On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression), we classified 894 renal cell carcinomas ...(RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences among clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with TFE3 gene fusion or chromatin modifier genes were present within a specific subtype and spanned multiple subtypes. Differences in patient survival and in alteration of specific pathways (including hypoxia, metabolism, MAP kinase, NRF2-ARE, Hippo, immune checkpoint, and PI3K/AKT/mTOR) could further distinguish the subtypes. Immune checkpoint markers and molecular signatures of T cell infiltrates were both highest in the subtype associated with aggressive clear cell RCC. Differences between the genomic subtypes suggest that therapeutic strategies could be tailored to each RCC disease subset.
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•Comprehensive molecular analysis of 894 primary renal cell carcinomas•Nine subtypes defined by systematic analysis of five genomic data platforms•Substantial molecular diversity represented within each major histologic type•Presumed actionable alterations include PI3K and immune checkpoint pathways
Chen et al. comprehensively analyze 894 renal cell carcinomas, incorporating data on DNA mutation and copy, DNA methylation, and gene expression. The cancers were thus classified into nine major subtypes, each one being distinct in terms of altered pathways and patient survival associations.
Inhibition of a main regulator of cell metabolism, the protein kinase mTOR, induces autophagy and inhibits cell proliferation. However, the molecular pathways involved in the cross-talk between these ...two mTOR-dependent cell processes are largely unknown. Here we show that the scaffold protein AMBRA1, a member of the autophagy signalling network and a downstream target of mTOR, regulates cell proliferation by facilitating the dephosphorylation and degradation of the proto-oncogene c-Myc. We found that AMBRA1 favours the interaction between c-Myc and its phosphatase PP2A and that, when mTOR is inhibited, it enhances PP2A activity on this specific target, thereby reducing the cell division rate. As expected, such a de-regulation of c-Myc correlates with increased tumorigenesis in AMBRA1-defective systems, thus supporting a role for AMBRA1 as a haploinsufficient tumour suppressor gene.
Immunotherapy has revolutionized the systemic treatment of solid tumors, including advanced urothelial carcinoma (aUC), providing durable responses with a favorable safety profile. Multiple immune ...checkpoint inhibitor agents have been approved in monotherapy in second-line setting, and for a selected group of chemo-naïve cisplatin-ineligible patients with high PD-L1 expression. Despite the incorporation of immunotherapy to the systemic treatment landscape of aUC, platinum-based chemotherapy remains the standard of care in frontline setting for vast majority of patients. Urothelial carcinoma is a chemosensitive disease with response rates of up to 50% to frontline chemotherapy. However, the response to chemotherapy is short lasting with vast majority of patients experiencing disease progression and death within months. In this context, maintenance therapy constitutes an attractive therapeutic strategy to maximize the time to treatment failure. Different cytotoxic and targeted agents have been investigated as maintenance therapy for aUC but have not shown an impact on survival. Avelumab has become the first and only drug to improve overall survival as maintenance therapy after frontline platinum-based therapy in aUC patients and the first drug to be approved in this setting. This article will review the rational for maintenance therapy, the different drugs investigated as maintenance therapy for aUC, and the impact of avelumab maintenance therapy as a new standard of care in the management of aUC.
Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) and other natural compounds produced by Cannabis sativa exhibit a wide array of therapeutic effects on the human body. As a result, extracts ...containing controlled amounts of different cannabinoids, called full spectrum extracts, have generated great interest and are currently being assayed for the management of many diseases including cancer. However, cannabinoids exhibit limited bioavailability due to their low solubility in water and moderate stability. Therefore, developing novel methods of cannabinoid administration or encapsulation that could help to improve the efficacy of treatments based on the use of these compounds is an issue of great interest. The purpose of this study was to develop biobased poly(thioether-ester)-PTEe nanoparticles containing full-spectrum Cannabis extract-CN and assay their potential efficacy in vitro cancer models. To do this we used two different approaches: 1) in-situ thiol-ene miniemulsion polymerization (Me-PTEe) and 2) thiol-ene miniemulsification/solvent evaporation method using PTEe synthesized previously by thiol-ene bulk polymerization (Se-PTEe). In both cases an α,ω-diene-diester monomer assembled from derivatives of castor oil was used. We found that CN-PTEe nanoparticles presented a high encapsulation efficiency with an average diameter of between 91 and 229 nm. Likewise, CN-PTEe nanoparticles reduced the viability to a similar extent as free CN of the cancer cell lines (B16F10, T98, and U87) but not of the non-tumoral NIH3T3 cells. Furthermore, treatment with CN-PTEe nanoparticles mimicked the working mechanism of non-encapsulated cannabinoids (inhibited the AKT signaling pathway and induced autophagy) in BF16F10 melanoma cells. These observations support the idea that the PTEe nanoparticles are effective CN nanocarriers and that they could be assayed in future studies to investigate their potential anticancer activity.
