Key Dates

Related Announcements

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PAR-20-292 -NCI Clinical and Translational Exploratory/Developmental Studies (R21 Clinical Trial Optional)

PAR-21-038 - Stephen I. Katz Early-Stage Investigator Research Project Grant (R01 Clinical Trial Not Allowed)

PAR-19-133 - Academic Research Enhancement Award for Undergraduate-Focused Institutions (R15 - Clinical Trial Required)

PAR-19-134 - Research Enhancement Award Program (REAP) for Health Professional Schools and Graduate Schools (R15 Clinical Trial Not Allowed

NOT-CA-22-006 - Notice of Correction to NOT-CA-21-101

Issued by

National Cancer Institute (NCI)

Purpose

This Notice of Special Interest (NOSI) seeks to highlight the interest of NCI’s Division of Cancer Treatment and Diagnosis (DCTD) to support investigation of the development of novel therapies for cancer-applied research encompassing chemistry and biology disciplines to support the discovery and testing of novel therapeutics offering improved safety and efficacy profiles for eventual translation to the clinic.

Background

It is estimated that nearly 1.9 million new cases of cancer will be diagnosed in the U.S in 2021, and systemic small molecule therapy will be a key component in the treatment approach for many of these patients. Despite the benefit that small molecule drugs have provided to cancer patients, their effectiveness continues to be limited, where the most common causes of clinical trial failures trace back to lack of efficacy, and life-threatening side-effects caused by nonspecific tissue distribution following dosing. The inability to achieve effectual drug concentrations specifically at the tumor site at a therapeutically acceptable dose, and off-target effects as a result of nonspecific tissue distribution following systemic administration, are pervasive challenges which have broadly undermined the true effectiveness of small molecule drugs. There is a growing recognition of the importance for the need to develop therapies which may overcome the challenges of dose-limiting toxicity, and to do so using methods which do not require specialized expertise or harbor costs which may be exorbitant for the academic research community.

It has been shown that site-specific accumulation of an active small molecule drug at a defined zone can be achieved through the deliberate design of molecules whose bioactivation is triggered in response to an endogenous cue at the site of action (e.g., targeted prodrugs), and thereby provide a means to overcoming dose-limiting toxicity. Moreover, these types of therapies may be developed using methods which are commonly available and do not entail costs that may be considered prohibitive. Furthermore, advances in tumor biology along with those in the development of enhanced analytical tools, the ADMET field, activity-based protein profiling, and increased patient profiling may now further facilitate the development of small molecule drugs whose activation occurs in response to features specific to cancer cells (ie tumor-site activated small molecules). While the exploitation of site-specific features for molecular activation offers the potential to yield drugs having localized effectual concentrations at a therapeutically acceptable dose, there remain a number of open questions to address. In addition, efforts across the community have been scattered and thus less efficient.

Research Objectives

This purpose of this NOSI is to foster a systematic effort that will leverage latest advancements in the field to address key questions that underlie the development tumor-site activated small molecules, in order to identify therapeutics with improved safety and efficacy profiles.

This NOSI encourages grant applications with chemistry, biochemistry, biology, pharmacology, and computational collaborative approaches that address one or more of the research gaps as outlined. The scope of this initiative includes (but is not limited to) studies evaluating:

1. Identification and characterization of the specificity and activity of transporters and metabolizing (activating) enzymes specific to tumor cells, their tumor microenvironment (TME), stromal, and extracellular matrix (ECM) features for drug targeting
2. Delineating mechanisms of tumor cell-specific uptake, localization, enzymatic activation of drugs
3. Effects of intratumoral heterogeneity (e.g., variability and loco-regional differences in tumor microenvironment physiology) on preferential uptake and enzymatic activation processes of candidate molecules
4. Design of small molecule agents whose self-triggered drug release occurs specifically in cancer cells in response to a tumor cell-specific cue, and evaluation in models of disease

Applications focused on the development of nanoparticle-based formulations, antibody drug conjugates, antibody-prodrug conjugates, biological products, and drug-device combinations are out of scope for this NOSI.

Application and Submission Information

This Notice applies to due dates on or after January 26, 2022, and subsequent receipt dates through January 08, 2024.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this NOSI:

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include NOT-CA-21-101 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Scientific/Research Contact(s)

Sharad K. Verma, PhD
National Cancer Institute (NCI)
Telephone: 202-657-3694
Email: sharad.verma@nih.gov

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

Crystal Wolfrey
National Cancer Institute (NCI)
Telephone: 240-276-6277
Email: wolfreyc@mail.nih.gov