MOLECULAR TARGET DRUG DISCOVERY FOR CANCER: EXPLORATORY GRANTS
Release Date: February 2, 2001
PA NUMBER: PAR-01-045
National Cancer Institute
Letter of Intent Receipt Date: May 17, 2001
Application Receipt Date: June 14, 2001
THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.
This Program Announcement (PA) replaces PAR-00-060, which was published in the
NIH Guide on February 18, 2000.
PURPOSE
The National Cancer Institute (NCI) defines new, extraordinary research
opportunities through stated goals in a "Bypass Budget". Among the
priorities of the 2001 and 2002 Bypass Budgets is a plan to identify and use
molecular targets for the discovery and clinical testing of new anticancer
agents based on the molecular mechanisms that underlie neoplastic
transformations, cancer growth and metastasis. Accordingly, the Developmental
Therapeutics Program, Division of Cancer Treatment and Diagnosis, National
Cancer Institute (NCI), and the Chemoprevention Agent Development Research
Group, the Division of Cancer Prevention, NCI invite
exploratory/developmental grant applications (R21) to exploit molecular
targets for drug discovery. New insights into our understanding of cancer
cell biology provide a new opportunity for a fundamental re-ordering of
approaches to cancer drug discovery. Current research in carcinogenesis has
identified many enzymes, genetic lesions, and their cellular constituents
associated with inhibition and progression of pre-cancers to invasive disease.
Rather than depending on in vitro and in vivo screens for antiproliferative
activity, investigators can now focus on new molecular targets and pathways
essential for the development and maintenance of the cancer phenotype. As a
result, the NCI is reorganizing its drug development programs from early drug
discovery phases to the conduct of clinical trials in order to bring forward
new types of agents based on strong rationales. The plan also involves
changes in the clinical evaluation of new agents that will include appropriate
measurements to verify target modulation.
In addition to the present announcement, the NCI announces a related
initiative in molecular target drug discovery for cancer treatment and
prevention utilizing an additional funding mechanism: Competing Supplements
for existing NCI awardees
(http://grants.nih.gov/grants/guide/pa-files/PAR-01-046.html) which can
extend the goals of active grants to include studies related to drug
discovery. See the Home Pages of either the Developmental Therapeutics
Program (http://dtp.nci.nih.gov) or the Chemoprevention Agent Development
Group (http://dcp.nci.nih.gov/cb) for further information or contact
individuals listed under INQUIRIES of this PA. Further information on
research opportunities regarding molecular targets in drug discovery can be
found in the NCI Bypass Budget, The Nation’s Investment in Cancer Research: A
Budget Proposal for Fiscal Year 2001 at http://2001.cancer.gov and for 2002 at
http://plan2002.cancer.gov
The purpose of this Program Announcement (PA) is to reorganize the front end
or gateway to drug discovery. Investigators are being asked to identify a
novel molecular target, or to validate the target as a basis for cancer drug
discovery, or to develop an assay for the target. Given the fact that some
investigators may already have considerable preliminary data on a signaling
pathway, they nevertheless may not have focused on the point of greatest
vulnerability in the pathway and therefore, perhaps the optimal point of drug
attack. This PA would support an investigator to validate a target and/or
develop an assay based on the target. Applicants may address targets related
to the treatment of established cancers, or the prevention of molecular
changes which may cause cancer. Investigators may use their own creativity in
defining their approach. For example, some may prefer to 1) use a genetic,
structural biology or molecular biology approach to target
identification/validation using information from genetic studies or studies of
pathways, whereas others may prefer to 2) identify the function of a
cellular target after first finding the target as a result of exploring
binding patterns of natural products or other ligands to the novel target.
The PA requires that the proposed target(s) in each application be novel and
not addressed by drugs already approved for clinical use.
This PA will expire on June 15, 2001 unless reissued. NIH Grants policies
apply to these awards.
