Redefining the Future of Cancer Drug Discovery: A Conversation with Professor Paul Workman
 
In the evolving landscape of oncology, few figures have shaped modern cancer drug discovery as profoundly as Paul Workman, Professor of Pharmacology and Therapeutics at the Institute of Cancer Research. Professor Workman has spent more than five decades at the forefront of translating cutting-edge science into transformative cancer medicines. From the era of cytotoxic chemotherapy to the rise of precision oncology, his career mirrors the extraordinary evolution of the field itself.
 
In this in-depth conversation, Professor Workman reflects on the scientific breakthroughs, cultural shifts, and technological innovations that have redefined cancer therapeutics—and shares his vision for the future of drug discovery.
 
From Cytotoxics to the Cancer Genome: A Paradigm Shift
 
When Professor Workman began his PhD in drug discovery in 1973, cancer treatment was dominated by cytotoxic agents—broad-spectrum chemotherapies given to nearly all patients, regardless of tumor biology. The therapeutic index was narrow, and toxicity was an unavoidable reality.
 
At the same time, however, a revolution was beginning in cancer biology. The 1970s and 1980s saw the discovery of oncogenes such as SRC and RAS, revealing that cancer is driven by specific genetic abnormalities. Yet translating these discoveries into medicines took decades, requiring a conceptual reset as well as scientific and medical transition.
 
The true paradigm shift arrived 25 years ago with the publication in 2001 of the first draft of the Human Genome Sequence. For oncology, this was transformative and progress has accelerated especially over the last decade. Cancer became the trailblazer for molecular medicine, leveraging genomic sequencing to identify driver mutations and actionable targets.
 
The result. The emergence of precision medicine.
 
Today, more than 90 FDA-approved cancer therapies are precision medicines linked to companion diagnostics—biomarkers that guide patient selection. Nearly half of oncology drug approvals since the late 1990s fall into this category. Most importantly, genomic sequencing in the clinic now enables approximately 30–36% of patients to receive a targeted therapy matched to their tumor biology—up from just 18% only a decade ago.
 
This progress is remarkable. Yet it also highlights a stark reality: around two-thirds of patients still lack an actionable, druggable target.
 
Drugging the Cancer Genome: The Challenge of “Undruggable” Targets
 
Professor Workman coined the term “drugging the cancer genome” to describe the central challenge of modern oncology. While we understand the genetic drivers of many cancers, a substantial proportion of them remain difficult—or historically impossible—to target with small molecules.
 
Kinases have been a major success story, beginning with imatinib and trastuzumab and continuing with EGFR and ALK inhibitors. But many cancer drivers are transcription factors or protein–protein interactions or other proteins lacking discernible druggable pockets. Examples include:
  • MYC
  • β-catenin
  • Until recently RAS, STAT3 and some forms of mutant p53
For years, these were deemed “undruggable.”
 
However, many are now yielding, owing to recent technological breakthroughs that are reshaping the landscape:
  • Structure--based drug discovery, including fragment-based approaches
  • Novel screening technologies including DNA-encoded libraries for diversity and also affinity selection-mass spectrometry to detect weak hits
  • Covalent inhibitors, which  have enabled targeting of difficult proteins such as mutant KRAS.
  • PROTACs and molecular glues which allow targeted degradation of proteins rather than simple inhibition.
  • Novel pocket discovery approaches have enabled inhibitors of challenging targets like the allosteric sites in KRAS and HIF-2α.
  • Mutant p53 reactivation drugs have emerged. 
These advances provide cautious optimism that the druggable portion of the cancer genome will expand significantly in the coming years.
 
Why Do So Many Drug Targets Fail?
 
Despite scientific advances, 95% of oncology drugs entering clinical development fail. Only 5% succeed to gain regulatory approval.
 
Why?
 
Professor Workman argues that target identification and validation remain critical weaknesses. Genetic identification of a target is not enough. Robust validation must include:
  • Corroboration across diverse tumor models
  • CRISPR knockout studies
  • Orthogonal chemical probe validation, also indicating small molecule tractability
  • Controls to mitigate off-target effects of genetic and pharmacological perturbants
  • Genetic rescue experiments to confirm on-target effects
  • Long-term therapeutic durability assessments
  • Prediction of therapeutic window ad optimal dose schedule
  • Prediction of resistance mechanisms
In some recent analyses, several drug candidates retained activity even when the nominal target was genetically knocked out—revealing off-target mechanisms that undermined the entire rationale.
 
Moreover, cancer’s adaption and Darwinian evolution present a persistent obstacle. Tumor cells mutate drug targets, rewire signalling pathways, switch cell states (plasticity) and thereby develop resistance. Durable responses commonly require anticipating these, often through rational combination strategies or sequential treatments enabled by liquid biopsies.
 
