[Federal Register Volume 74, Number 183 (Wednesday, September 23, 2009)]
[Notices]
[Pages 48572-48574]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-22848]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2009-N-0440]


Availability of Grant Funds for the Support of Cooperative 
Agreement Award to Georgetown University Entitled: Genome Wide 
Methylation Arrays for Detecting Markers of Increased Susceptibility to 
Mammary Cancer Caused by In-Utero Exposures to Endocrine Disruptors 
(U01)

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA), Center for Veterinary 
Medicine (CVM), and Office of New Animal Drugs (ONADE) is announcing 
the availability of grant funds for the support of a sole source, 
cooperative agreement award to Georgetown University, Lombardi Cancer 
Research Center and Department of Oncology entitled: ``Genome Wide 
Methylation Arrays for Detection Markers of Increased Susceptibility to 
Mammary Cancer Caused by In-Utero Exposures to Endocrine Disruptors 
(U01).'' The main purpose of this study is to help gain an 
understanding of the extent to which exposures to endocrine disruptors 
early in life increase later susceptibility to developing breast cancer 
by inducing heritable epigenetic changes in transcription factors, 
which are linked to increased breast cancer risk. The study is subject 
to the requirements of the Federal Food, Drug, and Cosmetic Act (the 
act) (21 U.S.C. 331, et seq.) regulations issued under it and 
applicable Department of Health and Human Services statutes and 
regulations.

DATES: Important dates are as follows:
    1. The application due date is 30 days from the publication in the 
Federal Register.
    2. The anticipated start date is September 2009.

FOR FURTHER INFORMATION CONTACT:
    Peer Review/Administrative Contact: Michelle Fuller, Center for

[[Page 48573]]

Veterinary Medicine (HFV-10), Food and Drug Administration, 7519 
Standish Pl., Rockville, MD 20855, 240-276-9736, FAX: 240-276-9744, e-
mail:[email protected].
    Scientific Contact: M. Cecilia Aguila, Center for Veterinary 
Medicine (HFV-153), Food and Drug Administration, 7500 Standish Pl. 
(rm. E478), Rockville, MD 20855, 240-276-8125, FAX: 240-276-8116, e-
mail: [email protected].
    For more information on this funding opportunity announcement 
(FOA), and to obtain detailed requirements, please refer to the full 
FOA located at http://www.fda.gov/cvm.

SUPPLEMENTARY INFORMATION:

I. Funding Opportunity Description

Request for Application: RFA FD09-020
Catalog of Federal Domestic Assistance Number: 93.103

A. Background

    More than 80,000 chemicals are registered for use in commerce in 
the United States and an estimated 2,000 new chemicals are introduced 
annually. These chemicals are used or present as contaminants in 
everyday items such as: Foods, personal care products, prescription 
drugs, household cleaners, and lawn care products (National Toxicology 
Program, 2002). Scientists are continually learning more about how 
these compounds interact with the body and the long-term impact of 
these interactions on our health. For example, many synthetic chemicals 
have been identified as known or suspected EDCs (endocrine disruptors), 
including DES (diethylstilbesterol), BPA (bisphenol A), and GEN 
(genistein). The long-term impact of these chemicals on human health is 
still largely unknown, particularly when the exposure levels are 
relatively low and do not cause any apparent toxic effects. EDCs may 
have estrogenic, antiestrogenic, androgenic, and/or anti-androgenic 
actions and /or they may disrupt adrenal and/or thyroid functions, too.
    The endocrine system participates in many important functions of an 
organism, such as sexual differentiation before birth, sexual 
maturation during puberty, reproduction in adulthood, growth, 
metabolism, digestion, cardiovascular and immune functions, and 
excretion. Hormones are implicated in the etiology of certain cancers 
of hormone-dependent tissues, such as those of the breast, uterus, and 
prostate gland. Environmentally released man-made chemicals are 
suspected of being responsible for numerous adverse effects on the 
endocrine function in wildlife species as well as in humans.
    EDCs may be harmful to human health following fetal exposure. This 
likely relates to epigenetic changes in gene methylation patterns 
occurring during gametogenesis and embryonic development. During these 
periods, most of our genes are demethylated, followed by remethylation; 
the timing and pattern of remethylation depends on the tissue lineage, 
intrauterine environment, and maternal nutrition and other exposures. 
Several genes have been identified whose expression is epigenetically 
altered in adult tissues in animals that have been exposed in utero to 
environmental contaminants with endocrine disrupting activity. 
Therefore, we hypothesize that in utero EDC exposures increase 
hypomethylation of genes, including those that regulate mammary stem 
cell behavior.
    It is increasingly evident that many diseases, including breast 
cancer, may originate during fetal life. Experimental findings and 
limited human data show that maternal exposures during pregnancy to 
synthetic estrogens such as DES or endocrine disruptors present in food 
may precipitate mammary gland development and increase breast cancer 
risk. To date, traditional toxicity tests such as the 2-year rodent 
bioassay have been the bases for most regulatory decisions regarding 
the carcinogenic potential of chemicals in the food. The agency 
recommends an in utero exposure in these bioassays for direct food and 
color additives. Therefore, only a limited number of chemicals have 
been studied by this approach. Additionally, these in vivo toxicology 
studies are not routinely used to predict the effects of in utero 
exposures on later susceptibility to various diseases.

