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###### Department of Health and Human Services

###### Food and Drug Administration

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

# AGENCY:

Food and Drug Administration, HHS.

# ACTION:

Notice.

# 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                               ( print 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:                        *michelle.fuller@fda.hhs.gov*.                    

*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:                         *Cecilia.aguila@fda.hhs.gov*.                    

                        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                           ( print 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:                     *gladys.bohler@fda.hhs.gov*.                

Dated: September 17, 2009.

David Horowitz,

Assistant Commissioner for Policy.

[FR Doc. E9-22848 Filed 9-22-09; 8:45 am]

BILLING CODE 4160-01-S