MOLECULAR ANATOMY OF HEAD & NECK CANCER: A GENOMIC/PROTEOMIC APPROACH RELEASE DATE: May 6, 2003 RFA: DE-04-003 National Institute of Dental and Craniofacial Research (NIDCR) (http://www.nidcr.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.121 LETTER OF INTENT RECEIPT DATE: 7/26/2003 APPLICATION RECEIPT DATE: 8/26/2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute of Dental and Craniofacial Research (NIDCR) invites applications that foster basic and translational research aimed at deciphering the complex molecular networks involved in the development of squamous cell carcinomas of the head and neck (HNSCCs). This Request for Applications (RFA) encourages research projects that focus on: 1) Correlation of the genomic state, gene transcription profiles, and repertoire of proteins expressed and their activities with the functional status of both normal and aberrant cells; 2) New and existing discoveries in genomics/proteomics to develop novel biomarkers for early detection of pre-neoplastic and neoplastic lesions which might also serve as candidate targets for therapy. Collaborative projects involving interdisciplinary teams of investigators are strongly encouraged. RESEARCH OBJECTIVES BACKGROUND Cancers of the oral cavity, larynx and pharynx, collectively referred to as squamous cell carcinomas of the head and neck (HNSCCs), represent the 6th most common cancer in the developed world, and are often associated with low survival and high morbidity rates. Surgery, radiation and/or chemotherapy have not improved the 50% overall 5-year survival of this devastating disease over the past thirty years. Moreover, because of their location, treatment can lead to long-term functional and cosmetic defects in survivors, which can have a significant impact on the quality of life. The high mortality rate may be, in part, due to the fact that head and neck cancers are being diagnosed at predominantly later stages of the disease. Thus, early diagnosis plays a key role in disease progression, treatment response, and ultimately the quality of life and patient survival. Elucidation of the molecular mechanisms leading to head and neck cancer may result in the identification of new biomarkers of diagnostic/prognostic value and aid in the clinical management of these patients. The discovery of these biomarkers can also be useful for identification of pre- neoplastic lesions, which are difficult to distinguish from other lesions that are not pre-neoplastic in nature. Such knowledge will be of great value in the prevention and prognosis of HNSCCs. Like other malignancies, alterations of genes that control cell growth, differentiation and motility play an important role in the development and progression of head and neck cancers. HNSCCs arise in a multi-step process resulting from sequential accumulation of genetic changes. These changes involve a combination of both inherited and acquired alterations in the DNA sequence, ranging from point mutations to deletions, amplifications, and translocations. Invariably, changes in the genetic information result in alterations in expression patterns, both at the transcriptional and post-transcriptional levels. A number of genetic alterations in HNSCCs have been identified, thus providing a preliminary molecular progression model in squamous cell carcinogenesis. One of the most common genetic changes that occurs early in the progression of these tumors is loss of chromosomal region 9p21, whose main effect is inactivation of the p16 tumor suppressor gene, an inhibitor of cyclin-dependent kinase. Other changes include a mutation in the p53 gene in half the cases, resulting in the progression from pre-invasive to invasive lesions and amplification of the cyclin D1 oncogene observed in about a third of primarily invasive tumors. Since early genetic changes do not always correlate with changes in morphology and clinical diagnoses, testing for genetic alterations in early lesions may be of significant diagnostic value. The completion of the human genome project and the recent development of novel, highly sensitive high-throughput techniques have now afforded the unique opportunity to perform a comprehensive molecular characterization of normal, pre-cancerous, and malignant cells. Novel and emerging proteomic approaches will build on and complement the information obtained from these genomic studies. Proteomics describes the level of expression and activity of each protein, as well as the complexity of protein-protein interactions within the cell. Proteins can undergo a number of post-translational modifications and are dynamic molecules, with their composition constantly changing, making the study of the proteome even more complex. Nonetheless, the importance of these revolutionary approaches lies in unraveling the nature of the molecular alterations responsible for HNSCC development, including those affecting intricate molecular networks coupling protein expression profiles with signaling, and regulatory networks controlling cell cycle progression and cell survival or death. These efforts will constitute the foundation for the complete understanding of the molecular pathogenesis of HNSCCs, thus facilitating the identification of new markers for the early detection of pre-neoplastic lesions and novel targets for pharmacological intervention of this devastating disease. The following are some examples of research topics relevant to this initiative: o Identification and characterization of the relationship between gene expression profiling and protein networks to identify key cellular processes involved in normal and cancerous growth; o Identification and characterization of the relationship between gene and protein expression profiles and/or the presence of virally encoded molecules