[Federal Register Volume 64, Number 238 (Monday, December 13, 1999)]
[Notices]
[Pages 69541-69543]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-32138]


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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 Further Development and 
Commercialization of Methods Designed To Screen and Use Modulators of 
Nitric Oxide Synthase 2 (NOS2) Activity for the Diagnosis and Treatment 
of Cancer

    The National Cancer Institute's Laboratory of Human Carcinogenesis 
(LHC) has identified and characterized in vitro and in vivo methods 
designed to screen modulators of NOS2 activity using cell lines that 
are deficient in the expression of the tumor suppressor gene, p53. 
Furthermore, LHC has created methods to predict the chemotherapeutic 
benefit of administering NOS2 inhibitors to cancer patients as a method 
for treating cancer.

AGENCY: National Institutes of Health, PHS, DHHS.

ACTION: Notice.

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SUMMARY: The National Cancer Institute (NCI) seeks a Cooperative 
Research and

[[Page 69542]]

Development Agreement (CRADA) Collaborator to aid NCI in the 
identification and characterization of modulators of nitric oxide 
synthase 2 (NOS2) activity and in the development, evaluation and 
commercialization of methods for treating cancer that involve the 
clinical use of novel NOS2 modulators. NOS2 is an inducible enzyme that 
produces nitric oxide (NO), a mutagenic and angiogenic molecule (1,2). 
To define a role of NO in tumor progression, NCI has generated human 
carcinoma cell lines that produce NO constitutively. NCI has determined 
that tumor-associated NO production may promote cancer progression by 
providing a selective growth advantage to tumor cells bearing a mutant 
form of the tumor suppressor and transcription factor, p53. 
Furthermore, NCI has determined that accelerated tumor growth in these 
cells is associated with an increased expression of the vascular 
endothelial growth factor (``VEGF''), leading to tumor 
neovascularization. NCI has generated methods for screening modulators 
of NOS2 activity using cells lines that contain a mutant p53 gene. In 
addition, NCI has generated methods for using these cell lines in 
screening assays that test the use of potential NOS2 inhibitors in the 
treatment of patients with tumors lacking p53 function.
    Several applications for this technology have been identified. They 
include the use of these methods as (1) diagnostic assays to determine 
the genetic and functional status of the p53 gene; (2) assays to 
predict the chemotherapeutic benefit of administering current NOS2 
inhibitors to cancer patients; and (3) assays to screen for novel 
modulators of NOS2 activity for use in the treatment of cancers. 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 ( February 11, 2000. Potential 
CRADA Collaborators will then have an additional thirty (30) days to 
submit a formal proposal.

ADDRESSES: Inquiries and proposals regarding this opportunity should be 
addressed to Holly S. Symonds, 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 Richard Rodriguez, Technology Licensing 
Specialist, Office of Technology Transfer, National Institutes of 
Health, 6011 Executive Blvd., Suite 325, Rockville, MD 20852, (Tel. 
301-496-7056, ext. 287; 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 NOS2 activity in cancers exhibiting a nonfunctional p53 and 
to the use of NOS2 inhibitors in the treatment of such cancers. The 
expected duration of the CRADA would be from one (1) to five (5) years.
    Increased expression of inducible nitric oxide synthase (NOS2) has 
been found in a variety of human cancers (3-6). NOS2 is an inducible 
enzyme that produces nitric oxide (NO), a mutagenic and angiogenic 
molecule (1,2). NO is an activator of the p53 tumor suppressor gene 
function (7-9), however, p53 will repress the expression of NOS2, both 
in vitro and in vivo (8,10,11). To investigate the role of NO in tumor 
progression, NCI created genetically engineered human carcinoma cell 
lines that constitutively produce endogenous NO. Using these cell 
lines, NCI has found that the effect of NO on tumor growth is p53-
dependent due to its ability to repress the expression of NOS2, and 
that endogenously produced NO accelerates tumor growth by inducing 
expression of the vascular endothelial growth factor (VEGF) and 
neovascularization.
    The NCI's data indicates that, in the presence of wild-type p53, 
constitutive expression of NOS2 in tumors could lead to a p53-mediated 
growth arrest in the epithelial cells closely surrounding the source of 
NO production. The growth inhibition of such cells would provide a 
strong selective pressure for a mutation to occur in the p53 gene. 
Indeed, tumors of the breast, brain, head and neck and colon that 
overexpress NOS2 have a high frequency of p53 mutations (3, 4, 6, 11, 
12). Tumor growth would then be further supported by the NO-mediated 
induction of VEGF and angiogenesis. Since p53 has been shown to 
regulate the production of NO by altering the activity of NOS2, NO 
production would remain unchecked, supporting the growth of the tumor 
(8, 10, 11). The loss of p53 function in p53 deficient or mutant cells 
would permit both the growth of tumor cells in the presence of moderate 
NO concentrations and the release of angiogenic factors such as VEGF. 
However, NCI suggests that such tumors with mutant p53 function could 
be therapeutically and prophylactically treated with NOS2 inhibitors.
    To address this possibility, NCI has developed a series of methods 
aimed at screening modulators of NOS2 activity using p53 mutant cells 
that express NOS2. In one method, modulators of NOS2 activity are 
screened in vitro, using p53 mutant cells that constitutively or 
endogenously express NOS2. The cells are exposed to potential NOS2 
inhibitors, and the level of VEGF expression is determined by various 
methods. In addition, the level of nitrate versus nitrite produced is 
measured to determine the level of NOS2 activity in the presence of the 
potential inhibitor compounds.
    To further assess the therapeutic benefit of a potential NOS2 
inhibitor, NCI has developed an in vivo method of screening modulators 
of NOS2 activity. In such method, p53 mutant cells that constitutively 
or endogenously express NOS2 are implanted into an immune deficient 
athymic nude mouse model and then are treated with potential NOS2 
inhibitor compounds. Modulation of NOS2 activity can be determined as 
above and also by measuring tumor growth in the treated animals as 
compared to untreated control animals.
    NCI suggests that the benefit of administering potential NOS2 
inhibitors to cancer patients may be assessed by determining the p53 
status and NOS2 expression pattern of the tumors. If a patient has a 
cancer that expresses NOS2 and is deficient in normal p53 activity, 
then the patient may be a candidate for treatment with NOS2 inhibitors. 
NCI has developed methods to both assess the benefit of such treatment 
and to administer potential NOS2 inhibitors to cancer patients in a 
clinical setting.
    NCI is seeking one or more CRADA Collaborators to further develop 
the above methods for preclinical, diagnostic and clinical uses. 
Specifically, NCI believes the methods could be applied to a drug 
screening protocol in which potential modulators of NOS2 could be 
identified and characterized. Furthermore, NCI predicts that the 
methods could be applied to a diagnostic kit for use in a

