It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The purpose of this Funding Opportunity Announcement (FOA) is to promote basic mechanistic research activity for the program referred to as the Alliance of Glycobiologists for Cancer Research . While changes in glycosylation have been demonstrated in virtually all epithelial cancer cells, there is limited understanding of the biological roles played by aberrant glycosylation in carcinogenesis. Through this FOA, the NCI encourages new multi-PI applications for research projects to examine whether altered glycosylation of proteins and lipids associated with malignancy, plays a causal role in the process or is the result of cellular transformation. All investigative teams with appropriate multi-PI expertise and capabilities, irrespective of any prior association with this Alliance, are encouraged to consider applying to this FOA.

A related FOA that seeks to identify glycan-based biomarkers for early detection of cancer is also offered at this time (PAR-17-206).

Influence of Complex Carbohydrates on Cellular Function

Glycosylated proteins and other glycoconjugates are important components of cells and play crucial roles in key physiological processes in normal tissues. Defects in glycosylation, in both proteins and lipids, have been linked to disease in humans including cancer. Tumor cells often display glycans with altered structures as compared to normal cells. The most widely occurring cancer-associated changes in glycosylation are sialylation, fucosylation, O-glycan truncation and N- and O-linked glycan branching. Increasing evidence indicates that tumor cell-associated glycans play an essential role in various processes occurring during malignancy, such as intra- and intercellular signaling, tumor cell dissociation and invasion, interactions with the tumor matrix, tumor angiogenesis, immune modulation and metastasis. In addition, mucins, proteoglycans and glycosaminoglycans in the extracellular matrix play an important role in modulating tumor cell behavior and tumor progression.

Role of Aberrant Glycosylation in Cancer

Alterations in glycosylation may influence the ability of cell-surface receptors to undergo appropriate oligomerization, and directly influence the sensitivity of these receptor systems to stimulation. For example, inhibition of complex O-glycan formation, a common feature of malignant cells, has been shown to impair sensitivity of apoptosis-inducing receptors DR4 and DR5 that relay TRAIL signaling. Similarly, upregulation of Ras-Raf-MAPK signaling pathways during oncogenesis causes increased expression of the enzyme mannoside acetyl-glycosaminyltransferase 5 (GnT-V). Increased enzyme expression has been related to tetraantennary N-glycan structures that lead to dysregulated epithelial contact inhibition and increased cellular motility, key features of cells undergoing neoplastic transformation. Downregulation of GnT-V in mouse mammary cancer cell lines is associated with a significant suppression of tumor growth and metastasis -. Glycosylation of the Notch extracellular domain has been shown to regulate Notch activity and enable in maintaining tumor cell "stemness" and mediate cancer metastasis . Alterations in glycosylation of cell surface proteins also significantly impacts tumor immunosurveillance, and plays a role in facilitating immunological tolerance to a neoplastic lesion and favors tumor cell survival. Tumor carbohydrate-mediated interactions with vascular adhesion molecules not only facilitate endothelial attachment but also mediate vascular spread of cancer cells.

Critical Questions to be Addressed

Despite their fundamental roles in cell biology, the role of abnormally glycosylated molecules in cancer progression remains an understudied area of research. This stems partly from the technical challenges encountered in analyzing complex carbohydrate structures and the fact that it is not evolutionarily conserved. Cellular biosynthesis of glycans is a non-template process, unlike DNA, RNA and protein synthesis and is influenced by the expression and activity of a number of enzymes involved in the glycosylation process, such as glycosyltransferases and glycosidases and on the availability of precursor monosaccharides. The glycosylation process is capable of generating a large variety of branched structures. In addition, the complexity of carbohydrate structural chemistry, makes it difficult to distinguish glycan isomers. However, there has been considerable technological advance in the field of glycomics that has allowed the characterization of glycans.

An important question that needs to be addressed is whether these changes in glycosylation seen in malignant cells is the cause or effect of transformation. Elucidating the molecular basis underlying these glycan modifications will contribute greatly to our understanding of tumor cell signaling, tumor cell dissociation and invasion, its ability to interact with its environment and in its ability to modulate the immune system.

