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2.
Artigo em Inglês | MEDLINE | ID: mdl-33358149

RESUMO

Close to 74,000 cases of renal cell carcinoma (RCC) are diagnosed each year in the United States. The past 2 decades have shown great developments in surgical techniques, targeted therapy and immunotherapy agents, and longer complete response rates. However, without a global cure, there is still room for further advancement in improving patient care in this space. To address some of the gaps restricting this progress, the Kidney Cancer Association brought together a group of 27 specialists across the areas of clinical care, research, industry, and advocacy at the inaugural "Think Tank: Coalition for a Cure" session. Topics addressed included screening, imaging, rarer RCC subtypes, combination drug therapy options, and patient response. This commentary summarizes the discussion of these topics and their respective clinical challenges, along with a proposal of projects for collaboration in overcoming those needs and making a greater impact on care for patients with RCC moving forward.

3.
JCI Insight ; 5(22)2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33208553

RESUMO

BACKGROUNDSurgery remains the frontline therapy for patients with localized clear cell renal cell carcinoma (ccRCC); however, 20%-40% recur. Angiogenesis inhibitors have improved survival in metastatic patients and may result in responses in the neoadjuvant setting. The impact of these agents on the tumor genetic heterogeneity or the immune milieu is largely unknown. This phase II study was designed to evaluate safety, response, and effect on tumor tissue of neoadjuvant pazopanib.METHODSccRCC patients with localized disease received pazopanib (800 mg daily; median 8 weeks), followed by nephrectomy. Five tumors were examined for mutations by whole exome sequencing from samples collected before therapy and at nephrectomy. These samples underwent RNA sequencing; 17 samples were available for posttreatment assessment.RESULTSTwenty-one patients were enrolled. The overall response rate was 8 of 21 (38%). No patients with progressive disease. At 1-year, response-free survival and overall survival was 83% and 89%, respectively. The most frequent grade 3 toxicity was hypertension (33%, 7 of 21). Sequencing revealed strong concordance between pre- and posttreatment samples within individual tumors, suggesting tumors harbor stable core profiles. However, a reduction in private mutations followed treatment, suggesting a selective process favoring enrichment of driver mutations.CONCLUSIONNeoadjuvant pazopanib is safe and active in ccRCC. Future genomic analyses may enable the segregation of driver and passenger mutations. Furthermore, tumor infiltrating immune cells persist during therapy, suggesting that pazopanib can be combined with immune checkpoint inhibitors without dampening the immune response.FUNDINGSupport was provided by Novartis and GlaxoSmithKline as part of an investigator-initiated study.

4.
Nat Rev Nephrol ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33144689

RESUMO

The molecular features that define clear cell renal cell carcinoma (ccRCC) initiation and progression are being increasingly defined. The TRACERx Renal studies and others that have described the interaction between tumour genomics and remodelling of the tumour microenvironment provide important new insights into the molecular drivers underlying ccRCC ontogeny and progression. Our understanding of common genomic and chromosomal copy number abnormalities in ccRCC, including chromosome 3p loss, provides a mechanistic framework with which to organize these abnormalities into those that drive tumour initiation events, those that drive tumour progression and those that confer lethality. Truncal mutations in ccRCC, including those in VHL, SET2, PBRM1 and BAP1, may engender genomic instability and promote defects in DNA repair pathways. The molecular features that arise from these defects enable categorization of ccRCC into clinically and therapeutically relevant subtypes. Consideration of the interaction of these subtypes with the tumour microenvironment reveals that specific mutations seem to modulate immune cell populations in ccRCC tumours. These findings present opportunities for disease prevention, early detection, prognostication and treatment.

