Key Dates

NOT-CA-21-076 - Notice of Intent to Publish: Pancreatic Ductal Adenocarcinoma Stromal Reprogramming Consortium Coordinating and Data Management Center (PSRC CDMC U24, Clinical Trial Not Allowed)

National Cancer Institute (NCI)

The purpose of this Notice is to announce the NCI's intention to issue a Funding Opportunity Announcement (FOA) that invites applications for PSRC U01 Research Projects. The purpose of the PSRC is to is to develop a comprehensive understanding of PDAC tumor progression, its microenvironment (TME) as a tumor fate determinant and the reciprocal tumor-TME interactions that drive clinical outcomes. The information obtained through these comprehensive studies should expose new biology-backed vulnerabilities that will inform the development and preclinical testing of novel interventions in PDAC. Central to the PSRC structural organization is the implementation of multidisciplinary team science approaches that iteratively bridge basic and translational research across the tumor-TME continuum in each Research Project, in trans-PSRC activities, and in collaboration with other NCI-funded mechanisms and programs whenever possible.

Each PSRC Research Project shall be structured to test hypotheses that bridge basic/mechanistic experiments, with preclinical/translational research in an integrated, synergistic and iterative fashion. It is anticipated that each PSRC Research Project will have a unique focus guided by an overarching central hypothesis that defines the Research Project. Collectively, PSRC Research Projects will operate as a consortium with national impact in developing new cancer biology-backed approaches to clinical challenges that have potential to inform therapeutic strategies to both predict and overcome PDAC progression and resistance to therapy. PSRC Research Projects will not support clinical trials designed to test for safety or treatment effectiveness; however, future clinical trials building on PSRC findings may be supported in a variety of ways, including, but not limited to NCI's Experimental Therapeutics Clinical Trials Network or National Clinical Trials Network.

This Notice is being provided to allow potential applicants sufficient time to develop a responsive, multicomponent PSRC proposal.

The FOA is expected to be published in Summer 2021 with an anticipated application due date in Fall 2021. Details of the planned pre-application webinar will be announced in the Guide after publication of the FOA.

The FOA will utilize the U01 (Research Project, Cooperative Agreements) activity code.

Details of the planned FOA are provided below.

The long-term goals of the PSRC are to: 1) allow the most advanced scientific and clinical teams of PDAC investigators to develop an integrated community to collectively and synergistically challenge the tumor as organizer dogma; 2) identify, characterize and introduce new targetable TME leads based on comprehensive basic/mechanistically dissected tumor-microenvironment dynamics; 3) develop and/or optimize basic and preclinical research platforms suitable for co-organizer evaluation; and 4) afford PSRC members and affiliates the option to utilize data generated from their PSRC project(s) to inform and/or conduct separately funded early clinical trials, particularly with agents developed at the grantee institution or in collaboration with industry.

PSRC Research Projects will be structured to efficiently bridge gaps between basic/mechanistic and preclinical/translational research on PDAC progression and resistance to therapy. Each PSRC Research Project shall be organized around a minimum of three (3) integrated, synergistic, and complementary research areas as follows:

• One (1) basic/mechanistic component and one (1) preclinical/translational component, and

• Relevant built-in capabilities to support project integration and iteration.

It is envisioned that the projects proposed for a PSRC Research Project will be unified by an overarching hypothesis focused on addressing significant challenges in PDAC progression and resistance to therapy across the tumor-TME continuum. Multi-PI applications are expected in order to maximize the potential of team science approaches, foster innovation, and combined capabilities that might be necessary to move the field forward within the context of the integrative and iterative PSRC Research Project and Consortium structure. Under-represented programmatic areas that examine tumor, tumor microenvironment, and host systems as drivers and enablers (i.e., tumor-TME co-organizer model) of PDAC progression and resistance to therapy are integral to this NCI Program. Examples of prioritized project areas for each of the three (3) components are as follows:

