Next Wave of Targets in the Treatment of Advanced Renal Cell Carcinoma

Abstract

While surgical resection has remained the mainstay of treatment in early-stage renal cell carcinoma (RCC), therapeutic options in the advanced setting have remarkably expanded over the last 20 years. Tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor (VEGF-TKIs) and anti-programmed cell death 1 (PD-1)/anti-programmed death-ligand 1 (PD-L1)-based immune checkpoint inhibitors (ICIs) have become globally accepted options in the upfront metastatic setting, with different ICI-based combination strategies improving overall survival compared to single-agent Sunitinib. Although some patients benefit from long-term responses, most eventually develop disease progression. Ongoing efforts to better understand the biology of RCC and the different mechanisms of acquired resistance have led to the identification of promising therapeutic targets. Belzutifan, a novel agent targeting the angiogenic pathway involving hypoxia-inducible factors (HIFs), has already been approved for the treatment of early-stage tumors associated with VHL disease and represents a very promising therapy in advanced RCC. Other putative targets include epigenetic regulation enzymes, as well as several metabolites such as adenosine, glutaminase and tryptophan, which are critical players in cancer cell metabolism and in the tumor microenvironment. Different methods of immune regulation are also being investigated, including CAR-T cell therapy and modulation of the gut microbiome, in addition to novel agents targeting the interleukin-2 (IL-2) pathway. This review aims to highlight the emergent novel therapies for RCC and their respective completed and ongoing clinical trials.

Advances in the management of renal cell carcinoma

“…Different combination strategies involving immune checkpoint inhibitors and several novel therapies that overcome acquired resistance and modulate immune responses are being actively studied. 48 Potentially promising therapeutic targets that remain under investigation include hypoxia-inducible factor 2 α inhibitor combinations, metabolomics, chimeric antigen receptor–T cell therapy, and modulation of the gut microbiome. 48 …”

“… 48 Potentially promising therapeutic targets that remain under investigation include hypoxia-inducible factor 2 α inhibitor combinations, metabolomics, chimeric antigen receptor–T cell therapy, and modulation of the gut microbiome. 48 …”

Percées dans la prise en charge de l’hypernéphrome

“…Même si certaines personnes peuvent bénéficier d’une réponse durable aux traitements à base d’inhibiteur du point de contrôle immunitaire, la maladie finit par progresser chez la majorité des personnes traitées. Les différentes stratégies d’association avec des inhibiteurs du point de contrôle immunitaire et plusieurs nouvelles thérapies qui permettent d’outrepasser une résistance acquise et de moduler la réaction immunitaire sont étudiées activement 48 . Des cibles thérapeutiques potentiellement prometteuses qui sont toujours à l’étude comprennent l’association d’inhibiteurs du facteur 2-α induit par l’hypoxie, la métabolomique, une thérapie par lymphocytes T porteurs de récepteurs antigéniques chimériques et la modulation du microbiome de l’intestin 48 .…”

The Metastasis Pattern of Renal Cell Carcinoma Is Influenced by Histologic Subtype, Grade, and Sarcomatoid Differentiation

“…While the overall 5-year relative survival rate for patients with kidney and renal pelvic cancers is 77.6%, the 5-year relative survival rate for patients with metastases is only 17.4%; in contrast, patients with localized disease had a 5-year relative survival rate of 92.9% [21]. Considering that approximately 15% of patients have metastatic disease at the time of diagnosis, a deeper understanding of the pathophysiology of metastatic RCC is important for improved treatment [21][22][23][24][25].…”