Cancer Drug Discovery

1. What inspired you to write Cancer Drug Discovery: Fascinating Anecdotes of Oncology Medicine, and what gap did you hope to fill in the existing literature on oncology drug discovery?

In the last decade, oncology has garnered the most drugs approved by the FDA among all therapeutic areas. Because of drug resistance from mutation, new cancer drugs are always needed. Novel targets, biologics (Chapter 4), and new modalities (Chapter 5) offer exciting opportunities for new cancer drugs. Before AI cures cancer (Chapter 6) for us, we can learn invaluable lessons from past successes and failures in cancer drug.

Indeed, many books have been written about cancer drug discovery. Most of them, however, focus primarily on the scientific aspects of the field—an important perspective that this book also covers. What distinguishes this book is its emphasis on the human side of drug discovery. Scientific breakthroughs are made by people whose upbringing, education, career paths, personalities, and life experiences often shape the way they approach research. Like everyone else, scientists make mistakes, face setbacks, and contend with human frailties. Throughout this book, I have sought to portray them not merely as researchers, but as people. This human perspective on cancer drug discovery has rarely been explored in other books.

2. Your book emphasizes learning from both breakthroughs and setbacks. Which historical lesson from cancer drug discovery do you believe remains most relevant for today's pharmaceutical researchers and biotech innovators?

The history of cancer drug discovery is defined by both remarkable breakthroughs and notable setbacks. Protein kinase inhibitors represent a paradigm shift in oncology; rooted in foundational research on protein phosphorylation in the 1950s, this work culminated in the development of Gleevec, the first approved kinase inhibitor. Today, more than 85 small-molecule and numerous biologic kinase inhibitors are available to treat various cancers, as well as inflammatory and autoimmune diseases.

Conversely, the field has faced significant challenges. Approaches such as combinatorial chemistry proved less effective than anticipated, and several highly publicized targets, including IDO-1 and SHP-2 inhibitors, ultimately failed to deliver clinical efficacy.

3. Oncology drug development has evolved dramatically over the past three decades. What scientific milestones do you consider the most transformative, and how have they reshaped the industry's approach to developing cancer therapies?

Beyond protein kinase inhibitors, the oncology landscape has been transformed by the emergence of monoclonal antibodies, immuno-oncology (I/O) agents—such as checkpoint inhibitors, PD-1 inhibitors in particular, antibody-drug conjugates (ADCs), and cell and gene therapies (CGT). These modalities have dramatically improved both the safety and efficacy of cancer treatment. Collectively, these advancements have fundamentally reshaped the pharmaceutical industry’s R&D strategy. At the turn of the century, small-molecule chemotherapies, while potent, were often defined by significant toxicity. Today, biologics account for more than half of cancer therapies, offering superior efficacy and markedly improved safety profiles.

4. Throughout your career in pharmaceutical companies and academia, what recurring challenges have you observed in translating promising laboratory discoveries into successful oncology medicines?

Translating promising laboratory discoveries into successful oncology medicines hinges on the effective integration of biomarkers into clinical trials. Perhaps the most prominent example of this strategy is Merck’s PD-1 inhibitor, pembrolizumab (Keytruda), which achieved extraordinary success by leveraging PD-L1 expression as a predictive biomarker.

This approach marked a paradigm shift in clinical trial design. By utilizing biomarkers to guide patient selection, researchers were able to identify populations most likely to respond, thereby optimizing the drug's therapeutic application. Specifically, the focused enrollment of patients exhibiting PD-L1 positivity and high microsatellite instability (MSI-H) significantly enhanced the clinical efficacy of pembrolizumab.

Although development for pembrolizumab began after that of Bristol Myers Squibb’s nivolumab, the strategic implementation of these biomarkers accelerated its clinical path. Pembrolizumab was granted “breakthrough therapy” designation and received FDA approval in September 2014, narrowly preceding nivolumab. Building on this momentum, the FDA designated Keytruda in 2017 as the first tissue-agnostic cancer treatment. This data-driven strategy proved immensely successful; by 2024, Keytruda had become the world's most lucrative drug, generating over $29.5 billion in annual revenue.

5. Precision oncology, targeted therapies, immunotherapy, and cell-based treatments are transforming cancer care. How do you see these modalities influencing the next generation of oncology drug discovery?

With the success of precision oncology, researchers, patients, doctors, and investors are less enamoured with conventional chemotherapies that come with atrocious toxicities along with the efficacy. However, I do see that efforts to enhance the efficacy of drugs such as platinum drugs while minimizing their toxicities will be appreciated.

6. Drug discovery is often portrayed as a linear process, but the reality is far more complex. Based on the stories in your book, what common misconceptions should young scientists and industry professionals avoid?

While some drug discovery programs progress relatively linearly, others follow a more tortuous path. Scientists at all career stages must therefore remain open-minded. For example, GLP-1 was discovered at the end of the last century; following John Eng’s foundational investigations, Amylin and Lilly secured FDA approval for the first GLP-1 agonist, exenatide (Byetta), in 2005 for the treatment of type II diabetes. Today, GLP-1 agonists are not only highly effective in treating diabetes but are also widely prescribed for weight management.

Similar narratives are evident in oncology, as documented in this book. For instance, the success of the first BTK inhibitor, ibrutinib, opened the floodgates for the development of irreversible covalent inhibitors. Furthermore, an increasing number of successful cancer therapies have effectively challenged the dogma of the "rule-of-five."

7. Many successful cancer drugs emerged through unexpected observations or scientific persistence. Can you share an example from your book that highlights the importance of curiosity and resilience in drug discovery?