RESEARCH OBJECTIVES
Background
The past 20 years have seen an explosion in the understanding of how cancer
cells work. Increasing knowledge of human carcinogenesis is providing many
new opportunities for study of molecular targets modulated by drugs that might
prevent cancer. Most of the insights have resulted from an improved
understanding of the genetic basis of carcinogenesis. Specific molecules have
been identified which cause the initiation and progressive growth of tumors.
From this work, a fundamental re-ordering of the approach to drug discovery
and development for the treatment and prevention of cancer has emerged. There
is the opportunity to move away from screening agents by their effects on
tumor cell growth, in vivo or in vitro, and targets that have been thoroughly
exploited. While it remains true that these methods might continue to be the
basis for the development of clinically useful agents, these agents may not be
the best lead compounds that effect a particular pathway of biologic
importance specific for cancer establishment or progression. Drugs discovered
by these early methods have historically demonstrated clear limitations in
clinical efficacy. The hope is that drugs targeting new, specific molecular
lesions in cancer cells will provide more selective and less toxic therapy or
prevention approaches, alone or in combination with other agents. The focus
of attention in this new approach to cancer drug discovery is a compound’s
effect against a novel molecular target, or a target operating in a defined
biochemical pathway, with the intent of causing a gain or loss in function to
reverse, stop, or delay cancer progression. The cancer cell selectivity of
lead compounds should be enhanced by screens based on a novel target or a
critical pathway that represent a true Achilles heel. Some possible ways that
preventive agents may modify molecular targets include interfering with tumor
initiation by: 1) modifying carcinogen activation by enzymes responsible for
activation or scavenging DNA reactive electrophiles or free radicals,
2) enhancing carcinogen detoxification processes by altering the activity of
detoxifying enzymes, 3) repairing structural/functional genetic defects by
enhancing endogenous DNA repair systems, 4) blocking tumor promotion and
progression including altering the expression of genes involved in cell
signaling, particularly those regulating cell proliferation, apoptosis and
differentiation.
The evaluation of drugs in the clinic which have emerged from these types of
approaches is beginning. A recent example is the discovery of STI-571, a
Novartis compound under investigation for the treatment of chronic myelogenous
leukemia (CML) and other cancers. STI-571 has been shown by Schindler et al.
in Science 289, 1938 (2000) to target the Bcr-Abl fusion protein, a tyrosine
kinase whose expression is considered to be the cause of CML. Other examples
which might be mentioned include the farnesyl transferase inhibitors (FTIs),
protein kinase (PK) antagonists of various sorts, matrix metalloprotease
inhibitors, and growth factor receptor or other effector antagonists
(herceptin, endothelin, tamoxifen, TRAIL, etc.). Recent cancer epidemiology
and pharmacogenetic studies have suggested the importance of genetic
polymorphisms affecting the ability to detoxify carcinogens, e.g.,
glutathione-S-transferase (GSTM1, GSTM2, GSTP1), N-acetyltransferase (NAT1,
NAT2), cytochrome P450 (CYP450IAI), and steroid 5-alpha-reductase type II
(SRD5A2). It is striking that in this process the pharmaceutical industry has
clearly seized a defining role in expeditiously advancing potentially useful
compounds to a clinical test. However, in each of the instances cited, the
pioneering studies on the targets to which these drugs are directed occurred
largely (if not exclusively) in the academic sector.
