Publications by authors named "Payal Kapur"

169 Publications

New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

Mod Pathol 2021 Mar 4. Epub 2021 Mar 4.

Department of Pathology MD Anderson Cancer Center, Houston, TX, USA.

The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.
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http://dx.doi.org/10.1038/s41379-021-00779-wDOI Listing
March 2021

Neoadjuvant SABR for Renal Cell Carcinoma Inferior Vena Cava Tumor Thrombus-Safety Lead-in Results of a Phase 2 Trial.

Int J Radiat Oncol Biol Phys 2021 Feb 5. Epub 2021 Feb 5.

Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address:

Purpose: To evaluate the feasibility, safety, oncologic outcomes, and immune effect of neoadjuvant stereotactic radiation (Neo-SAbR) followed by radical nephrectomy and thrombectomy (RN-IVCT).

Methods And Materials: These are results from the safety lead-in portion of a single-arm phase 1 and 2 trial. Patients with kidney cancer (renal cell carcinoma [RCC]) and inferior vena cava (IVC) tumor thrombus (TT) underwent Neo-SAbR (40 Gy in 5 fractions) to the IVC-TT followed by open RN-IVCT. Absence of grade 4 to 5 adverse events (AEs) within 90 days of RN-IVCT was the primary endpoint. Exploratory studies included pathologic and immunologic alterations attributable to SAbR.

Results: Six patients were included in the final analysis. No grade 4 to 5 AEs were observed. A total of 81 AEs were reported within 90 days of surgery: 73% (59/81) were grade 1, 23% (19/81) were grade 2, and 4% (3/81) were grade 3. After a median follow-up of 24 months, all patients are alive. One patient developed de novo metastatic disease. Of 3 patients with metastasis at diagnosis, 1 had a complete and another had a partial abscopal response without the concurrent use of systemic therapy. Neo-SABR led to decreased Ki-67 and increased PD-L1 expression in the IVC-TT. Inflammatory cytokines and autoantibody titers reflecting better host immune status were observed in patients with nonprogressive disease.

Conclusions: Neo-SAbR followed by RN-IVCT for RCC IVC-TT is feasible and safe. Favorable host immune environment correlated with abscopal response to SABR and RCC relapse-free survival, though direct causal relation to SABR has yet to be established.
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http://dx.doi.org/10.1016/j.ijrobp.2021.01.054DOI Listing
February 2021

Novel, emerging and provisional renal entities: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

Mod Pathol 2021 Feb 1. Epub 2021 Feb 1.

Department of Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in renal neoplasia, particularly focusing on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. In the era of evolving histo-molecular classification of renal neoplasia, morphology is still key. However, entities (or groups of entities) are increasingly characterized by specific molecular features, often associated either with recognizable, specific morphologies or constellations of morphologies and corresponding immunohistochemical profiles. The correct diagnosis has clinical implications leading to better prognosis, potential clinical management with targeted therapies, may identify hereditary or syndromic associations, which may necessitate appropriate genetic testing. We hope that this undertaking will further facilitate the identification of these entities in practice. We also hope that this update will bring more clarity regarding the evolving classification of renal neoplasia and will further reduce the category of "unclassifiable renal carcinomas/tumors". We propose three categories of novel entities: (1) "Novel entity", validated by multiple independent studies; (2) "Emerging entity", good compelling data available from at least two or more independent studies, but additional validation is needed; and (3) "Provisional entity", limited data available from one or two studies, with more work required to validate them. For some entities initially described using different names, we propose new terminologies, to facilitate their recognition and to avoid further diagnostic dilemmas. Following these criteria, we propose as novel entities: eosinophilic solid and cystic renal cell carcinoma (ESC RCC), renal cell carcinoma with fibromyomatous stroma (RCC FMS) (formerly RCC with leiomyomatous or smooth muscle stroma), and anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC). Emerging entities include: eosinophilic vacuolated tumor (EVT) and thyroid-like follicular renal cell carcinoma (TLFRCC). Finally, as provisional entities, we propose low-grade oncocytic tumor (LOT), atrophic kidney-like lesion (AKLL), and biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC).
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http://dx.doi.org/10.1038/s41379-021-00737-6DOI Listing
February 2021

The Evolution of Angiogenic and Inflamed Tumors: The Renal Cancer Paradigm.

Cancer Cell 2020 12 5;38(6):771-773. Epub 2020 Nov 5.

Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Gene expression analyses have identified subtypes of conventional renal cell carcinoma broadly distributed into angiogenic and proliferative/ immunogenic clades. Integration with genomic and functional experiments in animal models yields an evolutionary model. Evolutionary trajectories illustrate remarkable plasticity, particularly for a tumor that typically begins with inactivation of a single gene.
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http://dx.doi.org/10.1016/j.ccell.2020.10.021DOI Listing
December 2020

Acute interstitial nephritis, a potential predictor of response to immune checkpoint inhibitors in renal cell carcinoma.