This Program is designed to take advantage of recent advances in glycobiology, including mass spectrometry, nuclear magnetic resonance spectroscopy, lectin and antibody arrays, high performance liquid chromatography, capillary electrophoreses, glycoarrays and gas liquid chromatography to define mechanisms of altered glycosylations and its role in carcinogenesis.

The following is a non-exclusive list of questions that the FOA seeks to address and are examples of investigations relevant to tumor glycobiology:

• What are the precise mechanism(s) by which biochemical and structural changes in glycans regulate cancer initiation and progression? Are these changes caused by defined glycosyltransferases?
• Do glycan-binding proteins like galectins influence tumor progression, metastasis, and immune response to the tumor?
• Do glycans and their complementary glycan-binding proteins play a role in chronic inflammation?
• How is immune surveillance attenuated by altered glycosylation?
• How does altered tumor glycosylation impact leukocyte homing/recruitment?
• What is the role of proteoglycans in tumor angiogenesis?
• How does altered glycosylation influence the properties of cancer initiating cells?
• What is the impact of tumor microenvironment on altered glycans?
• What are the mechanisms by which altered cellular glycosylation allows cells to evade growth suppressive signals?
• How does aberrant glycosylation contribute to the metabolic reprogramming of tumor cells?
• It is recognized that abnormal protein folding and unfolded protein response (UPR) correlate with impaired glycosylation. How do aberrations in glycosylation promote endoplasmic reticulum (ER) stress?

Transdisciplinary Applicant Teams

A multi-PD/PI application with a glycobiologist and a cancer biologist as part of the investigator team will be required to be appropriate to this FOA and ensure that the team has the expertise and capabilities to effectively carry out the proposed research projects and productively contribute to trans-Alliance activities. It is expected that these capabilities will include at least the following areas:

A. Glycobiology Expertise. It is anticipated that the PD(s)/PI(s) will have expertise in tumor glycobiology. In addition to glycobiologists, investigators with expertise in related disciplines, such as proteomics, immunology, and cell biology may also strengthen the proposed projects.

B. Carbohydrate Analytical Expertise. Thorough characterization of the complex carbohydrates to be investigated requires expertise in glycomic technologies and strong analytical skills relevant to structural or synthetic carbohydrate methodologies. Groups that may not have these capabilities in house are strongly encouraged to establish collaborations with outside investigators having relevant expertise in complex carbohydrate chemistry.

C. Cancer Cell & Molecular Biology Expertise: The PD(s)/PI(s) will have expertise in biological assays involved in characterizing the tumor cells as well as its microenvironment.

Note: Even though technology development as such remains beyond the scope of this FOA, in planning their research projects, applicants are encouraged and expected to devote some efforts to the adaptation of important technical developments that may occur during the duration of the project.

Interactive Structure of the Alliance

The awardees funded under this FOA and the accompanying FOA (PAR-17-206) will form an interactive network termed the Alliance of Glycobiologists for Cancer Research with a Steering Committee as the governing body (for details see Section VI.2. Terms and Conditions of Cooperative Agreements). In addition to the support of individual research projects, the goal of this FOA is to facilitate complementary interactions across the Alliance. The planned interactions will include participation of the awardees in collaborative research projects that will be supported by dedicated set-aside funds (see Section IV. 2. Content and Form of Application Submission of this FOA). Collaborative research projects and other joint trans-Alliance activities will be reviewed by the Steering Committee and recommended for approval by the NCI.

Partnering with other Glycomics and Cancer-oriented Programs and Resources

The Alliance is expected to interact in partnership with several other major programs funded by the National Institutes of Health that focus on glycomics, basic cancer biology and/or cancer biomarkers.

Individual projects and the entire Alliance may benefit from access to resources available from the following glycomics-oriented programs supported by NIH:

1) The four Glycomics and Glycotechnology Resource Centers presently supported by the National Institute of General Medical Sciences (NIGMS) are focused on the unique analytical challenges of carbohydrates and glycoconjugates.