Objectives and Scope
The goal of this PA is to provide the means for investigators to generate
preliminary data leading to the discovery and validation of molecular targets
for cancer prevention or treatment intervention which can be developed into
drug discovery assays. Identification of a potential target might present
varying degrees of difficulty, but validation (an indication of a target’s
predictive capacity to aid in the selection of clinical drugs) is apt to be
uniformly more problematic. Leads for many existing clinical drugs were not
discovered through the use of macro-molecular targets but rather through in
vivo or in vitro anti-proliferative assays. Accordingly, the cornerstone of
this effort is the validation of targets of demonstrated importance. However,
the exploratory/development grants, herein described, should be projects that
seek preliminary data in the identification or validation of molecular targets
or their development into a screening tool. Approaches and projects
appropriate for this PA should be in one or more of three general areas as
follows:
First, investigative activities establishing a molecule as a potential cancer
drug discovery target can have as its focus any aspect of early dysplasia or
cancer cell biology that may reveal a vulnerability in the cancer cell. These
might include cell cycle checkpoints, DNA repair, cell stress, cell
immortalization or cell death pathways, cassettes of altered transcription
factor activity, activation of pathways allowing cell growth in hypoxic or
hypo-vascularized conditions, events involved in angiogenesis, cell invasion
and metastases, or strategies to modulate the immune system. Oncogenic viral
targets also would be appropriate. In fact, any difference between a cancer
and normal cell could potentially be exploitable as a therapeutic maneuver.
Modern science has afforded numerous opportunities to demonstrate the likely
value of this approach. These include: (1) engineered animals of various
sorts (transgene-expressing, knock-out, etc.), (2) smart assays designed to
give information, not only about phenotypic alteration, such as growth arrest
or cell death, but also about the effect on particular molecular targets of
pathways known or suspected to have biological relevance to cancer, (3) array
technology, where the action of a candidate drug lead against its target can
be placed rapidly in the context of expected action against other cellular and
indeed organ-specific molecules, and (4) cancer gene discovery programs, such
as the Cancer Genome Anatomy Project (CGAP) (http://www.ncbi.nlm.nih.gov/CGAP/),
which has identified numerous mutational sites in cancer cells, some of
which are possibly unique to specific types of cancer. Accordingly, a
requirement is to establish that a molecular target likely affects important
aspects of cancer cell function.
Second, the validation of new molecular targets, with the intent of
discovering new agents for the treatment or prevention of cancer, is an
important and necessary activity. At present, science appears to offer too
many targets. Therefore, projects should focus on determining which of these
numerous potential defects are sites of critical vulnerability which could be
exploited for intervention. Ideally one would expect to demonstrate that
manipulation of the target function would cause a phenotypic change in the
cancer cell. Clearly if a prime target is fully validated, such that the
target can be used to totally exploit a unique difference between a healthy
and a cancerous cell, control of cancer would then only await the discovery of
a drug molecule through a systematic screening and/or drug design program, in
real laboratory experience, validation occurs in stages or degrees.
Demonstration of some phenotypic or functional change that is desirable, such
as elimination or reversal of dysplasia, tumor shrinkage or change in a
validated surrogate marker, would provide evidence of the importance of a
target. Approaches to target validation might involve the use of antisense or
engineered animals, such as transgene-expressing or gene knock-outs. Small,
bioactive molecules, obtained either from natural products libraries or from
chemical libraries, may be used as ligands to select and validate proteins
from arrays. If an investigator chooses to utilize crude extracts of natural
products, as from the NCI Active Repository, expertise must be available for
chemical fractionation of the extracts. Thus, validation can be
conceptualized as a series of milestones. A proposal to reach validation
milestones could be responsive to this PA. There are many good rationales for
selecting targets, but validation requires considerable imagination and skill
on the part of the investigator. Therefore, also responsive to this PA would
be an insightful and clever validation of a target suggested by others as a
possible intervention point. While it is true that the ultimate validation
can only come from a successful clinical trial, having information on the
importance of the target prior to the trial should provide important feedback
in case therapies are ineffective.
Third, the target system should be amenable to conversion into a screen for
effectors of the target’s function (at minimum on a laboratory scale), or the
molecular structure determined through biophysical techniques as a prelude to
drug discovery studies . These aspects are critical components which would
form the thrust of any molecularly focused drug discovery effort. The
practical nature of drug discovery research is of high importance. While the
desirability of this approach might seem obvious, the tools for accomplishing
this task are only now becoming routinely available. These include sequence
information defining the primary structure of relevant target proteins or
other macromolecules, expression vectors for their large scale production,
biophysical (e.g. X-ray and NMR) and computational techniques to allow the
determination of three-dimensional structure, advances in screening technology
to allow ever increasing speed and efficiency in assessing large numbers of
candidate structures, and combinatorial chemistry to generate large numbers of
candidate drug structures.
