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R01CA254955

Project Grant

Overview

Grant Description
Intensive Tailored Exercise Training with NAD+ Precursor Supplementation to Improve Muscle Mass and Fitness in Adolescent and Young Adult Survivors of Hematopoietic Stem Cell Transplantation - Abstract

Advances in Hematopoietic Cell Transplantation (HCT) have led to improvements in survival. Adolescents and young adults (AYAs) who undergo HCT are at an especially high risk of developing sarcopenia (loss of skeletal muscle mass) due to the impact of HCT-related exposures on the immature musculoskeletal system.

We have shown that sarcopenia occurs earlier in HCT survivors than would be expected from advancing age alone. HCT survivors who are sarcopenic have a two-fold risk of non-relapse mortality and excess rates of premature cardiovascular disease. Therefore, to improve the lives of AYA HCT survivors, it is of critical importance to develop interventions to increase skeletal muscle mass, metabolism, strength, and function.

Skeletal muscle is highly reliant on mitochondrial energy production, as measured by oxidative phosphorylation (OXPHOS) capacity. Thus, one strategy to improve skeletal muscle function is to increase muscle OXPHOS in these survivors. Home-based exercise (aerobic and resistance) training is a well-established intervention to increase skeletal muscle mitochondrial OXPHOS, as well as mass, strength, and function.

Another approach is to use an "exercise mimetic", an intervention designed to recapitulate the physiologic benefits of exercise. Precursors of nicotinamide adenine dinucleotide (NAD+), a cofactor required for ATP production, are exercise mimetics. In humans, short-term oral nicotinamide riboside (NR) supplementation has been found to increase the NAD+ muscle metabolome and reduce chronic inflammation associated with aging.

Exercise combined with NAD+ precursor supplementation may yield additional benefits compared to either alone, but this approach has not been tested in AYA HCT survivors. We propose a randomized controlled trial with a 2x2 factorial design testing 16 weeks of exercise and NR in AYA survivors of HCT, with a primary outcome of muscle strength. We will also examine the effects of these interventions on exercise capacity, use an innovative non-invasive imaging technique to measure muscle mitochondrial function, and metabolomics to test circulating correlates of increased ATP production, including NAD+, acylcarnitines, and organic acids.

Individuals (n=80, ages 15-30y) will be recruited 6-24 mos post-HCT and randomized to 1 of 4 arms: exercise+NR, exercise alone, NR alone, or control. We will use DXA to measure lower leg lean muscle mass, non-invasive MRI to measure OXPHOS, dynamometry to test strength (primary outcome), and cardiopulmonary exercise testing to measure maximal oxygen uptake (VO2max; secondary outcome), at baseline and 16 wks.

We expect exercise+NR will produce larger changes than exercise alone in key outcomes, and that changes will be mediated by increases in muscle OXPHOS. This study will address a shared NCI and NHLBI research priority, namely how best to prevent the late development of complications following HCT, and thereby reduce the burden of HCT-related morbidity and mortality.

Our findings will inform strategies to prevent or mitigate the myriad downstream adverse effects of low muscle mass in AYA HCT survivors, an important area of focus for the NCI and NHLBI.
Funding Goals
TO IMPROVE SCREENING AND EARLY DETECTION STRATEGIES AND TO DEVELOP ACCURATE DIAGNOSTIC TECHNIQUES AND METHODS FOR PREDICTING THE COURSE OF DISEASE IN CANCER PATIENTS. SCREENING AND EARLY DETECTION RESEARCH INCLUDES DEVELOPMENT OF STRATEGIES TO DECREASE CANCER MORTALITY BY FINDING TUMORS EARLY WHEN THEY ARE MORE AMENABLE TO TREATMENT. DIAGNOSIS RESEARCH FOCUSES ON METHODS TO DETERMINE THE PRESENCE OF A SPECIFIC TYPE OF CANCER, TO PREDICT ITS COURSE AND RESPONSE TO THERAPY, BOTH A PARTICULAR THERAPY OR A CLASS OF AGENTS, AND TO MONITOR THE EFFECT OF THE THERAPY AND THE APPEARANCE OF DISEASE RECURRENCE. THESE METHODS INCLUDE DIAGNOSTIC IMAGING AND DIRECT ANALYSES OF SPECIMENS FROM TUMOR OR OTHER TISSUES. SUPPORT IS ALSO PROVIDED FOR ESTABLISHING AND MAINTAINING RESOURCES OF HUMAN TISSUE TO FACILITATE RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.
Place of Performance
Philadelphia, Pennsylvania 191044318 United States
Geographic Scope
Single Zip Code
Analysis Notes
Amendment Since initial award the total obligations have increased 350% from $771,376 to $3,469,202.
The Children's Hospital Of Philadelphia was awarded Exercise & NAD+ for Muscle Health in AYA HCT Survivors Project Grant R01CA254955 worth $3,469,202 from National Cancer Institute in September 2021 with work to be completed primarily in Philadelphia Pennsylvania United States. The grant has a duration of 5 years and was awarded through assistance program 93.394 Cancer Detection and Diagnosis Research. The Project Grant was awarded through grant opportunity Clinical Characterization of Cancer Therapy-induced Adverse Sequelae and Mechanism-based Interventional Strategies (R01 Clinical Trial Optional).

Status
(Ongoing)

Last Modified 8/20/25

Period of Performance
9/1/21
Start Date
8/31/26
End Date
80.0% Complete

Funding Split
$3.5M
Federal Obligation
$0.0
Non-Federal Obligation
$3.5M
Total Obligated
100.0% Federal Funding
0.0% Non-Federal Funding

Activity Timeline

Interactive chart of timeline of amendments to R01CA254955

Transaction History

Modifications to R01CA254955

Additional Detail

Award ID FAIN
R01CA254955
SAI Number
R01CA254955-724308913
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Nonprofit With 501(c)(3) IRS Status (Other Than An Institution Of Higher Education)
Awarding Office
75NC00 NIH National Cancer Institute
Funding Office
75NC00 NIH National Cancer Institute
Awardee UEI
G7MQPLSUX1L4
Awardee CAGE
0GXU0
Performance District
PA-03
Senators
Robert Casey
John Fetterman

Budget Funding

Federal Account Budget Subfunction Object Class Total Percentage
National Cancer Institute, National Institutes of Health, Health and Human Services (075-0849) Health research and training Grants, subsidies, and contributions (41.0) $1,354,550 100%
Modified: 8/20/25