DEVELOPMENT OF HIGH-YIELD TECHNOLOGIES FOR ISOLATING EXFOLIATED CELLS IN BODY
FLUIDS
RELEASE DATE: March 21, 2002
PA NUMBER: PA-02-086 (see replacement PA-04-035)
EXPIRATION DATE: November 16, 2003, unless reissued.
National Cancer Institute (NCI)
(http://www.nci.nih.gov/)
LETTER OF INTENT RECEIPT DATE: June 25, 2002, Sept. 30, 2002, Feb. 14, 2003
APPLICATION RECEIPT DATES: July 23, 2002, Oct. 28, 2002, March 14, 2003
This Program Announcement (PA) replaces PAR-01-019,
which was published in the NIH Guide on November 17, 2000.
THIS PA CONTAINS THE FOLLOWING INFORMATION
o Purpose of the PA
o Research Objectives
o Mechanism of Support
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 Award Criteria
o Required Federal Citations
PURPOSE OF THIS PA
To develop novel technologies for capturing, enriching, and preserving
exfoliated abnormal cells in body fluids or effusions and to develop methods
for concentrating the enriched cells for biomarker studies. In body fluids,
such as sputum, the number of exfoliated tumor cells is often small compared
to the number of non-neoplastic cells. Therefore, the detection of exfoliated
abnormal cells by routine cytopathology is often limited because few atypical
cells may be present in the specimen. Furthermore, there may be difficulty in
separating dysplastic cells from non-specific reactive changes and
degenerating cells or variation in diagnostic criteria. Furthermore,
exfoliated cells are frequently contaminated with normal cells, bacteria, and
other cellular debris, which makes molecular analysis difficult without
physical separation of the neoplastic cells. Thus, the development of
enrichment methods is a prerequisite for the routine detection of small
numbers of exfoliated cells and small amounts of subcellular materials in
biological fluids for molecular analysis.
RESEARCH OBJECTIVES
Background
The most common human tumors arise from epithelial surfaces (e.g. colon,
lung, prostate, oral cavity, esophagus, stomach, uterine cervix, bladder).
Their development often becomes apparent when tumor cells exfoliate
spontaneously into sputum, urine, or even into various effusions. The
molecular and genetic abnormalities within these exfoliated cells could be
used to detect and identify precancerous lesions or very early stage cancer
if highly sensitive technologies were clinically available to identify the
few abnormal cells among millions of normal cells. For example, detection
of widespread microsatellite instability (MSI), as demonstrated by expansion
or deletion of repeat elements of DNA, may be adapted for exfoliated cells in
general. With the advent of PCR-based detection of DNA from rare neoplastic
cells in body fluids, mutations have been detected in ras genes from the
stool of patients with colorectal cancer, and in p53 from the urine of
patients with bladder cancer and in the sputum of patients with lung cancer.
Similarly, DNA isolated from cells in urine samples can be used for mutation
detection. As these assays are complex and technically challenging, they
depend on the development of novel technologies for isolating and enriching
exfoliated cells.
Abnormal exfoliated cells can be routinely identified by cytologic
examination of brushings and fluids, for instance, from bronchi, pancreatic
ducts, voided urine and tapping of effusions. Currently fluids are usually
processed by centrifugation or membrane filtration. However, the detection of
abnormal exfoliated cells, for instance, cancer cells by routine
cytopathological examination may be limited because the number of abnormal
cells may be very small compared to the number of normal cells.
Alternatively, the cellular and nuclear changes in abnormal cells may be
minimal compared to normal cells. This is particularly true of urine
cytology, where many low-grade papillary lesions are often missed on
cytological examination. New PCR-based technologies may substantially
enhance the sensitivity, but current technologies for isolating exfoliated
cells are too cumbersome to be of practical utility.
Finding molecular and genetic biomarkers of early cancer represents an
extraordinary opportunity for the National Cancer Institute (NCI) and is
particularly important in detecting the emergence of precancerous cell
populations. In these earliest stages of neoplastic development, lesions
should be amenable to complete eradication. This has been well demonstrated
in cervical neoplasia, where screening for brushed exfoliated cells has
resulted in a 70% or greater reduction in cervical cancer mortality. Brushing
of the esophagus or stomach is commonly performed during endoscopic
examination.
Goals and Scope
In pursuit of these goals, the NCI invites applications, which address the
following areas:
1. development of novel technologies for identifying abnormal exfoliated
cells in body fluids,
2. development of novel technologies for capturing, enriching, and
preserving abnormal exfoliated cells in body fluids,
3. development of enrichment methods for the isolation of tumor cells and
tumor cell-associated macromolecules in body fluids,
4. development of sensitive, high-throughput molecular, cytomorphometric,
immunologic, and other relevant technologies to isolate tumor cells in
malignant effusions for detection of low tumor burden and to help distinguish
reactive cells from tumor cells.