5.
Sci Adv ; 6(40)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33008892

RESUMO

The methyltransferase SET domain-containing 2 (SETD2) was originally identified as Huntingtin (HTT) yeast partner B. However, a SETD2 function associated with the HTT scaffolding protein has not been elucidated, and no linkage between HTT and methylation has yet been uncovered. Here, we show that SETD2 is an actin methyltransferase that trimethylates lysine-68 (ActK68me3) in cells via its interaction with HTT and the actin-binding adapter HIP1R. ActK68me3 localizes primarily to the insoluble F-actin cytoskeleton in cells and regulates actin polymerization/depolymerization dynamics. Disruption of the SETD2-HTT-HIP1R axis inhibits actin methylation, causes defects in actin polymerization, and impairs cell migration. Together, these data identify SETD2 as a previously unknown HTT effector regulating methylation and polymerization of actin filaments and provide new avenues for understanding how defects in SETD2 and HTT drive disease via aberrant cytoskeletal methylation.

6.
World J Urol ; 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32936333

RESUMO

This brief report focuses on the evaluation and diagnosis of clinically localized renal masses in children and adults with Von Hippel-Lindau (VHL) disease. Counseling considerations pertinent to the urologists, medical oncologists, and multidisciplinary teams involved in the care of these patients are addressed. As practice patterns regarding the evaluation and management of VHL tumors can vary considerably, this report aims to provide guidance on some of the controversies associated with the diagnostic evaluation and initial management of localized renal masses in VHL patients.

7.
iScience ; 23(8): 101408, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32771978

RESUMO

Patient-derived cancer organoids hold great potential to accurately model and predict therapeutic responses. Efficient organoid isolation methods that minimize post-collection manipulation of tissues would improve adaptability, accuracy, and applicability to both experimental and real-time clinical settings. Here we present a simple and minimally invasive fine-needle aspiration (FNA)-based organoid culture technique using a variety of tumor types including gastrointestinal, thyroid, melanoma, and kidney. This method isolates organoids directly from patients at the bedside or from resected tissues, requiring minimal tissue processing while preserving the histologic growth patterns and infiltrating immune cells. Finally, we illustrate diverse downstream applications of this technique including in vitro high-throughput chemotherapeutic screens, in situ immune cell characterization, and in vivo patient-derived xenografts. Thus, routine clinical FNA-based collection techniques represent an unappreciated substantial source of material that can be exploited to generate tumor organoids from a variety of tumor types for both discovery and clinical applications.

8.
JCI Insight ; 5(16)2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32814710

RESUMO

Metabolic reprogramming dictates the fate and function of stimulated T cells, yet these pathways can be suppressed in T cells in tumor microenvironments. We previously showed that glycolytic and mitochondrial adaptations directly contribute to reducing the effector function of renal cell carcinoma (RCC) CD8+ tumor-infiltrating lymphocytes (TILs). Here we define the role of these metabolic pathways in the activation and effector functions of CD8+ RCC TILs. CD28 costimulation plays a key role in augmenting T cell activation and metabolism, and is antagonized by the inhibitory and checkpoint immunotherapy receptors CTLA4 and PD-1. While RCC CD8+ TILs were activated at a low level when stimulated through the T cell receptor alone, addition of CD28 costimulation greatly enhanced activation, function, and proliferation. CD28 costimulation reprogrammed RCC CD8+ TIL metabolism with increased glycolysis and mitochondrial oxidative metabolism, possibly through upregulation of GLUT3. Mitochondria also fused to a greater degree, with higher membrane potential and overall mass. These phenotypes were dependent on glucose metabolism, as the glycolytic inhibitor 2-deoxyglucose both prevented changes to mitochondria and suppressed RCC CD8+ TIL activation and function. These data show that CD28 costimulation can restore RCC CD8+ TIL metabolism and function through rescue of T cell glycolysis that supports mitochondrial mass and activity.

