> ![](media/image1.png) **MouseTracks**

**June[,]{.smallcaps} 2001**

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  Inside    
  This      
  Issue     

  1         Productive Principal Investigators

  1         Mouse Models of Cell Death...a review

  2         Calendar of Events

  5         Minutes from the IG's May 1, 2001 Meeting

  7         Agenda for IG's June Meeting
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PRODUCTIVE PRINCIPAL INVESTIGATORS, continued from page 1

pancreas (approximately 70-90% incidence), colon (approximately 50%) and
lung (approximately 25-50%). To construct mouse tumour models involving
K-ras, we used a new gene targeting procedure to create mouse strains
carrying oncogenic alleles of K-ras that can be activated only on a
spontaneous recombination event in the whole animal. Here we show that
mice carrying these mutations were highly predisposed to a range of
tumour types, predominantly early onset lung cancer. This model was
further characterized by examining the effects of germline mutations in
the tumour suppressor gene p53, which is known to be mutated along with
K-ras in human tumours. This approach has several advantages over
traditional transgenic strategies, including that it more closely
recapitulates spontaneous oncogene activation as seen in human cancers."

Another recent article, from Ron DePinho's laboratory, appeared in
Nature Genetics (Nat Genet 2001 Jun;28(2):155-9). The article, "Telomere
dysfunction and evolution of intestinal carcinoma in mice and humans,"
is summarized as follows:

"Telomerase activation is a common feature of advanced human cancers and
facilitates the malignant transformation of cultured human cells and in
mice. These experimental observations are in accord with the presence of
robust telomerase activity in more advanced stages of human colorectal
carcinogenesis. However, the occurrence of colon carcinomas in
telomerase RNA (Terc)-null, p53-mutant mice has revealed complex
interactions between telomere dynamics, checkpoint responses and
carcinogenesis. We therefore sought to determine whether telomere
dysfunction exerts differential effects on cancer initiation versus
progression of mouse and human intestinal neoplasia. In successive
generations of ApcMin Terc-/- mice, progressive telomere dysfunction led
to an increase in initiated lesions (microscopic adenomas), yet a
significant decline in the multiplicity and size of macroscopic
adenomas. That telomere dysfunction also contributes to human colorectal
carcinogenesis is supported by the appearance of anaphase bridges (a
correlate of telomere dysfunction) at the adenoma-early carcinoma
transition, a transition recognized for marked chromosomal instability.
Together, these data are consistent with a model in which telomere
dysfunction promotes the chromosomal instability that drives early
carcinogenesis, while telomerase restores genomic stability to a level
permissive for tumor progression. We propose that early and transient
telomere dysfunction is a major mechanism underlying chromosomal
instability of human cancer."

... from Entrez PubMed, June 4, 2001

IMPLEMENTATION GROUP MEMBERS

[Organ Site Committees]{.underline}

Breast Cancer Models - Colette Freeman

CNS Cancer Models - Iqbal Ali, Judy Mietz

Gastrointestinal Cancer Models - Susan McCarthy

Hematopoietic Cancer Models - Allan Mufson

Lung Cancer Models - Harold Seifried

Ovarian Cancer Models - Jane Fountain

Prostrate Cancer Models - Suresh Mohla

Skin Cancer and Melanoma Models - Jaye Viner

[Standing Committees]{.underline}

Genetic Modifier Tools - Carol Kasten-Sportes

Infrastructure - Kenneth Buetow, Jules Berman

Mouse Engineering - Daniel Gallahan

Pathology and Lab Medicine - Barbara Conley

Preclinical Trials - Wendy Patterson

Technologies - Jennifer Couch

STEERING COMMITTEE MEMBERS

Barbara Croft

Jorge Gomez

James Hanson

John Hoffman

Jim Jacobson

Ronald Lubet

Mary Wolpert

MINUTES -- IMPLEMENTATION and STEERING GROUP MEETING

May 1, 2001

ATTENDEES: I. Ali, J. Couch, B. Croft, C. Freeman, D. Gallahan, C.
Kasten-Sportes, R. Lubet, S. McCarthy, J. Mietz, A. Mufson, W.
Patterson, H. Seifried, S. Seweryniak, D. Singer, B. Slater, B.
Tarnowski, J. Viner

AGENDA ITEMS:

I.  Implementation Group's Role in the MMHCC - Dinah Singer

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1.  Looking back over the last two years, we've accomplished many things
    (the Website, micro arrays, the Repository, histology workshops,
    etc.) and we can see that our first wave has come to fruition. Now,
    in the next phase questions need to be asked. Where are we going?
    What should the MMHCC look like? Who should ask the questions?

