Biomarkers of Prognosis and Efficacy of Anti-angiogenic Therapy in Metastatic Clear Cell Renal Cancer

D’Aniello, Carmine; Berretta, Massimiliano; Cavaliere, Carla; Rossetti, Sabrina; Facchini, Gaetano; Iovane, Gelsomina; Mollo, Giovanna; Capasso, Mariagrazia; Pepa, Chiara Della; Pesce, Liuska; D'Errico, D; Buonerba, Carlo; Lorenzo, Giuseppe Di; Pisconti, Salvatore; Vita, Ferdinando De

doi:10.3389/fonc.2019.01400

Cited by 47 publications

(45 citation statements)

References 158 publications

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“…Angiogenesis plays a key role in RCC tumorigenesis and progression, directing the immune system through the abnormal formation of tumor vessels and the promotion of an immunosuppressive tumor microenvironment. Therefore, antiangiogenic treatments remain a valid therapeutic option in selected patients, since they modulate immune responses [10,21,22]. This activity is essential to enhancing the performance of immunotherapy agents, which have shown promising treatment outcomes also for advanced RCC [23].…”

Section: Discussionmentioning

confidence: 99%

Exploratory Pilot Study of Circulating Biomarkers in Metastatic Renal Cell Carcinoma

Zizzari

Napoletano

Filippo

et al. 2020

Cancers

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With the introduction of immune checkpoint inhibitors (ICIs) and next-generation vascular endothelial growth factor receptor–tyrosine kinase inhibitors (VEGFR–TKIs), the survival of patients with advanced renal cell carcinoma (RCC) has improved remarkably. However, not all patients have benefited from treatments, and to date, there are still no validated biomarkers that can be included in the therapeutic algorithm. Thus, the identification of predictive biomarkers is necessary to increase the number of responsive patients and to understand the underlying immunity. The clinical outcome of RCC patients is, in fact, associated with immune response. In this exploratory pilot study, we assessed the immune effect of TKI therapy in order to evaluate the immune status of metastatic renal cell carcinoma (mRCC) patients so that we could define a combination of immunological biomarkers relevant to improving patient outcomes. We profiled the circulating levels in 20 mRCC patients of exhausted/activated/regulatory T cell subsets through flow cytometry and of 14 immune checkpoint-related proteins and 20 inflammation cytokines/chemokines using multiplex Luminex assay, both at baseline and during TKI therapy. We identified the CD3+CD8+CD137+ and CD3+CD137+PD1+ T cell populations, as well as seven soluble immune molecules (i.e., IFNγ, sPDL2, sHVEM, sPD1, sGITR, sPDL1, and sCTLA4) associated with the clinical responses of mRCC patients, either modulated by TKI therapy or not. These results suggest an immunological profile of mRCC patients, which will help to improve clinical decision-making for RCC patients in terms of the best combination of strategies, as well as the optimal timing and therapeutic sequence.

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Section: Discussionmentioning

confidence: 99%

Exploratory Pilot Study of Circulating Biomarkers in Metastatic Renal Cell Carcinoma

Zizzari

Napoletano

Filippo

et al. 2020

Cancers

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“…Molecular markers can be classified according to their physiological location into tissue and soluble factors [43]. Among the above-mentioned traditional histological features, carbonic anhydrase IX (CaIX) [44], CXCR4 [45], HIF-1α and HIF-2α [46], have been reported to predict response to sorafenib or sunitinib as well as improved PFS despite no consistent impact on OS is reported. Furthermore, PD-L1 expression is associated with poor clinical outcome [47], without a predictive role of response to cabozantinib and axitinib plus anti-PD1/PD-L1 [4,[48][49][50][51].…”

Section: From the Cytogenetics To The Mutational Landscape Of Rccmentioning

confidence: 99%

“…The assessment of the soluble factors evaluation has also been extensively investigated in the prognostic stratification attempts, uncovering VEGF/VEGFR, LDH, IL-6, IL-8, osteopontin (OPN), HGF and TIMP1 to be significant drivers of patient's prognosis and response to therapy [52][53][54][55]. Remarkably, nucleotide polymorphisms (SNPs) of IL-8, HIF-1α and VEGF axis deemed significantly impacting the therapeutic outcome; however, no validation has been achieved in statistically powered clinical studies [46,56].…”