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•Biobased α,ω-diene-diester monomer prepared from castor oil derivatives.•Nanoparticles obtained by thiol-ene miniemulsion and solvent evaporation.•Full-spectrum Cannabis extract encapsulated with high encapsulation efficiency.•Nanoparticles presented efficient cytotoxic effect on cancer line cells.
Abiraterone and enzalutamide are currently approved for mCRPC patients. Both drugs have distinct mechanisms of action and may have different toxicity profile. There are limited data comparing the ...side effects of abiraterone and enzalutamide. We performed a meta-analysis of randomized controlled trials (RCT) to better characterize the risk of adverse events associated with both drugs.
We performed a literature search on MEDLINE for studies reporting abiraterone and enzalutamide side effects from January 1966 to July 31, 2015. Abstracts presented at ASCO meetings from 2004 to 2015 were selected manually. Phase III RCT were included in analysis. We assessed the risk of adverse events reported in RCT by performing two meta-analyses: abiraterone-prednisone vs. placebo-prednisone (2,283 pts) and enzalutamide vs. placebo (2,914 pts). Summary of incidence, relative-risks (RR), and 95% confidence intervals (CI) were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies.
Overall, enzalutamide was not associated with all-grade (RR 1.06 - 95% CI 0.67-1.65) or grade ≥3 (RR 0.81 - 95% CI 0.28-2.33) cardiovascular events, but was associated with increased risk of all-grade fatigue (RR 1.29 - 95% CI 1.15-1.44). On the other hand, abiraterone was associated with increased risk of all-grade (RR 1.28 - 95% CI 1.06-1.55) and grade ≥3 (RR 1.76 - 95% CI 1.12-2.75) cardiovascular events, but was not associated with all-grade (RR 0.85 - 95% CI 0.58-1.23) or grade ≥3 (RR 1.07 - 95% CI 0.97-1.19) fatigue.
In this meta-analysis, abiraterone was associated with an increased risk of cardiovascular events, while enzalutamide was associated with an increased risk of fatigue.
Chromophobe renal cell carcinoma (chRCC) is a histologically and molecularly distinct class of rare renal tumor. TCGA studies revealed low mutational burden, with only TP53 and PTEN recurrently ...mutated, and discovered alterations in TERT promoter and in the electron transport chain Complex I genes. However, knowledge on drug targetable genes is limited and treatments at metastatic stage do not follow a molecular rationale. In a large series of 92 chRCC enriched with metastatic cases, we performed an in-depth characterization of mTOR pathway alterations through targeted NGS and immunohistochemistry (IHC) of phospho-S6, tuberin, and PTEN. Mutations in mitochondria, telomere maintenance and other renal cancer related genes and p53 IHC, were also assessed. The impact on metastasis development and disease specific survival was determined, using TCGA-KICH series (n = 65) for validation. mTOR pathway mutations (MTOR, TSC1, TSC2) were present in 17% of primary tumors, most of them being classified as pathogenic. Mutations were associated with positive IHC staining of phospho-S6 and PTEN (P = 0.009 and P = 0.001, respectively) and with chRCC eosinophilic variant (P = 0.039), supporting a biological relevance of the pathway. mTOR pathway mutations were associated with worse clinical outcomes. Survival analysis gave a hazard ratio of 5.5 (P = 0.027), and this association was confirmed in TCGA-KICH (HR = 10.3, P = 0.006). TP53 mutations were enriched in metastatic cases (P = 0.018), and mutations in telomere maintenance genes showed a trend in the same direction. p53 IHC staining pattern was associated with the underlying TP53 defect, and negative PTEN IHC staining (82% of cases) suggested PTEN loss as a chRCC hallmark. In conclusion, our study provides with novel genomic knowledge in chRCC and identifies novel markers of poor survival. Furthermore, this is the first study showing that mTOR pathway mutations correlate with poor prognosis, and may help to identify patients with increased sensitivity to mTOR inhibitors.