J Immunother Cancer 2020 10;8(2)

Department of Internal Medicine, University of Texas Southwestern, Dallas, Texas, USA

Immune checkpoint inhibitors (ICIs) such as nivolumab and ipilimumab have improved outcomes in metastatic renal cell carcinoma (mRCC) patients, but they are also associated with immune-related adverse events (irAEs). As observed in melanoma, we hypothesized that patients experiencing an autoimmune reaction directed against the tissue of origin may be more likely to benefit from ICI. Specifically, we asked whether patients with immune-related acute interstitial nephritis (irAIN) exhibited improved outcomes. Using Kidney Cancer Explorer (KCE), a data portal and i2b2-based central database for clinical, pathological and experimental genetic data, we systematically identified all patients with mRCC at UT Southwestern Medical Center (UTSW) from 2014-2018 who received at least one dose of ICI. More recent cases were identified through a provider query. We extracted creatinine (Cr) values at baseline and over the entirety of each patient ICI treatment course using KCE. Patients with ≥ 1.5-fold Cr increase over baseline were investigated. The likelihood of irAIN was determined based on the work-up (biopsy, if available), or by clinical criteria (timing of kidney injury, exclusion of other etiologies, treatment with immunosuppressants and response). We identified 177 mRCC patients who received at least one dose of ICI, 36 of whom had ≥ 1.5-fold increase in Cr over baseline while on treatment. Of those, two had biopsy-proven irAIN and one was clinically diagnosed, resulting in an incidence of 1.7%. One additional biopsy-proven case past 2018 was identified through a provider query, for a total of four patients. Two received combination nivolumab and ipilimumab in the first line, whereas the remaining received nivolumab after first line therapy. irAIN onset ranged from 1.5 to 12 months. All four patients stopped ICI with recovery of renal function, at least partially, three after receiving systemic steroids. Notably, all four patients had a deep response. In conclusion, irAIN is a rare event, but it may portend a higher likelihood of response. One possible explanation is antigenic overlap between normal renal tubular cells and tumor cells.
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http://dx.doi.org/10.1136/jitc-2020-001198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607606PMC
October 2020

Anticancer Efficacy of Oral Docetaxel Nanoformulation for Metronomic Chemotherapy in Metastatic Lung Cancer.

J Biomed Nanotechnol 2020 May;16(5):583-593

Metronomic chemotherapy, giving low doses of chemotherapeutics (e.g., docetaxel) on a frequent schedule over a long time, may improve outcomes and reduce side effects for cancer patients. Oral medications are vital for applying metronomic chemotherapy. However, low solubility, low absorption, low drug availability in the targeted tissue, and side effects limit the development of oral chemotherapeutics. Many chemotherapeutics are intravenously delivered. In this work, we developed a new docetaxel granule that produces docetaxel-loaded self-assembled nanoparticle (180 nm) upon contact with water. The process of manufacturing docetaxel granules is scalable in industrial settings. The lung selectivity of docetaxel granule was observed in animals. The mechanistic studies demonstrated the nanoparticle bound with red blood cells, which selectively delivers docetaxel to the lungs. Finally, docetaxel granule (5 mg/kg twice per week) can profoundly inhibit the tumor growth of lung-metastatic cancer xenograft model over 24 days. The material-based lungselective oral nanoformulation provides an opportunity for conventionally intravenous chemotherapy drugs to be easily applied in oral administration for metronomic chemotherapy for cancer patients with lung cancers.
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http://dx.doi.org/10.1166/jbn.2020.2925DOI Listing
May 2020

Real-World Application of Pre-Orchiectomy miR-371a-3p Test in Testicular Germ Cell Tumor Management.

J Urol 2021 Jan 28;205(1):137-144. Epub 2020 Aug 28.

Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.

Purpose: Current serum tumor markers for testicular germ cell tumor are limited by low sensitivity. Growing evidence supports the use of circulating miR-371a-3p as a superior marker for malignant (viable) germ cell tumor management. We evaluated the real-world application of serum miR-371a-3p levels in detecting viable germ cell tumor among patients undergoing partial or radical orchiectomy.

Materials And Methods: Serum samples were collected from 69 consecutive patients before orchiectomy. Performance characteristics of serum miR-371a-3p were compared with conventional serum tumor markers (⍺-fetoproteinβ-human chorionic gonadotropinlactate dehydrogenase) between patients with viable germ cell tumor and those without viable germ cell tumor on orchiectomy pathology. Relative miR-371a-3p levels were correlated with clinical course. The Kruskal-Wallis test and linear and ordinal regression models were used for analysis.

Results: For detecting viable germ cell tumor, combined conventional serum tumor markers had a specificity of 100%, sensitivity of 58% and AUC of 0.79. The miR-371a-3p test showed a specificity of 100%, sensitivity of 93% and AUC of 0.978. Median relative expression of miR-371a-3p in viable germ cell tumor cases was more than 6,800-fold higher than in those lacking viable germ cell tumor. miR-371a-3p levels correlated with composite stage (p=0.006) and, among composite stage I cases, independently associated with embryonal carcinoma percentage (p=0.0012) and tumor diameter (p <0.0001). Six patients underwent orchiectomy after chemotherapy and were correctly predicted to have presence or absence of viable germ cell tumor by the miR-371a-3p test.

Conclusions: If validated, the miR-371a-3p test can be used in conjunction with conventional serum tumor markers to aid clinical decision making. A positive miR-371a-3p test in patients after preoperative chemotherapy or with solitary testes could potentially guide subsequent orchiectomy or observation.
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http://dx.doi.org/10.1097/JU.0000000000001337DOI Listing
January 2021

Basic Histopathologic Assessment of Germ Cell Tumors for Clinic and Research.

Methods Mol Biol 2021 ;2195:1-11

Department of Pathology, University of Texas Southwestern Medical Center and Children's Health, Dallas, TX, USA.

