scholarly journals Integrated mRNA and miRNA Transcriptomic Analyses Reveals Divergent Mechanisms of Sunitinib Resistance in Clear Cell Renal Cell Carcinoma (ccRCC)

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4401
Author(s):  
María Armesto ◽  
Maitane Marquez ◽  
María Arestin ◽  
Peio Errarte ◽  
Ane Rubio ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Gene Networks ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Cell Renal Cell Carcinoma ◽  
Angiogenic Therapy ◽  
Resistant Cells

The anti-angiogenic therapy sunitinib remains the standard first-line treatment for meta static clear cell renal cell carcinoma (ccRCC). However, acquired resistance develops in nearly all responsive patients and represents a major source of treatment failure. We used an integrated miRNA and mRNA transcriptomic approach to identify miRNA:target gene interactions involved in sunitinib resistance. Through the generation of stably resistant clones in three ccRCC cell lines (786-O, A498 and Caki-1), we identified non-overlapping miRNA:target gene networks, suggesting divergent mechanisms of sunitinib resistance. Surprisingly, even though the genes involved in these networks were different, they shared targeting by multiple members of the miR-17~92 cluster. In 786-O cells, targeted genes were related to hypoxia/angiogenic pathways, whereas, in Caki-1 cells, they were related to inflammatory/proliferation pathways. The immunotherapy target PD-L1 was consistently up-regulated in resistant cells, and we demonstrated that the silencing of this gene resulted in an increase in sensitivity to sunitinib treatment only in 786-O-resistant cells, suggesting that some ccRCC patients might benefit from combination therapy with PD-L1 checkpoint inhibitors. In summary, we demonstrate that, although there are clearly divergent mechanisms of sunitinib resistance in ccRCC subtypes, the commonality of miRNAs in multiple pathways could be targeted to overcome sunitinib resistance.

Evaluation of the spectrum selective RTK inhibitor sitravatinib in clear cell renal cell carcinoma (ccRCC) refractory to anti-angiogenic therapy (AAT).

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 4568-4568 ◽  
Author(s):  
Shubham Pant ◽  
Alexander I. Spira ◽  
Byoung Chul Cho ◽  
Sanjay Goel ◽  
Christopher J. Hoimes ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Angiogenic Therapy

scholarly journals Tumor Microenvironment Features as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors (ICI) in Metastatic Clear Cell Renal Cell Carcinoma (mccRCC)

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 231
Author(s):  
Audrey Simonaggio ◽  
Nicolas Epaillard ◽  
Cédric Pobel ◽  
Marco Moreira ◽  
Stéphane Oudard ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Microenvironment ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Cell Renal Cell Carcinoma ◽  
Genomic Signatures

Renal cell carcinoma (RCC) is the seventh most frequently diagnosed malignancy with an increasing incidence in developed countries. Despite a greater understanding of the cancer biology, which has led to an increase of therapeutic options, metastatic clear cell renal cell carcinoma (mccRCC) still have a poor prognosis with a median five-years survival rate lower than 10%. The standard of care for mccRCC has changed dramatically over the past decades with the emergence of new treatments: anti-VEGFR tyrosine kinase inhibitors, mTOR Inhibitors and immune checkpoint inhibitors (ICI) such as anti-Programmed cell-Death 1 (PD-1) and anti-anti-Programmed Death Ligand-1 (PD-L1) used as monotherapy or as a combination with anti CTLA-4 or anti angiogenic therapies. In the face of these rising therapeutic options, the question of the therapeutic sequences is crucial. Predictive biomarkers are urgently required to provide a personalized treatment for each patient. Disappointingly, the usual ICI biomarkers, PD-L1 expression and Tumor Mutational Burden, approved in melanoma or non-small cell lung cancer (NSCLC) have failed to distinguish good and poor mccRCC responders to ICI. The tumor microenvironment is known to be involved in ICI response. Innovative technologies can be used to explore the immune contexture of tumors and to find predictive and prognostic biomarkers. Recent comprehensive molecular characterization of RCC has led to the development of robust genomic signatures, which could be used as predictive biomarkers. This review will provide an overview of the components of the RCC tumor microenvironment and discuss their role in disease progression and resistance to ICI. We will then highlight the current and future ICI predictive biomarkers assessed in mccRCC with a major focus on immunohistochemistry markers and genomic signatures.

