Wistar Institute Develops Novel Drug Conjugate for Enhanced Cancer Therapy

Wistar Institute scientists have developed a new small molecule drug conjugate designed to enhance cancer therapy by combining an Aurora kinase A (AURKA) inhibitor with a tumor-targeting molecule. This approach aims to deliver treatment at higher doses directly to cancer cells while minimizing potential side effects on healthy tissues. The findings were published in Molecular Cancer Therapeutics.

"This approach aims to deliver treatment at higher doses directly to cancer cells while minimizing potential side effects on healthy tissues."

The Chimeric Molecule

The newly developed compound is a small molecule drug conjugate, created by linking an Aurora kinase A (AURKA) inhibitor to a molecule that targets HSP90.

• AURKA Inhibitor: This component is designed to block a protein crucial for cell division and tumor growth. While effective in previous clinical trials, its use has been limited by toxic side effects observed at therapeutically effective doses.
• HSP90 Targeting Molecule: HSP90 is a protein found at elevated levels in cancer cells, where it assists them in withstanding stress. By targeting HSP90, the researchers sought to concentrate the drug within cancerous tissues.

Research Findings

In a proof-of-concept study, the chimeric molecule demonstrated several outcomes:

• Binding: The molecule successfully bound to both AURKA and HSP90 proteins.
• Cellular Impact: When tested in cell samples from various cancer types, including head and neck, lung, and melanoma, the molecule was observed to halt cancer cell division and replication, which subsequently led to cell death.
• Preclinical Animal Models:
  • The compound concentrated in tumors at levels up to 10 times higher than when the AURKA inhibitor was administered alone.
  • It remained active within tumors for extended periods, detectable more than 24 hours after injection, a longer duration compared to the original AURKA inhibitor.
  • The compound was well tolerated in preclinical models, showing no significant toxicity.
• Combination Therapy: When combined with a WEE1 inhibitor, another cancer drug, the chimeric molecule demonstrated increased efficacy in controlling tumor growth.

"The compound concentrated in tumors at levels up to 10 times higher than when the AURKA inhibitor was administered alone."

Rationale and Future Outlook

According to researchers, this strategy addresses pharmacokinetic challenges, such as insufficient drug exposure within tumors, which can contribute to treatment failures. They believe this method has the potential to improve the therapeutic exposure of existing compounds in tumors.

Future plans for this research include applying the strategy to different molecules and cancer types. Additionally, researchers aim to develop an oral formulation for the chimeric molecule.

Support and Acknowledgments

This work was supported by grants from the National Institutes of Health (NIH), the Department of Defense (DOD), and the William Wikoff Smith Charitable Trust.