Recommendations for the Management of Rare Kidney Cancers

Giles, Rachel; Choueiri, Toni K.; Heng, Daniel Yick Chin; Albigès, Laurence; Hsieh, James J.; Linehan, W. Marston; Pal, Sumanta K.; Maskens, Deborah; Paseman, Bill; Jonasch, Eric; Malouf, Gabriel G.; Molina, Ana M.; Pickering, Lisa; Shuch, Brian; Srinivas, Sandy; Srinivasan, Ramaprasad; Tannir, Nizar M.; Bex, Axel

doi:10.1016/j.eururo.2017.06.040

Cited by 37 publications

(37 citation statements)

References 53 publications

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“…While there are many drugs under development toward that goal, we are not yet there for the different RCC subtypes (Posadas et al, 2017). Currently, there are no evidence-based guidelines for appropriate management of nonclear cell RCC (Ciccarese et al, 2017;Giles et al, 2017). The most common of these nonclear cell RCC subtypes is PRCC, which of itself is known to harbor at least two histological types PRCC1 and PRCC2 with different molecular makeup and clinical behavior (Saleeb et al, 2016;TCGA, 2016;Yang et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…These include first-line therapies vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs), for example, sunitinib and pazopanib, and second-line therapies the mammalian target of rapamycin (mTOR) inhibitors (everolimus and temsirolimus), and the recently approved PD-1 immune checkpoint inhibitor nivolumab (Ciccarese et al, 2015(Ciccarese et al, , 2017Kumar and Kapoor, 2017). There is, however, a substantial lack of evidence regarding the management of nonclear cell RCC (Giles et al, 2017). While they are treated empirically as CCRCCs, they do not respond as well as the CCRCC counterpart.…”

Section: Introductionmentioning

confidence: 99%

“…One major hindrance to these trials is the inclusion of all nonclear cell RCCs as one category, despite the fact that they are known to be phenotypically and molecularly diverse (Armstrong et al, 2016;Giles et al, 2017;Ravaud et al, 2015;Tannir et al, 2016). There is considerable need for therapies and clinical trials that take into account the oncogenic pathways specific to each of these RCC subtypes (Giles et al, 2017;Kumar and Kapoor, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…There are only two trials that have attempted to assess differences in response to therapy between the two subtypes of PRCC; however, small patient cohorts limited both trials (Escudier et al, 2016;Ravaud et al, 2015). There are currently clinical trials assessing the value of targeting the MET pathway in PRCC (Giles et al, 2017). MET pathway is significantly enriched in PRCC1 (Saleeb et al, 2016;TCGA, 2016); however, there are no trials focusing on the more aggressive PRCC2 phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Modulating ATP binding cassette transporters in papillary renal cell carcinoma type 2 enhances its response to targeted molecular therapy

et al. 2018

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Papillary renal cell carcinoma (PRCC) is the most common nonclear cell RCCs and is known to comprise two histological subtypes. PRCC2 is more aggressive and is molecularly distinct from the other subtypes. Despite this, PRCCs are treated together as one entity, and they show poor response to the current therapies that do not target pathways implicated in their pathogenesis. We have previously detected ABCC2 (an ABC transporter), VEGF, and mTOR pathways to be enriched in PRCC2. In this study, we assess the therapeutic potential of targeting these pathways in PRCC2. Twenty RCC cell lines from the Cancer Cell Encyclopedia were compared to the Cancer Genome Atlas PRCC cohort (290), to identify representative PRCC2 cell lines. Cell lines were further validated in xenograft models. Selected cell lines were treated in vitro and in vivo (mice models) under five different conditions, untreated, anti‐VEGF (sunitinib), ABCC2 blocker (MK571), mTOR inhibitor (everolimus) and sunitinib + MK571. Sunitinib +ABCC2 blocker group showed a significant response to therapy compared to the other treatment groups both in vitro (P ≤ 0.0001) and in vivo (P = 0.0132). ABCC2 blockage resulted in higher sunitinib uptake, both in vitro (P = 0.0016) and in vivo (P = 0.0031). Everolimus group demonstrated the second best response in vivo. The double‐treatment group showed the highest apoptotic rate and lowest proliferation rate. There is an urgent need for individualized therapies of RCC subtypes that take into account their specific biology. Our results demonstrate that combined targeted therapy with sunitinib and ABCC2 blocker in PRCC2 has therapeutic potential. The results are likewise potentially significant for other ABCC2 high tumors. However, the results are preliminary and clinical trials are needed to confirm these effects in PRCC2 patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Modulating ATP binding cassette transporters in papillary renal cell carcinoma type 2 enhances its response to targeted molecular therapy

et al. 2018

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“…Among RCC subtypes, chromophobe RCC (chRCC) is relatively indolent and occasionally (5–10%) metastasizes . However, due to its rarity, all chRCC patients after nephrectomy were monitored based on guidelines established for ccRCC patients .…”