[[Page 69543]]

clinical setting to determine whether or not a particular cancer 
patient is a candidate for such treatment with regards to the p53 
status of the tumor. Once identified and characterized, novel NOS2 
inhibitors may be administered to candidate cancer patients and 
evaluated in their ability to treat various tumors.
    The described methods are the subject of U.S. provisional patent 
application, USSN 60/109,563, filed on November 23, 1998 by the Public 
Health Service on behalf of the Federal Government. Furthermore, the 
initial report and characterization of the invention is described in: 
Ambs et al, Nature Medicine (1998) vol. 4, no.12:1371-1376.

References

1. Nguyen et al (1992) PNAS 89:3030-3034.
2. Jenkins et al (1995) PNAS 92:4392-4396.
3. Thomsen et al (1995) Br. J. Cancer 72:41-44.
4. Ellie et al (1995) Neuroreport 7:294-296.
5. Ambs et al (1998) Cancer Res. 58:334-341.
6. Gallo et al (1998) J. Natl. Cancer Inst. 90:587-596.
7. Messmer et al (1996) Biochem J. 319:299-305.
8. Forrester, K. et al (1996) PNAS 93:2442-2447.
9. Calmels et al (1997) Cancer Res. 57:3365-3369.
10. Ambs et al (1997) Faseb J. 11:443-448.
11. Ambs et al (1998) PNAS 95:8823-8828.
12. Thomsen et al (1997) Cancer Res. 57:3300-3304.

    Under the present proposal, the overall goal of the CRADA 
collaboration will involve the following:
    1. Use of the genetically engineered cells lines and assays in 
preclinical screening assays of potential NOS2 inhibitors; and
    2. Use of the cell lines and candidate NOS2 inhibitors in 
diagnostic, preclinical and clinical settings.

Party Contributiions:

    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 p53 and 
NOS2 and to screen for potential modulators of NOS2 activity.
    3. Planning research studies and interpreting research results.
    4. Carrying out research to validate the use of the NOS2-related 
methods and candidate NOS2 inhibitors in preclinical, diagnostic and 
clinical settings.
    5. Publishing research results.
    6. Developing additional potential applications of the 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. Producing candidate NOS2 inhibitors under cGMP conditions in 
sufficient quantities to support the CRADA studies.
    4. Carrying out research to validate the use of the NOS2-related 
methods and candidate NOS2 inhibitors in preclinical, diagnositc and 
clinical settings, including toxicologic and pharmacologic assays, as 
appropriate.
    5. Providing technical and/or financial support to facilitate 
scientific goals and for futher design of applications of the 
technology outlined in the agreement.
    6. 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.
    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: October 8, 1999.
Kathleen Sybert,
Chief, Technology Development and Commercialization Branch, National 
Cancer Institute, National Institutes of Health.
[FR Doc. 99-32138 Filed 12-10-99; 8:45 am]
BILLING CODE 4140-01-P