Wistar Institute Researchers Enhance Cancer Therapy with Targeted Drug Delivery
Scientists at the Wistar Institute have developed a novel approach to cancer treatment by combining a promising cancer therapy with a molecule designed to specifically target tumors. This new strategy aims to deliver higher doses of treatment directly to cancerous cells while minimizing the harmful effects on healthy tissue, potentially overcoming a significant hurdle in cancer drug development.
An Aurora kinase A (AURKA) inhibitor is viewed as a lethal synthetic molecule in cancer therapy, but the problem is you can’t dose it high enough, because then it starts to spill over and target normal cells, causing toxicity. By using this cancer-targeting approach, we can direct this molecule, which is already in clinical use, to cancer cells, increasing its exposure in the tumor itself.
Joseph Salvino, Ph.D., coauthor
Salvino is a professor in the Molecular and Cellular Oncogenesis Program at the Ellen and Ronald Caplan Cancer Center, and the scientific director of Wistar’s Molecular Screening & Protein Expression Facility.
Building a Targeted Drug Conjugate
The research team created a “small molecule drug conjugate” – essentially linking two existing molecules together. One component is an Aurora kinase A (AURKA) inhibitor. AURKA is a protein that plays a crucial role in cell division and tumor growth. While AURKA inhibitors have shown promise in clinical trials, their use has been limited by toxic side effects. The second component is a molecule that selectively binds to HSP90, a protein often overexpressed in cancer cells to help them cope with stress. By targeting HSP90, the researchers hypothesized they could concentrate the AURKA inhibitor within the tumor environment, reducing its impact on healthy cells.
The study, published in Molecular Cancer Therapeutics, demonstrated that the newly created chimeric molecule effectively binds to both AURKA and HSP90 proteins. Testing on cell samples from various cancer types – including head and neck, lung, and melanoma – revealed that the conjugate halted cancer cell division and replication, ultimately leading to cell death.
Enhanced Tumor Concentration and Reduced Toxicity
Further investigation involved preclinical animal models. The results showed that the chimeric molecule accumulated inside tumors at concentrations up to ten times higher than when the original AURKA inhibitor was administered alone. Importantly, the compound remained active within the tumor for a significantly longer period – still detectable 24 hours after injection, compared to the rapid disappearance of the original inhibitor. The conjugate also exhibited a favorable safety profile in these models, with no significant toxicity observed.
The researchers also explored combining the new molecule with a WEE1 inhibitor, another cancer drug. This combination proved even more effective in controlling tumor growth, suggesting a potential synergistic effect.
Addressing Pharmacokinetic Challenges
Salvino explained that a common reason for drug failure in clinical trials is insufficient drug exposure within the tumor, often due to pharmacokinetic limitations – how the body processes the drug. “Our approach will take an existing compound and improve its pharmacokinetic properties, enhancing its exposures in the tumor,” he stated. This strategy focuses on optimizing how the drug is absorbed, distributed, metabolized, and excreted by the body, ensuring a greater concentration reaches the intended target.
Broad Applicability and Future Directions
The researchers believe this approach has the potential to be applied to a wide range of cancer types beyond those initially tested. They are now focused on extending this strategy to different molecules and cancer types. A key goal is to develop a formulation of the chimeric molecule that can be administered orally, offering a more convenient treatment option for patients.
The development of targeted drug conjugates represents a significant advancement in cancer therapy, building on the broader trend of precision medicine. As highlighted in recent research [1], combining antibody-drug conjugates (ADCs) with other therapies is gaining traction to overcome limitations like drug resistance and off-target effects. Similarly, [2] emphasizes the promise of targeted drug conjugates in achieving precise drug delivery while minimizing harm to healthy cells. The evolution of these technologies, from antibody-based conjugates to small molecule conjugates like the one developed at Wistar, is paving the way for more effective and less toxic cancer treatments, as detailed in [3] and [4]. Further refinement of linker strategies and delivery vehicles, as discussed in [5], will likely play a crucial role in maximizing the therapeutic potential of these innovative approaches.
