Targeted protein degradation is an emerging oncology modality that eliminates disease-driving proteins rather than inhibiting them – addressing tumor that have become resistant to standard therapies or rely on protein conventional drugs cannot reach.
In this Q&A, Medpace’s Blythe Thomson, MD, Senior Vice President, Medical Department, Hematology & Oncology discusses the clinical development considerations unique to degraders, including trial design, pharmacokinetics, and the patient populations most likely to benefit.
Sr. Vice President, Medical Department
Hematology & Oncology
Evolving Clinical Trials with Advanced Medicine
Tell us about your experience in oncology clinical trials. How have you seen the oncology drug development landscape evolve?
As a Hematologist/Oncologist, I have always been a life-long advocate of the rigor and structure of a clinical trial. That partnership between patients in clinical trials and their oncology partners has proven to be highly successful in adult and pediatric hematology/oncology. The age-adjusted cancer death rate has dropped from its peak in 1991 by 34% as of 2023, averting approximately 4.8 million deaths[1]. Additionally, over the past 40 years, the Children’s Oncology Group have increased the cancer cure rate for children from less than 10% to over 80 % today.[2] With increasing knowledge of the molecular mechanisms underlying malignancy, the trials have transitioned from very broad “one size fits all” cytotoxic chemotherapy to precise molecularly targeted agents with reduced toxicity and improved survival.
What are the benefits of degraders for the patient population in a clinical trial?
With the emergence of precision oncology in the early 2000, knowledge of molecular alterations in tumor cells became critical and tyrosine kinase inhibitors (TKI) became some of the first targeted agents in oncology. TKI’s rely on structured and targetable pockets, critical in oncogenesis, and left behind the “undruggable” targets many of whom are critical transcription factors or disordered proteins. Unfortunately, TKI’s over time can experience decreased efficacy due to the emergence of resistance pathways. Monoclonal antibodies have also emerged in oncology care and offered potential of significant benefit. Again, however, antibodies rely on transmembrane proteins but leave some intracellular oncogenic proteins undruggable. Targeted protein degradation has emerged as a novel approach to the undruggable or resistant tumor. Targeted protein degradation uses the ubiquitin-proteosome pathway, which is present to degrade dysfunctional proteins and maintain protein homeostasis. The degraders use this pathway to select the oncogenic protein and then pair with a ubiquitin ligase leading to the protein degradation. There are two classes of targeted protein degraders: proteolysis-targeting chimera (PROTAC) and molecular glues, both of which are currently being developed in multiple clinical oncology trials. The advantage of the targeted protein degradation is the apparent lack of resistance mechanisms and increase of druggable targets.
Are there any unique considerations for developing successful clinical trials when utilizing degraders?
One unique characteristic of PROTACs is their ability to engage with a protein of interest at low concentrations, deliver the onco-protein to the proteosome with subsequent degradation and then be available to engage with new proteins of interest. This sustained and prolonged activity has created unique pharmacokinetic profiles with clinical activity at low concentrations, as compared to conventional TKI which often require high concentrations for clinical activity. This has led to unique bell-shaped curves of activity for some PROTACs. Molecular glue will be unlikely to experience the same phenomenon due to their requirement of sequential binding to E3 ligase prior to protein of interest interaction.
What does the competitive landscape for degraders mean for clinical trial design and endpoint selection?
Similar to all oncological clinical trials, there is brisk competition in the degrader landscape. Due to our significant experience with degraders, Medpace is uniquely positioned to work with Sponsors to create clinical trials with novel adaptive designs that meet regulatory requirements, to collaborate with our academic and community oncology partners to move novel agents quickly to patients in need, and to rapidly pivot based on clinical experience.
Where do you see the greatest untapped potential for degraders in oncology?
I think the two patient populations that may receive the most potential benefit are:
- Patients with tumors that are highly reliant on a protein that drives cell proliferation, differentiation and cancer cell survival for example estrogen receptor positive breast cancer or androgen receptor driven prostate cancer
- Patients with tumors that have become resistant to standard targeted TKI. Initial trials in these populations have demonstrated early promising clinical activity.
What should Sponsors look for in a CRO partner when advancing a degrader program into the clinic?
When a Sponsor is selecting a CRO partner for any novel therapy, they should consider several critical factors: experience in the disease, relationships with key clinical sites, flexibility to respond to the generated data, and ability to expand quickly based on the clinical advancement of the program. Medpace has significant experience with novel hematology/oncology therapies including degraders and welcome the opportunity to work with Sponsors on these fascinating new approaches to cancer care.
Turning Oncologic Innovation into Execution
Bringing next-generation therapies to patients requires more than scientific insight; it demands operational precision, global coordination, and clinical expertise embedded at every stage. Medpace’s full-service CRO model is built to support biopharma innovators with deep oncology specialization, in-house medical leadership, and proven execution across solid tumors and hematologic malignancies.
References
- Cancer Facts and Figures, 2026. American Cancer Society.
- https://childrensoncologygroup.org/what-is-a-clinical-trial. Accessed 13-Feb-2026