SPECIAL REQUIREMENTS
Patent Coverage. Since the discovery of new targets, assays and improved
anticancer treatment and prevention is the objective of this effort, and since
transfer of intellectual property to industrial laboratories for extended
developmental purposes is facilitated by the existence of adequate patent
coverage, it is essential that applicants provide plans to assure such
coverage. Each applicant must therefore provide a detailed description of the
approach to be used for obtaining patent coverage and for licensing where
appropriate, in particular where the invention may involve investigators from
more than one institution. Procedures must be described for resolution of
legal problems should they arise. Your attention is drawn to P.L. 96-517 as
amended by P.L. 98-620 and 37 CFR Part 401. Instructions were also published
in the NIH Guide for Grants and Contracts, Vol. 19, No. 23, June 22, 1990.
A formal statement of patent procedures and plan for transfer of materials
embodying intellectual property to other parties as well as a detailed
description of procedures to be followed for resolution of legal problems
which may develop, signed and dated by the organizational official authorized
to enter into intellectual property arrangements for each applicant and
collaborators, if any, must be developed. The signed agreement must be
submitted prior to award to Dr. John A. Beisler at the address provided below
under INQUIRIES.
Applicants proposing to access the Natural Products Repository of the NCI must
obtain and execute the Natural Products Repository Material Transfer Agreement
(MTA) prior to receiving an award. Similarly, applicants proposing to access
the synthetic repository of the NCI must obtain and execute the synthetic MTA
prior to receiving an award. These agreement forms are available at
http://dtp.nci.nih.gov. (On the panel, left side, click on "Organization",
select "Natural Products Branch", select "Natural Products Repository", then
scroll down to and select "Material Transfer Agreement"). For information
concerning the NCI synthetic or natural product repositories go to the
Developmental Therapeutics web site, http://dtp.nci.nih.gov (On the panel,
left side, click on "Samples and Services").
For applications involving natural products, the applicant must provide a
formal statement signed by an authorized representative of the applicant
institution which assures that an equitable portion of royalties or profits
arising from drugs discovered, if any, will benefit indigenous peoples,
research collaborators, research institutions or governmental entities as
appropriate, in the country of origin of the natural product sample from which
the drug was derived. Plans for the procurement of proper collection and
export permits must be provided. The signed document must be submitted prior
to award to Dr. Gordon Cragg at the Developmental Therapeutics Program web
site, http://dtp.nci.nih.gov (On the panel, left side, click on
"Organization", select "Natural Products Branch" then click on "Organization/
Staff Directory").
A plan must be developed for disposition of natural products samples, chemical
libraries, etc. The signed document must be submitted prior to award to Dr.
John A. Beisler at the address provided below under INQUIRIES.
The four documents listed above will not be included with review material, and
therefore, will NOT be required at the time of application. However, awards
will not be made until they are received and approved by NCI.
MECHANISM OF SUPPORT
The funding instrument to be used for these awards is the
exploratory/developmental grant (R21). The R21 mechanism provides limited
funds for short-term research projects, especially for generating preliminary
data to establish a new, more comprehensive research study. The
exploratory/developmental grant (R21) mechanism was designed to give resources
to an investigator, who may then accumulative data to assess the feasibility
of a line of research. Therefore, this is a preferred mechanism for projects
that would clearly be premature for a traditional research project.
Responsibility for the planning, direction, and execution of the proposed
project will be solely that of the applicant. The total project period for an
R21 application submitted in response to this PA may not exceed TWO years.
Although the size of award may vary with the scope of research proposed, it is
expected that applications will stay within the budgetary guidelines for an
exploratory/developmental project, direct costs are limited to $100,000 (four
budget modules) per year unless the application includes consortium costs,
including Facilities and Administrative (F&A) costs awarded to the
collaborating institution, in which case the limit is $125,000 in direct costs
(five modules) per year. These grants are non-renewable and continuation of
projects developed under this program must be through other grant mechanisms.
