Anti-cancer Drugs: Pre-clinical Discovery and Development

Anti-Cancer Drug Development Overview

• Objective: To understand the historical progression and methodologies in the discovery and development of anti-cancer drugs.

Historical Context

• Mid 20th Century: Development depended heavily on mouse cancer cell lines.
  • Focus was on identifying chemicals to inhibit cancer cell proliferation and survival through cell culture methods.
  • First drugs were discovered by applying chemicals to these cell lines to identify effective treatments.

Early Animal Models of Cancer

• Types of Models:
  • Virally or chemically induced cancers in mice led to the derivation of mouse cancer cell lines.
  • Transplantable tumors: Cancer cells from inbred mouse strains could be implanted and grow in other mice of the same strain, due to genetic similarity (syngeneity).
  • Benefit: This model reduces tissue rejection, ensuring a reproducible cancer model, facilitating research.

Advancements in Cancer Models

• Human Cancer Cell Lines:
  • Developed to better mimic human cancer biology than mouse cell lines.
  • Xenograft Models: Utilized to implant human cancer cells into immunodeficient mice, allowing study of human tumors in a live environment.

Drug Development Challenges

• Cell Culture vs. Animal Models:
  • Cell culture fails to replicate the complex host cancer environment.
  • Animals provide better approximations of:
  • Tumor microenvironment,
  • 3D tumor structure,
  • Host-cancer interactions,
  • Host-drug interactions.

Late 20th Century Developments

• New strategies were required as existing methods exhausted the potential of traditional chemotherapy.
  • Identifying molecular therapeutic targets became essential.
  • Recognition of Cancer Diversity: Cancer is not a single disease; understanding its biology was key to developing effective treatments.
  • Improved capability to design drugs aimed at specific biological targets.

Molecularly Targeted Therapy

• Basic Concept:
  • Drugs specifically inhibit molecular targets in cancer cells to stop their survival and proliferation.

Criteria for Good Molecular Targets

• Must be essential for cancer cell function.
• Should have selective expression in cancer cells versus normal cells.
• Minimal redundancy is ideal to prevent alternative survival pathways.
• Targets should be “druggable” and measurable for optimal patient treatment matching.

Types of Molecular Targets

• Receptors & Ligands: Inhibition of ligand binding to receptor.
• Enzymes: Target protein kinases to prevent phosphorylation actions.
• Protein-Protein Interactions: Block formation to disrupt signaling pathways.

Target Identification and Validation

1. Identify Therapeutic Targets:

   • Use tools like DNA/RNA sequencing to identify mutated genes.
   • Distinguish between driver and passenger mutations to focus on treatment pathways.

2. Validation:

   • Use methods such as RNA interference or CRISPR-Cas9 to test gene expression modifications.

3. Drug Discovery:

   • Screens of chemical libraries and rational drug design based on target structure.

4. Testing: Assess the drug's effectiveness and specificity against targets; consider off-target effects.

   • Notable example: ALK inhibitors tested for efficacy against targeted cancer pathways.

5. Pre-Clinical Pharmacology and Toxicology:

   • Evaluate ADME (Absorption, Distribution, Metabolism, Excretion) properties and overall safety profile before human trials.

Transition to Clinical Trials

• Successful pre-clinical tests can lead to clinical trials to evaluate drug efficacy and safety in human patients.

Successes

• Development of hundreds of molecularly targeted therapies that personalize cancer treatment according to individual tumor biology.

Challenges Ahead

• Gaps remain in targeting all types of cancer effectively.
• Drug resistance and off-target effects still pose significant hurdles.
• Continued research is vital for addressing unsolved problems in cancer treatment.