Section: Category Three Classification: Genomic Correlates With Clinimentioning

confidence: 99%

Genomic classifications of renal cell carcinoma: a critical step towards the future application of personalized kidney cancer care with pan‐omics precision

Hsieh

Cao

et al. 2018

The Journal of Pathology

105

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Over the past 20 years, classifications of kidney cancer have undergone major revisions based on morphological refinements and molecular characterizations. The 2016 WHO classification of renal tumors recognizes more than ten different renal cell carcinoma (RCC) subtypes. Furthermore, the marked inter-and intra-tumor heterogeneity of RCC is now well appreciated. Nevertheless, contemporary multi-omics studies of RCC, encompassing genomics, transcriptomics, proteomics, and metabolomics, not only highlight apparent diversity but also showcase and underline commonality. Here, we wish to provide an integrated perspective concerning the future 'functional' classification of renal cancer by bridging gaps among morphology, biology, multi-omics, and therapeutics. This review focuses on recent progress and elaborates the potential value of contemporary pan-omics approaches with a special emphasis on cancer genomics unveiled through next-generation sequencing technology, and how an integrated multi-omics approach might impact precision-based personalized kidney cancer care in the near future.

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Characterizing the tumor microenvironment in rare renal cancer histological types

Synnott

Poeta

Costantini

et al. 2021

The Journal of Pathology CR

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The tumor microenvironment (TME), including immune cells, cancer-associated fibroblasts, endothelial cells, adjacent normal cells, and others, plays a crucial role in influencing tumor behavior and progression. Here, we characterized the TME in 83 primary renal tumors and matched metastatic or recurrence tissue samples (n = 15) from papillary renal cell carcinoma (pRCC) types 1 (n = 20) and 2 (n = 49), collecting duct carcinomas (CDC; n = 14), and high-grade urothelial carcinomas (HGUC; n = 5). We investigated 10 different markers of immune infiltration, vasculature, cell proliferation, and epithelial-to-mesenchymal transition by using machine learning image analysis in conjunction with immunohistochemistry. Marker expression was compared by Mann-Whitney and Kruskal-Wallis tests and correlations across markers using Spearman's rank correlation coefficient. Multivariable Poisson regression analysis was used to compare marker expression between histological types, while accounting for variation in tissue size. Several immune markers showed different rates of expression across histological types of renal carcinoma. Using pRCC1 as reference, the incidence rate ratio (IRR) of CD3+ T cells (IRR [95% confidence interval, CI] = 2.48 [1.53-4.01]) and CD20+ B cells (IRR [95% CI] = 4.38 [1.22-5.58]) was statistically significantly higher in CDC. In contrast, CD68+ macrophages predominated in pRCC1 (IRR [95% CI] = 2. 35 [1.42-3.9]). Spatial analysis revealed CD3+ T-cell and CD20+ B-cell expressions in CDC to be higher at the proximal (p < 0.0001) and distal (p < 0.0001) tumor periphery than within the central tumor core. In contrast, expression of CD68+ macrophages in pRCC2 was higher in the tumor center compared to the proximal (p = 0.0451) tumor periphery and pRCC1 showed a distance-dependent reduction, from the central tumor, in CD68+ macrophages with the lowest expression of CD68 marker at the distal tumor periphery (p = 0.004). This study provides novel insights into the TME of rare kidney cancer types, which are often understudied. Our findings of differences in marker expression and localization by histological subtype could have implications for tumor progression and response to immunotherapies or other targeted therapies.

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Recommendations for the Management of Rare Kidney Cancers

Cited by 37 publications

References 53 publications

Modulating ATP binding cassette transporters in papillary renal cell carcinoma type 2 enhances its response to targeted molecular therapy

Modulating ATP binding cassette transporters in papillary renal cell carcinoma type 2 enhances its response to targeted molecular therapy

Genomic classifications of renal cell carcinoma: a critical step towards the future application of personalized kidney cancer care with pan‐omics precision

Characterizing the tumor microenvironment in rare renal cancer histological types

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