Protein Degraders of NSD2 for Targeted Treatment of Head and Neck Cancers

SHORT DESCRIPTION
Targeted protein degraders that selectively eliminate NSD2 for improved treatment of head and neck cancers.

• Gary Schiltz*
  • Weinberg College of Arts and Sciences, Department of Chemistry
• Yanis Boumber

* Principal Investigator

NU Tech ID: NU 2023-140

IP STATUS

U.S. Patent Pending

DEVELOPMENT STAGE

TRL-4 - Prototype Validated in Lab: Laboratory-scale models have demonstrated key functionalities, showing effective degradation of NSD2 in cancer cell lines.

BACKGROUND
Head and neck cancers collectively account for more than 660,000 new cases and 325,000 deaths worldwide each year, with laryngeal carcinoma representing roughly 30–40% of these malignancies and about 185,000 cases and 100,000 deaths annually. Laryngeal cancer (LC) is particularly impactful because it threatens both survival and core functions such as voice, swallowing, and airway protection. In the U.S., localized disease carries a 5‑year survival of ~80%, but survival drops to ~50% with nodal spread and ~35% with distant metastases, and global outcomes are worse in low‑resource settings. Current treatments combine surgery (ranging from endoscopic laser resection to total laryngectomy), radiation, and platinum‑based chemoradiotherapy, and while early‑stage disease can often be controlled with single‑modality radiotherapy or organ‑preserving surgery, advanced tumors frequently require multimodal therapy or laryngectomy, leading to permanent tracheostomy, loss of natural voice, dysphagia, chronic aspiration risk, and substantial quality‑of‑life impairment. Even with modern chemoradiation and organ‑preserving approaches, many patients experience local recurrence, long‑term dysphonia and swallowing dysfunction, and high rates of unmet supportive‑care needs. underscoring a persistent unmet need for more effective, larynx‑sparing therapies that maintain oncologic control while better preserving function and reducing late toxicity. 

ABSTRACT
Recent reports indicate that loss-of-function mutations in histone methyltransferases NSD1 and NSD2 occur in roughly 20% of LC cases that define a novel prognostic subtype associated with dramatically extended overall survival. Northwestern researchers have leveraged these findings and developed a series of small molecule degraders that selectively target the NSD2 protein, a protein crucial for tumor cell viability in head and neck squamous cell carcinomas, including LC. The molecules are designed to induce the proteolysis of NSD2 by recruiting an E3 ubiquitin ligase, disrupting oncogenic signaling pathways more effectively than traditional enzymatic inhibitors. Preliminary laboratory studies demonstrate that degrading the entire NSD2 protein produces a more profound effect in reducing cancer cell proliferation and inducing apoptosis. The technology offers a novel and promising pathway toward improved treatments for head and neck squamous cell carcinomas, laryngeal carcinoma, and other NSD2-driven cancers.

APPLICATIONS

• Head and neck squamous cell carcinomas: Provides a novel targeted treatment option aimed at malignant cells.
• Laryngeal carcinoma: Offers a novel therapeutic strategy for patients with aggressive LC and limited treatment options.
• Other cancers: Potentially applicable to cancers where NSD2 plays a critical role in tumor survival.

ADVANTAGES

• Novel mechanism of action: Provides an innovative treatment approach where traditional therapies fall short.
• Overcomes limitations of traditional enzymatic inhibition: Degrading the entire NSD2 protein yields more potent effects on tumor cell viability.
• Enhances therapeutic efficacy: Targets a critical oncogenic pathway to potentially improve patient outcomes.
• Broad applicability: offer a novel treatment for other cancers driven by NSD2 activity.

PUBLICATIONS

N/A