Tumor-infiltrating immune cells have been linked to prognosis and response to immunotherapy; however, the levels of distinct immune cell subsets and the signals that draw them into a tumor, such as ...the expression of antigen presenting machinery genes, remain poorly characterized. Here, we employ a gene expression-based computational method to profile the infiltration levels of 24 immune cell populations in 19 cancer types.
We compare cancer types using an immune infiltration score and a T cell infiltration score and find that clear cell renal cell carcinoma (ccRCC) is among the highest for both scores. Using immune infiltration profiles as well as transcriptomic and proteomic datasets, we characterize three groups of ccRCC tumors: T cell enriched, heterogeneously infiltrated, and non-infiltrated. We observe that the immunogenicity of ccRCC tumors cannot be explained by mutation load or neo-antigen load, but is highly correlated with MHC class I antigen presenting machinery expression (APM). We explore the prognostic value of distinct T cell subsets and show in two cohorts that Th17 cells and CD8
T/Treg ratio are associated with improved survival, whereas Th2 cells and Tregs are associated with negative outcomes. Investigation of the association of immune infiltration patterns with the subclonal architecture of tumors shows that both APM and T cell levels are negatively associated with subclone number.
Our analysis sheds light on the immune infiltration patterns of 19 human cancers and unravels mRNA signatures with prognostic utility and immunotherapeutic biomarker potential in ccRCC.
Nivolumab-ipilimumab demonstrated a survival benefit over sunitinib in first-line setting for metastatic renal cell carcinomas (mRCCs) and is becoming a new standard of care for naïve patients with ...intermediate or poor risk prognosis (International mRCC Database Consortium). The efficacy of subsequent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) after nivolumab-ipilimumab failure remains unclear.
Medical records of mRCC patients treated with nivolumab-ipilimumab, who received subsequent TKI, as part of Checkmate 214 study were reviewed in 13 institutions. Baseline characteristics, outcome data including progression-free survival (PFS), response, overall survival (OS) and toxicities were retrospectively collected.
Overall 33 patients received subsequent TKI after nivolumab-ipilimumab failure. Median follow-up from start of subsequent TKI is 22 months (19–NR). Best response was assessed in 30 patients: 12 partial responses (36%), 13 stable diseases (39%) and five progressive diseases (15%). Median PFS from start of TKI was 8 months 5–13. Median PFS with first-generation (sunitinib/pazopanib) and second-generation TKI (axitinib/cabozantinib) was 8 months 5–16 and 7 months (5–NA), respectively. PFS in second line was significantly longer in patients with a long first-line duration of response to the double immune checkpoint blockade (≥6 months) with 8 versus 5 months for short responder (<6 months) (p = 0.03). OS rate was 54% at 12 months. Toxicity was as expected: 42% developed at least one toxicity grade ≥3.
This is the first report of outcomes with TKI, after first-line nivolumab-ipilimumab failure. Median PFS suggests a sustained benefit of TKI and supports trials investigating the optimal sequence.
•First report of tyrosine kinase inhibitor (TKI) activity in patients after nivolumab-ipilimumab failure in mRCC.•Median TKIs progression free survival is 8 months (95% confidence interval: 5–13).•No difference was observed between first and second generation of TKI.•75% of patients had a clinical benefit with 36% of partial response.•Investigating the optimal sequence for each patient must be the next priority.
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