The earliest anticipated award date is April 1, 2002.
Although no funds for this PA will be used to support intramural projects, NIH
intramural applicants must verify that the amount of the resources allocated
from intramural sources does not exceed $100,000 in direct costs. For further
budget information pertaining specifically to NIH intramural applications, see
APPLICATION PROCEDURES below regarding ADDITIONAL INSTRUCTIONS FOR NIH
INTRAMURAL PROJECT APPLICANTS .
Specific application instructions have been modified to reflect MODULAR
GRANT and JUST-IN-TIME streamlining efforts being examined by the NIH.
Complete and detailed instructions and information on Modular Grant
applications can be found at
http://grants.nih.gov/grants/funding/modular/modular.htm.
ELIGIBILITY REQUIREMENTS
These exploratory/developmental grant applications (R21) may be submitted by
foreign and domestic, for-profit and non-profit organizations, public and
private, such as universities, colleges, hospitals, laboratories, units of
State and local governments, and eligible agencies of the Federal Government.
Domestic applications may include international components. Applications may
also be submitted by an intramural laboratory from the National Institutes of
Health. For this PA, NIH investigators may submit applications, but they may
not request or receive funds from this program. Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to apply as
principal investigators.
INQUIRIES
Inquiries are encouraged. The opportunity to clarify any issues or questions
from potential applicants is welcome.
Direct inquiries regarding programmatic issues in cancer treatment to:
John A. Beisler, Ph.D.
Developmental Therapeutics Program
National Cancer Institute
EPN Room 8153
6130 Executive Boulevard
Bethesda, MD 20892-7456
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 496-8783
FAX: (301) 402-5200
Email: beislerj@exchange.nih.gov
Direct inquiries regarding programmatic issues in cancer prevention:
Winfred F. Malone, Ph.D.
Chemopreventative Agent Development Research Group
National Cancer Institute
EPN Room 200A
6130 Executive Boulevard
Bethesda, MD 20892-7322
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 594-0460
FAX: (301) 402-0553
Email: malonew@mail.nih.gov
Direct inquiries regarding fiscal matters to:
Ms. Barbara A. Fisher
Grants Administration Branch
National Cancer Institute
Executive Plaza South 243
Bethesda, MD 20892-7150
Telephone: (301) 846-1015
Fax: (301) 846-5720
Email: fisherb@gab.nci.nih.gov
Direct inquiries regarding review issues to:
Ms. Toby Friedberg
Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8109, MSC 8329
Bethesda, MD 20892-8329
Rockville, MD 20852 (for express/courier service)
Telephone (301) 496-3428
Fax: (301) 402-0275
Email: tf12w@nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit by May 17, 2001, a letter of intent
that includes a descriptive title of the proposed research, name, address, and
telephone number of the Principal Investigator, identities of other key
personnel and participating institutions, and number and title of the PA in
response to which the application may be submitted. Although a letter of
intent is not required, is not binding, and does not enter into the review of
subsequent application, the information that list contains allows NCI staff to
estimate the potential review workload and plan the review.
The Letter of Intent should be sent to Dr. John A. Beisler at the address
listed under INQUIRIES.
APPLICATION PROCEDURES
The modular grant concept establishes specific modules in which direct costs
may be requested as well as a maximum level for requested budgets. Only
limited budgetary information is required under this approach. The JUST-IN-
TIME concept allows applicants to submit certain information only when there
is a possibility for an award. It is anticipated that these changes will
reduce the administrative burden for the applicant, reviewers and NCI staff.
