Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19ARF-p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.

Renal medullary carcinoma (RMC) is defined by the loss of the SMARCB1 tumor suppressor and represents one of the most aggressive kidney cancers, predominantly affecting young individuals of African descent with the sickle cell trait. RMC exhibits rapid progression, and poor response to standard therapies, with a median survival of only 13 months following diagnosis. In pursuit of more effective treatments, we launched two clinical trials specifically for patients with RMC evaluating anti-PD1 + anti-CTLA4 immune checkpoint therapy (ICT) with nivolumab + ipilimumab (ClinicalTrials.gov identifier: NCT03274258) and anti-PD1 + anti-LAG3 ICT using nivolumab + relatlimab (ClinicalTrials.gov identifier: NCT05347212). However, both trials were terminated early for futility due to resistance and hyperprogression by the established consensus Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 radiological criteria in Matos et al. Clin Cancer Res. 2020 (PMID: 31757877). Co-clinical experiments testing the same ICT regimens in our immunocompetent somatic mosaic genetically engineered mouse model (GEMM) of RMC demonstrated similar patterns of resistance and hyperprogression with ICT compared with IgG control. The combination of anti-PD1 with either anti-CTLA4 or anti-LAG3 significantly accelerated primary tumor progression and markedly increased metastatic burdens in the lung and liver of RMC mice. Comprehensive analyses, including longitudinally collected single-cell RNA sequencing from human RMC patient samples and RNA sequencing of GEMM RMC tumors revealed significant transcriptional reprogramming, enhanced tumor proliferation, activation of oncogenic pathways, and a shift toward myeloid-specific gene expression by RMC tumor cells in response to ICT. In our RMC mouse models, tumor cells have been engineered to express green fluorescent protein (GFP), enabling us to distinguish them from non-malignant mouse cells. Accordingly, multiplex immunofluorescence (mIF) revealed that tumor tissues from mice treated with ICT showed a significant increase of tumor cells co-expressing GFP and myeloid markers such as CD68, F4/80 and S100A9. Differential patterns of resistance and hyperprogression when RMC mice were treated with monotherapies targeting PD1, CTLA4, or LAG3. To counteract ICT-induced hyperprogression, we tested the CEBPB/p300 complex inhibitor IACS16898 which successfully induced tumor responses when combined with ICT in our RMC GEMM. IACS16898 treatment significantly reduced the expression of myeloid-associated markers on GFP+ tumor cells. Our study not only elucidates a novel mechanism of resistance and hyperprogression to PD1 plus either CTLA4 or LAG3 inhibition in SMARCB1-deficient cancers but also provides a foundation for targeting oncogenic and resistance pathways in RMC treated with distinct immunotherapy regimens. Jing Qian, Melinda Soeung, Xinmiao Yan, Kai Yu, Ciro Zanca, Li Zhang, Ziheng Chen, Luigi Perelli, Jianfeng Chen, Rebecca Slack Tidwell, Hania Khan, Fei Duan, Menuka Karki, Rong He, Courtney N. Le, Truong N.A. Lam, Nirjar Bhattacharya, Mariah N. Williams, David H. Peng, Rutvi Shah, I-Lin Ho, Ningping Feng, Niki Millward Zacharias, Rahul Anil Sheth, Tharakeswara K. Bathala, Priya Rao, Najat C. Daw, Durga N. Tripathi, Cheryl L. Walker, Ruiping Wang, Minghao Dang, Enyu Dai, Fuduan Peng, Yunhe Liu, Akshaya S. Jadhav, Wenhua Lang, Claudio A. Arrechedera, Leticia Campos Clemente, Hsinyi Lu, Cara L. Haymaker, Ignacio I. Wistuba, Andrew Futreal, Andrea Viale, Timothy Heffernan, Giulio F. Draetta, Nazir M. Tannir, Jianjun Gao, Linghua Wang, Giannicola Genovese, Pavlos Msaouel. Unravelling the mechanisms of resistance and hyperprogression of renal medullary carcinoma to immune checkpoint therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 646.

PURPOSE:Renal medullary carcinoma (RMC) is a highly aggressive malignancy defined by the loss of the SMARCB1 tumor suppressor. It mainly affects young individuals of African descent with sickle cell trait, and it is resistant to conventional therapies used for other renal cell carcinomas. This study aimed to identify potential biomarkers for early detection and disease monitoring of RMC. EXPERIMENTAL DESIGN:Integrated profiling of primary untreated RMC tumor tissues and paired adjacent kidney controls was performed using RNA sequencing and histone chromatin immunoprecipitation sequencing. The expression of serum cancer antigen 125 (CA-125), was prospectively evaluated in 47 patients with RMC. Functional studies were conducted in RMC cell lines to assess the effects of SMARCB1 reexpression. RESULTS:MUC16, encoding for CA-125, was identified as one of the top upregulated genes in RMC tissues, with concomitant enrichment of active histone marks H3K4me3 and H3K27ac at its promoter. Elevated serum CA-125 levels were found in 31 of 47 (66%) patients with RMC and correlated significantly with metastatic tumor burden (P = 0.03). Functional studies in RMC cell lines demonstrated that SMARCB1 reexpression significantly reduced MUC16 expression. CONCLUSIONS:The correlation between serum CA-125 levels and metastatic burden suggests that CA-125 is a clinically relevant biomarker for RMC. These findings support further exploration of CA-125 for disease monitoring and targeted therapeutics in RMC.

