Targeting CISD1-mediated ferropoptosis in head and neck cancer

Late-stage, HPV-negative (HPV-) head and neck squamous cell carcinoma (HNSCC) (or HNC-) is the most lethal HNSCC subtype. HNC- occurs at the highest incidence in the Appalachian region, where a large segment of this population is rural, economically disadvantaged and medically underserved. The Appalachian population has the highest tobacco use in the nation, a behavior directly linked to disparities in HNC- incidence and mortality. As such, there is a pressing need to identify novel therapeutic targets for efficacious treatment of HPV- cancers in Appalachia and beyond. Increased iron-regulation contributes to rending cancer cells resilient to conventional chemotherapeutic treatment. CISD1 (MitoNEET) is a redox-active iron-sulfur [2Fe-2S] containing protein that functions in the outer mitochondrial membrane to regulate cellular bioenergetics and support Fe-S cluster repair during cellular stress encountered in chemotherapy. Ferroptosis is a specialized form of programmed cell death that results from iron dysregulation. Informatic studies indicate that CISD1 overexpression is a novel ferroptosis- related prognostic marker across multiple cancer types, where its overexpression in HNC- and other cancers is associated with poor overall and progression-free survival. Our pilot data shows that CISD1 is overproduced in several Appalachian HNC- cell lines and PDX tumors. Loss of CISD1 function by pharmacologic inhibition or knockout reduces cell proliferation in several cancer types through mitochondrial-based bioenergetic mechanisms. Since Fe-S cluster biosynthesis is upregulated in cancer compared to non-cancerous cells, CISD1 inhibitory ligands represent a novel class of chemotherapeutics with the potential to avoid overt toxicity in normal cells. However, the optimal delivery mechanism of selective ligands targeting CISD1 to test efficacy in HNC- is not known. Our central hypothesis is that CISD1 inhibition serves as novel chemotherapeutic approach in the treatment of HNC- to cause mitochondrial dysfunction and ferroptosis-mediated reduction of cell proliferation and survival. Aim 1 will determine the role of CISD1 on ferroptosis in the HNC- through gain and loss of function assays. Aim 2 will develop a novel lipid nanoparticle formulation to deliver the first in class CISD1 inhibitor NL- 1 in combination with CISD1-targeting siRNA and the approved HNSCC-targeted therapeutic cetuximab (Erbitux) to patient-derived xenografts of HNC- in mice for enhanced anti-cancer activity. Results from this proposal will provide a foundation for future studies that will mechanistically address a novel tumor-supporting mechanism identified from this work as a driver of HNC- disease aggressiveness. This work will be the first to demonstrate CISD1 as a potential a new target for further therapeutic development in order to improve treatment of this highly refractory disease in the Appalachian and other populations with disparate HNC- incidence and mortality. Project Number: 1R21DE033813-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Werner Geldenhuys (+1 co-PI) | Institution: WEST VIRGINIA UNIVERSITY, MORGANTOWN, WV | Award Amount: $418,000 | Activity Code: R21 | Study Section: Advancing Therapeutics A Study Section [ATA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11057747