The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants with the modifications noted below. NIH intramural
project applicants must follow the directions below under the section heading:
ADDITIONAL INSTRUCTIONS FOR NIH INTRAMURAL PROJECT APPLICANTS". Application
kits are available at most institutional offices of sponsored research and may
be obtained from the Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone 301/710-0267, E-mail: grantsinfo@nih.gov
. The title and number of the program announcement must be typed on line 2 of
the face page of the application form and the YES box must be marked. For
those applicants with internet access, the 398 kit may be found at:
http://grants.nih.gov/grants/forms.htm
Applicants are strongly encouraged to call program contacts listed in
INQUIRIES above with any questions regarding the adherence to the guidelines
of their proposed project to the goals of this PA.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS
BUDGET INSTRUCTIONS
Modular Grant applications will request direct costs in $25,000 modules, up to
a total direct cost request of $100,000 per year ($125,000 if there are
consortium/contractual costs). The total direct costs must be requested in
accordance with the program guidelines and the modifications made to the
standard PHS 398 application instructions described below:
o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs
(in $25,000 increments) and Total Costs [Modular Total Direct plus Facilities
and Administrative (F&A) costs] for the initial budget period. Items 8a and
8b should be completed indicating the Direct and Total Costs for the entire
proposed period of support.
o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398. It is not required and will not be accepted with the
application.
o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 4 of the PHS 398. It is not required
and will not be accepted with the application.
o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative
page (see http://grants.nih.gov/grants/funding/modular/modular.htm for sample
pages). At the top of the page, enter the total direct costs requested for
each year. This is not a form page.
o Under Personnel, list all project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should
be provided. However, the applicant should use the NIH appropriation language
salary cap if applicable and the NIH policy for graduate student compensation
in developing the budget request.
For Consortium/Contractual costs, provide an estimate of total costs (direct
plus Facilities and Administrative) for each year, each rounded to the nearest
$1,000. List the individuals/organizations with whom consortium or
contractual arrangements have been made, the percent effort of all personnel,
and the role on the project. The total cost for a consortium/contractual
arrangement is included in the overall requested modular direct cost amount.
Include the Letter of Intent to establish a consortium.
Provide an additional narrative budget justification for any year to year
variation in the number of modules requested.
o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual"s qualifications for a specific
role in the proposed project, as well as to evaluate the overall
qualifications of the research team. A biographical sketch is required for
all key personnel, following the instructions below. No more than three pages
may be used for each person. A sample biographical sketch may be viewed at
http://grants.nih.gov/grants/funding/modular/modular.htm
- Complete the educational block at the top of the form page,
- List position(s) and any honors,
- Provide information, including overall goals and responsibilities, on
research
projects ongoing or completed during the last three years,
- List selected peer-reviewed publications, with full citations.
o CHECKLIST - This page should be completed and submitted with the
application. If the F&A rate agreement has been established, indicate the
type of agreement and the date. All appropriate exclusions must be applied in
the calculation of the F&A costs for the initial budget period and all future
budget years.
The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information
is necessary following the initial review.
Applications not conforming to these guidelines will be considered
unresponsive to this PA and will be returned without further review.
Submit a signed, typewritten original of the application, including the
checklist, and three signed, exact, single-sided 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)
To expedite the review process, at the time of submission, send two additional
signed photocopies of the application to:
Ms. Toby Friedberg
Referral Officer
National Cancer Institute
6116 Executive Boulevard, Room 8109, MSC 8329
Bethesda, MD 20892-8329
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Applications must be received by the receipt date at the beginning of this
program announcement. If an application is received after that date, it will
be returned to the applicant without review. The Center for Scientific Review
(CSR) will not accept any application in response to this PA that is
essentially the same as a research project application 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 an application must
follow the guidance in the PHS Form 398 application instructions for the
preparation of revised applications, including an introduction addressing the
previous critique.
SPECIAL INSTRUCTIONS FOR ALL APPLICANTS
The PA title, MOLECULAR TARGET DRUG DISCOVERY FOR CANCER: EXPLORATORY
GRANTS, and number of this PA must be typed on line 2 of the face page of the
application form and the YES box must be marked.