These centers include:

• The National Center for Functional Glycomics;
• The National Center for Biomedical Glycomics;
• The Resource for Integrated Glycotechnology; and
• The Mass Spectrometry Resource.

2) The NIH Common Fund Glycoscience Program is of particular relevance to the Alliance of Glycobiologists for Cancer Research concerning the development of new tools and technologies to facilitate research of complex carbohydrates. For more detailed information on this see the list of funded laboratories provided under Funded Research.

3) The Programs of Excellence in Glycosciences supported by the National Heart, Lung, and Blood Institute (NHLBI) have common interests with the Alliance in how carbohydrates and their binding proteins function in disease. Applicants may consider these programs for sharing resources and expertise.

All applicants are encouraged to consider the resource capabilities of these programs in planning their research projects. These programs may serve as a valuable source of potential collaborators in glycomics-related areas.

4) The Early Detection Research Network (EDRN), which is funded by NCI, is a consortium to promote clinical validation of cancer biomarkers for early detection, risk assessment, and diagnosis. As the development of promising glycan biomarkers by the Alliance of Glycobiologists for Cancer Research progresses, they should be considered for clinical validation studies. The EDRN will collaborate with this Alliance to facilitate validation of glycomic cancer biomarkers in several ways including:

• Assistance with study design and statistical analysis is available from the EDRN Data Management and Coordinating Center.
• The EDRN Clinical Validation Centers may assist with patient accrual and collection of clinical specimens for validation studies.
• Specimen reference sets are available from the EDRN for testing biomarkers in blinded studies for verification purposes.
• EDRN Biomarker Reference Laboratories may be able to participate in the development and standardization of specific tests and offer cross-laboratory confirmation of test results.

5) The Consortium for Molecular and Cellular Characterization of Screen-Detected Lesions (MCL) funded by the NCI, is comprised of multi-disciplinary teams involved in a comprehensive molecular and cellular characterizations of tumor tissue, cell and microenvironment components to distinguish screen-detected early lesions from interval and symptom-detected cancers.

Trans-Alliance Activities

To facilitate interactions of the Alliance and its investigators with other relevant NIH programs, representatives of these programs are expected to participate in the Alliance Steering Committee.

See Section VIII. Other Information for award authorities and regulations.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization 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 support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

Multiple PD/PI applications could have different responsibilities with respect to one or more of the following functions: 1) analysis and metrics, 2) medical care interventions, and 3) behavioral interventions.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Neeraja Sathyamoorthy, Ph.D.
Division of Cancer Biology
National Cancer Institute (NCI)
Telephone: 240-276-6220
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed. Sites should have a history of successful transdisciplinary and multidisciplinary collaboration.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed. Key personnel are encouraged to have a successful record of multicenter and multidisciplinary scientific collaboration. Investigators with a record of transdisciplinary collaboration are encouraged.

All instructions in the SF424 (R&R) Application Guide must be followed.

• Applicants must include in the budgets for the second and subsequent years $65,000 direct costs as a set-aside for Network collaborative projects. This budget item should be indicated as Other Direct costs as Funds for Network Collaborative Projects".
• Applicants must also budget funds for two investigators (e.g., the PD/PI and another senior member of the team) for travel to attend one Alliance meeting each year.
• Given the nature of the anticipated projects, a substantial commitment (of at least 1.2 person-months) is expected for any individual designated as the PD/PI (either as a single PD/PI or as one of multiple PDs/PIs) on the application. PDs/PIs on Alliance awards will be required to maintain commitment at least at this minimal level throughout the entire project period (see Terms and Conditions of Cooperative Agreements under Section VI.2. of this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific aims: In addition to the specific aims and approach(es), applicants should include the relevance of the research to the objectives of this FOA.

