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Unraveling age-induced mechanisms of therapeutic resistance in cancer

Award Number: R01AG100153
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Unraveling age-induced mechanisms of therapeutic resistance in cancer - PROJECT SUMMARY Lung cancer accounts for the largest number of cancer-associated deaths in the United States. While great strides have been made due to the introduction of immunotherapies and targeted therapies against oncogenic drivers, many patients do not respond to these treatments or acquire resistance and relapse following initial response. Thus, there remains a dire need to identify new therapeutic approaches that can effectively treat lung cancers and prolong survival in these patients. We postulate that part of the problem is the lack of consideration in preclinical research and clinical trials of the main risk factor of lung tumorigenesis, the aging process. This is especially relevant for the hard-to-treat KRAS-driven lung cancer, whose incidence compared to other oncogenic drivers is enriched in older patients. Our published studies support this premise and have revealed a causal link between the systemic metabolic reprogramming that occurs as a function of aging and the progression of lung cancer into metastatic disease. This puts aging and the consequent changes that occur in the host at the center stage coordinating the different aspects required for the evolution of malignant phenotypes. Our subsequent studies expanded on these to uncover that age-induced circulatory accumulation of glucocorticoid hormones (GCs), whose levels extends to the lung cancer tumor microenvironment (TME), drive KRAS-driven lung cancer resistance to chemo and targeted therapies in the context of old age. Thus, here we propose that the GC signaling pathway, an evolutionarily conserved homeostatic signaling axis, becomes deregulated with aging leading to a state of intrinsic resistance to lung cancer therapies in the elderly. This hypothesis will be tested through three specific aims. Aim 1 will focus on evaluating the dependence of age-induced intrinsic therapy resistance of KRAS-driven lung cancer on GC signaling. Aim 2 will focus on understanding the molecular mechanisms underlying GC-signaling-mediated induction of drug resistance. Aim 3, on the other hand, will focus on mapping the dependences imposed by the old lung TME onto therapy resistant KRAS-driven lung cancer and their validation as therapeutic targets to circumvent therapy resistance in the context of old age. Consequently, the proposed studies will put the importance of considering age in the spotlight, thereby supporting different treatment paradigms to be implemented in patients according to their physiology. They will also highlight inhibitors of GC signaling as much needed tools to enhance sensitivity to standard of care therapies, improving therapeutic outcome for older patients. Moreover, our studies will put forward circulatory GCs as easily translatable biomarkers for the identification of patients that could profit more from these therapies at the onset of their treatments. Lastly, they will also identify new and age-relevant therapeutic targets against targeted- therapy-resistant KRAS-driven lung cancer with the overarching goal of fueling the development of improved treatment options for the most common and vulnerable lung cancer patients: the elderly.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $707,102 )
2026	2026	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Aging Research	000	1	6/26/2026	NEW	$707,102
														Subtotal = $707,102

Grand Total All Awards = $707,102

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Unraveling age-induced mechanisms of therapeutic resistance in cancer

Award Number: R01AG100153

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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