The plans below, if appropriate for the proposed work, should be included in
the application after the LITERATURE CITED section. Formal agreements signed
by an authorized representative of the applicant institution will be required
before award.
o A plan for patent coverage and licensing, for transfer of materials
embodying intellectual property to other parties, for resolution of legal
problems should they arise.
o A plan for an assurance to return benefits to the country of origin in
the use of natural products.
o A plan for the disposition of natural products samples and chemical
libraries.
o A signed Materials Transfer Agreement (MTA) if products from the Natural
Products Repository will be obtained.
ADDITIONAL INSTRUCTIONS FOR NIH INTRAMURAL PROJECT APPLICANTS
The research grant application form PHS 398 (rev. 4/98) is also to be used by
NIH intramural project applicants in applying for these grants. Applications
kits may be obtained from the Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone (301) 710-0267, E-mail: grantsinfo@nih.gov
The title and number of the PA must be typed on line 2 of the face page of the
application form and the YES box must be marked. The 398 kit may also be
found on the internet at
http://grants.nih.gov/grants/funding/phs398/forms_toc.html. The PHS 398
application form should be used with the following modifications:
o On the Face Page, fill out only items 1, 2, 3 (leave 3c blank), 4 and 5.
The remainder of the items should be left blank, and the application must not
be signed by either the PI or an NIH Institute official.
o Do not submit "Other Support", Checklist", "Personnel Report", or "Personal
Data" pages.
o The PI must obtain the approval of the NIH Institute Scientific Director
when applying as a principal investigator in the MTDD program under the terms
and conditions of the PA. A copy of that letter of approval must be provided
as part of a cover letter, addressed to the NCI Referral Officer, for the
application.
o The budget page should supply the time and effort for each project
participant, but no other budget figures should be included. The resources
available for the project and the research environment should be carefully
described, but no budget figures should be included. The NIH Institute
Scientific Director, as part of the letter of approval for participation, must
verify that no more than $100,000 direct costs of intramural resources will be
allocated to the project described in the application, and provide assurance
that the conduct of the project will comply with the DHHS regulations for
research involving human subjects (if applicable) and with the PHS policy on
vertebrate animal research.
o For NIH intramural applicants, a letter of approval must be submitted from
their Institute Intramural Scientific Director to allocate resources to the
project.
o Submit an unsigned, typewritten original of the application, and five
photocopies to:
Ms. Toby Friedberg
Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8109, MSC 8239
Bethesda, MD 20892-8239
Rockville, MD 20852 (for express/courier service)
Do not send the application or any copies to the Center for Scientific Review.
NIH intramural project applications must be received by July 18, 2000. If an
application is received after that date, it will be returned to the applicant
without review.
REVIEW CONSIDERATIONS:
Upon receipt, applications will be reviewed for completeness by CSR and for
adherence to the guidelines to this PA by the National Cancer Institute.
Incomplete applications will be returned to the applicant without further
consideration. Applications that are complete will be evaluated for
scientific and technical merit by an appropriate peer review group convened by
the Division of Extramural Activities of the NCI in accordance with the review
criteria stated below. As part of the initial merit review, a process will be
used by the initial review group in which all applications will receive a
written critique and 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, assigned a priority score, and
receive a second level review by the National Cancer Advisory Board.
Review Criteria
The five criteria to be used in the evaluation of grant applications are
listed below:
The goals of NIH-sponsored research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.
Within this framework, the specific goals of this PA are to provide support to
enable investigators without preliminary data to discover and/or validate new
molecular targets with the potential for developing assays for the discovery
of new agents to treat or prevent cancer. For example, these exploratory/
developmental grants may be to identify or characterized (de novo, or from the
literature) a target, to generate data for a validation, or to develop a
method to render a validated target into a drug assay. Meritorious projects
will include imaginative intervention points and insightful validation
approaches, which overall will reveal an exploitable site of critical
vulnerability.
