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Editorial [Hot Topic: Kidney Cancer: State of the Art in 2011 (Guest Editor: Ulka Vaishampayan)]
No full textRecent Developments in the Therapeutic Landscape in Renal Cancer
No full textUlka Vaishampayan is an endowed Chair and Professor of Oncology and is the Chair of the Solid Tumor Division, Department of Oncology at Wayne State University (WSU), Detroit, Michigan. She is also the Director of Phase I clinical trials at the Barbara Ann Karmanos Cancer Institute, Detroit, Michigan. Her focus of research and clinical experience is early therapeutics, drug development and clinical trials with a focus on genitourinary (GU) malignancies. She is the site Principal Investigator (PI) of the NIH UO-1 grant for clinical trials and the co-PI of the DOD PCCTC research grant at WSU. She is a member of the ASCO education committee and the chair of the GU-non prostate track. With 100+ peer reviewed publications archived in PubMed, she has published widely in esteemed journals such as New England Journal of Medicine, Journal of Clinical Oncology, Clinical Cancer Research, Cancer, and Journal of Urology. She has also authored numerous review articles, editorials, and book chapters.</jats:p
A phase 1 study of buparlisib and bevacizumab in patients with metastatic renal cell carcinoma progressing on vascular endothelial growth factor-targeted therapies
No full textAbstract not availableRana R. McKay, Guillermo De Velasco, Lillian Werner, Joaquim Bellmunt, Lauren Harshman, Christopher Sweeney, Jonathan E. Rosenberg, Michelle Hirsch, Sabina Signoretti, Eliezer M. Van Allen, Meghara Walsh, Ulka Vaishampayan, David F. McDermott, and Toni K. Choueir
Landmark Trials in Renal Cancer
No full textThe therapy of kidney cancer has made multiple major advances. Eleven agents are now approved by FDA for treatment of metastatic RCC and one agent is approved for adjuvant therapy for localized high risk disease post nephrectomy. In addition the trials addressing the role of surgery also represent major strides in therapy. All these advances in RCC therapeutics have occurred through clinical trials. This paper is a summary of landmark trials that have been critical in the therapeutic development journey in advancing the care and improving outcomes in kidney cancer. The front line therapies are summarized starting with immunotherapy with high dose interleukin-2 to targeted therapies such as bevacizumab (monoclonal antibody), receptor tyrosine kinases such as sorafenib, sunitinib, and pazopanib and MTOR inhibitors lke temsirolimus in the front line setting. Recently the combinations of ipilimumab and nivolumab as well as bevacizumab and atezolizumab have demonstrated promising efficacy in metastatic disease and these regimens are likely to receive FDA approval. In second line and beyond, therapies such as everolimus, nivolumab, lenvatinib+ everolimus and Cabozantinib have proven benefit. Adjuvant post nephrectomy trials have been conducted with conflicting results. Majority have shonwn lack of benefit, however one study conducted in T3/T4/N1 disease revealed statistically significant disease free survival favoring ajuvant sunitinib therapy leading to FDA approval. This paper summarizes the data from the reported trials and discusses recent developments in RCC therapeutics.</jats:p
Hypoxia Inducible Factor-2α (HIF-2α) Pathway Inhibitors
Full text linkHypoxia creates a stressful environment for the cells triggering adaptive changes in the transcription factors called hypoxia inducible factors (HIF), which help to meet the metabolic and angiogenic requirements of cells. HIF-2 is one such factor that is implicated in the progression of various cancers, especially the ones associated with Von Hippel–Lindau (VHL) disease. HIF-2 factor has an unstable component alpha and a stable component beta. HIF-2α detects hypoxia and dimerizes with HIF-beta (Aryl hydrocarbon receptor nuclear translocator [ARNT]) through per-ARNT-sim (PAS)-mediated signaling domains. These domain sites are recognized as targets for HIF-2 inhibitors. HIF-2 inhibitors block this heterodimerization and prevent the expression of target genes which are oncogenic, including VEGF, PDGF, CAIX, and Oct4. VHL disease caused by the deficiency of VHL gene product results in decreased degradation of HIF-2α, leading to increased activation of these transcription factors. Tumors driven by the deficiency of VHL gene product are natural candidates for HIF-2 inhibitor therapy. These inhibitors have emerged as a promising class of targeted therapies for renal cell carcinoma (RCC), particularly in cases resistant to conventional treatments. In this review, we explore the role of hypoxia and HIF transcription factors in tumor formation and progression, highlighting the role and development of HIF-2 pathway inhibitors as potential cancer therapies. We discuss the major key inhibitors, with focus on belzutifan and review the various trials investigating its efficacy in monotherapy as well as in combination therapies in RCC. Additionally, we explore its development in pheochromocytoma, hemangioblastoma, and pancreatic neuroendocrine tumors. We also highlight emerging HIF-2α inhibitors currently in clinical trials, namely casdatifan, NKT-2152, and DFF332. Finally, we address the major toxicities and management of these inhibitors.
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