This chapter introduces the macroscopic and light microscopic features of testicular germ cell tumors (GCT) commonly encountered in clinical practice. Accurate diagnosis of these histologically diverse neoplasms is essential not only for clinical management but also for serving as the basis for interpretation of research findings. We will focus on general histopathologic concepts and discuss the use of immunohistochemistry (IHC) as an aid to the diagnosis.
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http://dx.doi.org/10.1007/978-1-0716-0860-9_1DOI Listing
March 2021

Epigenetic silencing of the ubiquitin ligase subunit FBXL7 impairs c-SRC degradation and promotes epithelial-to-mesenchymal transition and metastasis.

Nat Cell Biol 2020 09 24;22(9):1130-1142. Epub 2020 Aug 24.

Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA.

Epigenetic plasticity is a pivotal factor that drives metastasis. Here, we show that the promoter of the gene that encodes the ubiquitin ligase subunit FBXL7 is hypermethylated in advanced prostate and pancreatic cancers, correlating with decreased FBXL7 mRNA and protein levels. Low FBXL7 mRNA levels are predictive of poor survival in patients with pancreatic and prostatic cancers. FBXL7 mediates the ubiquitylation and proteasomal degradation of active c-SRC after its phosphorylation at Ser 104. The DNA-demethylating agent decitabine recovers FBXL7 expression and limits epithelial-to-mesenchymal transition and cell invasion in a c-SRC-dependent manner. In vivo, FBXL7-depleted cancer cells form tumours with a high metastatic burden. Silencing of c-SRC or treatment with the c-SRC inhibitor dasatinib together with FBXL7 depletion prevents metastases. Furthermore, decitabine reduces metastases derived from prostate and pancreatic cancer cells in a FBXL7-dependent manner. Collectively, this research implicates FBXL7 as a metastasis-suppressor gene and suggests therapeutic strategies to counteract metastatic dissemination of pancreatic and prostatic cancer cells.
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http://dx.doi.org/10.1038/s41556-020-0560-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484425PMC
September 2020

SPARC is a key mediator of TGF-β-induced renal cancer metastasis.

J Cell Physiol 2021 Mar 11;236(3):1926-1938. Epub 2020 Aug 11.

Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Aberrant expression of transforming growth factor-β1 (TGF-β1) is associated with renal cell carcinoma (RCC) progression by inducing cancer metastasis. However, the downstream effector(s) in TGF-β signaling pathway is not fully characterized. In the present study, the elevation of secreted protein acidic and rich in cysteine (SPARC) as a TGF-β regulated gene in RCC was identified by applying differentially expressed gene analysis and microarray analysis, we further confirmed this result in several RCC cell lines. Clinically, the expression of these two genes is positively correlated in RCC patient specimens. Furthermore, elevated SPARC expression is found in all the subtypes of RCC and positively correlated with the RCC stage and grade. In contrast, SPARC expression is inversely correlated with overall and disease-free survival of patients with RCC, suggesting SPARC as a potent prognostic marker of RCC patient survival. Knocking down SPARC significantly inhibits RCC cell invasion and metastasis both in vitro and in vivo. Similarly, in vitro cell invasion can be diminished by using a specific monoclonal antibody. Mechanistically, SPARC activates protein kinase B (AKT) pathway leading to elevated expression of matrix metalloproteinase-2 that can facilitate RCC invasion. Altogether, our data support that SPARC is a critical role of TGF-β signaling network underlying RCC progression and a potential therapeutic target as well as a prognostic marker.
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http://dx.doi.org/10.1002/jcp.29975DOI Listing
March 2021

Prospective performance of clear cell likelihood scores (ccLS) in renal masses evaluated with multiparametric magnetic resonance imaging.

Eur Radiol 2021 Jan 8;31(1):314-324. Epub 2020 Aug 8.

Department of Urology, University of Texas Southwestern, Dallas, TX, USA.

Objectives: Solid renal masses have unknown malignant potential with commonly utilized imaging. Biopsy can offer a diagnosis of cancer but has a high non-diagnostic rate and complications. Reported use of multiparametric magnetic resonance imaging (mpMRI) to diagnose aggressive histology (i.e., clear cell renal cell carcinoma (ccRCC)) via a clear cell likelihood score (ccLS) was based on retrospective review of cT1a tumors. We aim to retrospectively assess the diagnostic performance of ccLS prospectively assigned to renal masses of all stages evaluated with mpMRI prior to histopathologic evaluation.

Methods: In this retrospective cohort study from June 2016 to November 2019, 434 patients with 454 renal masses from 2 institutions with heterogenous patient populations underwent mpMRI with prospective ccLS assignment and had pathologic diagnosis. ccLS performance was assessed by contingency table analysis. The association between ccLS and ccRCC was assessed with logistic regression.

Results: Mean age and tumor size were 60 ± 13 years and 5.4 ± 3.8 cm. Characteristics were similar between institutions except for patient age and race (both p < 0.001) and lesion laterality and histology (both p = 0.04). The PPV of ccLS increased with each increment in ccLS (ccLS1 5% [3/55], ccLS2 6% [3/47], ccLS3 35% [20/57], ccLS4 78% [85/109], ccLS5 93% [173/186]). Pooled analysis for ccRCC diagnosis revealed sensitivity 91% (258/284), PPV 87% (258/295) for ccLS ≥ 4, and specificity 56% (96/170), NPV 94% (96/102) for ccLS ≤ 2. Diagnostic performance was similar between institutions.

