The Pursuit of Precision in Cancer Drug Development
“The future will not be defined by a single breakthrough.” So, what comes next?
In 1959, two researchers in Pennsylvania, Peter C. Nowell and David A. Hungerford, noticed something unusual under their microscopes: an abnormally tiny chromosome in the cells of patients with chronic myeloid leukemia (CML). That genetic anomaly—later named the Philadelphia chromosome—was the first consistent chromosomal abnormality linked to a specific type of human cancer.
Several years later, American physician and geneticist Janet Rowley discovered why the chromosome appeared intriguingly small. It was the result of a translocation; pieces of chromosomes 9 and 22 had swapped places. This genetic rearrangement created the BCR-ABL fusion gene, which produces an abnormal tyrosine kinase protein. The protein continuously signals myeloid cells to grow and divide, driving the development of the disease.
Four decades after the Philadelphia chromosome was first identified, a small-molecule protein tyrosine kinase inhibitor, imatinib mesylate (Gleevec), was approved by the US Food and Drug Administration (FDA) for the treatment of patients with CML. Beyond transforming CML treatment, Gleevec served as a crucial proof of concept for targeted therapy, proving that targeting the molecular drivers of cancer could result in real clinical benefits for patients.
Now, despite an expanding list of therapeutic targets, progressing a candidate molecule from preclinical development through to clinical trials and subsequent approval remains an arduous, costly endeavor. As advances in cancer biology continue to improve our understanding of individual tumors, identifying the patients most likely to benefit from new therapies is becoming an increasingly important part of successful drug development.
Dr. David Parkinson has witnessed the evolution of cancer therapeutics firsthand. Having worked across academia, government, biotechnology, and pharmaceutical development—including overseeing the clinical development of Gleevec at Novartis—Parkinson has a unique perspective on how the field has evolved. He now serves as principal, drug discovery at the Ellison Medical Institute.
When asked about the standout moments of his career, he finds it difficult to single out one example. Instead, his response reflects a perspective that puts the people advancing progress and those who ultimately benefit from it at the heart of his work.
“It would be difficult to characterize a single achievement," he said. "I am proud of the care and service I was able to bring to my patients as a practicing medical oncologist. I am also enormously proud of the many students and junior staff with whom I have worked over the years, many of whom have gone on to make significant contributions to cancer medicine and drug development.”
Alongside his clinical work, Parkinson has helped shape drug development policy through organizations including the FDA and the Institute of Medicine (now the National Academy of Medicine). These experiences have given him insight into the broader systems that determine whether promising medicines ultimately reach patients.
That said, there is one program he highlights.
“With respect to cancer drug development itself, the development of Gleevec, and all the terrific opportunities to work alongside so many talented individuals to help bring that therapy efficiently to drug approval and to patients with CML, remains something of which I am particularly proud,” noted Parkinson.
Gleevec reshaped expectations across oncology and inspired the search for molecularly targeted therapies in many other cancers. Yet, Parkinson is careful not to romanticize the process.
“Drug development is complicated, and not every program is successful,” he said. “I am also very proud of the many dedicated individuals across the organizations where I have worked or served on boards of directors who committed themselves to rigorously determining whether therapies were truly effective and deserving of broader use.”
Understanding why a program fails can be just as valuable as celebrating one that succeeds. Scientific breakthroughs may grab the headlines, but developing a medicine requires countless tough decisions, careful evaluation, and recognizing when evidence is insufficient.
Targeted therapy to precision medicine
The field has advanced considerably since Gleevec first reached patients. More than 200 targeted cancer drugs have now been approved by major regulators such as the FDA, many for multiple cancer types. For Parkinson, the next challenge is making better use of those therapies by understanding which patients are most likely to benefit, an approach central to precision medicine.
“The drug discovery process is evolving in real time,” he explained. “Advances in our understanding of cancer biology, together with technological improvements that enable us to target historically challenging pathways, continue to expand our ability to develop more precise therapeutics.”
Equally important, he said, is "the ever-growing ability to characterize the biology of an individual patient's tumor in greater detail at a specific point in time and correlate those findings with targeted treatment approaches."
Large-scale initiatives such as the American Association for Cancer Research's Project GENIE®, which links genomic sequencing data with clinical outcomes across hundreds of thousands of patients, are beginning to provide researchers with the scale of evidence needed to identify meaningful biological patterns.
“Large-scale genomic sequencing efforts in clinically annotated patient populations, supported by new computational technologies and AI, promise a more efficient road towards developing effective therapies in the future,” noted Parkinson. “It is an extremely exciting time.”
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“Biological understanding and technological advances increasingly allow us to target nearly any relevant pathway therapeutically,” he added.
Why cancer drug development remains challenging
Although Parkinson is optimistic about where the field is heading, he is equally clear about the challenges that remain: “Technological advances aside, clinical development today remains enormously complicated, inefficient, and expensive.”He continued: “The challenge of identifying the relevance of a given target within a particular patient, or even a specific subgroup of patients, remains significant. Establishing the value of that therapeutic approach convincingly in real-world patient populations is daunting.”
Those scientific challenges are compounded by practical ones. Even where existing treatments offer only modest benefit, new therapies must demonstrate clear advantages over the current standard of care. Reimbursement decisions add further complexity, while misconceptions surrounding clinical research also influence the perception of and willingness to participate in clinical trials. The scientific complexity of these programs can add to the challenge.
Research has suggested that the industry's increasing focus on new therapeutic targets, which tend to be characterized by greater uncertainty and difficulty, has contributed to higher attrition rates, longer development times, and fewer new molecular entities reaching the market.
“Funding mechanisms that support the long, expensive, and inherently risky clinical development process towards drug approval are often inconsistent, unreliable, and quite challenging for highly novel approaches,” Parkinson said.
None of these challenges have simple solutions—but that doesn't mean there aren't solutions.
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“Are there ways to address these and other bureaucratic limitations? I believe there are, and I continue to work alongside others on addressing many of these issues. Still, the inherently complicated process of developing new therapies will remain just that—complex,” cautioned Parkinson.
So, where are the greatest opportunities for progress? According to Parkinson, they “come from more precise biological characterization of individual patients, enabling more efficient and informed use of targeted therapies.”
By demonstrating clear benefits within carefully characterized patient populations, drug developers can run smaller, faster, and potentially less expensive clinical trials while also simplifying regulatory approval and reimbursement discussions.
“Most importantly,” Parkinson added, “this approach will help patients receive the treatments most likely to benefit them.”
Looking beyond the next “breakthrough”
When asked where the field should be paying closer attention, Parkinson highlighted several developments that are already beginning to influence the field.
“Advances in discovery technologies are enabling the development of highly specific therapeutics, including drugs against previously 'undruggable' and often unrecognized targets,” he said.
At the same time, he noted that liquid biopsy approaches based on circulating tumor DNA and RNA are allowing clinicians to monitor cancers throughout treatment in unprecedented detail. Combined with increasingly sophisticated computational analyses and AI, these technologies are changing how cancer therapies are discovered and developed.
For Parkinson, there is no single development to watch.
“The future will not be defined by a single breakthrough, but by a series of meaningful advances, each illuminating a different aspect of cancer biology and bringing us closer to more precise, effective treatments.”
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