The 16th International VHL Medical Symposium recently took place in Milan, Italy. More than 200 scientists, clinicians, and patient advocates attended, sharing valuable insights and research advancements aimed at improving the lives of people living with VHL disease. If you couldn’t attend, don’t worry! Here’s a recap of three major takeaways you missed.
Belzutifan: A Closer Look at How It Works and What’s Next
Belzutifan (Welireg), a HIF-2α inhibitor class drug, has been an exciting development in treating VHL-related tumors. But research is still ongoing to understand exactly how it works, why resistance occurs in some cases, and who might benefit the most.
Understanding Belzutifan’s Mechanism
Belzutifan specifically targets the HIF-2α protein, which is overactive in tumors associated with VHL. Dr. James Brugarolas explained that belzutifan binds to a unique part of HIF-2α called the PasB domain, blocking it from pairing with other proteins and stopping the signals that promote tumor growth. Belzutifan was specially designed to be highly specific to HIF-2α, meaning it can effectively inhibit HIF-2α without affecting other proteins—a level of specificity that, as Dr. Brugarolas noted, “rivals that of antibodies.”
Why Does Resistance Happen?
Despite its promise, some patients develop resistance to belzutifan over time. Understanding these resistance mechanisms is critical for developing ways to overcome them, possibly by combining belzutifan with other treatments.
Who Benefits the Most?
Researchers are also studying which patients respond best to belzutifan. Dr. Ramaprasad Srinivasan pointed out that while belzutifan works well for many, side effects like anemia (low red blood cell count) and hypoxia (low oxygen levels) can limit its use for some. Identifying patients who can tolerate it—and benefit from it—will help tailor treatment plans more effectively. Some experts at the symposium suggested that lower or flexible dosing regimens might be explored to maximize benefits while minimizing side effects.
Why This Matters for You: The more scientists understand about belzutifan, the better they can tailor its use. If you’re considering or currently taking belzutifan, talk to your doctor about these latest findings, which may impact your treatment plan or help prevent resistance.
New Treatment Options in Development Give Fresh Hope
Belzutifan is just one approach in a larger effort to find effective treatments for VHL disease. Researchers at the symposium discussed promising new options, including small interfering RNA (siRNA) therapies, protein degradation techniques, and synthetic lethality strategies.
siRNA Therapies: Shutting Down Problem Genes
Dr. James Brugarolas shared insights into using siRNA (small interfering RNA) molecules, which can “silence” specific genes, like HIF-2α, that drive tumor growth. This approach would involve delivering the siRNA directly to tumor cells by carrying them in microscopic particles. Though more studies are needed to resolve the side effects that were observed in early clinical trials, this technique could potentially prevent VHL-related tumors from forming or growing by switching off the problematic genes.
Protein Degradation: Clearing Out Harmful Proteins
Another promising area of research is protein degradation, which essentially flags harmful proteins in tumor cells for destruction. Dr. Qing Zhang explained how this approach might be used to selectively degrade cancer-promoting proteins. This method could work in combination with other treatments to disrupt tumor growth from multiple angles, potentially reducing the likelihood of resistance.
Synthetic Lethality and Synthetic Essentiality: Targeting Cancer-Specific Weaknesses
Dr. Qing Zhang’s research on synthetic lethality and Dr. Xin Lu’s work on synthetic essentiality showed how targeting specific weaknesses in cancer cells with defective (mutant) versions of the VHL protein could selectively kill these cells without harming normal ones. For example, using a drug that blocks a protein important to VHL mutant cells but is not important to cells with normal versions of VHL may cause only the mutant cells to die, sparing healthy tissue.
Why This Matters for You: New treatment strategies like siRNA therapies, protein degradation, and synthetic lethality are designed to target VHL-related tumor cells more specifically, giving hope that more treatment options will eventually be available for VHL.
Personalized Medicine: Recognizing the Uniqueness of Each VHL Patient
One of the biggest themes at the symposium was the importance of personalized medicine. Each VHL patient is unique, and researchers and clinicians are increasingly studying and tailoring treatments based on individual genetic profiles and tumor characteristics.
Single-Cell Sequencing: A Personalized Diagnostic Tool
Dr. Irene Franco and Dr. Isaline Rowe discussed how studying individual cells within normal tissues and tumors is helping researchers understand what drives VHL-related tumor formation and identify genetic mutation patterns within VHL-related tumors. This single-cell technology allows scientists to gain a much deeper understanding of specific features which affect how tumors form, behave, and respond to treatment. By identifying these differences, clinicians can better predict which treatments will work best for each patient.
MR-Linac: Precision Radiation Therapy for VHL Patients
Dr. Rachel van Leeuwaarde presented a cutting-edge radiation therapy technique called MR-Linac (MRI-guided linear accelerator). This technology uses real-time MRI imaging to guide radiation therapy, allowing for highly precise targeting of tumors. MR-Linac can be especially helpful for VHL patients with tumors in difficult-to-reach areas or near sensitive organs. The beam can be turned on and off in real time, ensuring radiation is focused only on the tumor while sparing healthy tissue.
MR-Linac provides a non-surgical option for patients for whom surgery might be too risky or not feasible. As Dr. van Leeuwaarde explained, “radiotherapy can be considered when partial nephrectomy is not possible, if the tumor is near critical structures, or if belzutifan is not an option.” This makes MR-Linac a valuable addition to the personalized treatment options available for VHL patients.
Collaborative, Multidisciplinary Approaches
The symposium’s live tumor board sessions demonstrated the value of a collaborative, multidisciplinary approach to treating VHL disease. Experts from various fields, including endocrinology, urology, oncology, ophthalmology, and radiology, came together to discuss complex cases. Teamwork and tumor board sessions like this allow for well-rounded treatment plans that consider each patient’s unique needs and circumstances. For VHL patients with complicated cases that could benefit from such discussions, please invite your physician to register for or submit your case for discussion at the VHL Alliance’s Monthly Virtual Tumor Board.
Why This Matters for You: Personalized medicine means your treatment plan can be tailored just for you. Advances in single-cell technologies, collaborative approaches, and clinical techniques like MR-linac are bringing us closer to a future where treatments are as unique as each VHL patient, potentially leading to better results and fewer side effects.
Final Thoughts
The 16th International VHL Medical Symposium highlighted groundbreaking advancements in understanding and treating VHL disease. From belzutifan insights to new treatments and personalized approaches, there’s a lot of hope on the horizon for patients and families affected by VHL. If you are interested in learning more, please check out the video presentations below!
By keeping up with these developments, you can build on your existing knowledge and feel more empowered to make informed decisions alongside your healthcare team. If any of these new treatments or personalized approaches sound interesting, speak with your healthcare team—they can guide you in making the best choices for your specific situation.