9.
Cancer Lett ; 489: 19-28, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32512023

RESUMO

The relationship between kidney cancer, specifically clear cell renal cell carcinoma (ccRCC), and the hypoxia signaling program has been extensively characterized. Its underlying role as the primary driver of the disease has led to the development of the most effective targeted therapies to date. Cellular responses to hypoxia or mutations affecting the von Hippel-Lindau (VHL) tumor suppressor gene stabilize the hypoxia inducible factor (HIF) transcription factors which then orchestrate elaborate downstream signaling events resulting in adaptations to key biological processes, such as reprogramming metabolism. The direct link of hypoxia signaling to glucose uptake and glycolysis has long been appreciated; however, the HIF family of proteins directly regulate many downstream targets, including other transcription factors with their own extensive networks. In this review, we will summarize our current understanding of how hypoxia signaling regulates other metabolic pathways and how this contributes to the development and progression of clear cell renal cell carcinomas.

10.
J Clin Invest ; 130(6): 2731-2732, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32478677
12.
JCI Insight ; 5(11)2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32493845

RESUMO

Recently, we reported that expression of endogenous retroviruses (ERVs) is associated with response to immune checkpoint blockade (ICB) in renal cell carcinoma (RCC). We show that decitabine, a DNA hypomethylating agent, activates transposable element (TE) expression (LINE1 and ERVs ERV3-2 and ERV4700) and antiviral signaling to potentially enhance response to ICB in kidney cancer cell lines and primary cells. KO of RIGI and MDA5 dsRNA sensors attenuated activation of antiviral signaling associated with DNA hypomethylation, and RIGI and MDA5 IPs showed increased ERV binding with decitabine treatment. Bioinformatic analyses showed the decitabine-induced signature could be associated with increased immune infiltration and response to ICB. Cytokine secretion induced by decitabine could modestly improve T cell activation and robustly enhanced T cell migration. In a small retrospective cohort of metastatic clear cell RCC (ccRCC) patients treated with anti-PD1/PDL1 blockade, activation of some antiviral genes was significantly higher in responders. Thus, we identified a potential strategy to induce TE expression through inhibition of DNA methylation in modulating T cell action via regulation of the innate antiviral pathway.

13.
Elife ; 92020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32367803

RESUMO

Breakthroughs in anti-tumor immunity have led to unprecedented advances in immunotherapy, yet it is now clear that the tumor microenvironment (TME) restrains immunity. T cells must substantially increase nutrient uptake to mount a proper immune response and failure to obtain sufficient nutrients or engage the appropriate metabolic pathways can alter or prevent effector T cell differentiation and function. The TME, however, can be metabolically hostile due to insufficient vascular exchange and cancer cell metabolism that leads to hypoxia, depletion of nutrients, and accumulation of waste products. Further, inhibitory receptors present in the TME can inhibit T cell metabolism and alter T cell signaling both directly and through release of extracellular vesicles such as exosomes. This review will discuss the metabolic changes that drive T cells into different stages of their development and how the TME imposes barriers to the metabolism and activity of tumor infiltrating lymphocytes.

14.
Nat Commun ; 11(1): 2135, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358509

RESUMO

A non-immunogenic tumor microenvironment (TME) is a significant barrier to immune checkpoint blockade (ICB) response. The impact of Polybromo-1 (PBRM1) on TME and response to ICB in renal cell carcinoma (RCC) remains to be resolved. Here we show that PBRM1/Pbrm1 deficiency reduces the binding of brahma-related gene 1 (BRG1) to the IFNγ receptor 2 (Ifngr2) promoter, decreasing STAT1 phosphorylation and the subsequent expression of IFNγ target genes. An analysis of 3 independent patient cohorts and of murine pre-clinical models reveals that PBRM1 loss is associated with a less immunogenic TME and upregulated angiogenesis. Pbrm1 deficient Renca subcutaneous tumors in mice are more resistance to ICB, and a retrospective analysis of the IMmotion150 RCC study also suggests that PBRM1 mutation reduces benefit from ICB. Our study sheds light on the influence of PBRM1 mutations on IFNγ-STAT1 signaling and TME, and can inform additional preclinical and clinical studies in RCC.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/microbiologia , Fatores de Transcrição/metabolismo , Animais , Complexo Antígeno-Anticorpo/genética , Complexo Antígeno-Anticorpo/metabolismo , Carcinoma de Células Renais/genética , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Feminino , Imunofluorescência , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imuno-Histoquímica , Neoplasias Renais/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Mutação , Fosforilação , Fator de Transcrição STAT1/metabolismo , Análise Serial de Tecidos , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Transcriptoma/genética
15.
J Natl Cancer Inst ; 2020 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-32359162