Section: From the Cytogenetics To The Mutational Landscape Of Rccmentioning

confidence: 99%

“…Proteomics-based subtyping of ccRCC, either according to Brannon et al (two clusters, ccA and ccB) [65], Chen et al (three clusters, CC-e.1, CC-e.2, CC-e.3) [66], or KIRC analysis (four clusters m1-m4) [67] consistently deconvolute the biologic taxonomy of disease phenotype. Moreover, the combination of the singular subtypes can dissect three different clinical behaviors: 1) good prognosis group (cluster ccA, CC-e.2, and m1), involved chromatin modifier genes mutations, such as PBRM1; 2) poor prognosis group (cluster ccB, CC-e.3, m3), associated with higher expression of CDKN2A and hypoxia-related genes, chromatin remodeling genes mutation including SETD2 or BAP1, PI3K/AKT/mTOR pathway genes mutations, epithelial-mesenchymal transition, hypermethylation, and a metabolic shift with higher glutathione and dipeptide levels; 3) intermediate prognosis group (cluster 3, CC-e.1, m2, and m4) associated with BAP1 mutations and base-excision repair [46]. Additionally, data obtained from 942 surgical series pinpoint a molecular signature consisting of 16 genes that could predict post-surgery relapse and could be translated into clinical trials [68].…”

Section: Molecular Classificationmentioning

confidence: 99%

“…(Figure 2 Due to the dynamic plethora of therapeutic options available to date, it is critical to identify criteria driving personalized approaches. Indeed, real-life clinical practice faces the significant challenge of patient selection by tailoring a TKI-vs. ICI-based and mono-vs. combination-therapeutic strategy [46,97]. Currently, besides the obvious impact of clinical individual risk profiling and comorbidities potentially influencing the safety issues, the single decision-making tool is represented by the risk stratification considered by the regulatory agencies.…”

Section: Therapeutic Window Driven By Angiogenesis and The Immune Sysmentioning

confidence: 99%

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Anti-Angiogenesis and Immunotherapy: Novel Paradigms to Envision Tailored Approaches in Renal Cell-Carcinoma

Argentiero

Solimando

Krebs

et al. 2020

Preprint

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Although decision making strategy based on clinico-histopathological criteria is well established, renal cell carcinoma (RCC) represents a spectrum of biological ecosystems characterized by distinct genetic and molecular alterations, diverse clinical courses and potential specific therapeutic vulnerabilities. Given the plethora of drugs available, the subtype-tailored treatment to RCC subtype holds the potential to improve patient outcome, shrinking treatment-related morbidity and cost. The emerging knowledge of the molecular taxonomy of RCC is evolving, whilst the antiangiogenic and immunotherapy landscape maintained and reinforced their potential. Although several prognostic factors of survival in patients with RCC have been described, no reliable predictive biomarkers of treatment individual sensitivity or resistance have been identified. In this review, we summarize the available evidence able to prompt more precise and individualized patient selection in well-designed clinical trials, covering the unmet need of medical choices in the era of next-generation anti-angiogenesis and immunotherapy.

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Synthesis, Biological Evaluation and in Silico Studies of Novel Urea/Thiourea Derivatives of Lenalidomide

Tok,

Abas,

Başoğlu

et al. 2024

J Biochem & Molecular Tox

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Designing new compounds from existing chemotherapeutic drugs to enhance inhibitory effects on tumor cells while overcoming multidrug resistance is one of the important strategies for new drug discovery in medicinal chemistry. A new series of urea and thiourea derivatives based on Lenalidomide as potential anticancer agents have been designed and synthesized. In vitro anticancer activity assay against Caki cancer cells and HUVEC endothelial cells revealed that 1‐(4‐methylphenyl)‐3‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐1‐oxoisoindolin‐4‐yl]urea (11) exhibited the highest anticancer activity and selectivity in the series with IC50 values of 9.88 and 179.03 µM, respectively. Among the compounds, 11 showed significant HDAC1 inhibiton of 68.02 ± 2.44% at 10 µM concentration. TGF‐β, Bax, Bcl‐2 protein levels and scratch assay were analyzed in Caki cells. As a result, compound 11 induced apoptosis in Caki cells. In this study, it has been demonstrated that compound 11 can be a lead compound for further detailed investigation in renal cancer treatment. Through molecular docking studies, it was determined that the most active compound, 11, forms stable interactions with key residues in the enzyme's active site, particularly engaging in hydrogen bonds with GLY149 and coordinating with the zinc ion in the HDAC1 active site. These interactions are crucial for the observed inhibitory activity. Molecular dynamics simulation revealed the binding event of the most active compound with class I histone deacetylase and the stability of the complex in a biological environment.

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Biomarkers of Prognosis and Efficacy of Anti-angiogenic Therapy in Metastatic Clear Cell Renal Cancer

Cited by 47 publications

References 158 publications

Exploratory Pilot Study of Circulating Biomarkers in Metastatic Renal Cell Carcinoma

Exploratory Pilot Study of Circulating Biomarkers in Metastatic Renal Cell Carcinoma

Anti-Angiogenesis and Immunotherapy: Novel Paradigms to Envision Tailored Approaches in Renal Cell-Carcinoma

Synthesis, Biological Evaluation and in Silico Studies of Novel Urea/Thiourea Derivatives of Lenalidomide

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