[Federal Register Volume 65, Number 59 (Monday, March 27, 2000)]
[Notices]
[Pages 16209-16211]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-7381]


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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 Screening, Development and 
Commercialization of Novel Inhibitors of GADD45 Polypeptide Activity 
for the Treatment of Cancer

AGENCY: National Institutes of Health, PHS, DHHS.

ACTION: Notice.

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    The National Cancer Institute's Laboratory of Human Carcinogenesis 
(LHC) has created and characterized in vitro and in vivo methods 
designed to screen for modulators of GADD45 polypeptide activity. 
Furthermore, LHC has developed methods for sensitizing proliferating 
cells to DNA damaging agents by inhibiting GADD45 polypeptide activity. 
Identification of novel inhibitors of GADD45 using LHC's screening 
assays would provide potential new treatments for cancer.

SUMMARY: The National Cancer Institute (NCI) seeks a Cooperative 
Research and Development Agreement (CRADA) Collaborator to aid NCI in 
the screening, development and commercialization of novel compounds for 
the treatment of cancer. These methods focus on the identification of 
small molecule inhibitors of GADD45 polypeptide activity.
    NCI has developed a series of in vitro and in vivo assays to screen 
for modulators of GADD45 polypeptide activity. These assays may 
identify novel small molecule inhibitors of GADD45 activity that, when 
used in conjunction with current chemotherapeutics, reduce the toxicity 
of and enhance the effectiveness of current treatments of cancer. NCI 
is looking for a CRADA Collaborator with a demonstrated record of 
success in cancer diagnostics and therapeutics. The proposed term of 
the CRADA can be up to five (5) years.

DATES: Interested parties should notify the Technology Development and 
Commercialization Branch of the NCI in writing of their interest in 
filing a formal proposal no later than May 26, 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: Inquiries and proposals regarding this opportunity should be 
addressed to Holly Symonds Clark, 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) for the technology described in 
U.S. Provisional Patent Application Serial No. 60/126,069, filed March 
25, 1999, for ``Methods for Identifying Modulators of GADD45 
Polypeptide Activity'' (Harris et al.) 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; 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 collaborate with NCI in the further development and 
commercialization of screening assays and methods relating to the 
analysis of small molecule inhibitors of GADD45 polypeptide activity. 
The expected duration of the CRADA would be from one (1) to five (5) 
years.
    Mammalian cells cycle through a series of ordered stages that 
involve various cellular components during normal cellular growth (for 
reviews: 1, 2). A normal cell can arrest cell cycle progression when 
DNA damage is incurred. Cell cycle ``checkpoints'' exist at two 
different stages in cell cycle progression: the G1 to S (replication) 
stage and the G2-M (mitosis) stage. These checkpoints are essentially 
stages in which the cell ``stalls'' its cell cycle to repair any 
damaged DNA that may exist prior to entry into mitosis. The G2-M 
checkpoint prevents the improper segregation of chromosomes likely to 
be important in human tumorigenesis (3, 4). The G2-specific kinase 
composed of Cdc2 and cyclin B1 is a regulator of the cell cycle 
transition from G2 to M (1). NCI has recently reported the 
identification of one of the gene products that controls the G2-M 
checkpoint: the ubiquitously expressed polypeptide, GADD45. GADD45 was 
originally identified on the basis of its rapid transcriptional 
induction following ultraviolet (UV) irradiation (5). Induction of 
GADD45 has also been observed following various types of pathological 
stimuli including various environmental stresses, hypoxia, IR, 
genotoxic drugs and growth factor withdrawal (6). The GADD45-induced 
G2/M checkpoint is at least in part mediated through inactivation of 
the Cdc2/cyclin B1 kinase (1).
    NCI believes that the GADD45-mediated G2-M checkpoint could be a 
new target for the development of anti-cancer agents. Inhibitors of 
GADD45 activity at the G2-M checkpoint could destroy the cell's ability 
to stall its proliferative cycle to correct damaged DNA. Cancer cells 
are often deficient in the G1-S checkpoint, thus, the G2-M

[[Page 16210]]

