Targeting STAT3 with Novel Thiomorpholino Antisense Oligonucleotides for Cancer Therapy

Vesicle Therapeutics, Inc. (VTI) is developing a targeted antisense oligonucleotide (ASO) using innovative thiomorpholino chemistry (TMO) to treat head and neck cancer, particularly squamous cell carcinoma (HNSCC). Head and neck cancer ranks as the sixth most common cancer type, with up to 90% of these tumors being squamous cell carcinoma (HNSCC). The survival rate remains low due to the relatively low responsiveness to treatments and severe drug resistance. Various therapeutic approaches have been attempted to inhibit STAT3, but no STAT3-specific therapeutics have been approved yet. VTI’s ASO is designed to selectively inhibit the oncogenic STAT3α isoform while preserving the tumor-suppressive STAT3β, aiming to treat the tumor and its microenvironment (TME) more effectively and with less toxicity than current approaches. Our preliminary results show that the STAT3 TMO is effectively taken up by both tumor and immune cells, accumulates in the nucleus, alters the STAT3α/STAT3β ratio favorably, and suppresses myeloid cell expansion induced by tumor cells, all with low systemic toxicity. The Phase I project focuses on synthesizing sufficient quantities of STAT3 TMO, evaluating its effects on gene expression, determining its pharmacokinetics, and assessing its safety and efficacy in preclinical models. Positive outcomes from proposed studies will set the stage for developing a novel isoform selective STAT3 targeted therapy for treating head and neck cancer and improving patient outcomes. Project Number: 1R41CA287794-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: XUEDONG LIU | Institution: VESICLE THERAPEUTICS INC., NIWOT, CO | Award Amount: $400,000 | Activity Code: R41 | Study Section: Special Emphasis Panel[ZRG1 CDPT-R (12)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11182768