W. Marston Linehan

Germline mutations in the von Hippel-Lindau tumor suppressor gene (VHL) predispose individuals to a variety of tumors, including renal carcinoma, hemangioblastoma of the central nervous system, and pheochromocytoma. Here, a cellular transcription factor, Elongin (SIII), is identified as a functional target of the VHL protein. Elongin (SIII) is a heterotrimer consisting of a transcriptionally active subunit (A) and two regulatory subunits (B and C) that activate transcription elongation by RNA polymerase II. The VHL protein was shown to bind tightly and specifically to the Elongin B and C subunits and to inhibit Elongin (SIII) transcriptional activity in vitro. These findings reveal a potentially important transcriptional regulatory network in which the VHL protein may play a key role.

von Hippel-Lindau (VHL) disease is an autosomal dominant disorder that causes retinal hemangioblastomas, hemangioblastomas of the central nervous system, endolymphatic sac tumors, renal cell carcinomas, pancreatic cysts and tumors, pheochromocytomas, and epididymal cystadenomas, among other less common manifestations. Although this entity has been recognized for almost 70 years, recent developments in the genetics and imaging of VHL disease have greatly improved understanding of the disease and its natural history. This review describes the major events that led to the discovery of the gene for VHL and will familiarize the reader with recent developments in the magnetic resonance Imaging, computed tomographic, and ultrasound findings of this entity. Despite advances in the genetic understanding of this disease, imaging techniques will continue to play a major role in the diagnosis, management, and treatment of VHL.

The VHL tumor suppressor gene is inactivated in patients with von Hippel-Lindau disease and in most sporadic clear cell renal carcinomas. Although VHL protein function remains unclear, VHL does interact with the elongin BC subunits in vivo and regulates RNA polymerase II elongation activity in vitro by inhibiting formation of the elongin ABC complex. Expression of wild-type VHL in renal carcinoma cells with inactivated endogenous VHL resulted in unaltered in vitro cell growth and decreased vascular endothelial growth factor (VEGF) mRNA expression and responsiveness to serum deprivation. VEGF is highly expressed in many tumors, including VHL-associated and sporadic renal carcinomas, and it stimulates neoangiogenesis in growing solid tumors. Despite 5-fold differences in VEGF mRNA levels, VHL overexpression did not affect VEGF transcription initiation or elongation as would have been suggested by VHL-elongin association. These results suggest that VHL regulates VEGF expression at a post-transcriptional level and that VHL inactivation in target cells causes a loss of VEGF suppression, leading to formation of a vascular stroma.

Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, including non-small cell lung cancer. However, the clinical benefit of targeting ALK using tyrosine kinase inhibitors (TKI) is almost universally limited by the emergence of drug resistance. Diverse mechanisms of resistance to ALK TKIs have now been discovered, and these basic mechanisms are informing the development of novel therapeutic strategies to overcome resistance in the clinic. In this review, we summarize the current successes and challenges of targeting ALK. SIGNIFICANCE: Effective long-term treatment of ALK-rearranged cancers requires a mechanistic understanding of resistance to ALK TKIs so that rational therapies can be selected to combat resistance. This review underscores the importance of serial biopsies in capturing the dynamic therapeutic vulnerabilities within a patient's tumor and offers a perspective into the complexity of on-target and off-target ALK TKI resistance mechanisms. Therapeutic strategies that can successfully overcome, and potentially prevent, these resistance mechanisms will have the greatest impact on patient outcome. Cancer Discov; 7(2); 137-55. ©2017 AACR.