Polymer matrix composites (PMCs) are consisting of reinforcing fillers embedded into polymer matrices. Nowadays, PMCs are widely used as structural materials and replacing the traditional materials. These are used in automotive, railways, missiles and marine industries, defence, aerospace and other applications. Because of the increasing demand for lightweight, corrosion and chemically resistant as well as electrically insulating and high flame retardant materials, the global composite market is growing at a Compound Annual Growth Rate (CAGR) of 4.1% from 2018 to 2023. This chapter describes the information regarding the reinforcing fillers and matrices (both thermoplastics and thermosetting) as well as the composite manufacturing processes and applications. Polymer nanocomposites are also discussed. This chapter also includes a special topic of self-healing composites including its prospects and technological demand.

Abstract Renal medullary carcinoma (RMC) is a rare but highly aggressive SMARCB1-deficient kidney cancer that mainly afflicts young individuals of African descent and has few treatment options. Despite the advancements in immune checkpoint therapy (ICT) for other kidney cancers, its efficacy against RMC remains elusive. The majority of RMC patients treated with ICT have experienced aggressively progressive disease as the best response. This hyperprogression was confirmed in our prospective clinical trial of nivolumab plus ipilimumab specifically designed for RMC patients (ClinicalTrials.gov identifier: NCT03274258). To elucidate the mechanisms of resistance to ICT in RMC, we generated high-quality single-cell RNA sequencing data on 23,880 cells from 7 patients at baseline and 2 patients exhibiting hyperprogression after ICT intervention. Our analysis revealed that RMC tumor cells undergo a distinct transcriptional reconfiguration following ICT therapy. This reconfiguration is manifested by upregulation of S100A9 and activation of the MEK/ERK pathway, indicating that RMC tumor cells adopt myeloid-affiliated transcriptional circuits, potentially promoting cell proliferation and leading to hyperprogression. Using a mouse model of RMC, we further demonstrated in a controlled setting that ICT causes hyperprogressive disease via activation of MEK/ERK pathway and an increase of S100A9 positive tumor cells. This process can be reversed by inhibiting master regulators of this “myeloid mimicry” mechanism, such as the CEBPB/p300 complex in our mouse model of RMC, thus restoring sensitivity to ICT. These findings provide novel insights into RMC resistance to ICT and suggest valuable directions for the development of therapeutic strategies. Citation Format: Melinda Soeung, Xinmiao Yan, Li Zhang, Luigi Perelli, Jianfeng Chen, Becky Slack Tidwell, Hania Khan, Courtney N. Le, Truong N. Lam, Nirjar Bhattacharya, Rutvi Shah, I-Lin Ho, Ziheng Chen, Sebastian R. Lundgren, Ningping Feng, Ciro Zanca, Menuka Karki, Niki Marie Zacharias Millward, Rong He, Rahul A. Sheth, Bathala K. Tharakeswara, Priya Rao, Najat C. Daw, Durga N. Tripathi, Cheryl L. Walker, Guangchun Han, Yanshuo Chu, Ruiping Wang, Minghao Dang, Enyu Dai, Fuduan Peng, Yunhe Liu, Akshaya S. Jadhav, Wenhua Lang, Claudio A. Arrechedera, Leticia Campos Clemente, Edwin R. Parra-Cuentas, Hsinyi Lu, Cara Haymaker, Ignacio I. Wistuba, Andrew Futreal, Timothy Heffernan, Andrea Viale, Giulio F. Draetta, Nizar M. Tannir, Jianjun Gao, Linghua Wang, Giannicola Genovese, Pavlos Msaouel. Hyperprogression due to myeloid mimicry in renal medullary carcinoma treated with nivolumab plus ipilimumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2702.

SETD2 loss promotes chromosomal abnormalities.

Micronuclei are a Common Feature among ccRCC-derived Cell Lines.

