tissue specimens, and the incorporation of consumer representation into the peer review process. Dr. Klausner expressed his enthusiasm for the group and felt that they will make an invaluable contribution to the NCI.

The meeting was adjourned at 8:50 p.m. on March 1, 1998.