UNISON - nivolumab then ipilimumab + nivolumab in advanced non-clear cell renal cell carcinoma (ANZUP 1602): Part 1—Nivolumab monotherapy.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 325-325
Author(s):  
Craig Gedye ◽  
David William Pook ◽  
Laurence Eliot Miles Krieger ◽  
Carole A. Harris ◽  
Jeffrey C. Goh ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Disease Control ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Cell Renal Cell Carcinoma ◽  
Papillary Type

325 Background: Immune checkpoint inhibitors (ICI) are active in many cancers, but people with rare variant, non clear-cell renal cell carcinoma (nccRCC) have been excluded from most clinical trials in RCC. UNISON (NCT03177239) aimed to test 2 hypotheses; the activity of nivolumab in nccRCC (Part 1), and the benefit of adding ipilimumab to nivolumab, in people whose cancers progress on nivolumab (Part 2). Methods: 83 participants (pts) with advanced nccRCC with good (ECOG0/1) performance status, were enrolled including papillary type 1 (17%), papillary type 2 (28%), chromophobe (18%), Xp11 translocation (6%), hereditary leiomyomatosis renal cell carcinoma syndrome-associated renal cell carcinoma (6%), RCC unclassified (10%) and other (15%) histological subtypes. Participants took nivolumab (N) 240mg every two weeks in Part 1 in total. If they experienced progression and remained eligible they could take N (3mg/kg) plus ipilimumab (I; 1mg/kg) every 3 weeks for up to 4 doses (Part 2). Pts with disease control after N or N + I could continue N for up to 1 year. UNISON was powered to distinguish a clinically-relevant improvement in objective tumor response rate (OTRR) from 15% to 30% in people taking N+I in Part 2 in pts whose cancers were refractory to single-agent first-line N. Here we report results of Part 1. Results: Pts experience of N appeared similar to previous reports, with most experiencing mild adverse events. 12 treatment related SAE occurred in 11 patients (13%). 14 pts (17%) experienced treatment delays, or permanent treatment discontinuation (10%). The median time on treatment was 5.1 months. The OTRR was 17% with 3 complete responses and 11 partial responses. The median duration of response was 21 months. Stable disease occurred in 49% of pts and disease progression in 34%. The disease control rate at 6 months was 45% (95% CI: 34%, 56%). The median PFS was 4.0 months (95% CI: 3.6, 7.4). The 6 month progression-free survival (PFS) was 45% (95% CI: 34-55) and the 12 months PFS was 30% (95% CI: 21%, 40%). Conclusions: Pts with nccRCC treated with N experience similar adverse events compared to pts with other cancers. A substantial minority of people with nccRCC derive benefit, but many pts have cancers refractory to anti-PD1, similar to other reports. The activity of I and N in this PD1-refractory population is of considerable interest and will be reported at a later date. Clinical trial information: NCT03177239 .

PD-L1 Expression and Treatment Implications in Metastatic Clear Cell Renal Cell Carcinoma: A Systematic Review

Kidney Cancer ◽  
2021 ◽  
Vol 5 (1) ◽  
pp. 31-46
Author(s):  
Albert Jang ◽  
Patrick L. Sweeney ◽  
Pedro C. Barata ◽  
Vadim S. Koshkin
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Cell Renal Cell Carcinoma ◽  
Hand Search ◽  
Full Text Review ◽  
Predictive And Prognostic Biomarker

BACKGROUND: Over the past decade, immune checkpoint inhibitors (ICIs) have increasingly become the standard of care for various advanced malignancies, including metastatic clear cell renal cell carcinoma (mccRCC). Most ICIs currently used in clinical practice inhibit the interaction between the programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) complex. A deeper understanding of this interaction and PD-L1 expression in tumors has led to more effective therapies in the treatment of advanced cancers, but the debate regarding the utility of PD-L1 as a biomarker continues. OBJECTIVE: We aimed to systematically evaluate the role of PD-L1 in mccRCC in terms of expression and treatment implications. METHODS: Following PRISMA guidelines, we performed a systematic literature search using PubMed and Embase through August 31, 2020. Titles and abstracts were screened to identify articles for full-text review. A hand search was also performed using Google Scholar and the bibliography to relevant studies. RESULTS: A total of 26 articles were identified, and relevant data were extracted and organized. The available information regarding PD-L1 expression in mccRCC from both prospective clinical trials and retrospective studies were summarized. We discussed the utility of PD-L1 as a predictive and prognostic biomarker in mccRCC, its association with other potential biomarkers, and the pattern and level of expression of PD-L1 in primary versus metastatic tumors. CONCLUSIONS: Although significant progress has been made, much more remains to be learned regarding the differences between PD-L1+ and PD-L1- ccRCC tumors, in terms of both the underlying biology and clinical responses to immunotherapy and other agents.