Conclusions: We confirm the optimal diagnostic performance of mpMRI to identify ccRCC in all clinical stages. High PPV and NPV of ccLS can help inform clinical management decision-making.

Key Points: • The positive predictive value of the clear cell likelihood score (ccLS) for detecting clear cell renal cell carcinoma was 5% (ccLS1), 6% (ccLS2), 35% (ccLS3), 78% (ccLS4), and 93% (ccLS5). Sensitivity of ccLS ≥ 4 and specificity of ccLS ≤ 2 were 91% and 56%, respectively. • When controlling for confounding variables, ccLS is an independent risk factor for identifying clear cell renal cell carcinoma. • Utilization of the ccLS can help guide clinical care, including the decision for renal mass biopsy, reducing the morbidity and risk to patients.
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http://dx.doi.org/10.1007/s00330-020-07093-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755825PMC
January 2021

First Do No Harm: A Cautious, Risk-adapted Approach to Testicular Cancer Patients.

Rev Urol 2020 ;22(2):85-89

Department of Urology, University of Texas Southwestern Medical Center Dallas, TX.

Current guidelines regarding treatment for germ-cell tumors (GCTs) emphasizes cautious progression focusing on stage-specific treatments. Presented herein is the case of a 30-year-old man who, through monitoring of serum alpha-fetoprotein (AFP) levels and surveillance imaging, avoided excessive treatment. This case demonstrates how an experienced clinician, familiar with natural history of GCTs, can appropriately classify level of risk and allow a patient to preserve natural fertility. Furthermore, we highlight the potential for miRNA analysis in staging and management of GCTs. This case serves to underscore the importance of acting with caution in the pursuit of the best outcome for our patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393682PMC
January 2020

Magnetic Resonance Imaging Radiomics Analyses for Prediction of High-Grade Histology and Necrosis in Clear Cell Renal Cell Carcinoma: Preliminary Experience.

Clin Genitourin Cancer 2021 Feb 23;19(1):12-21.e1. Epub 2020 May 23.

Department of Radiology, UT Southwestern Medical Center, Dallas, TX; Department of Urology, UT Southwestern Medical Center, Dallas, TX; Kidney Cancer Program, UT Southwestern Medical Center, Dallas, TX; Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX. Electronic address:

Introduction: Percutaneous renal mass biopsy results can accurately diagnose clear cell renal cell carcinoma (ccRCC); however, their reliability to determine nuclear grade in larger, heterogeneous tumors is limited. We assessed the ability of radiomics analyses of magnetic resonance imaging (MRI) to predict high-grade (HG) histology in ccRCC.

Patients And Methods: Seventy patients with a renal mass underwent 3 T MRI before surgery between August 2012 and August 2017. Tumor length, first-order statistics, and Haralick texture features were calculated on T2-weighted and dynamic contrast-enhanced (DCE) MRI after manual tumor segmentation. After a variable clustering algorithm was applied, tumor length, washout, and all cluster features were evaluated univariably by receiver operating characteristic curves. Three logistic regression models were constructed to assess the predictability of HG ccRCC and then cross-validated.

Results: At univariate analysis, area under the curve values of length, and DCE texture cluster 1 and cluster 3 for diagnosis of HG ccRCC were 0.7 (95% confidence interval [CI], 0.58-0.82, false discovery rate P = .008), 0.72 (95% CI, 0.59-0.84, false discovery rate P = .004), and 0.75 (95% CI, 0.63-0.87, false discovery rate P = .0009), respectively. At multivariable analysis, area under the curve for model 1 (tumor length only), model 2 (length + DCE clusters 3 and 4), and model 3 (DCE cluster 1 and 3) for diagnosis of HG ccRCC were 0.67 (95% CI, 0.54-0.79), 0.82 (95% CI, 0.71-0.92), and 0.81 (95% CI, 0.70-0.91), respectively.

Conclusion: Radiomics analysis of MRI images was superior to tumor size for the prediction of HG histology in ccRCC in our cohort.
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http://dx.doi.org/10.1016/j.clgc.2020.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680717PMC
February 2021

Primary Renal Sarcoma With Gene Fusion in an 18-Year-Old Male: A Rare Lesion With a Diagnostic Quandary.

Int J Surg Pathol 2021 Apr 10;29(2):194-197. Epub 2020 Jul 10.

Department of Pathology, 89063UT Southwestern Medical Center, Dallas TX, USA.

Primary renal sarcoma with gene fusion is a rare tumor with only 7 cases reported in the English literature. The morphologic features of this tumor strikingly overlap with clear cell sarcoma of the kidney and synovial sarcoma. Accurate diagnosis can be challenging. In this article, we report a case of an 18-year-old male who presented with hematuria. Subsequent imaging study showed a left renal mass with level II (infra-hepatic) inferior vena cava thrombus, which was resected. Detailed pathologic findings and immunohistochemical and molecular studies revealed an ovoid to spindle cell renal mass with a gene fusion.
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http://dx.doi.org/10.1177/1066896920941087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7800313PMC
April 2021

Summary From the First Kidney Cancer Research Summit, September 12-13, 2019: A Focus on Translational Research.