Serendipity is ubiquitous in cancer drug discovery. In 1967, physicist Barnett Rosenberg discovered the chemotherapeutic potential of cisplatin while researching the impact of electric currents on cell growth. Similarly, the 1975 development of the hybridoma technique by Georges Köhler and César Milstein stands as a testament to the power of curiosity, arising from their decision to fuse two distinctive cell lines. Finally, when Avram Hershko and Aron Ciechanover elucidated the mechanism of the ubiquitin-proteasome system (UPS), they could not have foreseen the critical role this system plays in the degradation of proteins and other macromolecules.

These three examples underscore the essential roles that curiosity and resilience play in drug discovery.

8. As artificial intelligence, machine learning, and computational chemistry become increasingly integrated into pharmaceutical R&D, how do you envision these technologies changing oncology drug discovery over the next decade?

With the exponential growth of AI techniques and our expanding knowledge of oncology, cancer drug discovery is poised for a revolution over the next decade. This progress is particularly transformative in two areas: diagnostics and drug discovery, specifically regarding target identification and the modelling of drug-target interactions. Tools such as AlphaFold will significantly accelerate the rate at which drug candidates are advanced. Furthermore, the integration of big data will enable clinical trials to be conducted with greater efficiency and precision. Nevertheless, I strongly believe that AI will not independently "cure" cancer within the next decade.

9. Regulatory expectations, clinical trial design, and biomarker-driven development continue to evolve. What lessons from historical oncology programs can help companies navigate today's increasingly complex development landscape?

The landscape of regulatory expectations, clinical trial design, and biomarker-driven development is evolving rapidly. Within oncology drug discovery, the "China factor" has become a central focus; indeed, many pharmaceutical CEOs now cite artificial intelligence and China as the two primary variables defining their strategic outlook. While AI is transforming the daily practice of discovery, Chinese biotechnology is fundamentally shifting the broader development ecosystem. Last year saw a record-breaking volume of out-licensing deals involving Chinese biotech firms, particularly in biologics. However, the FDA’s recent rejection of a drug based exclusively on clinical trials conducted in China serves as a critical reminder of the regulatory complexities that remain for global developers.

10. Having worked across large pharmaceutical companies, biotechnology firms, and academia, how do these different environments contribute uniquely to innovation in cancer drug discovery?

The drug discovery ecosystem thrives on the synergy between academia, small biotech, and big pharma, as each plays a vital and complementary role.

• Academia serves as the foundation for innovation, acting as an indispensable driver for identifying new drug targets, elucidating novel mechanisms of action, and pioneering breakthrough synthetic modalities.
• Small biotech companies provide the agility necessary to explore high-risk, high-reward opportunities. Their nimble structure allows them to pivot quickly and maintain a singular focus on specific targets, pathways, or therapeutic areas, making them uniquely suited to advance first-in-class projects.
• Big pharma contributes essential institutional knowledge and the robust infrastructure required for complex, large-scale drug development.

Given these distinct comparative advantages, it is increasingly common for big pharma to prioritize late-stage development and commercialization, effectively acting as an engine for clinical maturation while relying on external licensing to secure early-stage innovation from academia and smaller biotech firms.

11.  Drug resistance remains one of the greatest challenges in oncology. Based on historical successes and failures, what strategies do you believe hold the greatest promise for overcoming therapeutic resistance?

Resistance is an inherent challenge in cancer therapy, as tumor evolution consistently leads to the emergence of mutations that render initial treatments ineffective. For example, the development of EGFR inhibitors has already progressed to the fourth generation to address evolving resistance profiles.

A proven strategy for overcoming such resistance is to shift the therapeutic modality to bypass the mutation's effect. Successful approaches include:

• Covalent Inhibition: When mutations undermine the efficacy of reversible competitive inhibitors, transitioning to irreversible covalent inhibitors can often restore potency.
• Allosteric Modulation: Switching from traditional active-site competitive inhibitors to allosteric inhibitors can circumvent resistance by targeting distal sites that remain unaffected by active-site mutations.
• Targeted Protein Degradation: The emergence of molecular glues and PROTACs offers a powerful new paradigm, as these technologies can eliminate the target protein entirely, effectively overcoming the limitations of conventional competitive inhibition.

By diversifying the chemical and biological strategies used to target the same driver, the industry continues to stay one step ahead of tumor evolution.

12. Your book blends scientific rigor with engaging storytelling. Why do you believe storytelling is an effective way to communicate complex pharmaceutical research and inspire future generations of medicinal chemists and drug developers?

In the age of AI, a vast expanse of scientific knowledge is available at our fingertips. However, AI cannot replicate the art of teaching with nuance and wit, nor can it identify the uniquely human attributes—such as intuition, tenacity, and creative leaps—that have historically driven breakthrough drug discovery. While machine learning is playing an increasingly significant role in our workflows, human inspiration remains an indispensable catalyst in the pursuit of scientific innovation.

13.  For researchers, pharmaceutical executives, and biotech innovators working in oncology today, what are the three most important principles they should carry forward from the history of cancer drug discovery?

Embrace novel therapeutic modalities: Immuno-oncology (I/O) and cell and gene therapies (CGT), such as CAR-T, are rapidly revolutionizing the oncology landscape. While traditional small molecules and biologics remain the bedrock of our cancer-fighting arsenal, emerging modalities are increasingly vital.

Monitor innovation from China’s burgeoning biotech sector: Keep a close watch on the breakthroughs emerging from this rapidly evolving industry.

Leverage AI strategically, but exercise caution: While AI is a powerful tool, it is not infallible—particularly in chemistry, where I have frequently encountered inaccuracies. Always verify AI-generated results.

--PFAm Issue 08--