Cancer Drug Development: Views from Industry
In the realm of cancer drug development, several critical factors come into play, including target validation, addressing unmet medical needs, evaluating therapeutic indices, and assessing druggability. These elements are essential for shaping effective therapies and advancing our understanding of cancer treatment.
One of the fundamental aspects of drug development is confirming the validity of potential drug targets. Two key insights from target validation studies are worth noting:
• First, it’s often more challenging to shrink an established cancer in vivo than to inhibit tumor formation or growth. This emphasizes the importance of focusing on therapies that not only prevent cancer development but also have a pronounced impact on existing tumors.
• Second, while metabolic targets identified through large screens may seem promising, their effectiveness in vivo can vary significantly. Therefore, thorough validation is crucial to ensure that these targets are viable for drug development.
Patient-Derived Xenograft (PDX) trials have emerged as valuable tools for predicting the effectiveness of targeted therapies. Treating PDX models akin to Phase 1 trials can expedite drug development, offering insights into how therapies will perform in clinical settings. This approach often outperforms studying heterogeneity in a limited number of models, as PDX trials provide a broader spectrum of insights.
Identifying druggable targets is a pivotal step in cancer drug development. Several strategies have been employed in this pursuit.
• First, the development of mutant-selective inhibitors has been promising. These inhibitors specifically target cancer-associated mutations, increasing their precision and minimizing off-target effects.
• Second, focusing on dispensable lineages, such as B cells and certain solid tumors like breast and prostate cancer, has shown potential, although this approach may not be applicable to all cancer types, such as pancreatic cancer.
• Third, preclinical models, including mouse knockouts and platforms like DepMap, aid in assessing druggability by offering insights into target function.
Challenges in Drugging the Undruggable:
Around 60% of proteins in various pathways lack catalytic activity, posing significant challenges in targeting them directly. Approaches to address this issue include:
1. Disrupting Protein Interactions: This involves the development of direct competitive inhibitors (e.g., Venetoclax targeting BCL2) or allosteric inhibitors, as seen in HIF2a and KRAS G12C inhibitors like sotorasib and adagrasib.
2. Degraders and PROTACs: Heterobifunctional degraders are a promising avenue, although they require clinical validation. Initially, most efforts in this field focused on already druggable proteins like ER, AR, RAF, and EGFR. However, recent advancements in technology are enabling the targeting of previously undruggable proteins.
3. Phenotypic/Cell-Based Screens: High-throughput screens on cell lines that reflect the function of a specific target have gained traction. This approach enables the identification of novel drug candidates based on their impact on cancer cells’ behavior.
In conclusion, cancer drug development demands a comprehensive approach that encompasses target validation, leveraging predictive models like PDX trials, assessing druggability through various strategies, and innovating to tackle the challenge of drugging the undruggable. These lessons from target validation studies and the evolving approaches to druggability provide valuable insights into the complex journey of developing effective cancer therapies.