scholarly journals BRCA1-Associated Protein 1 (BAP-1) as a Prognostic and Predictive Biomarker in Clear Cell Renal Cell Carcinoma: A Systematic Review

Kidney Cancer ◽  
2021 ◽  
pp. 1-13
Author(s):  
Shuchi Gulati ◽  
Melissa Previtera ◽  
Maria F. Czyzyk-Krzeska ◽  
Primo Nery Lara
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarker ◽  
Cell Renal Cell Carcinoma ◽  
Thymic Epithelial Tumors

BACKGROUND: The gene that encodes BRCA1-associated protein 1 (BAP1) has been reported to be dysregulated in several human cancers such as uveal melanoma, malignant pleural mesothelioma, hepatocellular carcinoma, thymic epithelial tumors, and clear-cell renal cell carcinoma (ccRCC). The gene is located on the human chromosome 3p21.3, encoding a deubiquitinase and acts as a classic two-hit tumor suppressor gene. BAP1 predominantly resides in the nucleus, where it interacts with several chromatin-associated factors, as well as regulates calcium signaling in the cytoplasm. As newer therapies continue to evolve for the management of RCC, it is important to understand the role of BAP1 mutation as a prognostic and predictive biomarker. OBJECTIVE: We aimed to systematically evaluate the role of BAP1 mutations in patients with RCC in terms of its impact on prognosis and its role as a predictive biomarker. METHODS: Following PRISMA guidelines, we performed a systematic literature search using PubMed and Embase through March 2021. Titles and abstracts were screened to identify articles for full-text and then a descriptive review was performed. RESULTS: A total of 490 articles were initially identified. Ultimately 71 articles that met our inclusion criteria published between 2012–2021 were included in the analysis. Data were extracted and organized to reflect the role of BAP1 alterations as a marker of prognosis as well as a marker of response to treatments, such as mTOR inhibitors, VEGF tyrosine kinase inhibitors, and immune checkpoint inhibitors. CONCLUSIONS: Alterations in BAP1 appear to be uniformly associated with poor prognosis in patients with RCC. Knowledge gaps remain with regard to the predictive relevance of BAP1 alterations, especially in the context of immunotherapy. Prospective studies are required to more precisely ascertain the predictive value of BAP1 alterations in RCC.

Clinical outcomes of checkpoint inhibitors in metastatic non-clear cell renal cell carcinoma and clear cell renal cell carcinoma with variant features.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17065-e17065
Author(s):  
Guy vin Chang ◽  
Moataz Ellithi ◽  
Radowan Elnair ◽  
Jonathan Bleeker
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Cell Renal Cell Carcinoma ◽  
Durable Response ◽  
Rhabdoid Features

e17065 Background: Checkpoint inhibitors (CPI) are a well-established treatment option for advanced clear cell renal cell carcinoma (ccRCC); however, there is a paucity of data on efficacy of CPI on advanced non-clear cell renal cell carcinoma (nccRCC) and ccRCC with variant (sarcomatoid or rhabdoid) features. Recently, small series have demonstrated benefit for CPI in these entities. Methods: We performed a retrospective review of patients with metastatic nccRCC or ccRCC with variant features, who received a single agent CPI (nivolumab or pembrolizumab) or combination therapy (nivolumab and ipilimumab) between Feb 2016 – Oct 2019 at our integrated community-based health system. The primary endpoint was objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). We used Kaplan-Meier survival analysis for PFS and OS. Results: A total of 26 patients met eligibility criteria; 11 patients with nccRCC (papillary n = 6, chromophobe n = 1, unclassified n = 4), 12 patients with sarcomatoid ccRCC, 2 patients with rhabdoid ccRCC, and 1 patient with both sarcomatoid and rhabdoid features. Sixteen patients received nivolumab, 3 received pembrolizumab, and 7 received a combination of nivolumab and ipilimumab. CPI was halted in 4 patients due to adverse effects including arthralgia, hyperthyroidism, hepatitis, and colitis. Among these 26 patients, 5 patients (19.2%) achieved complete response (CR), 3 patients (11.5%) achieved partial response (PR), and 10 patients (38.5%) had stable disease (SD). All patients who achieved CR or PR had a durable response throughout the follow-up period. At the median follow-up of 16.4 months, median PFS was 14.3 months, and median OS was not reached. Conclusions: In this retrospective series, the ORR of CPI in metastatic nccRCC and ccRCC with variant features was 30.7%, and disease control rate was 69.2%. These findings suggest that CPI may provide significant clinical benefit in patients with nccRCC and ccRCC with sarcomatoid and/or rhabdoid features. Sample size may limit inference and additional studies are needed.

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