Improved tolerability prediction and side-effect prediction are needed. 
 
 
Lessons from HSP90: Targeting Networks, Not Just Individual Drivers
 
Professor Workman’s pioneering work on HSP90 inhibitors illustrates the complexity of targeting biological networks.
 
HSP90 is a molecular chaperone responsible for stabilizing multiple oncogenic client proteins. Inhibiting it offered the tantalizing possibility of hitting multiple drivers simultaneously—a “combinatorial effect in a single molecule.”
 
While promising activity was observed, including responses in trastuzumab-refractory HER2-positive and ALK-translocated cancers, clinical development faced significant challenges:
  • Gastrointestinal toxicity
  • Fatigue
  • Unexpected ocular toxicity (fully reversible, but concerning to patients, clinicians and regulators)
Ultimately, these tolerability concerns and competition from more selective single target therapies led limited widespread adoption, although pimitespib was approved in Japan.
 
Despite the frustration, the experience with HSP90 yielded critical insights:
  • Complex targets can produce powerful biological effects.
  • Unexpected on-target resistance mechanisms can emerge (e.g., activation of HSF1 stress response after HSP90 inhibition).
  • Targeting stress pathways may unlock new synthetic lethal opportunities.
Building on this work, Workman’s team discovered NXP800 which blocks the transcriptional activity of HSF1and is now in clinical trials for ARID1A-mutant ovarian and potentially also endometrial cancers —demonstrating how deep biological insight can translate into new therapeutic avenues.
 
Embracing Complexity: Are We Ready?
 
Modern oncology increasingly acknowledges that cancer is not a single-driver disease but a complex, adaptive system.
 
While drug discovery traditionally reduces problems to single molecular targets, tumors operate through dynamic networks. The question becomes: can we design strategies that anticipate biological adaptation?
 
Possible approaches include:
  • Rational upfront combinations
  • Sequential therapy guided by real-time molecular monitoring
  • Bispecific antibodies
  • Targeted immune modulation with improved predictive biomarkers
  • Engineered CAR-T approaches
  • Vaccines
  • Degrader technologies
One particularly promising advancement is circulating tumor DNA (ctDNA) sequencing, which enables clinicians to detect emerging resistance mutations long before clinical progression. This allows faster intervention and potentially improved long-term outcomes.
 
Underexplored Frontiers
 
Looking ahead, Professor Workman identifies several areas ripe for further exploration:
 
1. Stress Pathway Biology
 
Oncogenic transformation is inherently stressful for cells. Cancer cells activate protective pathways to survive. Targeting these stress responses may reveal new forms of synthetic lethality beyond BRCA–PARP paradigms.
 
2. Epigenetics
 
Although early expectations have not yet fully materialized, epigenetic regulation remains a promising but underexploited field.
 
3. Synthetic Lethality Expansion
 
Beyond BRCA mutations, identifying robust synthetic lethal interactions remains a major opportunity.
 
4. Artificial Intelligence
 
AI is transforming, or has the potential to transform transform:
  • Target identification
  • Drug design
  • PK/PD modeling
  • Tolerability prediction
  • Preclinical-to-clinical translation
As regulatory initiatives such as the FDA’s Project Optimus emphasize optimal dosing strategies, better predictive modeling becomes increasingly important.
 
The Pharmacologic Audit Trail
 
A concept central to Professor Workman’s thinking on clinical development, and underpinning Project Optimus, is his “pharmacologic audit trail” framework
 
This approach integrates:
  • Biomarkers for patient selection
  • Measures of PK and PD (target engagement/modulation)
  • Molecular markers of response
  • Longitudinal molecular analysis, including resistance monitoring
Rather than treating drug development as a linear progression, the audit trail ensures mechanistic understanding from bench to bedside—and back again.
 
The Road Ahead
 
While we may not have a crystal ball or a magic wand, Professor Workman enthuses that the trajectory of oncology inspires optimism. We understand cancer genetics and biology more deeply than ever before, though there is much to learn. We possess powerful new technical enablers. And we are increasingly able to track tumor evolution in real time.
 
The next decade will likely focus less on discovering entirely new pathways and more on:
  • Expanding the druggable genome
  • Improving target validation rigor
  • Embracing biological complexity
  • Anticipating and overcoming resistance
  • Developing rational combinations
  • Leveraging AI
 
As Professor Workman prepares to deliver his keynote at Drug Discovery Europe 2026 in Berlin, these themes will take center stage—offering both reflection on past achievements and a forward-looking roadmap for the future of cancer drug discovery.
 
The revolution that began with oncogene discovery is far from over. In many ways, it is only just beginning.