Basic/mechanistic science may involve but are not limited to studies on

• • Functional role of stromal cells (endothelial cells, neurons, adipocytes) and the microbiome in driving/instructing epithelial cell phenotype and adoption of invasive/metastatic potential.
  • Mechanistic elucidation of inherent or acquired cancer associated fibroblasts (CAF) cell state/subtype(s) involvement in tumor evolution or response to therapy.
  • Defining the (multi)-functional role of key tumor-cell centric mutations/driver genes/epigenetic modulation in TME elements.
  • Evaluation and biological characterization of TME response to standard of care or experimental therapeutics originally designed to target tumor mass.
  • Functional role of tumor-associated and/or normal extracellular matrix (ECM) in reprogramming epithelial cell behavior, plasticity or resistance to therapy.
  • Evaluation of ECM density and heterogeneity in eliciting tumor cell response to tissue stiffness, chemokine/cytokine distribution and nutrient availability/bioenergetic changes.
  • Effects of targeted ECM remodeling in stromal cell-tumor cell dynamics.

Preclinical/translational science may involve but are not limited to:

• In depth characterization of the human PDAC TME over the course of the disease, pre- and post- interventions combined with mechanistic studies beyond correlations or cataloging of cell types in the microenvironment.
• Novel interventions targeting components of the PDAC TME including stroma, immune response, epithelial-mesenchymal transition, tumor vascularization, etc.
• Models mimicking the interactions between PDAC and its microenvironment.
• Data generated from Lynch syndrome- and/or microsatellite instability-associated PDAC responses to combination therapies and their utilization for the design of interventions in PDAC not-associated with these conditions.
• Development of prediction assays for PDAC patient stratification in combination therapy interventions.
• Preclinical testing of targeted therapies or in combination with radiation, or chemotherapy.
• Research in age, sex, and racial/ethnic disparities-associated PDAC microenvironment and the potential to use of targeted therapies in these populations.
• Exploration of the role of TME components in the metastatic spread of PDAC
• Study of TME in distal/metastatic sites

Built-in capabilities to develop and optimize models, approaches and technologies to feed into both the basic and translational studies – including capabilities that would enable comprehensive basic/mechanistic-pre-clinical/translational studies in underrepresented areas of age, sex, and racial/ethnic disparities – may pertain but are not limited to

• Access to catalogued specimens from collaborative early phase clinical trial(s).
• Collection/library of organoid cultures or patient-derived xenografts from PDACs, which maintain the original architecture of the tumor, to allow sufficient expansion for a detailed molecular/multi-omic analyses.
• Novel or repurposed PDAC platforms – including repurposed in vivo genetic models - to interrogate complex ECM-stromal cell-tumor cell interactions (with non-immune cells at its core) in tumor progression and resistance to therapy – along with companion human tissues (biopsies from clinical trials, rapid autopsies, or patient-derived models).
• Computational and systems biology infrastructure to develop in silico tumor evolution models.

Individual PSRC Research Projects are not expected to exhaustively tackle the myriad of research perspectives as exemplified above, but collectively the PSRC Consortium may uncover strong, yet previously unknown, common candidate pathways and determinants of interest worthy of testing across sites; along with the identification of common technical, logistical and experimental challenges. Consortium-level collaboration(s) will be facilitated though steering committee activities, establishment of cross-cutting PSRC-wide topical interest groups, coordination through the PSRC Coordinating and Data Management Center (U24, CDMC). Technical and scientific exchange will be enabled through the Cooperative Agreement process and use of a restricted funds to support collaborative pilot studies not originally envisioned by applicants.

Applications are not being solicited at this time. 

Please direct all inquiries to:

Peter Ujhazy, MD, PhD
Division of Cancer Treatment & Diagnosis
National Cancer Institute (NCI)
Telephone: 240-276-5686
Email: [email protected]

Jeffrey Hildesheim, Ph.D.
Division of Cancer Biology
National Cancer Institute (NCI)
Telephone: 240-276-6213
Email: [email protected]