Michael Basin, MD, urology resident, SUNY Upstate Medical University, discusses the design of a preclinical investigation into the pharmacological inhibition of the molecular chaperone Hsp70 and how it relates to belzutifan (Welireg) resistance in clear cell renal cell carcinoma (RCC).

At the 2023 American Urological Association Annual Meeting, Basin and colleagues presented preclinical research into the relationship between Hsp70 and belzutifan resistance. Notably, 

belzutifan was approved by the FDA in August of 2021

 for the treatment of patients who present with von Hippel-Lindau (VHL) disease and require therapy for associated RCC, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors that do not require immediate surgery.

The molecular chaperone Hsp70 assists in stabilizing client proteins, leading to protection from degradation. To conduct this research, investigators predominantly utilized cell-based assays and biochemical analyses conducted on RCC cell lines that were VHL null, which are predominantly seen in clear cell RCC cell lines, , Basin says. Previously established information regarding mutations known to be associated with resistance to HIF–2α inhibition were then expressed in various cell lines, which were then targeted with belzutifan and an Hsp70 inhibitor, Basin explains. 

It was found that inhibition of Hsp70 led to reduced levels of HIF2α, preventing tumor cell proliferation

 and exhibiting proof of concept that Hsp70 could represent another potential target in belzutifan-resistant RCC.

Regarding the adverse effect (AE) profile, Hsp70 inhibition alone is associated with gastrointestinal AEs, liver toxicity, and some ocular issues, Basin continues. When used as a monotherapy, the agent does have significant toxicity; however, it is hoped that when Hsp70 inhibition is given as a part of a combination regimen, lower doses can be given and synergistic effects could reduce AEs, thereby making the treatment more tolerable, Basin concludes.

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Michael Basin, MD, discusses the design of a preclinical investigation into the pharmacological inhibition of the molecular chaperone Hsp70 and how it relates to belzutifan resistance in clear cell renal cell carcinoma.


Dr Basin on the Methods for Investigating Hsp70 Inhibition in Belzutifan-resistant in RCC

Michael Basin, MD, urology resident, SUNY Upstate Medical University, discusses how the pharmacological inhibition of the molecular chaperone Hsp70 overcomes belzutifan (Welireg) resistance in clear cell renal cell carcinoma (RCC).

Systemic therapies, including combination therapy with VEGF TKIs and checkpoint inhibitors and dual checkpoint blockade have redefined the treatment landscape in RCC. Additionally, in August 2021, the 

 for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated RCC, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors that do not require immediate surgery. Although these approaches have shown improved outcomes in the advanced setting, not all patients will respond to these agents due to acquired or inherent resistance, Basin says.

As such, investigators sought to determine the relationship between Hsp70 and belzutifan resistance. Hsp70 is a molecular chaperone that helps stabilize client proteins, protecting them from degradation. Through its interaction with hypoxia-inducible factor (HIF)–2α, Hsp70 may help maintain HIF2α stability in clear cell RCC. To investigate this further, cell line models of VHL-null clear cell RCC were treated with belzutifan. Immunoblotting was used to measure HIF2a expression and degradation levels. Findings from the analysis showed that inhibition of Hsp70 led to reduced levels of HIF2α, preventing tumor cell proliferation, Basin explains. These data show proof-of-principle that Hsp70 could represent another potential target in cases of resistant RCC. 

Next steps for this research include the evaluation of the Hsp70 inhibitor alone and in combination with belzutifan in patient-derived xenograft models of clear cell RCC. In addition to potentially enhanced efficacy, the combination of these agents could also help reduce toxicities observed with molecular chaperone inhibitors, Basin concludes.

Michael Basin, MD, discusses how the pharmacological inhibition of the molecular chaperone Hsp70 overcomes belzutifan resistance in clear cell renal cell carcinoma.

Michael Basin, MD

Articles

Dr Basin on the Methods for Investigating Hsp70 Inhibition in Belzutifan-resistant in RCC

Dr Basin on Pharmacological Inhibition of Hsp70 in Belzutifan-Resistant RCC