Research Strategy: This section should clearly describe these additional elements:

• Will the proposed research provide new insights into the mechanisms by which biochemical and structural changes in glycans regulate cancer initiation or progression?
• If biological models are proposed, state the appropriateness of using such models for cancer glycobiology.
• Provide a brief statement on new reagents, capabilities or technologies that would accelerate the success of this research that partnering programs included in this Alliance could feasibly develop in the near future.
• Trans-Network Activities. In addition to the standard description of the proposed individual Research Project, applicants are expected to include (within the overall page limit for Research Strategy section) a brief description of their unique capabilities that may be useful for joint trans-Alliance activities and outline general directions that, in their opinion, will particularly warrant joint exploration through collaborative projects. Applicants must state their willingness to participate in joint activities of the Alliance, including:
• interactions with other Alliance awardees;
• participation in planning Alliance-sponsored workshops and symposia and attending these events
• serving on the Steering Committee and adhering to its decisions and recommendations;
• sharing research resources with other members of the Alliance as appropriate and consistent with achieving the goals of the program.

Applicants must address any specific plans that might be needed to comply with Cooperative Agreement Terms and Conditions of Award as stated in Section VI.2.A of this FOA.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• The Data Sharing Plans are expected to address sharing research resources and relevant data (especially those pertinent to joint activities and pilot projects) with other Alliance awardees, consistent with achieving the goals of the program.
• Awardees will also be expected to submit all discovered novel glycan structures and glycomic profiles to appropriate public databases as indicated under Terms and Conditions of Cooperative Agreements consistent with achieving the goals of the program.

Appendix:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Form only available in FORMS-E application packages for use with due dates on or after January 25, 2018.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study: All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy.

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific for this FOA:

• Is the proposed project sufficiently focused on gaining new insights into how complex carbohydrates contribute to cancer initiation or progression?
• What is the likelihood that the proposed projects will lead to biomarkers useful for early cancer detection, diagnosis, or risk assessment or lead to new cancer prevention interventions?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Specific for this FOA:

• To what degree does the investigative team have requisite expertise in cancer biology, glycobiology, and biostatistics?
• How well is the team prepared for collaborations at the trans-Alliance level?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Specific for this FOA:

• How appropriate are the biological models proposed for the goals of the Alliance program?
• Are there appropriate plans and capabilities to adapt new technologies applicable to the proposed research that may become available during the duration of the project?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Not Applicable.

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NCI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Coordinating all project activities scientifically and administratively at the awardee institution and with any collaborating institutions. The PD(s)/PI(s) will assume accountability to officials of the awardee organization and to the NCI for the performance and the proper conduct of the research supported by the U01 mechanism in accordance with the terms and conditions stated in the FOA.
• Defining objectives and approaches, including research design and study development, coordinating activities of the components of his/her team, overseeing data collection and quality control, and overseeing data analyses and publication of study results.
• Working in close coordination with the NCI Project Scientist and the Steering Committee to integrate the awardee’s program within the broader scope of the Alliance.
• Accepting and implementing the goals, priorities, procedures, and policies agreed upon by the Steering Committee to the extent consistent with applicable grant regulation.
• Participating in the activities of the Steering Committee including attending the annual Steering Committee meetings. In cases where a PD/PI cannot attend a meeting or conference call, he/she must designate another senior investigator as a representative from their laboratory or team to attend on their behalf.
• Proposing individually or together with other awardees collaborative research projects to be supported by the restricted set-aside Network Collaborative Funds and conducting those collaborative projects approved by the Steering Committee and the NCI.
• Collaborating on common research designs or protocols, including methods and requirements for joint participation and collaboration as directed by the Steering Committee, and handling of data, including appropriate sharing of methods and data.
• Ensuring compatibility of pertinent bioinformatics data with NIH-recommended standards.
• Ensuring that novel glycan structures and glycomic profiles are submitted in a timely manner to the analytical glycomics data repository of the Consortium for Functional Glycomics (http://www.functionalglycomics.org/glycomics/publicdata/glycoprofiling-new.jsp) maintained at the Massachusetts Institute of Technology supported by NIGMS.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• Two NCI Project Scientists (one from the Division of Cancer Biology and one from the Division of Cancer Prevention) will have substantial scientific programmatic involvement during conduct of this activity, through technical assistance, initiation of collaborative projects, data sharing and analysis, composition of reports, and coordination within the Alliance and with the other collaborating NIH sponsored programs.
• Because of the Alliance’s diverse research agenda, and the number of tasks that have to be accomplished to achieve its goals, NIH staff members from other Institutes/Centers with relevant expertise will participate as needed. Specifically, it is expected that representatives of NIGMS and NHLBI will be involved to facilitate interactions between the awardees and various glycomic resources sponsored by those institutes. In addition, staff members from the Biometry Branch, Division of Cancer Prevention, NCI, will assist the Alliance on issues of study design, sample size, and other statistical computations. Other NCI staff members may assist and advise the Alliance on relevant programmatic and scientific issues through the NCI Project Scientist.
• The NCI Project Scientists will convene the initial meeting of the Steering Committee, and will serve as voting members.
• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Add any additional bullets by typing in front of the existing bullet, above.