Applicants should not only address the technology of enriching and isolating
exfoliated cells, but they should also address their viability of exfoliated
cells and usefulness for cytologic and molecular studies.
MECHANISM OF SUPPORT
This PA will use the National Institutes of Health (NIH)
exploratory/developmental (R21) grant award mechanism. As an applicant, you
will be solely responsible for planning, directing, and executing the
proposed project. The total project period for an application submitted in
response to this PA may not exceed TWO years.
Direct costs are limited to $100,000 (four budget modules) per year unless
the application includes consortium costs, in which case the limit is
$125,000 direct cost (five budget modules) per year. These grants are non-
renewable and continuation of projects developed under this PA will be
through the traditional unsolicited investigator initiated grant program.
This PA uses just-in-time concepts. It also uses the modular budgeting
format. (see https://grants.nih.gov/grants/funding/modular/modular.htm).
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 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:
Sudhir Srivastava, Ph.D., M.P.H.
Division of Cancer Prevention
National Cancer Institute
Executive Plaza North, EPN 3142
Rockville, MD 20852
Telephone: (301) 496-3893
FAX: (301) 402-8990
Email: ss1a@nih.gov
Or
Mukesh Verma, Ph.D.
Division of Cancer Prevention
National Cancer Institute
Executive Plaza North, EPN 3144
Rockville, MD 20852
Telephone: (301) 496-3983
FAX: (301) 402-8990
Email: mv66j@nih.gov
o Direct your questions about peer review issues to:
Referral Officer
National Cancer Institute
Division of Extramural Activities
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: ncidearefof@mail.nih.gov
o Direct your questions about financial or grants management matters to:
Mr. Brian E. Martin
Grants Management Specialist
National Cancer Institute
Executive Plaza South, Room 243
6120 Executive Blvd. MSC 7148
Bethesda, MD 20892-7148
Telephone: (301) 846-1014
FAX: (301) 846-5720
Email: bm215c@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 PA
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 NCI 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:
Sudhir Srivastava, Ph.D., M.P.H.
Division of Cancer Prevention
National Cancer Institute
Executive Plaza North, EPN 3142
Rockville, MD 20852
Telephone: (301) 496-3983
FAX: (301) 402-8990
Email: ss1a@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 by the receipt dates listed at the
beginning of this program announcement.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications must be
submitted in 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.
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of
the application, including the checklist, and three 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)
At the time of submission, two additional copies of the application must be
sent to:
Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329
Rockville, MD 20852 (for express/courier service)
APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE
WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries
(i.e. FEDEX, UPS, DHL, etc.) (https://grants.nih.gov/grants/guide/notice-
files/NOT-CA-02-002.html) This change in practice is effective immediately.
This policy is similar to and consistent with the policy for applications
addressed to Centers for Scientific Review as published in the NIH Guide
Notice https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html.
APPLICATION PROCESSING: Applications must be received by the receipt dates
described on the first page of this PA. 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
Upon receipt, applications will be reviewed for completeness by the CSR and
for adherence to the guidelines of this PA by the NCI program staff.
Applications not adhering to the guidelines of this PA, and those
applications that are incomplete as determined by CSR or by NCI program
staff, will be returned to the applicant without review.
Applications that are complete and adhere to the guidelines of this PA 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, 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 Those that receive a priority score will undergo a second level review by
the National Cancer Advisory 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
REQUIRED FEDERAL CITATIONS
MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components
involving Phase I and II clinical trials must include provisions for
assessment of patient eligibility and status, rigorous data management,
quality assurance, and auditing procedures. In addition, it is NIH policy
that all clinical trials require data and safety monitoring, with the method
and degree of monitoring being commensurate with the risks (NIH Policy for
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12,
1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html).
Clinical trials supported or performed by NCI require special considerations.
The method and degree of monitoring should be commensurate with the degree of
risk involved in participation and the size and complexity of the clinical
trial. Monitoring exists on a continuum from monitoring by the principal
investigator/project manager or NCI program staff or a Data and Safety
Monitoring Board (DSMB). These monitoring activities are distinct from the
requirement for study review and approval by an Institutional review Board
(IRB). For details about the Policy for the NCI for Data and Safety
Monitoring of Clinical trials see:
http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. For Phase I and II
clinical trials, investigators must submit a general description of the data
and safety monitoring plan as part of the research application. See NIH
Guide Notice on "Further Guidance on a Data and Safety Monitoring for Phase I
and II Trials" for additional information:
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html.
Information concerning essential elements of data safety monitoring plans for
clinical trials funded by the NCI is available:
http://www.cancer.gov/clinical_trials/
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 (https://grants.nih.gov/grants/guide/notice-
files/NOT-OD-02-001.html), a complete copy of the updated Guidelines are
available at
https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.ht
m. 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
https://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
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. A
continuing education program in the protection of human participants in
research in now available online at: http://cme.nci.nih.gov/
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. 93.393 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.