The reviewers will comment on the five criteria listed below in their written
critiques of the applications in order to judge the likelihood that the
proposed research will have a substantial impact on the pursuit of these
goals. Each of these criteria will be addressed and considered by the
reviewers in assigning the overall score weighting them as appropriate for
each application. Note that the application does not need to be strong in all
categories to be judged likely to have a major scientific impact and thus
deserve a high priority score. For example, an investigator 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 this study address an important problem? If the aims
of the application are achieved, how will scientific knowledge be advanced?
What will be the effect of these studies on the concepts or methods that drive
this field? Is the proposed molecular target of importance to development and
maintenance of the transformed phenotype? Is the target new and not one which
has been the object of other evaluative studies? What is the likelihood that
assays using this target will lead to a new class of agents for the prevention
or treatment of cancer?
2. Approach. Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate to the aims of the
project? Does the applicant acknowledge potential problem areas and consider
alternate tactics? How well has the applicant addressed the major goals of
the PA: identification of a novel target, its validation as an intervention
point, or assay development? What is the likelihood that a high-throughput
screen can be developed with the target? Has the applicant designed an
appropriate set of experiments to demonstrate a critical site of vulnerability
in the cancer cell which can exploited for treatment or prevention? If crude
natural product extracts are proposed, are strategies for compound isolation
and identification adequate? If structural biology studies are proposed, are
plans adequate for the production of materials and have appropriate
collaborations been arranged? If screening is proposed, are data handling
procedures adequate, and is the assay validated and appropriate for large-
scale or high throughput use?
3. Innovation. Does the project employ novel concepts, approaches, or
methods? Are the aims original and innovative? Does the project challenge
existing paradigms or develop new methodologies or technologies? Will the
approaches advance the use of new, validated molecular targets for new drug
discovery?
4. Investigator. Is the investigator appropriately trained and suited to
carry out this work? Is the research proposed appropriate to the experience
level of the principal investigator and other researchers (if any)?
5. Environment. Does the scientific environment in which the 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
valuable collaborative arrangements? Is there evidence of institutional
support?
The initial review group will also examine: the appropriateness of the
proposed budget and duration, the adequacy of plans to include both genders
and minorities and their subgroups as appropriate for the scientific goals of
the research and plans for the recruitment and retention of subjects, the
adequacy of plans for including children as appropriate for the scientific
goals of the research, or justification for exclusion, the provisions of
human and animal subjects, and the safety of the research environment.
For intramural applications, all of the above applies except applications will
not be reviewed for completeness by CSR, the proposed budget will not be
reviewed by the review group.
AWARD CRITERIA
Applications will compete for available funds with all other recommended
applications. The following will be considered in making funding decisions:
Quality of the proposed project as determined by peer review, availability of
funds, and program priority.
SCHEDULE
Letter of Intent Receipt: May 17, 2001
Application Receipt Date: June 14, 2001
Review by NCAB Advisory Board: February 2002
Earliest Anticipated Start Date: April 1, 2002
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided 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 research involving human subjects should read the
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research," published in the NIH Guide for Grants and Contracts on
August 2, 2000
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html
A complete copy of the updated Guidelines is available at
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm The
revisions relate to NIH defined Phase III clinical trials and require: a) all
applications or proposals and/or protocols to 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) all
investigators to report accrual, and to conduct and report analyses, as
appropriate, by sex/gender and/or racial/ethnic group differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS.
It is the policy of NIH 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 clear and compelling 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 was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html.
Investigators also may obtain copies of the policy from the program staff
listed under INQUIRIES. Program staff may also provide additional relevant
information concerning the policy.
REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS
All investigators proposing research involving human subjects should read the
above-referenced policy that was published in the NIH Guide for Grants an
Contracts, June 5, 2000 (Revised August 25, 2000), and is available at the
following URL address
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.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. Reviewers are cautioned 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, Molecular Target Drug Discovery
for Cancer, is related to priority areas of human cancer treatment and
prevention. 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.
93.395, Cancer Treatment Research. 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 and Federal Regulations 42
CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review.
The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and promote the non-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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