[Federal Register Volume 65, Number 213 (Thursday, November 2, 2000)]
[Notices]
[Pages 65863-65864]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-28120]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


National Cancer Institute: Opportunity for a Cooperative Research 
and Development Agreement (CRADA) for the Identification and 
Development of Chemical Compounds That Interact With the Polo-Box of 
Polo Kinases, as Potential Therapeutic Targets for the Inhibition of 
Cellular Proliferation

AGENCY: National Institutes of Health, PHS, DHHS

ACTION: Notice.

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SUMMARY: Members of the polo subfamily of protein kinases play 
important roles in cell proliferation, and regulation of polo kinases 
may be crucial in the control of cell division. The polo kinases 
contain a distinct region of homology in the C-terminal non-catalytic 
domain, termed the polo-box. Scientists from the National Cancer 
Institute (NCI) have demonstrated that over-expression of this non-
catalytic C-terminal domain in budding yeast results in a dominant-
negative inhibition of cell division. NCI seeks a Cooperative Research 
and Development Agreement (CRADA) Collaborator to aid in the 
identification and development of chemical compounds that interact with 
the polo-box of polo kinases, as potential therapeutic targets for the 
inhibition of cellular proliferation.

DATES: Interested parties should notify this office in writing of their 
interest in filing a formal proposal no later than January 2, 2000. 
Potential CRADA Collaborators will then have an additional thirty (30) 
days to submit a formal proposal. CRADA proposals submitted thereafter 
may be considered if a suitable CRADA Collaborator has not been 
selected.

ADDRESSES: Inquires and proposals regarding this opportunity should be 
addressed to Laurie W. Whitney, Ph.D., Technology Development 
Specialist (Tel: 301-496-0477, FAX: 301-402-2117), Technology 
Development and Commercialization Branch, National Cancer Institute, 
6120 Executive Blvd., Suite 450, Rockville, MD 20852. Inquiries 
directed to obtaining patent license(s) needed for participation in the 
CRADA opportunity should be addressed to Vasant Gandhi, J.D., Ph.D., 
Technology Licensing Specialist, Office of Technology Transfer, 
National Institutes of Health, 6011 Executive Blvd., Suite 325, 
Rockville, MD 20852, (Tel: 301-496-7056, ext. 224, FAX: 301-402-0220).

SUPPLEMENTARY INFORMATION: A Cooperative Research and Development 
Agreement (CRADA) is the anticipated joint agreement to be entered into 
with NCI pursuant to the Federal Technology Transfer Act of 1986 and 
Executive Order 12591 of April 10, 1987 as amended by the National 
Technology Transfer Advancement Act of 1995. NCI is looking for a CRADA 
partner to aide NCI in the identification and development of chemical 
compounds which act as polo-box inhibitors. The expected duration of 
the CRADA would be from one (1) to five (5) years.
    Members of the polo subfamily of protein kinases appear to play 
pivotal roles in cell division and proliferation. These include 
mammalian Plk, Snk, and Fnk/Prk, Xenopus laevis Plx1, Drosophila 
melanogaster polo, Schizosaccharomyces pombe Plo1, and Saccharomyces 
cerevisiae Cdc5. The polo subfamily members are characterized by the 
presence of a distinct region of homology in the C-terminal non-
catalytic domain, termed the polo-box, which is essential for 
subcellular localization and mitotic functions of the polo kinases. 
Regulation of polo kinases may be crucial in the control of cell 
division. In mammalian cells, Plk is expressed at high levels in 
mitotically active cells and in tumors of various origins. Constitute 
expression of Plk in NIH3T3 cells induces oncogenic focus formation, 
and these Plk-transformed cells can form tumors in nude mice. These 
data suggest that Plk expression is closely related to cellular 
proliferation, and that uncontrolled Plk expression may lead to the 
development of cancers in humans. Genetic and biochemical analyses 
indicate that polo kinases regulate diverse cellular events at various 
stages of the M phase. In addition to their roles in spindle formation 
and centrosome maturation, polo kinases appear to regulate important 
biochemical steps at the G2/M transition, such as activation of Cdc2 
through Cdc25C phosphatase, DNA damage checkpoint adaptation, and 
activation of the anaphase-promoting complex (APC) in various 
eukaryotic systems. In addition, recent data suggest that polo kinases 
play important roles in cytokinesissea.
    In budding yeast, overexpression of the non-catalytic C-terminal 
domain of either Plk or Cdc5 (plk<greek-D>N or cdc5<greek-D>N), but not 
the corresponding polo-box mutant, results in severe connected cell 
morphology. Provision of functional Cdc5 remedies this phenotype, 
indicating that over-expression of cdc5<greek-D>N or plk<greek-D>N 
results in a dominant-negative inhibition of cell division and

