It was recently announced that UT Southwestern will be the site of a second kidney cancer SPORE program in the United States. But what does that $11 million grant really mean for kidney cancer patients? KCCure spoke with UT Southwestern’s principle investigator Dr. Jim Brugarolas about the significance of a new class of drugs called HIF-2 inhibitors and how they’ll change the landscape for kidney cancer treatment.
Targeted therapies that inhibit VEGF (such as Sutent) have been around for more than a decade, but these drugs don’t work for some patients and the side effects can be toxic. How might these new HIF2 drugs differ from the current treatments?
Brugarolas: The HIF-2 inhibitors differ in both activity and toxicity. As we report in Nature, HIF-2 inhibitors have greater anti-tumor activity than sunitinib (Sutent). This is probably the case because HIF-2 has other effects on tumors besides blocking VEGF signaling, which is the main target of sunitinib.
Some patients initially do well on drugs like Sutent, but over time, they stop working. Do you think these tumors will still be sensitive to HIF-2 inhibitors?
Brugarolas: Yes. In fact, our research shows that tumors that have become resistant to sunitinib remain sensitive to the HIF-2 inhibitor. This is also the case in patients. About 10 of my patients participated in the phase I trial with the HIF-2 inhibitor, and several patients had extensive prior treatments. The most striking case was a patient we included in Nature who had been treated with seven prior therapies and was on the HIF-2 inhibitor and had disease control for more than 11 months.
How does the HIF-2 inhibitor look in terms of side-effects and toxicity?
Brugarolas: Antiangiogenesis drugs, which include Sunitinib (Sutent), sorafenib (Nexavar), pazopanib (Votrient), axitinib (Inlyta), cabozantinib (Cabometyx) and levantinib (Lenvima) are all VEGF receptor inhibitors and block VEGF signaling everywhere – both in cancer cells and non-cancer cells. This blockade is likely responsible for the cardiovascular toxicity, including hypertension, and likely contributes to renal toxicity. In contrast, the HIF-2 inhibitor blocks VEGF almost exclusively in the tumor. The result is less toxicity for the patient.
Clinical trials have already started with these new drugs. What new clinical trials will be opening for patients in the near future?
Brugarolas: The current trial, open at UT Southewestern, involves a combination with nivolumab. A second arm is planned with cabozantinib. For a patient to participate, they should have not been treated with either nivolumab or cabozantinib. One of the critical questions with all kidney cancer therapies, including HIF-2 inhibitors, is that they do not work for everyone. In my view, the most important trial we can do presently is a biomarker trial. We have identified candidate biomarkers we reported in our Nature paper that we hope to test in patients so we can identify those patients that are most likely to benefit from the HIF-2 inhibitor.
What applicability do you think these new drugs have for other cancers?
Brugarolas: Clear cell RCC is the obvious cancer to begin with for developing these inhibitors. The reason for this is that HIF-2 is constitutively activated as a result of VHL loss, which occurs in up to 90% of clear cell tumors. Nevertheless, HIF-2 may also be significant in other cancers, including deadly brain cancers called glioblastomas.