RESUMO

Kidney cancer is one of the ten most common cancers both in the United States and worldwide. Until this year, there had not previously been a conference focused on translational studies in the broad and heterogeneous group of kidney cancers. Therefore, a group of researchers, clinicians, and patient advocates dedicated to renal cell carcinoma (RCC) launched the Kidney Cancer Research Summit (KCRS) to spur collaboration and further therapeutic advances in these tumors. This commentary aims to summarize the oral presentations and serve as a record for future iterations of this meeting. The KCRS sessions addressed the tumor microenvironment, novel methods of drug delivery, single cell sequencing strategies, novel immune checkpoint blockade and cellular therapies, predictive biomarkers and rare variants of kidney cancers. In addition, the meeting included 2 sessions to promote scientific mentoring and kidney cancer research collaborations. A subsequent KCRS will be planned for the fall of 2020.

16.
Arterioscler Thromb Vasc Biol ; 40(6): e153-e165, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32295422

RESUMO

OBJECTIVE: Macrophages have been described in calcific aortic valve disease, but it is unclear if they promote or counteract calcification. We aimed to determine how macrophages are involved in calcification using the Notch1+/- model of calcific aortic valve disease. Approach and Results: Macrophages in wild-type and Notch1+/- murine aortic valves were characterized by flow cytometry. Macrophages in Notch1+/- aortic valves had increased expression of MHCII (major histocompatibility complex II). We then used bone marrow transplants to test if differences in Notch1+/- macrophages drive disease. Notch1+/- mice had increased valve thickness, macrophage infiltration, and proinflammatory macrophage maturation regardless of transplanted bone marrow genotype. In vitro approaches confirm that Notch1+/- aortic valve cells promote macrophage invasion as quantified by migration index and proinflammatory phenotypes as quantified by Ly6C and CCR2 positivity independent of macrophage genotype. Finally, we found that macrophage interaction with aortic valve cells promotes osteogenic, but not dystrophic, calcification and decreases abundance of the STAT3ß isoform. CONCLUSIONS: This study reveals that Notch1+/- aortic valve disease involves increased macrophage recruitment and maturation driven by altered aortic valve cell secretion, and that increased macrophage recruitment promotes osteogenic calcification and alters STAT3 splicing. Further investigation of STAT3 and macrophage-driven inflammation as therapeutic targets in calcific aortic valve disease is warranted.


Assuntos
Estenose da Valva Aórtica/patologia , Valva Aórtica/patologia , Calcinose/patologia , Macrófagos/fisiologia , Fator de Transcrição STAT3/fisiologia , Animais , Valva Aórtica/imunologia , Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/imunologia , Estenose da Valva Aórtica/fisiopatologia , Transplante de Medula Óssea , Calcinose/imunologia , Calcinose/fisiopatologia , Movimento Celular , Óxidos S-Cíclicos/farmacologia , Modelos Animais de Doenças , Expressão Gênica , Genótipo , Humanos , Inflamação/patologia , Macrófagos/química , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteogênese , Receptor Notch1/análise , Receptor Notch1/genética , Receptor Notch1/fisiologia , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética
17.
Clin Genitourin Cancer ; 18(5): 378-386.e1, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32147364