[[Page 65864]]

that an intact polo-box is required for this event. These data raise an 
intriguing possibility that conditional expression of the polo-box 
domain may selectively inhibit the mitotic functions of polo kinases. 
Furthermore, our observation suggests that the polo-box peptide may act 
as a potential anti-cancer therapeutic agent. Alternatively, isolation 
of small chemical compounds that bind to the polo-box and interfere 
with its function may yield a strategy to regulate highly proliferative 
malignant cells. We have developed two yeast strains that conditionally 
express the polo-box domains of Plk (KLY1212) or Cdc5 (KLY1083). 
Isolation of chemical compounds alleviating the dominant-negative cell 
division defect of these strains may lead to identification of polo-box 
inhibitors. Since the polo-box is an essential and unique domain for 
polo kinases, these inhibitors may likely provide selective tools to 
control the cell proliferation without interfering with other protein 
kinases.
    The described methods are the subject of a U.S. provisional patent 
application filed May 23, 2000 by the Public Health Service on behalf 
of the Federal Government. Furthermore, the initial report and 
characterization of the invention is described in: Song S, and Lee KS. 
A novel function of Saccharomyces cerevisiae CDC5 in cytokinesis 
(submitted for publication). Further reference to the invention can be 
found in: (1) Song S, Grenfell TX, Garfield S, Erikson RL, and Lee KS. 
(2000). Essential function of the polo-box of Cdc5 in subcellular 
localization and induction of cytokinetic structures. Mol. Cell. Biol. 
20, 286-298, and (2) Lee KS, Grenfell TZ Yarm, FR, and Erikson RL 
(1998). Mutation of the polo-box disrupts localization and mitotic 
functions of the mammalian polo kinase Plk. Proc. Natl. Acad. Sci. USA 
95:9301-9306.
    Under the present proposal, the goal of the CRADA will involve the 
following:
    (1) Identification and isolation of chemical compounds that 
alleviate the dominant-negative cell division defect of yeast strains 
that conditionally express the polo-box domains of Plk or Cdc5.
    (2) Development of these chemical compounds as tools to control 
cellular proliferation without interfering with other protein kinases.

Party Contributions

    The role of the NCI in the CRADA may include, but not be limited 
to:
    1. Providing intellectual, scientific, and technical expertise and 
experience to the research project.
    2. Providing the CRADA Collaborator with information and data 
relating to polo kinases.
    3. Planning research studies and interpreting research results.
    4. Carrying out research with validates and expands on the role of 
the dominant-negative inhibition of cell proliferation found using the 
intact polo-box.
    5. Publishing research results.
    6. Developing additional potential applications related to 
inhibition of cell proliferation using polo-box inhibitors.
    The role of the CRADA Collaborator may include, but not be limited 
to:
    1. Providing significant intellectual, scientific, and technical 
expertise or experience to the research project.
    2. Planning research studies and interpreting research results.
    3. Providing technical and/or financial support to facilitate 
scientific goals and for further design of applications of the 
technology outlined in the agreement.
    4. Publishing research results.
    Selection criteria for choosing the CRADA Collaborator may include, 
but not be limited to:
    1. A demonstrated record of success in the areas of isolation, 
purification, characterization, and therapeutic development of chemical 
compounds.
    2. A demonstrated background and expertise in cancer-related 
sciences.
    3. The ability to collaborate with NCI on further research and 
development of this technology. This ability will be demonstrated 
through experience and expertise in this or related areas of technology 
indicating the ability to contribute intellectually to ongoing research 
and development.
    4. The demonstration of adequate resources to perform the research 
and development of this technology (e.g. facilities, personnel and 
expertise) and to accomplish objectives according to an appropriate 
timetable to be outlined in the CRADA Collaborator's proposal.
    5. The willingness to commit best effort and demonstrated resources 
to the research and development of this technology, as outlined in the 
CRADA Collaborator's proposal.
    6. The demonstration of expertise in the commercial development and 
production of products related to this area of technology.
    7. The level of financial support the CRADA Collaborator will 
provide for CRADA-related Government activities.
    8. The willingness to cooperate with the national Cancer Institute 
in the timely publication of research results.
    9. The agreement to be bound by the appropriate DHHS regulations 
relating to human subjects, and all PHS policies relating to the use 
and care of laboratory animals.
    10. The willingness to accept the legal provisions and language of 
the CRADA with only minor modifications, if any. These provisions 
govern the distribution of future patent rights to CRADA inventions. 
Generally, the rights of ownership are retained by the organization 
that is the employer of the inventor, with (1) the grant of a license 
for research and other Government purposes to the Government when the 
CRADA Collaborator's employee is the sole inventor, or (2) the grant of 
an option to elect an exclusive or nonexclusive license to the CRADA 
Collaborator when the Government employee is the sole inventor.

    Dated: October 17, 2000.
Kathleen Sybert,
Chief, Technology Development and Commercialization Branch, National 
Cancer Institute, National Institutes of Health.
[FR Doc. 00-28120 Filed 11-1-00; 8:45 am]
BILLING CODE 4140-01-M