Key Dates

Related Announcements

• December 18, 2024 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed). See PA-25-301
• November 12, 2024 - Cancer Prevention and Control Clinical Trials Grant Program (R01 Clinical Trial Required). See PAR-25-167
• December 2, 2024 - NCI Continuing Umbrella of Research Experiences (CURE) Non-Mentored Research Scientist Career Development Award (K22 Clinical Trial Required). See PAR-24-318
• December 2, 2024 - NCI Continuing Umbrella of Research Experiences (CURE) Mentored Clinical Scientist Research Career Development Award (K08 Clinical Trial Not Allowed). See PAR-24-320
• September 3, 2024 - Mechanisms that Impact Cancer Risk after Bariatric Surgery (R01 Clinical Trial Optional). See PAR-25-043.
• September 3, 2024 - Mechanisms that Impact Cancer Risk After Bariatric Surgery (R21 Clinical Trial Not Allowed). See PAR-25-044
• April 24, 2024 - NIH Pathway to Independence Award (Parent K99/R00 - Independent Clinical Trial Not Allowed). See PA-24-194
   

Issued by

National Cancer Institute (NCI)

Purpose

The purpose of this NOSI is to promote studies examining the mechanisms by which obesity drives aggressive prostate cancer (PCa) risk. About 80% of overall PCa is non-aggressive. The biologic mechanisms driving both overall and aggressive PCa are uncertain. The identification of differences in the mechanisms driving aggressive vs. overall (mostly non-aggressive) disease are critical to optimizing clinical care among men who develop the disease. PCa has an outsized impact on African Americans who are more likely to develop aggressive disease and twice as likely to die from the disease compared to other racial and ethnic groups.

Background

Among hormonally driven cancers, multiple studies document an association between obesity and the risk of both postmenopausal breast and endometrial cancer, and substantive (> 5% total body weight) weight loss lowers the risk of these cancers. On the other hand, the bulk of evidence links obesity with a lower overall PCa risk but a greater risk of high grade, more aggressive disease compared to that of men of normal weight. Most men have low or intermediate risk disease, with only about one in five having high risk disease. Reasons to explain the divergent effects of obesity on overall PCa incidence vs. the aggressive nature of the disease are likely multifactoral, including:

1) the hemodilutional effect of obesity on circulating levels of PSA, resulting in a delayed PCa diagnosis; 

2) difficulty palpating the prostate gland in obese men on digital rectal exam; and 

3) molecular mechanisms driving disease development. The focus of this NOSI is on the mechanisms that drive overall (primarily composed of non-aggressive disease) vs. aggressive PCa risk.

Potential Mechanisms Impacting Obesity's Influence on PCa Risk

The molecular mechanisms linking obesity to overall and aggressive PCa are not clearly delineated.

• Estrogens and androgens. Estrogens (E) drive the development of both postmenopausal breast and endometrial cancer, while androgens linked to PCa are precursor hormones which can be converted by aromatase to estrogens. E levels are higher in obese than normal weight men. Preclinical studies suggest that E may play a role in promoting PCa development and progression. Obesity is associated with low testosterone (T) levels, and lower T levels have been associated with increased risk of aggressive prostate cancer.
• VAT. The assessment of obesity in determining its role in PCa risk has generally been based on body mass index (BMI), which does not control for extra muscle mass among body builders or loss of muscle in the elderly. The two primary storage sites for adipose tissue (AT) are around the abdominal viscera (VAT) and subcutaneously (SAT). VAT is more abundant in men (10-20% of total) than women (5-8% of total). VAT releases more in?ammatory and growth factors compared with SAT, and VAT content has been linked to aggressive PCa, especially in black men.
• Insulin resistance and insulin-like growth factor (IGF)-1. Obesity increases insulin resistance and IGF-1. Diet-induced hyperinsulinemia accelerates tumor growth in different PCa xenograft models. Higher serum C-peptide, a surrogate of insulin levels, have been associated with increased PCa-specific mortality, and metformin, which lowers insulin levels, appears to reduce PCa risk in men with type 2 diabetes. High levels of IGF-I and insulin have been positively linked to PCa risk and mortality.
• Chronic inflammation. Obesity increases chronic inflammation, in part through the production of inflammatory cytokines (adipokines) such as TNF-α, IL-6, IL-8 and MCP-1 which are produced in adipocytes. Adipokine production is increased in obese individuals, and the expression of individual cytokines that influence cancer risk differs among obese and normal weight individuals. Periprostatic adipose tissue (PPAT) provides locally secreted growth factors and adipokines. There is preliminary evidence, for example, that PPAT-derived IL-6 levels are directly associated with elevated Gleason grade, suggesting a paracrine role for PPAT in modulating PCa aggressiveness.

Research Objectives

Studies should determine if the biologic mechanism(s) driving aggressive vs. non-aggressive PCa are different through the investigation of preclinical models and/or human prostate studies.

Questions important to address for both overall and aggressive PCa include, but are not limited to:

• What is the role of androgens and estrogens?
• Do race, age and other clinical factors influence the mechanism(s) driving disease development?
• How does the insulin/IGF-1 axis influence disease risk?
• What role do adipokines play in disease risk?
• How do paracrine effects from PPAT growth factors and adipokines influence risk?

Applicants are strongly encouraged to review the individual NOFOs (see below in Table) for specific language pertaining to the “Clinical Trial” qualifiers (i.e., Required; Optional; Not Allowed). Please note that if a project proposes a clinical trial, it can also incorporate preclinical investigations to help evaluate mechanistic endpoints.

Application and Submission Information

This NOSI applies to Application Due Dates on or after February 5, 2025, and subsequent receipt dates through January 7, 2028. This NOSI expires January 08, 2028. 

Submit applications for this initiative using one of the following notices of funding opportunities (NOFO) or any reissues of these NOFOs through the expiration date of this Notice.

Please note that the target NOFOs listed below and used for submission to this NOSI are either “Clinical Trial Required” or "Clinical Trial Optional" or “Clinical Trial Not Allowed”. 

Applicants are strongly encouraged to review the individual NOFOs for specific language pertaining to the “Clinical Trial” qualifiers (i.e., Required; Optional; Not Allowed).

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-25-002" (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.

Inquiries

Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:

Scientific/Research Contact(s)

Howard Parnes, MD
National Cancer Institute (NCI)
Telephone: 240-276-7045
Email: [email protected]

Edward Sauter, MD, PhD
National Cancer Institute (NCI)
Telephone: 240-276-7657
Email: [email protected]

Contacts for Basic/Translational Science Questions
 

Edward Sauter, MD, PhD
National Cancer Institute (NCI)
Telephone: 240-276-7657
Email: [email protected]

Chen Suen, PhD
National Cancer Institute (NCI)
Telephone: 240-276-7095
Email: [email protected]

Wanping Xu, PhD
National Cancer Institute (NCI)
Telephone: 240-276-6230
Email: [email protected]

Financial/Grants Management Contact(s)

Crystal Wolfrey
National Cancer Institute (NCI)
Telephone: 240-276-6277
Email: [email protected]