Drugs for solid cancer: the productivity crisis prompts a rethink

Area of Science:

• Oncology
• Translational Medicine
• Drug Development

Background:

• Significant advancements in cancer drug discovery contrast with stalled clinical translation of novel therapies.
• Src kinase is implicated in solid cancer progression, yet Src inhibitors show modest clinical efficacy, highlighting a translational gap.

Purpose of the Study:

• To examine key steps in drug development using Src inhibitors as a model for drugs targeting invasion and metastasis.
• To identify roadblocks hindering the translation of promising cancer drug candidates from preclinical studies to clinical success.

Main Methods:

• Analysis of preclinical evidence versus clinical trial outcomes for Src inhibitors in solid cancers.
• Evaluation of the role of metastasis in cancer morbidity and mortality.
• Review of current regulatory frameworks in relation to cancer disease natural history and key complications.

Main Results:

• A discrepancy exists between strong preclinical data for Src and solid cancers and modest clinical trial outcomes.
• Tumor shrinkage in preclinical and clinical studies may not accurately predict successful therapeutic outcomes.
• Key translational challenges include inadequate preclinical models, non-meaningful clinical trial endpoints, and underappreciation of metastasis.

Conclusions:

• Current regulations and trial designs may not align with the natural history of cancer, particularly local invasion, metastasis, and resistance.
• Aligning preclinical and clinical studies, regulatory approaches, and adopting mechanistic trial endpoints are crucial for overcoming translational roadblocks.
• The necessary components for a novel translational paradigm in cancer drug development are largely available.