Areas of Joint Responsibility

The NCI Project Scientist and the PD/PIs of the U01 awards funded under the FOA will be jointly responsible for the formation of a Steering Committee.

The Steering Committee will serve as the main governing body of the Alliance. The Steering Committee will have major scientific management oversight and responsibility for developing, facilitating the conduct and monitoring progress of collaborative projects and reporting study results. All awardees will be required to accept and implement policies approved by the Steering Committee.

The Steering Committee will be composed of the following voting members:

• One PD/PI or designee from each of the Alliance awardees (if there are multiple PDs/PIs, they may rotate as members of the Steering Committee);
• Two NCI representatives (NCI Project Scientist or a designee) who will have one vote for the NCI.

The Steering Committee will select the Chair and Co-chair from among the voting members who are the Alliance PDs/PIs (the NCI representative cannot serve as a chair or co-chair).

The Steering Committee may invite other individuals to participate as non-voting members as needed. To facilitate and enhance the activities of the Alliance, such individuals are expected to include representatives of related glycomic and biomarker oriented partnering programs and representatives of NIH Institutes/Centers supporting those partnering programs. Thus, non-voting members may include:

• A PD/PI representing each partnering glycomic-oriented programs supported by the National Institute of General Medical Sciences (NIGMS) and National Heart, Lung, and Blood Institute (NHLBI);
• A PD/PI representing the EDRN; and
• Program Directors from the NIGMS and the NHLBI to represent those glycomic-oriented programs that will serve as resources to the Alliance.

The Steering Committee will establish subcommittees or working groups to advise the Steering Committee as needed. The NIH staff members (including voting and non-voting members of the Steering Committee) may serve on subcommittees as appropriate. External experts may be included on the subcommittees or working groups, e.g., to assist in the evaluation of proposals for pilot/joint projects.

The Steering Committee will convene after all the awards under this FOA are made and meet at an annual face-to-face Steering Committee meeting and by monthly conference calls. Attendance at these meetings and conference calls is considered an essential part of the award.

Responsibilities of the Steering Committee include, but are not limited to:

• Formulating, updating, and refining policies and procedures of the Alliance awardees, including those pertaining to the collaborative research projects that will be supported by the set-aside funds for Network Collaborative Projects;
• Evaluating (with the participation of external experts if needed) proposals for collaborative projects supported by the set-aside funds for Network Collaborative Projects and other joint trans-Alliance research activities.
• Making recommendations to the NCI for adjusting the scientific scope of funded projects.

The Steering Committee will track Alliance research progress and facilitate as appropriate the process of preparing the results of laboratory investigations and clinical studies for publication in peer-reviewed journals to ensure its timely manner and adherence to the publication policies of the Alliance.

If there is any Alliance-wide validation study to be conducted, the Steering Committee, in consultation with the NCI, will select an investigator to lead such effort.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Neeraja Sathyamoorthy, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6220
Email: [email protected]

Referral Officer
National Cancer Institute (NCI)
Telephone: 240-276-6390
Email: [email protected]

Rogers R Gross II, M.B.A.
National Cancer Institute (NCI)
Telephone: 240-276-7589
Email: [email protected]

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.