Vol 18, No 1 2020
Kidney cancer is among the 10 most common cancers in both men and women, leading to approximately 74,000 new cases and to more than 14,000 deaths annually in United States alone.1 Early stage, localized renal cell carcinoma (RCC) has a significant cure fraction and a survival rate of 92%, whereas the treatment of late stage recurrent metastatic RCC remains highly challenging, with a minority of patients with metastatic RCC surviving past 5 years.2 Given that RCC is chemo-resistant and radiation-resistant, novel targeted therapies were required for the prevention and management of advanced and/or metastatic RCC.
Studies found that the majority of localized and advanced clear cell RCCs (ccRCCs) are characterized by mutational inactivation and allelic loss of the von Hippel-Lindau (VHL) tumor-suppressor gene.3 The groundbreaking discoveries made by William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza on the involvement of the VHL gene in various fundamental processes, including but not limited to sensing and adapting to the changing oxygen environment eventually led to the Nobel prize in physiology and medicine in 2019. These key insights not only paved the way for our understanding of a key factor in ccRCC tumorigenesis, but also provided the basis for the development of VHL-hypoxia pathway-targeted therapies that includes tyrosine kinase inhibitors (TKIs) for treatment of RCC and other diseases.
von Hippel-Lindau disease is a rare autosomal dominant hereditary neoplastic disorder triggered by germline mutations in the VHL tumor-suppressor gene with an incidence of roughly 1 in 36,000 births.4 Individuals with VHL disease are at increased risk of recurrent and bilateral kidney cysts and ccRCC, as well as retinal, cerebellar and spinal hemangioblastomas, pheochromocytomas, pancreatic cysts, serous cystadenomas and neuroendocrine tumors, endolymphatic sac tumors and epidymal and round ligament cysts.5 The discovery of the VHL gene in 19936 was driven by a desire to understand and treat VHL disease. The impact of this seminal discovery on our understanding of disease manifestations in patients with VHL disease and on individuals with sporadic ccRCC cannot be overstated. We now know that the majority of sporadic ccRCC cases also exhibit somatic loss-of-function mutations in the VHL gene,3 loss of 3p chromosome, or hypermethylation of the VHL locus.7,8
The mechanistic understanding of VHL protein (pVHL) function, driven by Kaelin’s group and others formed the cornerstone of our current understanding of ccRCC biology. Through additional work performed by a number of investigators and organizations including The Cancer Genome Atlas (TCGA), we now know VHL loss serves as the initiating truncal event for ccRCC tumorigenesis, eventually followed by additional mutational and chromosomal copy number altering changes that foster tumor growth and lethality.8-11
Bill Kaelin and colleagues were instrumental in characterizing the VHL gene and its function. In 1995, Iliopoulos, Kibel, Gray and Kaelin showed that the reintroduction of a wild-type but not a mutant VHL cDNA into the 786-0 VHL(-/-) RCC cell line abrogated its ability to form tumors in nude mouse xenograft assays, reinforcing the concept that VHL is a bona fide tumor suppressor gene.12 In the same year, the Kaelin group showed that pVHL interacts with with elongins C and B to form the VBC complex.13 In 1996, Iliopoulos et al demonstrated that pVHL was involved in negatively regulating hypoxia-inducible genes.14 Over the next few years, further refinement of the VBC complex,15 and the solution of the crystal structure of the VBC complex, led to a broader understanding of pVHL function.
The next major step was the identification of HIF as the substrate for the VBC complex. In 1991, Greg Semenza reported that HIF bound to enhancers near the human erythropoietin gene.16 Over the following decade Dr. Semenza and his colleagues further characterized HIF function, demonstrating its dimerization, DNA binding, and transactivation properties.17 In 1996 Jiang et al showed that vascular endothelial growth factor was HIF regulated.18
The third piece in the overall puzzle was the mechanism of oxygen sensing, elegantly discovered by Peter Ratcliffe and colleagues. Dr. Ratcliffe’s lab had been working on elucidating the key factors in erythropoietin gene activation since the early 1990s.19 In 1999, Max-well et al reported that pVHL was required to degrade HIF in an oxygen and iron-dependent manner,20 and in 2001 Jaakola et al reported this interaction was prolyl hydroxylation dependent.21
Further modeling showed that overexpression of a VHL- binding defective HIF2a variant was sufficient for tumorigenesis in a mouse model, suggesting that HIF overexpression is one of the major drivers of the malignant phenotype. A review of the myriad functions of HIF1a and HIF2a show that each HIF isoform has both unique and over- lapping target genes, including angiogenesis, metabolism and glycolysis22 (Figure 1).
The development of agents targeting the consequences of VHL loss shifted the treatment landscape from cytokine based immunotherapeutics, such as IFNα and IL-2 towards targeted therapeutics fifteen years ago.33,34 Given that ccRCC are highly vascular tumors with overexpression of angiogenic vascular endothelial growth factor (VEGF) which is a downstream target of HIF, currently approved therapies include inhibitors of VEGF35,36 and VEGFR tyrosine kinases (TKIs).33,34,37-41 Patients with VHL disease also demonstrated some benefit from these agents, with a 33% objective response rate (ORR) in ccRCC after sunitinib treatment42 and a 51% ORR in ccRCC after pazopanib treatment.43 The key challenge with all of these agents is that there is significant on and off target toxicity, and a near inevitable failure to cure or ultimately control tumor growth. There is no clear explanation for these findings, but there is undoubtedly room for a further refinement of VHL-HIF axis blocking agents.
The first-in-class clinical HIF-2aα inhibitor PT-2385 caused dramatic tumor regressions in patient-derived xenografts.46 Clinical data from PT-2385 in pretreated patients with metastatic clear cell renal carcinoma (mRCC) were encouraging in a Phase I, dose-escalation trial, and demonstrated a favorable safety profile.47 PT2977/MK-6482 is the second generation of the HIF2 inhibitor and was tested in a 55 patient phase Ib-II study.48 This study, which was presented at the European Society of Medical Oncology meeting in the fall of 2019, described 55 patients with advanced cc RCC who had received at least one prior therapy and who were treated with 120 mg orally once daily dose of PT2977/MK6482. We found that PT2977/MK6482 was well tolerated and had a favorable safety profile. The most common Grade 3 adverse events and on-target effects of HIF2α inhibition were found to be anemia in 26% of patients and hypoxia in 15%, and only 2 patients experienced grade 4 toxicities. Despite having a study population treated with a median of three prior therapies, the ORR was 24%, the median progression-free survival (PFS) was an impressive 11 months (95% CI 6-17), and the 12-month PFS rate was 49%. PT2977/MK6482 is currently being tested in a randomized phase III study in patients with treatment refractory metastatic ccRCC (NCT04195750).
Recently, the approval of combination TKI- checkpoint blocking antibody therapy has resulted in a new treatment paradigm for many patients with ccRCC. 49,50 Tissue based studies suggest antiangiogenic agents are capable of increasing T-cell recruitment to the tumor microenvironment,51 providing a mechanistic rationale for this type of combination therapy. Further investigations into the way VHL-HIF targeting agents can synergize with checkpoint blocking antibodies will undoubtedly further improve the treatment of patients with RCC.