Abstract
Advanced imaging techniques for diagnosis have increased awareness on the benefits of brain screening, facilitated effective control of extracranial disease, and prolonged life expectancy of metastatic renal cell carcinoma (mRCC) patients. Brain metastasis (BM) in patients with mRCC (RCC-BM) is associated with grave prognoses, a high degree of morbidity, dedicated assessment, and unresponsiveness to conventional systemic therapeutics. The therapeutic landscape of RCC-BM is rapidly changing; however, survival outcomes remain poor despite standard surgery and radiation, highlighting the unmet medical needs and the requisite for advancement in systemic therapies. Immune checkpoint inhibitors (ICIs) are one of the most promising strategies to treat RCC-BM. Understanding the role of brain-specific tumor immune microenvironment (TIME) is important for developing rationale-driven ICI-based combination strategies that circumvent tumor intrinsic and extrinsic factors and complex positive feedback loops associated with resistance to ICIs in RCC-BM via combination with ICIs involving other immunological pathways, anti-antiangiogenic multiple tyrosine kinase inhibitors, and radiotherapy; therefore, novel combination approaches are being developed for synergistic potential against RCC-BM; however, further prospective investigations with longer follow-up periods are required to improve the efficacy and safety of combination treatments and to elucidate dynamic predictive biomarkers depending on the interactions in the brain TIME.
Highlights
IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
Via combination with Immune checkpoint inhibitors (ICIs) involving other immunological pathways, anti-antiangiogenic multiple tyrosine kinase inhibitors, and radiotherapy; novel combination approaches are being developed for synergistic potential against Renal cell carcinomas (RCC)-Brain metastasis (BM); further prospective investigations with longer follow-up periods are required to improve the efficacy and safety of combination treatments and to elucidate dynamic predictive biomarkers depending on the interactions in the brain tumor immune microenvironment (TIME)
RCC is essentially a metabolic disease characterized by a reprogramming of energetic metabolism, and many genes that are mutated in RCC encode proteins that have roles in cellular processes regulating oxygen and glucose consumption [54]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Renal cell carcinomas (RCC) comprise a heterogeneous histologic subtype of malignant neoplasms arising from the nephron, and widely vary with respect to the underlying pathogenesis, genomic/molecular characteristics, and clinical treatment, including the susceptibility to conventional therapeutics [1,2,3,4,5,6,7,8]. Sequential events in the molecular etiopathogenesis of Von Hippel–Lindau (VHL)-inactivated metastatic RCC (mRCC) can be summarized as constitutive activation of the hypoxia-inducible factor (HIF) pathway due to loss of VHL activity, fostering global changes in the metabolome, genome, and epigenome in apoptotic, cell cycle regulatory, and mismatch repair pathways, angiogenesis, metabolic adaptations, and immune evasion [1,2,3,4,5,9,10]. The 5-year OS rate for mRCC remains under 30% despite the TKI-based approach [11,12,13,14]
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