during tumor progression; o Characterization of the molecular changes during tumor progression in squamous epithelial cells and the stroma as well as exploration of the molecular interplay between squamous epithelial cells and the cellular components of the stroma; o Use of genomic, expressional and proteomic technologies to identify the molecular determinants responsible for malignant progression of oral pre-malignancies; o Elucidation of the molecular events leading to the acquisition of an invasive and metastatic phenotype; o Examination of specific signal transduction networks functionally altered during tumorigenesis; o Use of protein microarrays (e.g., arrayed antibodies and MALDI mass spectrometry) to study changes in protein abundance, phosphorylation states, protein-protein interactions, protein expression patterns etc. in squamous epithelium; o Establishment and characterization of cell cultures, organotypic cultures, and animal model systems to decipher the mechanisms of HNSCC initiation and progression; o Epigenetic characterization of head and neck tumors i.e., use of CGH arrays, promoter methylation arrays, and transcription factor analysis during tumor progression; o Use of gene and protein expression profiling for staging as well as predicting prognosis of HNSCCs; o Use of high-throughput genomic and proteomic analyses to study squamous carcinoma cell growth, differentiation, apoptosis, and senescence; o Use of bioinformatics tools to analyze data related to gene and protein expression, interaction, and modification, and their relationship to genetic alterations in HNSCCs. The collaboration between individuals with diverse backgrounds in molecular biology, genetics, bioinformatics, genomics, proteomics etc. is strongly encouraged. MECHANISM OF SUPPORT This RFA will use NIH R01 (Investigator-Initiated Research Project Grant) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator- initiated applications and will be reviewed according to the customary peer review procedures. The earliest award date is April 2004. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. This RFA uses just-in-time concepts. It also uses the modular budgeting format. (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. FUNDS AVAILABLE The NIDCR intends to commit approximately $3.0 million total costs (direct plus indirect costs) in FY 04 or FY 05 to fund 8 to 9 R01s in response to this RFA. An applicant may request a project period of up to five years and a budget for direct costs of up to $250,000 per year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIDCR provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Yasaman Shirazi, Ph.D. Director, Epithelial Cell Regulation and Transformation Program Division of Basic and Translational Sciences National Institute of Dental and Craniofacial Research 45 Center Drive, Room 4AN-18C Bethesda, MD 20892-6402 Telephone: (301) 594-4812 FAX: (301) 480-8318 Email: Yasaman.Shirazi@nih.gov o Direct your questions about peer review issues to: H. George Hausch, Ph.D. Acting Director, Division of Extramural Activities National Institute of Dental and Craniofacial Research National Institutes of Health 45 Center Drive, Room 4AN-44F Bethesda, MD 20892-6402 Telephone: (301) 594-2904 FAX: (301) 480-8303 Email: George.Hausch@nih.gov o Direct your questions about financial or grants management matters to: Mary Daley Chief Grants Management Officer Division of Extramural Activities National Institute of Dental and Craniofacial Research 45 Center Drive, Room 4AN-44B Bethesda, MD 20892-6402 Telephone: (301) 594-4808 FAX: (301) 480-3562 Email: md74u@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Yasaman Shirazi, Ph.D. Director, Epithelial Cell Regulation and Transformation Program Division of Basic and Translational Sciences National Institute of Dental and Craniofacial Research 45 Center Drive, Room 4AN-18C Bethesda, MD 20892 Telephone: (301) 594-4812 FAX: (301) 480-8318 Email: Yasaman.Shirazi@nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step- by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist and three photocopies in one package to: Center For Scientific Review National Institutes Of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application package must be sent to: H. George Hausch, Ph.D. Acting Director, Division of Extramural Activities National Institute of Dental and Craniofacial Research National Institutes of Health 45 Center Drive, Room 4AN-44F Bethesda, MD 20892-6402 Telephone: (301) 594-2904 FAX: (301) 480-8303 Email: George.Hausch@nih.gov APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes. While the investigator may still benefit from the previous review, the RFA application is not to state explicitly how. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by NIDCR. Incomplete applications will be returned to the applicant without further consideration. And, if the application is not responsive to the RFA, NIH staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the (IC) in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the NIDCR National Advisory Council or Board. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS DATA SHARING: The adequacy of the proposed plan to share data. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: July 26, 2003 Application Receipt Date: August 26, 2003 Peer Review Date: November 2003 Council Review: January 2004 Earliest Anticipated Start Date: April 2004 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub- populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/ guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/ women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/ NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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