Novel Approaches with HIF-2α Targeted Therapies in Metastatic Renal Cell Carcinoma

Abstract

Germline inactivation of the Von Hippel-Lindau (VHL) tumor suppressor is the defining hallmark in hereditary VHL disease and VHL-associated renal cell carcinoma (RCC). However, somatic VHL mutations are also observed in patients with sporadic RCC. Loss of function VHL mutations result in constitutive activation of hypoxia-inducible factor-2 alpha (HIF-2α), which leads to increased expression of HIF target genes that promote angiogenesis and tumor growth. As of 2023, belzutifan is currently the only approved HIF-2α inhibitor for both VHL-associated and sporadic metastatic RCC (mRCC). However, there is potential for resistance with HIF-2α inhibitors which warrants novel HIF-2α-targeting strategies. In this review, we discuss the potential resistance mechanisms with belzutifan and current clinical trials evaluating novel combinations of belzutifan with other targeted therapies and immune checkpoint inhibitors which may enhance the efficacy of HIF-2α targeting. Lastly, we also discuss newer generation HIF-2α inhibitors that are currently under early investigation and outline future directions and challenges with HIF-2α inhibitors for mRCC.

Correctly identifying the cells of origin is essential for tailoring treatment and understanding the emergence of cancer stem cells and late metastases

“…Thus, not only neuroendocrine carcinomas but also the more benign variant NETs often show metastases at an asymptomatic stage ( 75 , 76 ). This pattern is akin to CCRCCs ( 77 ), which most likely also are of neuroendocrine origin ( 21 , 22 , 33 ). Melanoma, originating from melanocytes derived from neural crest cells, also demonstrates early metastasis as well as cellular plasticity ( 78 ).…”

“…Moreover, we tracked the progression of an ECL cell carcinoid to a highly malignant cancer ( 20 ) and the evident transformation potential of long-term trophic stimulation of differentiated cells, leading to the development of highly malignant tumors. Similarly, the inactivation of the von Hippel-Lindau factor, whether hereditary or sporadic, results in the activation of hypoxia-inducible factor 2α (HIF-2α) ( 21 ), which chronically stimulates the erythropoietin (EPO) cell, being the cell of origin of the most prevalent type of renal cancer (clear cell renal cell cancer) ( 22 ). Moreover, the progression to pituitary carcinoma after bilateral adrenalectomy may also be seen as a consequence of long-term growth stimulation ( 23 ) like the occurrence of postmenopausal estrogen receptor-positive breast cancer after sex steroid hormone treatment ( 24 ).…”

“…Moreover, more tumors develop from NE cells than presently recognized. For instance, we have shown that the most prevalent type of kidney cancer, clear cell renal cell cancer (CCRCC), most likely originates from EPO cells ( 21 , 22 , 33 ). Clinically, these tumors exhibit similarities to NETs, including early metastases, low response to cytotoxic drugs, and, parallel to hormonal overstimulation in NETs, erythrocytosis in a subset of patients.…”