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NOT-CA-21-064 - Notice of Intent to Publish a Funding Opportunity Announcement for Coordinating and Data Management Center for Acquired Resistance to Therapy Network (ARTNet) (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 Acquired Resistance to Therapy Network(ARTNet). The ARTNet FOA is a reissuance of RFA CA-17-009, which created a Drug Resistance and Sensitivity Network (DRSN) as part of the Cancer Moonshot initiative to accelerate clinical research on drug combinations. While precision oncology approaches are helpful for patient selection based on intrinsic mutations, few strategies exist for acquired resistance including a paucity of research platforms developed from resistant-recurrent tumors. The purpose of the ARTNet is to build upon the DRSN and reprioritize focus on addressing the mechanistic underpinnings of acquired resistance to the full range of treatment modalities (e.g., radiation, chemotherapeutics, targeted agents, immuno-oncology tactics, combined modality treatments).

The FOA will utilize the U54 (Specialized Center-Cooperative Agreements) mechanism. Each ARTNet site shall be structured to test hypotheses that bridge basic experiments, preclinical modeling, and translational research in a synergistic and iterative fashion. It is anticipated that each ARTNet site will respectively have a unique thematic focus guided by an overarching central hypothesis that defines it. Collectively, ARTNet sites will operate as a network with national impact in developing new cancer biology concepts that have potential to inform therapeutic strategies and overcome acquired resistance. ARTNet sites will not support clinical trials.

This Notice is being provided to allow potential applicants sufficient time to develop a responsive, multicomponent ARTNet application. 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 after the publication of the FOA.

Given the paucity of research models developed from tumors with acquired therapy resistance, limited data exist to resolve how host context (e.g., tumor stage, effected tissue bed, age, sex, germline SNPs, and microenvironmental status) are determinants in the trajectory of acquired resistance in combination with various treatment-induced stressors. Disentangling mechanisms of adaptation in both tumor and stromal cells that are the underpinnings of acquired resistance and disease recurrence are urgently needed to promote better hypothesis-driven understanding and accelerate the path towards the clinic.

ARTNet sites will be structured to efficiently bridge gaps between basic, preclinical, and clinical translational research on acquired resistance. Each ARTNet site shall be organized around a minimum of three (3) synergistic and complementary research projects as follows:

• Two (2) basic/mechanistic projects and 1 preclinical/translational project, or
• Two (2) preclinical/translational projects and 1 basic/mechanistic project, and
• Relevant cores to support project integration and iteration.

It is envisioned that the projects proposed for an ARTNet site will be unified by an overarching scientific theme focused on addressing significant challenges in acquired resistance and disease recurrence that defines it. The ARTNet FOA will be agnostic to treatment modality or cancer type(s), however, the rationale for these choices must be clearly articulated in the context of the site’s theme and proposed acquired resistance hypotheses to be tested. Multi-PI and/or multiple institutional applications will be encouraged 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 ARTNet organizational structure. Applications that holistically examine tumor, tumor microenvironment, and host systems as drivers and enablers of acquired resistance and responses to therapy in under-represented programmatic areas will be encouraged. Examples of prioritized project areas include, but are not limited to:

• Pathways and systems, including regulatory nodes involved in varying cell state dynamics (senescence, quiescence, dormancy, stemness) and other adaptive mechanisms in acquired resistance and recurrence;
• Role of the tumor microenvironmental responses (originating in stromal cells, extracellular matrix) in driving therapy resistance;
• Understanding the rewiring of multiple cell death and therapy survival pathways involving organelle networks and adaptive cell-cell cooperation;
• Defining the roles of host context and microbiota to inform the trajectory of acquired resistance and therapeutic outcome;
• Adaptive dose and timing regimens of combined modality treatments (e.g., chemoradiation, synthetic lethal combinations); and
• Role of cancer health disparities in acquired resistance;

Individual ARTNet sites are not expected to exhaustively tackle the myriad of angles as exemplified above, but collectively the network may uncover strong – yet previously unknown – common candidate pathways and determinants of interest and worthy of testing across sites; along with the identification of common technical, logistical and experimental challenges. For these reasons, NCI expects a steering committee and cross-cutting set of working groups to be established by the ARTNet as a whole; and for resources, tools and expertise to be freely exchanged between the program participants and the scientific community at large. This exchange will also be facilitated through the Cooperative Agreement process and use of a restricted fund to support collaborative pilot studies not originally envisioned by applicants.

Applications are not being solicited at this time. 

Please direct all inquiries to:

For specific inquiries related to radiotherapy and radiation biology:

Michael Graham Espey, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-7619
Email: [email protected]

For specific inquiries related to tumor biology and microenvironment:

Jeffrey Hildesheim, Ph.D.
National Cancer Institute
Telephone: 240-276-6230
Email: [email protected]

For specific inquiries related to preclinical evaluation for cancer therapy:

Percy Ivy, M.D.
National Cancer Institute
Telephone: 240-276-6107
Email: [email protected]