J Natl Cancer Inst 2021 Mar;113(3):234-243

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Kidney cancer is one of the 10 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 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.
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http://dx.doi.org/10.1093/jnci/djaa064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936057PMC
March 2021

Corrigendum to ''Ontological analyses reveal clinically-significant clear cell renal cell carcinoma subtypes with convergent evolutionary trajectories into an aggressive type'' [EBioMedicine 51 (2020) 102526].

EBioMedicine 2020 05 24;55:102707. Epub 2020 Apr 24.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2020.102707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184150PMC
May 2020

Pancreatic tropism of metastatic renal cell carcinoma.

JCI Insight 2020 04 9;5(7). Epub 2020 Apr 9.

Kidney Cancer Program, Simmons Comprehensive Cancer Center.

Renal cell carcinoma (RCC) is characterized by a particularly broad metastatic swath, and, enigmatically, when the pancreas is a destination, the disease is associated with improved survival. Intrigued by this observation, we sought to characterize the clinical behavior, therapeutic implications, and underlying biology. While pancreatic metastases (PM) are infrequent, we identified 31 patients across 2 institutional cohorts and show that improved survival is independent of established prognostic variables, that these tumors are exquisitely sensitive to antiangiogenic agents and resistant to immune checkpoint inhibitors (ICIs), and that they are characterized by a distinctive biology. Primary tumors of patients with PM exhibited frequent PBRM1 mutations, 3p loss, and 5q amplification, along with a lower frequency of aggressive features such as BAP1 mutations and loss of 9p, 14q, and 4q. Gene expression analyses revealed constrained evolution with remarkable uniformity, reduced effector T cell gene signatures, and increased angiogenesis. Similar findings were observed histopathologically. Thus, RCC metastatic to the pancreas is characterized by indolent biology, heightened angiogenesis, and an uninflamed stroma, likely underlying its good prognosis, sensitivity to antiangiogenic therapies, and refractoriness to ICI. These data suggest that metastatic organotropism may be an indicator of a particular biology with prognostic and treatment implications for patients.
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http://dx.doi.org/10.1172/jci.insight.134564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205259PMC
April 2020

PTRF independently predicts progression and survival in multiracial upper tract urothelial carcinoma following radical nephroureterectomy.

Urol Oncol 2020 05 18;38(5):496-505. Epub 2019 Dec 18.

Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan. Electronic address:

Objectives: Polymerase I and transcript release factor (PTRF) has been implicated in cancer biology but its role in upper tract urothelial carcinoma (UTUC) is unknown. From a pilot transcriptome, we identified PTRF was significantly upregulated in high stage UTUC. Bladder cancer transcriptome from The Cancer Genome Atlas (TCGA) supported our finding and high PTRF level also predicted poor survival. We, therefore, investigated the correlation of PTRF with patients' clinicopathologic characteristics and outcomes in a multiracial UTUC cohort.

Materials And Methods: By immunohistochemical staining, PTRF expression was determined using H-score. PTRF expression of 575 UTUCs from 8 institutions, including 118 Asians and 457 Caucasians, was compared with various clinicopathologic parameters. Human urothelial cancer cell lines were used to evaluate the level of PTRF protein and mRNA expression, and PTRF transcript level was assessed in fresh samples from 12 cases of the cohort. The impact of PTRF expression on disease progression, cancer-specific death and overall mortality was also examined.

Results: High PTRF expression was significantly associated with multifocality (P = 0.023), high pathologic tumor stage (P < 0.00001), nonurothelial differentiation (P = 0.035), lymphovascular invasion (P = 0.003) and lymph node metastasis (P = 0.031). PTRF mRNA expression was also markedly increased in advanced stage UTUC (P = 0.0003). High PTRF expressing patients had consistently worse outcomes than patients with low PTRF expression regardless of demographic variation (all P < 0.005). In multivariate analysis, high PTRF expression was an independent predictor for progression-free survival (hazard ratio [HR] 1.70, 95% confidence interval [CI] 1.07-2.69, P = 0.025), cancer-specific survival (HR 2.09, 95% CI 1.28-3.42, P = 0.003), and overall survival (HR 2.04, 95% CI 1.33-3.14, P = 0.001).

Conclusions: Results indicate that PTRF is a predictive biomarker for progression and survival and an independent prognosticator of UTUC. Elevated PTRF could probably propel clinically aggressive disease and serve as a potential therapeutic target for UTUC.
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http://dx.doi.org/10.1016/j.urolonc.2019.11.010DOI Listing
May 2020

Ontological analyses reveal clinically-significant clear cell renal cell carcinoma subtypes with convergent evolutionary trajectories into an aggressive type.

EBioMedicine 2020 01 16;51:102526. Epub 2019 Dec 16.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States. Electronic address:

Background: Clear cell renal cell carcinoma (ccRCC) is a particularly challenging tumor type because of its extensive phenotypic variability as well as intra-tumoral heterogeneity (ITH). Clinically, this complexity has been reduced to a handful of pathological variables such as stage, grade and necrosis, but these variables fail to capture the breadth of the disease. How different phenotypes affect patient prognosis and influence therapeutic response is poorly understood. Extensive ITH illustrates remarkable plasticity, providing a framework to study tumor evolution. While multiregional genomic analyses have shown evolution from an ancient clone that acquires metastatic competency over time, these studies have been conducted agnostic to morphological cues and phenotypic plasticity.

