CANCER THERAPY-RELATED USE OF GENETICALLY ENGINEERED MICE Release Date: January 28, 2002 PA NUMBER: PAR-02-051 PARTICIPATING INSTITUTES AND CENTERS (ICs): National Cancer Institute (NCI) (http://cancer.gov) Application Receipt Date: April 19, 2002 This Program Announcement expires on April 20, 2002, unless reissued. THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism(s) of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA The goal of this program announcement is to encourage the use of genetically engineered mouse cancer models for cancer therapy-related goals. Mouse cancer-prone models with heritable genetic alterations are usually derived to explore mechanisms that underlie basic cancer or tumor biology. Through in- depth phenotyping, these models are often discovered to have molecular genetic profiles and histopathology that are similar to the molecular signatures and tumor progression of human malignancies. Because of the similarities, the models may be appropriate to identify molecular targets for therapy or to test new molecularly targeted agents. The models may be credentialed with new agents through systematic preclinical trials to discover how well the mice mimic the clinical course of human cancer in response, or development of resistance, to therapy. Or the model strains may be used to discover the genetic determinants of response to therapeutic agents. RESEARCH OBJECTIVES Background With increasing frequency, there are new genetically engineered mice (GEMs) available that develop tumors whose molecular genetic profiles and histopathobiology are similar to the molecular signatures and tumor progression of human malignancies. However, the majority of GEMs are generated to explore hypotheses of basic cancer or tumor biology and genetics or to verify gene function in vivo. There is mounting evidence that GEMs may prove appropriate for identification of molecular targets for therapy or for testing new agents directed at such targets or pathways. However, these uses are largely unexplored. Additionally, few model developers use new agents to undertake systematic, preclinical trials to discover how well their models parallel the clinical course of human cancer in response, or development of resistance, to therapy. At the present time, it is not fully evident how informative or predictive GEMs are for human cancer therapy-related applications. Because GEMs are immune-competent animals, they may better indicate the role of immune cells and secreted factors in response to therapy than do cultured cells or human xenografts in immune-compromised host animals. Additionally, GEMs may be used to define the role of particular genes in response to new agents. GEMs may also allow testing of single or multiple agents at various stages of tumor progression, including at the very early manifestations of malignancy. Cell lines from, or xenografts of, human tumors are not representative of pre- malignant or early lesions whose response to therapy may differ substantially from tumors that have accumulated substantial stochastic genetic changes. For example, several anti-angiogenesis agents were tested in an engineered model with defined stages of tumor progression. One agent was effective in eliminating the early lesions, but was ineffective at a later stage. In contrast, a second inhibitor had no effect on early lesions but substantial inhibition of late-stage tumor growth. There are other examples of GEMs that effectively mimic the clinical course of response to therapy and development of resistance. Subsequent analysis of non-responding mice or those that eventually became resistant may reveal additional genetic lesions or other changes that account for the observed differences. Non-responding mice are useful for derivation and testing of new classes of agents to overcome resistance. Because these cancer models are developed on various strains of inbred mice or on mixed genetic backgrounds, they may also be valuable to delineate the genetic determinants of response or resistance to therapy. Summary This PA is intended to encourage those who develop GEMs for studies of tumor biology to delineate how appropriate they are for cancer therapy-related research, and to define the practical limitations to use of GEMs for preclinical therapy research. Where it is advisable, the applicants to this PA should include collaborators who are expert in, for example, translational research, clinical trials, imaging research, and statistical analysis. Applicants are also encouraged to consider subcontracts with companies who can provide relevant services that are unavailable at their institutions. The following are examples of topics that are responsive to this PA; however, appropriate subjects are not limited to those given below. 1. Preclinical trials of appropriate agents in relevant GEMs to determine if the timing and penetrance of the tumor phenotype limits the value of the model for this use. 2. Preclinical trials to credential appropriate GEMs for how well they reflect the observed clinical course of human cancers. 3. Appropriate experiments to determine the pharmacodynamics and pharmacokinetics of specific agents in GEMs. 4. Preclinical trials that incorporate use of high-throughput technologies or small-animal imaging to monitor delivery of agents or response to therapy. 5. Preclinical trials to determine efficacy of new single or multiple agents at different stages of tumor progression. 6. Preclinical trials that examine which aspects of trial design are appropriate for experiments with GEMs. 7. Examination of GEMs and their corresponding normal background strains for genetic determinants of therapeutic response. MECHANISM OF SUPPORT This PA will use the NIH R01 award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. This PA uses just-in-time concepts. It also uses the modular budgeting format. (see https://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. 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 o Faith-based organizations 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 your inquiries concerning this PA and welcome the opportunity 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: Cheryl L. Marks, Ph.D. Division of Cancer Biology National Cancer Institute Executive Plaza North, Room 5000 Bethesda, MD 20892-7380 Telephone: (301) 594-8778 FAX: (301) 496-8656 Email: cm74v@nih.gov o Direct your questions about financial or grants management matters to: Mr. Ted Williams Grants Administration Branch National Cancer Institute Executive Plaza South, Room 243 Bethesda, MD 20892 Telephone: (301) 496-8785 FAX: (301) 496-8601 Email: williate@mail.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 https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the receipt date listed on the first page of this program announcement. 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 https://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 https://grants.nih.gov/grants/funding/modular/modular.htm. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIH staff member within one of NIH institutes or centers who has agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1) Contact the NCI program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study; 2) Obtain agreement from the NCI staff that the NCI will accept your application for consideration for award; and, 3) Identify, in a cover letter sent with the application, the staff member and the Institute/Center who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and five signed 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) APPLICATION PROCESSING: Applications must be received by or mailed before the receipt date listed on the first page of this program announcement. The CSR will not accept any application in response to this PA that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a second level review by the appropriate 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, your application will also be reviewed with respect to the following: PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. INCLUSION: 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 included in the section on Federal Citations, below) BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities 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 https://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. 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 PA 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 No. 93.396, 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 https://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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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