B. Research Objectives

    The main purpose of the this study is to help gain an understanding 
of the extent to which exposures to endocrine disruptors early in life 
increase later susceptibility to developing breast cancer by inducing 
heritable epigenetic changes in transcription factors, which are linked 
to increased breast cancer risk. This will be accomplished, first, by 
exposing pregnant rodents to estrogen and estrogen-like endocrine 
disruptors at doses previously found to increase mammary cancer among 
offspring. Focus will be on the resulting hypomethylated genes that 
express high levels of transcription factors, which regulate 
proliferation, apoptosis, and differentiation of mammary epithelial 
cells. Second, humans will be exposed to maternal diet containing 
plant-derived compounds with hormonal activity during pregnancy to 
determine if the diet induces epigenetic changes among daughters in the 
same transcription factors identified in rodents. Third, the study will 
utilize genetically modified animal models to determine if the 
epigenetic changes identified in global methylation arrays are causally 
linked to an increased susceptibility to developing mammary cancer in 
vivo.
    The data from this study will be used to develop the Prenatal 
Endocrine Disruption and Mammary Tumor Susceptibility assay (PEDMATS), 
which will provide a novel approach for predicting the safety of 
chemicals with endocrine activity. Consequently, the agency will 
benefit from the proposed study, which combines mechanism-focused 
toxicology studies and modern molecular biology tools, and addresses 
the question of the cellular target of breast cancer initiation; i.e., 
mammary stem and progenitor cells. PEDMATS would help the agency to 
predict the potential breast cancer risk for chemicals that have been 
identified as having, or that may have, endocrine activity, and for 
which there are no valid rodent carcinogenicity bioassays. Another 
valuable feature of this approach is the potential that the PEDMATS 
studies can be integrated into the current reproductive and 
developmental toxicity assessment battery used to evaluate the safety 
of new drugs.

C. Eligibility Information

    Georgetown University is uniquely qualified to conduct this 
research. It has the expertise to study genetic markers in breast 
cancer in animal models and humans. Importantly, Georgetown University 
has expertise and proven ability in identifying genes affected in 
breast cancer. The data analysis is a critical component of the 
hybridization array experiments and poses a number of challenges due to 
the large amount of data generated even in a single experiment. 
Sophisticated, statistically principled data mining tools should be 
used. These state-of-the-art clustering pattern analyses use standard 
Finite Normal Mixture models and probabilistic component subspaces, 
multimodal clusters being automatically identified using Akaide 
information criterion and minimal information analysis. Georgetown 
University, Lombardi Cancer Center recently developed a simple approach 
for the exploration of limited gene expression data sets. To reduce 
dimensionality, a simple univariate statistical analysis (t-test) to 
compare gene expression data is

[[Page 48574]]

used. The reduced dimensional data set is visualized in three 
dimensions using these novel algorithms. These visualized algorithms 
derive the first three principal components from Fisher's matrix and 
project the multidimensional data into three dimensional gene 
expression data space. Exploration of the reduced dimensional data set 
allows for the identification of discriminant genes that are either 
assembled into a predictive neural network, and/ or selected for 
functional studies. These approaches have proved useful in recent 
studies conducted by Dr. Hilakivi-Clarke (Georgetown University, 
Lombardi Cancer Center) in identifying genes affected by timing of 
dietary exposures on breast cancer risk and are the preferred 
approaches for this study.
    Georgetown University, Lombardi Cancer Research Center Animal Core 
Facility has an AAALAC (Association for Assessment and Accreditation of 
Laboratory Animal Care) accredited animal facility where the animals 
can be housed. Georgetown can provide the software, hardware, and 
sophisticated, statistically principled data mining tools. In addition, 
Georgetown University is already collaborating in an on-going women 
study in Finland measuring hormone and adipokine levels from blood 
samples.
    This is a sole source award to Lombardi Comprehensive Cancer Center 
and Department of Oncology, Georgetown University, Washington, DC.

II. Award Information/Funds Available

    Awards are made under the authorization of section 301 of the 
Public Health Service Act (PHS Act) (42 U.S.C. 241), as amended, and 
under Federal regulations at 42 CFR part 52 and 45 CFR parts 74 and 92.

A. Award Amount

    The total amount CVM expects to award is $100,400 in the first year 
and $104,400 in the second year for a total award of $204,800; total 
award amount includes direct and indirect costs.

B. Length of Support

    The project period will be from September 2009 to August 31, 2011. 
The first budget period will be from September 2009 to August 31, 2010.
    The second year award will depend on the availability of funds and 
recipient approved performance.

III. Paper Application, Registration, and Submission Information

    To submit a paper application in response to this FOA, applicants 
should first review the full announcement located at http://www.fda.gpo/cvm. Persons interested in applying for a grant may obtain 
application forms and instructions at http://grants.nih.gov/grants/forms.htm. For all paper application submissions, the following steps 
are required:
     Step 1: Obtain a Dun and Bradstreet (DUNS) Number
     Step 2: Register With Central Contractor Registration 
(CCR)
     Step 3: Register With Electronic Research Administration 
(eRA) Commons
    Steps 1 (DUNS Number) and 2 (CCR), in detail, can be found at 
http://www07.grants.gov/applicants/organization_registration.jsp. Step 
3 (eRA Commons), in detail, can be found at https://commons.era.nih.gov/commons/registration/registrationInstructions.jsp.
    After you have followed these steps, submit paper applications to 
the Grants Management Contact at the following address:
    Gladys M. Bohler, Division of Acquisition Support and Grants (HFA-
500), Food and Drug Administration, 5630 Fishers Lane, rm. 2105, 
Rockville, MD 20857, 301-827-7168, FAX: 301-827-7101, e-mail: 
[email protected].

    Dated: September 17, 2009.
David Horowitz,
Assistant Commissioner for Policy.
[FR Doc. E9-22848 Filed 9-22-09; 8:45 am]
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