Methods: We established a systematic ontology of ccRCC phenotypic variability by developing a multi-scale framework along three fundamental axes: tumor architecture, cytology and the microenvironment. We defined 33 parameters, which we comprehensively evaluated in 549 consecutive ccRCCs retrospectively. We systematically evaluated the impact of each parameter on patient outcomes, and assessed their contribution through multivariate analyses. We measured therapeutic impact in the context of anti-angiogenic therapies. We applied dimensionality reduction by t-distributed stochastic neighbor embedding (t-SNE) algorithms to tumor architectures for the study of tumor evolution superimposing tumor size and grade vectors. Evolutionary models were refined through empirical analyses of directed evolution of tumor intravascular extensions, and metastatic competency (as determined by tumor reconstitution in a heterologous host).

Findings: We discovered several novel ccRCC phenotypes, developed an integrated taxonomy, and identified features that improve current prognostic models. We identified a subset of ccRCCs refractory to anti-angiogenic therapies. We developed a model of tumor evolution, which revealed converging evolutionary trajectories into an aggressive type.

Interpretation: This work serves as a paradigm for deconvoluting tumor complexity and illustrates how morphological analyses can improve our understanding of ccRCC pleiotropy. We identified several subtypes associated with aggressive biology, and differential response to targeted therapies. By analyzing patterns of spatial and temporal co-occurrence, intravascular tumor extensions and metastatic competency, we were able to identify distinct trajectories of convergent phenotypic evolution.
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http://dx.doi.org/10.1016/j.ebiom.2019.10.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000318PMC
January 2020

HIF-2 Complex Dissociation, Target Inhibition, and Acquired Resistance with PT2385, a First-in-Class HIF-2 Inhibitor, in Patients with Clear Cell Renal Cell Carcinoma.

Clin Cancer Res 2020 02 14;26(4):793-803. Epub 2019 Nov 14.

Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.

Purpose: The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). Although considered undruggable, structural analyses at the University of Texas Southwestern Medical Center (UTSW, Dallas, TX) identified a vulnerability in the α subunit, which heterodimerizes with HIF1β, ultimately leading to the development of PT2385, a first-in-class inhibitor. PT2385 was safe and active in a first-in-human phase I clinical trial of patients with extensively pretreated ccRCC at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control ≥4 months was achieved in 42% of patients.

Patients And Methods: We conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW ( = 10), who were treated at the phase II dose or above, involving multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNA-sequencing studies.

Results: PT2385 inhibited HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations. PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. In contrast, HIF-1 complexes were unaffected. Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E) in HIF2α, which interferes with drug binding and precluded HIF-2 complex dissociation. In addition, we identified an acquired mutation elsewhere, suggesting a possible alternate mechanism of resistance.

Conclusions: These findings demonstrate a core dependency on HIF-2 in metastatic ccRCC and establish PT2385 as a highly specific HIF-2 inhibitor in humans. New approaches will be required to target mutant HIF-2 beyond PT2385 or the closely related PT2977 (MK-6482).
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024660PMC
February 2020

Histone lysine demethylase KDM4B regulates the alternative splicing of the androgen receptor in response to androgen deprivation.

Nucleic Acids Res 2019 12;47(22):11623-11636

Department of Internal Medicine-Cardiology Division, UT Southwestern Medical Center, Dallas, TX 75390, USA.

Alternative splicing is emerging as an oncogenic mechanism. In prostate cancer, generation of constitutively active forms of androgen receptor (AR) variants including AR-V7 plays an important role in progression of castration-resistant prostate cancer (CRPC). AR-V7 is generated by alternative splicing that results in inclusion of cryptic exon CE3 and translation of truncated AR protein that lacks the ligand binding domain. Whether AR-V7 can be a driver for CRPC remains controversial as the oncogenic mechanism of AR-V7 activation remains elusive. Here, we found that KDM4B promotes AR-V7 and identified a novel regulatory mechanism. KDM4B is phosphorylated by protein kinase A under conditions that promote castration-resistance, eliciting its binding to the splicing factor SF3B3. KDM4B binds RNA specifically near the 5'-CE3, upregulates the chromatin accessibility, and couples the spliceosome to the chromatin. Our data suggest that KDM4B can function as a signal responsive trans-acting splicing factor and scaffold that recruits and stabilizes the spliceosome near the alternative exon, thus promoting its inclusion. Genome-wide profiling of KDM4B-regulated genes also identified additional alternative splicing events implicated in tumorigenesis. Our study defines KDM4B-regulated alternative splicing as a pivotal mechanism for generating AR-V7 and a contributing factor for CRPC, providing insight for mechanistic targeting of CRPC.
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http://dx.doi.org/10.1093/nar/gkz1004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145715PMC
December 2019

SCINA: A Semi-Supervised Subtyping Algorithm of Single Cells and Bulk Samples.

Genes (Basel) 2019 07 12;10(7). Epub 2019 Jul 12.

Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Advances in single-cell RNA sequencing (scRNA-Seq) have allowed for comprehensive analyses of single cell data. However, current analyses of scRNA-Seq data usually start from unsupervised clustering or visualization. These methods ignore prior knowledge of transcriptomes and the probable structures of the data. Moreover, cell identification heavily relies on subjective and possibly inaccurate human inspection afterwards. To address these analytical challenges, we developed SCINA (Semi-supervised Category Identification and Assignment), a semi-supervised model that exploits previously established gene signatures using an expectation-maximization (EM) algorithm. SCINA is applicable to scRNA-Seq and flow cytometry/CyTOF data, as well as other data of similar format. We applied SCINA to a wide range of datasets, and showed its accuracy, stability and efficiency, which exceeded most popular unsupervised approaches. SCINA discovered an intermediate stage of oligodendrocytes from mouse brain scRNA-Seq data. SCINA also detected immune cell population changes in cytometry data in a genetically-engineered mouse model. Furthermore, SCINA performed well with bulk gene expression data. Specifically, we identified a new kidney tumor clade with similarity to FH-deficient tumors (FHD), which we refer to as FHD-like tumors (FHDL). Overall, SCINA provides both methodological advances and biological insights from perspectives different from traditional analytical methods.
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http://dx.doi.org/10.3390/genes10070531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678337PMC
July 2019

Correlating Anticancer Drug Delivery Efficiency with Vascular Permeability of Renal Clearable Versus Non-renal Clearable Nanocarriers.

Angew Chem Int Ed Engl 2019 08 24;58(35):12076-12080. Epub 2019 Jul 24.

Department of Chemistry and Biochemistry, The University of Texas at Dallas, 800 W. Campbell Rd., Richardson, TX, 75080, USA.

Enhancing tumor targeting of nanocarriers has been a major strategy for advancing clinical translation of cancer nanomedicines. Herein, we report a head-to-head comparison between 5 nm renal clearable and 30 nm non-renal clearable gold nanoparticle (AuNP)-based drug delivery systems (DDSs) in the delivery of doxorubicin (DOX). While the two DDSs themselves had comparable tumor targeting, we found their different vascular permeability played an even more important role than blood retention in the delivery and intratumoral transport of DOX, of which tumor accumulation, efficacy, and therapeutic index were enhanced 2, 7, and 10-fold, respectively, for the 5 nm DDS over 30 nm one. These findings indicate that ultrahigh vascular permeability of renal clearable nanocarriers can be utilized to further improve anticancer drug delivery without the need for prolonged blood retention.
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http://dx.doi.org/10.1002/anie.201905738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416736PMC
August 2019

Current Challenges in Diagnosis and Assessment of the Response of Locally Advanced and Metastatic Renal Cell Carcinoma.

Radiographics 2019 Jul-Aug;39(4):998-1016. Epub 2019 Jun 14.

From the Department of Radiology (A.D.d.L., A.P., D.N.C., I.P.), Advanced Imaging Research Center (D.N.C., I.P.), Department of Pathology (P.K.), Department of Urology (P.K.), Kidney Cancer Program-Simmons Comprehensive Cancer Center (P.K., H.H., J.B., I.P.), and Department of Internal Medicine (H.H., J.B.), UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390.

Locally advanced and metastatic renal cell carcinoma (RCC) present a specific set of challenges to the radiologist. The detection of metastatic disease is confounded by the ability of RCC to metastasize to virtually any part of the human body long after surgical resection of the primary tumor. This includes sites not commonly included in routine surveillance, which come to light after the patient becomes symptomatic. In the assessment of treatment response, the phenomenon of tumor heterogeneity, where clone selection through systemic therapy drives the growth of potentially more aggressive phenotypes, can result in oligoprogression despite overall disease control. Finally, advances in therapy have resulted in the development of immuno-oncologic agents that may result in changes that are not adequately evaluated with conventional size-based response criteria and may even be misinterpreted as progression. This article reviews the common challenges a radiologist may encounter in the evaluation of patients with locally advanced and metastatic RCC. RSNA, 2019.
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http://dx.doi.org/10.1148/rg.2019180178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677287PMC
May 2020

PD-L1 detection using Zr-atezolizumab immuno-PET in renal cell carcinoma tumorgrafts from a patient with favorable nivolumab response.

J Immunother Cancer 2019 06 3;7(1):144. Epub 2019 Jun 3.

Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Background: Programmed death-ligand 1 (PD-L1) expression in metastatic renal cell carcinoma (RCC) correlates with a worse prognosis, but whether it also predicts responsiveness to anti-PD-1/PD-L1 therapy remains unclear. Most studies of PD-L1 are limited by evaluation in primary rather than metastatic sites, and in biopsy samples, which may not be representative. These limitations may be overcome with immuno-positron emission tomography (iPET), an emerging tool allowing the detection of cell surface proteins with radiolabeled antibodies. Here, we report iPET studies of PD-L1 in a preclinical tumorgraft model of clear cell RCC (ccRCC) from a patient who had a favorable response to anti-PD-1 therapy.

Case Presentation: A 49-year-old man underwent a cytoreductive nephrectomy in 2017 of a right kidney tumor invading into the adrenal gland that was metastatic to the lungs and a rib. Histological analyses revealed a ccRCC of ISUP grade 4 with extensive sarcomatoid features. IMDC risk group was poor. Within two hours of surgery, a tumor sample was implanted orthotopically into NOD/SCID mice. Consistent with an aggressive tumor, a renal mass was detected 18 days post-implantation. Histologically, the tumorgraft showed sarcomatoid differentiation and high levels of PD-L1, similar to the patient's tumor. PD-L1 was evaluated in subsequently transplanted mice using iPET and the results were compared to control mice implanted with a PD-L1-negative tumor. We labeled atezolizumab, an anti-PD-L1 antibody with a mutant Fc, with zirconium-89. iPET revealed significantly higher Zr-atezolizumab uptake in index than control tumorgrafts. The patient was treated with high-dose IL2 initially, and subsequently with pazopanib, with rapidly progressive disease, but had a durable response with nivolumab.

