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Small molecule modulators for mitochondrial RNA-induced viral mimicry in lung cancer

Award Number: R01CA308037
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Small molecule modulators for mitochondrial RNA-induced viral mimicry in lung cancer - SUMMARY The overarching goal of this study is to develop small molecule modulators as a new therapeutic strategy in treating therapy resistant and immune cold KRAS/LKB1 (KL) mutant, non-small cell lung cancer (NSCLC) patients. We have identified the RNA exonuclease polynucleotide phosphorylase (PNPase) as a novel cancer target. Inactivation of PNPase leads to the accumulation of cytosolic mitochondrial double-stranded RNA (mtdsRNA), which mimics viral infection in lung tumors. PNPase resides in the mitochondrial intermembrane space and is responsible for the degradation of excess mtdsRNA. Inactivation of PNPase results in the accumulation and escape of excess mtdsRNA into the cytoplasm. We have discovered that mtdsRNA functions as a novel damage-associated molecular patterns (DAMPs) that mimics viral infection in tumor cells. As a direct consequence of mtdsRNA-induced anti-viral responses following PNPase inhibition, tumors remodel their lipid homeostasis through the Type-l interferon (IFN-l) pathway and lipid droplet (LD) biogenesis, respectively. Importantly, PNPase-induced mtdsRNA export represents a new and unexplored signaling mechanism in lung cancer; however, there remains a gap in studying this pathway, particularly because novel compound tools are lacking, which would increase translation-based studies. In preliminary studies, we have developed first-in-field PNPase inhibitors (mtPNPi's) from molecular docking studies. mtPNPi's bind to PNPase and induce the formation of cytosolic mtdsRNAs and LD biogenesis that sensitize tumors to lipid peroxidation and ferroptosis. Our study goals are contained within three thematically connected specific aims. In Aim 1, we will synthesize small molecule libraries to investigate structure-activity relationship studies from first-generation mtPNPi's, with the goal of increasing specificity and limiting binding to off-target proteins. In Aim 2, the small molecules will be tested in endpoint studies to identify top hits that have the highest therapeutic efficacy in cancer cells. Finally, in Aim 3, top hits will be screened and refined to identify lead compound(s) using a variety of human NSCLC and pancreatic ductal adenocarcinoma (PDAC) cancer cell lines. Our study team has extensively characterized PNPase and its mitochondrial function in NSCLC and recently in PDAC. Results from this proposal will lead to the generation of robust mtPNPi's for mechanistic studies of the pathway(s) by which mtdsRNAs induce viral mimicry in therapy resistant cancers and pave the way for pre-clinical translational studies. In follow-on pre- clinical studies, the success of these compounds will be directly tested in in vivo models using genetically engineered mouse models, patient-derived xenografts, and human tumor biopsies from NSCLC and PDAC patients. Ultimately, the proposed study will deepen our mechanistic understanding of how mtdsRNA sensing and viral mimicry are regulated in cancer. The development of selective mtPNPi's holds significant clinical promise to improve patient outcomes and survival.


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 = $540,204 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	1	8/28/2026	NEW	$540,204
														Subtotal = $540,204

Grand Total All Awards = $540,204

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Small molecule modulators for mitochondrial RNA-induced viral mimicry in lung cancer

Award Number: R01CA308037

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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