checkpoint is necessary for the repair of damaged DNA in cancer cells. 
Currently, high levels of radiation and chemotherapy are necessary to 
target cancer cells that are stalled at the G2-M checkpoint. Such 
levels of treatment are often toxic to normal cells also undergoing 
proliferation. However, when both checkpoints are abolished in cancer 
cells, the cells proceed at a greater rate, without stalling, into 
mitosis where they are susceptible to DNA damaging chemotherapeutic 
agents. Thus, in the presence of a G2-M checkpoint inhibitor, a reduced 
amount of radiation or chemotherapeutic agent is needed to kill all of 
a population of cancer cells. A reduced level of DNA damaging agent 
would also lessen the toxicity to normal cells since many of these 
cells would be stalled at their intact G1-S checkpoints. In effect, the 
use of a G2-M checkpoint inhibitor would selectively target cancer 
cells by ``sensitizing'' them to the anti-cancer treatments. NCI 
believes that small molecule inhibitors of GADD45 polypeptide activity 
could be used to abolish the G2-M checkpoint in cancer cells. Indeed, a 
previous report has found that blocking GADD45 expression by 
constitutive antisense oligonucleotide expression sensitized a human 
colon carcinoma cell line to killing by UV irradiation and by 
cisplatin, a DNA-damaging cancer chemotherapy drug (7). Thus, the 
identification of novel inhibitors of GADD45 activity would provide a 
new means to treat cancers in conjunction with current chemotherapy 
methods. In the clinic, such combined treatment would reduce the 
uncomfortable side-effects of current anti-cancer treatments, thus, 
improving the quality of life for cancer patients.
    NCI has developed several in vitro and in vivo methods for assaying 
for modulators of GADD45 polypeptide activity. The methods focus on the 
ability to assess the binding activities of the GADD45 polypeptide 
during the cell cycle. NCI has identified a functional domain of GADD45 
that is involved in the G2-M checkpoint and in binding to the cell 
cycle regulator, cdc2. Deletion analysis indicates that the central 
region of this functional domain mediates the G2/M arrest. 
Specifically, the central region contains a unique acidic motif that 
appears to be important for the induction of a G2/M arrest because 
changes in the acidic residues abolish the G2/M checkpoint. Small 
molecule compounds that are designed to target the region of the GADD45 
polypeptide would affect 1. GADD45/cdc2 binding, 2. the GADD45 
polypeptide-mediated dissociation of the cdc2/cyclinB1 protein complex, 
and 3. the ability of the cdc2/cyclinB1 complex to phosphorylate 
histone H1. NCI suggests that the small acidic motif may, in itself, be 
a possible small molecule, dominant negative inhibitor of GADD45 
activity. Once other small molecule GADD45 modulators are identified, 
NCI would be interested in a collaboration to further characterize all 
candidate GADD45 modulators using preclinical and clinical assays.
    NCI is seeking a CRADA Collaborator to aid in the screening, 
development and commercialization of small molecule inhibitors of 
GADD45 polypeptide activity for use in the preclinical and clinical 
treatment of cancer. NCI has developed various in vitro and in vivo 
methods that could be applied to a drug screening protocol in which 
potential modulators of GADD45 could be identified and characterized. 
Once identified and characterized, novel GADD45 inhibitors may be 
administered to candidate cancer patients and evaluated in their 
ability to treat various tumors in conjunction with current 
chemotherapeutic treatments. The described methods are the subject of 
U.S. provisional patent application, USSN 60/126,069, filed on March 
25, 1999 by the Public Health Service on behalf of the Federal 
Government. Furthermore, the initial report and characterization of the 
invention is described in Wang, X.W. et al, PNAS, vol. 96: 3706-3711.

References

1. Nurse, P., 1994, Cell 79: 547-550.
2. Sherr, C.J., 1996, Science 274: 1672-1677.
3. Hartwell, L.H. and M.B. Kastan, 1994, Science 266: 1821-1828.
4. Paulovich, A.G., et al., 1997, Cell 88: 315-321.
5. Fornace, A.J., Jr., et al., 1989, Mol. Cell Biol. 9: 4196-4203.
6. Papathanasiou, M.A., et al., 1991, Mol. Cell Biol. 11: 1009-1016.
7. Smith, M.L., et al., 1996, Oncogene 13: 2255-2263.

    Under the present proposal, the overall goal of the CRADA 
collaboration will involve the following:
    1. To use the current technology developed by NCI to screen for 
modulators of GADD45 polypeptide activity.
    2. To conduct preclinical and clinical assays to test the 
effectiveness of the candidate GADD45 polypeptide modulators in the 
treatment of different cancers.

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 the methods developed to assess the activity of the GADD45 
polypeptide.
    3. Planning research studies and interpreting research results.
    4. Carrying out research to validate the use of the GADD45-related 
methods and candidate GADD45 polypeptide modulators in preclinical, 
diagnostic and clinical settings.
    5. Publishing research results.
    6. Developing additional potential applications of the screening 
methods.
    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 screening of 
chemotherapeutic agents.
    2. A demonstrated background and expertise in cancer research and 
treatment.
    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.

[[Page 16211]]

    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 to 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: March 20, 2000.
Karen Maurey,
Deputy Chief, Technology Development and Commercialization Branch, 
National Cancer Institute, National Institutes of Health.
[FR Doc. 00-7381 Filed 3-24-00; 8:45 am]
BILLING CODE 4140-01-P