Cross-talk between social determinants of health and MTOR pathway, the missing link in fatigue

Debilitating post-treatment fatigue following stereotactic body radiotherapy (SBRT) to treat prostate cancer is a significant public health concern due to its negative impact on health-related quality of life, higher comorbidities, and shorter survival. To date, there are limited effective targeted fatigue therapies. Limited therapeutic options are due in part to inconsistent evidence on the individual and combined influence of social determinants of health (SDOH) risk factors such as dietary adversity (i.e., food insecurity, poor dietary quality), socioeconomic deprivation at the neighborhood level, and genetic factors that could ultimately influence biological pathways altering cancer-related fatigue (CRF) risk. Importantly, we recently showed associations between lower dietary quality and post-treatment CRF among food insecure prostate cancer individuals. One pivotal pathway that may link dietary adversity to CRF risk is the mammalian rapamycin complex 1 (mTOR/mTORC1) which is involved in autophagy to regulate cell growth and in energy homeostasis. Our recent work (NR020039) using next- generation RNA sequencing (RNAseq) from whole blood followed by gene and pathway ontology analyses identified novel significant associations between the expression of HAS1, PIK3R1, RASA4, SMAD1, TIRAP, and VEPH1– all related to mTORC1 – with CRF at 1 month after SBRT, suggesting a key role for the mTOR pathway in CRF. Our evidence highlights the importance of understanding if these risk factors individually or combined elevate the severity of CRF. The proposed research is guided by a model of SDOH, and dysregulation of the mTOR pathway in post-treatment fatigue. An experienced team of scientists will conduct the proposed project, employing rigorous methods using “-omic” approaches to investigate our central hypothesis, by leveraging our K23 NR020039, that genes involved in mTORC1 and related pathways are differentially expressed in CRF. We anticipate that dysregulation of mTOR-pathway genes, dietary adversity, and other SDOH will be enriched in men with prostate cancer who experience CRF. To attain our objective, in a new independent cohort (n=150) at pre, and 1 month after SBRT, we propose to: 1) validate dysregulation of 6 mTOR pathway genes in an independent cohort (Aim 1); and 2) determine the impact of dietary adversity, and other SDOH on post-treatment CRF (Aim 2a) and analyze the contribution of the 6 mTOR pathway genes and dietary adversity on post-treatment CRF (Aim 2b). At the end of this project, the proposed research will advance management strategies for cancer-related symptoms by providing proof of the principle of underlying factors that increase risk of fatigue and support further development and replication of serum biomarkers of fatigue severity and modifiable biologically relevant therapeutic targets to treat fatigue and improve outcomes in this population. Project Number: 1R21CA288925-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Velda Gonzalez-Mercado | Institution: NEW YORK UNIVERSITY, NEW YORK, NY | Award Amount: $427,085 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZCA1 SRB-2 (M2)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11211019