Over the past several decades, research has transformed what scientists know about cancer. Foundational advances in genomics and molecular biology have revealed many of the proteins, pathways and mechanisms that drive cancer with a level of detail that would have seemed impossible just a generation ago.
But knowing more has not always translated into achieving more for patients.
This gap reflects one of the main hurdles in oncology: that cancer is not one disease, but many. Tumors are shaped by distinct biological drivers, evolve over time and can develop resistance to treatment.
That growing knowledge has helped move oncology toward more targeted, mechanism-driven approaches that account for the specific biology of disease and the patients most likely to benefit.
Still, even when the right target is identified, finding an effective way to intervene has proven to be a challenge. Scientists have increasingly embraced this challenge, however, and are seeking new ways to act on the biological drivers of disease.
Bristol Myers Squibb’s oncology pipeline reflects this broader evolution, with research spanning multiple approaches, including the evolution of immuno-oncology, antibody-drug conjugates, cell therapies, radiopharmaceuticals and combination strategies. Together, these approaches are designed to address cancer from multiple angles, including tumor-intrinsic drivers, the tumor microenvironment and cell-surface targets.
Among these approaches, (TPD) offers a compelling example of how scientific advances are expanding what may be possible for historically “undruggable” disease-driving targets. More broadly, TPD reflects the continued evolution of oncology research: as scientists uncover more about the biological drivers of cancer, new modalities are creating additional ways to act on those insights.
Why hasn’t understanding biology been enough?
Many cancer medicines are designed to work through an occupancy-driven approach: a drug binds to a disease-causing protein and inhibits its activity, interrupting a pathway that helps cancer cells survive or grow. These approaches have transformed care across oncology and other therapeutic areas, but they also have limits. Some proteins lack accessible binding sites altogether, making them difficult to inhibit. Others may continue signaling through alternate pathways. In many cases, cancer cells can develop resistance, meaning a treatment that was initially effective may no longer work as intended.
Rather than inhibiting a protein, why not eliminate it entirely?
Targeted protein degradation introduces a different, event-driven approach. Rather than relying only on a drug remaining bound to a target, degraders are designed to trigger the selective removal of the disease-related protein altogether by leveraging the cell’s natural protein disposal system. This may broaden the range of biological targets researchers can address, open up the possibility of targeting other mechanisms of disease involving protein interactions, and offer an alternative way to address a target where conventional inhibition is not enough.
Some of the earliest protein degraders demonstrated meaningful clinical impact before researchers fully understood how they worked. Through years of research and discoveries made through the study of immunomodulatory drugs (IMiDs) used in hematology, scientists uncovered how these therapies interact with the cell’s natural protein degradation pathways, helping establish the scientific foundation for TPD.
Today, that foundation is supporting a rapidly evolving field. Researchers are designing degraders with increasing precision. What began as a scientific observation has become a growing therapeutic platform with the potential to address a broad range of disease-driving proteins across hematology and solid tumors.
Building on this shift toward more precise, mechanism-driven research, advances in artificial intelligence and machine learning are helping accelerate discovery. Researchers can now analyze increasingly complex biological datasets, model molecular interactions and identify promising opportunities more efficiently than ever before. These technologies are helping scientists generate stronger hypotheses and move more quickly from biological understanding to therapeutic design.
Together, these advances — from a clearer view of disease mechanisms to AI-enabled discovery — are helping advance TPD across oncology, malignant and non-malignant hematology and potentially other therapeutic areas, including neuroscience and immunology.
How can multiple degrader approaches help advance targeted protein degradation?
Cancer is driven by mechanistic diversity, and different disease settings may call for distinct scientific approaches. To realize the full potential of TPD, researchers are expanding the degrader toolkit.
That thinking is reflected in Bristol Myers Squibb’s oncology pipeline, to match the complexity of cancer. It is also reflected within the company’s TPD research. Rather than pursuing a single degradation strategy, the company is advancing multiple TPD modalities designed to address different drivers and disease contexts. The goal is to broaden the number of ways researchers can act on difficult-to-address targets and, ultimately, support more tailored approaches for patients.
CELMoD agents, a type of molecular glue, exemplify how growing mechanistic insights can create entirely new therapeutic opportunities. The CELMoD modality explores how altering cereblon’s protein-binding properties may help promote interactions that can lead to the degradation of specific disease-related proteins.
While CELMoD agents offer a unique approach to TPD, certain proteins may require alternative degradation strategies. Ligand-directed degraders (LDDs) are larger three-part molecules that can be designed to target proteins that may require a more direct binding strategy for degradation. LDDs are designed around a specific target-binding component and are engineered to link target proteins with the cell’s degradation machinery, enabling their removal.
Each modality offers distinct scientific advantages and may be better suited to specific biological mechanisms, disease settings and treatment strategies. Together, these and other modalities demonstrate the versatility of TPD, complementing the broader range of oncology approaches being explored to address cancer from multiple angles.
How could targeted protein degradation continue to evolve?
After early protein degraders helped show that disease-driving proteins could be selectively removed, a new question emerged: how could that capability be directed with greater precision? One emerging area of investigation draws on lessons from antibody-drug conjugates: degrader-antibody conjugates (DACs), which pair antibody-guided targeting with a protein degrader payload. DACs are being explored as a way to direct TPD toward tumors in settings where precise delivery may be important to driving potency.
More broadly, this approach reflects how oncology innovation often builds by combining findings across fields — biology, chemistry, engineering and computational science — to design approaches that better meet the complexity of cancer.
What could drive the next breakthrough in cancer research?
The history of cancer research is a story of continually expanding knowledge and continually evolving ways to act on it. Each generation of scientific progress has created new opportunities to understand disease and intervene more effectively.
Targets once considered difficult to address are becoming active areas of investigation. Emerging technologies are helping accelerate discovery. The convergence of scientific innovations is opening entirely new avenues for exploration, helping researchers pursue disease-driving mechanisms that have previously been difficult to drug. Targeted protein degradation is one example of this shift. As part of Bristol Myers Squibb’s broader oncology research, it reflects a larger effort to address the biological diversity of cancer through a wider range of therapeutic approaches.
The challenges facing cancer research remain significant. But so too does the opportunity. The future of cancer research will not be defined by a single discovery, but by the ability to connect deeper biological insights and act on them — translating that understanding into more meaningful outcomes for patients.