Conclusions: To our knowledge, this is the first report of non-invasive detection of PD-L1 in renal cancer using molecular imaging. This study supports clinical evaluation of iPET to identify RCC patients with tumors deploying the PD-L1 checkpoint pathway who may be most likely to benefit from PD-1/PD-L1 disrupting drugs.
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http://dx.doi.org/10.1186/s40425-019-0607-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545669PMC
June 2019

Activation of sphingosine kinase by lipopolysaccharide promotes prostate cancer cell invasion and metastasis via SphK1/S1PR4/matriptase.

Oncogene 2019 07 31;38(28):5580-5598. Epub 2019 May 31.

Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.

Gram-negative bacteria have been found to be a major population in prostatitis and prostate cancer (PCa) tissues. Lipopolysaccharide (LPS), a major compound of Gram-negative bacteria, with stimulatory activities in some cancer types, but has not been fully studied in PCa. In this study, we examined the effect of LPS on the invasion of PCa cells. Interestingly, LPS can enhance the invasiveness of PCa, but had no significant effect on PCa cell viability. Using protease inhibitor screening and biochemical analyses, matriptase, a member of the membrane-anchored serine protease family, is found to play a key role in LPS-induced PCa cell invasion. Mechanistically, Toll-like receptor 4 (TLR4, LPS receptor)-sphingosine kinase 1 (SphK1) signaling underlies LPS-induced matriptase activation and PCa cell invasion. Specifically, LPS induced the S225 phosphorylation of SphK1 and the translocation of SphK1 to plasma membrane, leading to the production of sphingosine 1-phosphate (S1P), ERK1/2 and matriptase activation via S1P receptor 4 (S1PR4). This phenomenon is further validated using the patient-derived explant (PDE) model. Indeed, there is a significant correlation among the elevated SphK1 levels, the Gleason grades of PCa specimens, and the poor survival of PCa patients. Taken together, this study demonstrates a potential impact of LPS on PCa progression. Our results provide not only a new finding of the role of bacterial infection in PCa progression but also potential therapeutic target(s) associated with PCa metastasis.
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http://dx.doi.org/10.1038/s41388-019-0833-3DOI Listing
July 2019

Tuning the In Vivo Transport of Anticancer Drugs Using Renal-Clearable Gold Nanoparticles.

Angew Chem Int Ed Engl 2019 06 14;58(25):8479-8483. Epub 2019 May 14.

Department of Chemistry and Biochemistry, The University of Texas at Dallas, 800 W. Campbell Rd., Richardson, TX, 75080, USA.

Precise control of in vivo transport of anticancer drugs in normal and cancerous tissues with engineered nanoparticles is key to the future success of cancer nanomedicines in clinics. This requires a fundamental understanding of how engineered nanoparticles impact the targeting-clearance and permeation-retention paradoxes in the anticancer-drug delivery. Herein, we systematically investigated how renal-clearable gold nanoparticles (AuNPs) affect the permeation, distribution, and retention of the anticancer drug doxorubicin in both cancerous and normal tissues. Renal-clearable AuNPs retain the advantages of the free drug, including rapid tumor targeting and high tumor vascular permeability. The renal-clearable AuNPs also accelerated body clearance of off-target drug via renal elimination. These results clearly indicate that diverse in vivo transport behaviors of engineered nanoparticles can be used to reconcile long-standing paradoxes in the anticancer drug delivery.
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http://dx.doi.org/10.1002/anie.201903256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555664PMC
June 2019

Downregulation of Human DAB2IP Gene Expression in Renal Cell Carcinoma Results in Resistance to Ionizing Radiation.

Clin Cancer Res 2019 07 18;25(14):4542-4551. Epub 2019 Apr 18.

Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.

Purpose: Renal cell carcinoma (RCC) is known to be highly radioresistant but the mechanisms associated with radioresistance have remained elusive. We found DOC-2/DAB2 interactive protein (DAB2IP) frequently downregulated in RCC, is associated with radioresistance. In this study, we investigated the underlying mechanism regulating radioresistance by DAB2IP and developed appropriate treatment.

Experimental Design: Several RCC lines with or without DAB2IP expression were irradiated with ionizing radiation (IR) for determining their radiosensitivities based on colony formation assay. To investigate the underlying regulatory mechanism of DAB2IP, immunoprecipitation-mass spectrometry was performed to identify DAB2IP-interactive proteins. PARP-1 expression and enzymatic activity were determined using qRT-PCR, Western blot analysis, and ELISA. ubiquitination assay was used to test PARP-1 degradation. Furthermore, mice xenograft model and patient-derived xenograft (PDX) model were used to determine the effect of combination therapy to sensitizing tumors to IR.

Results: We notice that DAB2IP-deficient RCC cells acquire IR-resistance. Mechanistically, DAB2IP can form a complex with PARP-1 and E3 ligases that is responsible for degrading PARP-1. Indeed, elevated PARP-1 levels are associated with the IR resistance in RCC cells. Furthermore, PARP-1 inhibitor can enhance the IR response of either RCC xenograft model or PDX model.

Conclusions: In this study, we unveil that loss of DAB2IP resulted in elevated PARP-1 protein is associated with IR-resistance in RCC. These results provide a new targeting strategy to improve the efficacy of radiotherapy of RCC.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635020PMC
July 2019