RESUMO

INTRODUCTION: Computed tomography (CT) has limited diagnostic accuracy for staging of muscle-invasive bladder cancer (MIBC). [18F] Fluorodeoxyglucose positron emission tomography (FDG-PET)/magnetic resonance imaging (MRI) is a novel imaging modality incorporating functional imaging with improved soft tissue characterization. This pilot study evaluated the use of preoperative FDG-PET/MRI for staging of MIBC. PATIENTS AND METHODS: Twenty-one patients with MIBC with planned radical cystectomy were enrolled. Two teams of radiologists reviewed FDG-PET/MRI scans to determine: (1) presence of primary bladder tumor; and (2) lymph node involvement and distant metastases. FDG-PET/MRI was compared with cystectomy pathology and computed tomography (CT). RESULTS: Eighteen patients were included in the final analysis, most (72.2%) of whom received neoadjuvant chemotherapy. Final pathology revealed 10 (56%) patients with muscle invasion and only 3 (17%) patients with lymph node involvement. Clustered analysis of FDG-PET/MRI radiology team reads revealed a sensitivity of 0.80 and a specificity of 0.56 for detection of the primary tumor with a sensitivity of 0 and a specificity of 1.00 for detection of lymph node involvement when compared with cystectomy pathology. CT imaging demonstrated similar rates in evaluation of the primary tumor (sensitivity, 0.91; specificity, 0.43) and lymph node involvement (sensitivity, 0; specificity, 0.93) when compared with pathology. CONCLUSIONS: This pilot single-institution experience of FDG-PET/MRI for preoperative staging of MIBC performed similar to CT for the detection of the primary tumor; however, the determination of lymph node status was limited by few patients with true pathologic lymph node involvement. Further studies are needed to evaluate the potential role for FDG-PET/MRI in the staging of MIBC.

19.
Consult Psychol J ; 71(3): 141-160, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31787830

RESUMO

The transition to academic leadership entails learning to utilize an enormous new collection of skills. Executive leadership coaching is a personalized training approach that is being increasingly used to accelerate the onboarding of effective leaders. Vanderbilt University Medical Center has invested in a robust coaching strategy that is offered broadly to institutional leaders. This case study details the early transformational learning of leadership skills by one new institutional leader in the first two years in an academic leadership role, telling the first-person account of the experience of being coached while independently leading a division of hematology and oncology at a highly ranked medical center. Over two years' time, assessed in 6-month intervals, the academician transitions into the role, and using scenarios from regular practice in this position, learns to incorporate core leadership principles into the daily activities of running a division. The transition to academic leadership involves a transformation; a conversion that can be accelerated, guided, and applied with a greater deal of sophistication through intentional coaching, and the application of principles of behavioral science and psychology. Much like the process of coaching a high performing athlete, an elite academician can be trained in skills that enhance their game and succeed in creating a winning team. The academic medical center (AMC) is an interesting social organization, made up of highly accomplished and well-educated people, brought together around a variety of missions and motivations: education, patient service, research, community building, financial margins, and citizenship to name a few. Moreover, the leadership of AMCs almost entirely comes from within this community, drawing people with talents in science, teaching, clinical research, and service into roles that industries reserve usually for MBAs, lawyers, and other professionals who undergo rigorous guided training. Fortunately, academics are well-equipped with skills in lifelong learning, focused curiosity, and tend to be ambitious to a fault. Thus, there is a steady pipeline of budding leaders in AMC's eager to tackle new challenges that will further their missions. Like major industries in the public and private sectors, the demands of leadership are significant. How to navigate the transitions from physician, teacher, or scientist to academic leader is not covered easily in any text. Vanderbilt University Medical Center has adopted a model of Leadership Coaching, akin to the Trusted Leadership Advisor model (Wasylyshyn, 2017). This case study details the experience of one new leader (first author), freshly plucked from the medical science proving ground. Accounts and description of the experiences and intentions of the leadership coach, Dick Kilburg, provide insight into the processes applied in facilitating this transition. Finally, observations of the transition from the vantage point of the primary supervisor (Department Chair, Nancy Brown) provide a further description of the coaching effect on the early development of an AMC leader. The experience of the client, Kimryn Rathmell (Kim), is told in first person narrative format-fitting for the intense and personal experience that accompanies the transition to a leadership role.

20.
Oncotarget ; 10(59): 6391-6392, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31695846

RESUMO

[This corrects the article DOI: 10.18632/oncotarget.26567.].

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