2.  Clearly the IG should develop the NCI perspective, so an important
    question is, what is the role of the IG?

3.  As mandated in the RFA, the IG (described the Advisory Group to the
    Program Director) is advisory to the MMHCC. This advisory role
    encompasses:

-   Being a conduit between the PIs and the NCI

-   Providing an infrastructure

-   Becoming the \"memory

-   Formulating directions

4.  Realizing the concerns of the IG are different than the PI\'s and
    the Steering committee\'s [what issues need to be addressed by the
    IG]{.underline}?

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1)  Validation

> \- Model makers need to be matched with users

-   Models have this property: exhibit one cancer but actually can be a
    good meld for another cancer

\- Characterization is so important

\- Validation is up to the PIs but also needs to be external

2\) Criteria for success?

-   MMHCC builds the models, the scientific community uses and validates
    them

-   There are few models in the system for drug testing.

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-   What about trying known drugs in a known predictive model?

-   We can evaluate what\'s been accomplished. Some mouse models are
    good for human pathology, but may be not good for treatment. In
    brain, we don\'t think about prevention.

-   IG doesn\'t evaluate the models, so questions are, where are we,
    where do we want to go? What are the issues?

-   It is not clear about the boundaries of the Steering Committee
    versus the IG

3\) The boundaries are distinct but overlapping:

Steering Committee - develops models, technology, how to use the models

Implementation Group - (1) think about clinical trials, the IG could
bring the Pharmas in, find

out what they\'re looking for?

\(2\) long term strategizing

\(3\) make linkages and connections

II.Recommendations

1.  1\. Change the meeting structure of the IG:

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(1) for strategizing and looking at big vision questions:

> \- Meet four times a year

2.  \- Structure the meetings around the Steering Committee meetings - a
    debriefing

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(2) for notification and implementation of upcoming workshops, website
    issues, meet the months in between the strategizing IG meetings

\(3\) IG attendance at the Steering committee meetings.

3.  \- It is not necessary for everyone to attend every Steering
    committee meeting but we

do need some level of participation.

2\. Facilitate communication among IG members by emailing \"what\'s
new\" information (links

to website)

III\. Action Items

4.  1.Future IG meeting agendas:

    June - upcoming workshops, website issues, other business

    July - no meeting (Steering Committee meeting, July 9-12, San
    Francisco)

    August - debriefing of July Steering Committee meeting, strategizing
    session

    September - upcoming workshops, website issues, other business

    2\. Notebooks

IV.Next meeting, Tuesday, June 5, 2:00 pm, EPN-E

#### Agenda

#### Implementation and Steering Group Meeting

#### June 5, 2001

2:00 pm, EPN-E

1\. Review and revisions of minutes from IG Meeting, May 1, 2001

2\. Role of the IG

3\. Updates.

a\) Websites:

\(b\) Reports from MMHCC workshops/meetings:

[May 3-4, 2001, Bethesda]{.underline}

Pre-clinical Trials Standing Committee, Validation Meeting

Vicky Richon/Kevin Shannon; Wendy Patterson, IG; Mary Wolpert, Steering

[May 15-17, 2001, Bar Harbor]{.underline}

The Jackson Laboratories

Technologies Standing Committee, Microarray Workshop

Raju Kucherlapati; Dan Gallahan, IG

[May 18, 2001, Rockville]{.underline}

Division of Cancer Biology, EPN

Website Oversight Committee, NCI BioInformatics and DCB staff

Terry Van Dyke, Tyler Jacks, David Threadgill, Ken Buetow, Jeff Green

[May 24-25, 2001, Nashville]{.underline}

Gastrointestinal Organ Site Committee, Pancreas Workshop

Bob Coffey, Steve Leach; Susan McCarthy, IG

c\) Upcoming MMHCC workshops/meetings:

[June 12, 2001, Madison]{.underline}

Genetic Modifiers Standing Committee, Genetics Workshop

(note: the Genetics Workshop preceeds the Wisconsin Symposium on the
Analysis of Human Biology: Genes, Genomes and Molecules, June 12-16,
2001)

Joanna Groden; Carol Kasten-Sportes, IG

[June 20-22, 2001, Boston]{.underline}

Lung Organ Site Committee, Lung Workshop

Tyler Jacks, David Tuveson; Harold Seifried, IG

[July 9-12, 2001, San Francisco]{.underline}

MMHCC Steering Committee Meeting

(handout: tentative agenda)

[July 19-20, 2001, Westfields]{.underline}

Breast Cancer Think Tank (BCTT)

Jeff Green, Eva Lee, Dan Medina; Colette Freeman, IG

4\. Other business

5\. Next meetings:

[July 3, 2001meeting]{.underline}: cancelled

[August 7, 2001 meeting]{.underline}: agenda -- Scientific Advisory
function

[September 4, 2001 meeting]{.underline}: agenda -- logistics (workshops,
websites, etc.)