BackgroundRenal medullary carcinoma (RMC) is a highly aggressive cancer in need of new therapeutic strategies. The neddylation pathway can protect cells from DNA damage induced by the platinum-based chemotherapy used in RMC. We investigated if neddylation inhibition with pevonedistat will synergistically enhance antitumour effects of platinum-based chemotherapy in RMC. MethodsWe evaluated the IC50 concentrations of the neddylation-activating enzyme inhibitor pevonedistat in vitro in RMC cell lines. Bliss synergy scores were calculated using growth inhibition assays following treatment with varying concentrations of pevonedistat and carboplatin. Protein expression was assessed by western blot and immunofluorescence assays. The efficacy of pevonedistat alone or in combination with platinum-based chemotherapy was evaluated in vivo in platinum-naive and platinum-experienced patient-derived xenograft (PDX) models of RMC. ResultsThe RMC cell lines demonstrated IC50 concentrations of pevonedistat below the maximum tolerated dose in humans. When combined with carboplatin, pevonedistat demonstrated a significant in vitro synergistic effect. Treatment with carboplatin alone increased nuclear ERCC1 levels used to repair the interstrand crosslinks induced by platinum salts. Conversely, the addition of pevonedistat to carboplatin led to p53 upregulation resulting in FANCD2 suppression and reduced nuclear ERCC1 levels. The addition of pevonedistat to platinum-based chemotherapy significantly inhibited tumour growth in both platinum-naive and platinum-experienced PDX models of RMC (p < .01). ConclusionsOur results suggest that pevonedistat synergises with carboplatin to inhibit RMC cell and tumour growth through inhibition of DNA damage repair. These findings support the development of a clinical trial combining pevonedistat with platinum-based chemotherapy for RMC.

Multiple Setd2w/f MEF clones display reduced aTubK40me3 protein (A) and relative Setd2 mRNA (B) levels

Present embodiment is an account of work done on impregnation of thermoplastic polyether imide (PEI) [ULTEM 1000] into high-temperature biphenyl-based phthalonitrile (PN) thermosetting resin to form a semi-interpenetrating network (s-IPN) in order to find an optimum composition with little compromise on glass transition temperature (Tg) and thermal stability of base resin system. The PEI has been cured with PN resin in varied ratios of 5–30 mass% in arithmetic progression to study its effect on thermal and physical properties. Fourier transform infrared spectroscopy, differential scanning calorimetry and thermos-gravimetric (TG) measurements of the s-IPN compositions were carried out to assess the extent of curing, curing enthalpy, glass transition (Tg), thermal stability and char yield, respectively. The dynamic mechanical analysis (DMA), measurements were done to ascertain the effect of PEI component in PN system on its storage modulus, Tg under dynamic load with respect to temperature. PN95 composition having PN/PEI ratio in 95:05 stoichiometry has demonstrated the best desirable properties with respect to PEI content with least compromise in Tg temperature. More than 5 mass% PEI has resulted in drastic change in Tg of s-IPN from > 673 K to 525 K in case of 10 mass% PEI as evaluated by DMA. The morphological analysis of 30% PEI-containing s-IPN showed interesting cross-linked patterns probably formed by the fibrillar orientation of the thermoplastic resin in the PN matrix.

CENP/B and CREST status of micronuclei

Reduced SETD2 levels promote genomic instability without compromising H3K36 trimethylation.

You have accessJournal of UrologyCME1 May 2022PD43-01 PEVONEDISTAT SENSITIZES RENAL MEDULLARY CARCINOMA CELLS TO CARBOPLATIN BY DISRUPTING DNA DAMAGE REPAIR MECHANISMS Daniel Shapiro, Niki Millward Zacharias, Durga Tripathi, Jean-Philippe Bertocchio, Melinda Soeung, Rong He, Jianjun Gao, Priya Rao, Truong Lam, Luigi Perelli, Alessandro Carugo, Timothy Heffernan, Cheryl Walker, Giannicola Genovese, Nizar Tannir, Christopher Wood, Jose Karam, and Pavlos Msaouel Daniel ShapiroDaniel Shapiro More articles by this author , Niki Millward ZachariasNiki Millward Zacharias More articles by this author , Durga TripathiDurga Tripathi More articles by this author , Jean-Philippe BertocchioJean-Philippe Bertocchio More articles by this author , Melinda SoeungMelinda Soeung More articles by this author , Rong HeRong He More articles by this author , Jianjun GaoJianjun Gao More articles by this author , Priya RaoPriya Rao More articles by this author , Truong LamTruong Lam More articles by this author , Luigi PerelliLuigi Perelli More articles by this author , Alessandro CarugoAlessandro Carugo More articles by this author , Timothy HeffernanTimothy Heffernan More articles by this author , Cheryl WalkerCheryl Walker More articles by this author , Giannicola GenoveseGiannicola Genovese More articles by this author , Nizar TannirNizar Tannir More articles by this author , Christopher WoodChristopher Wood More articles by this author , Jose KaramJose Karam More articles by this author , and Pavlos MsaouelPavlos Msaouel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002604.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Renal medullary carcinoma (RMC) is an aggressive SMARCB1(-) cancer with median survival of only 13 months. Current management consists of carboplatin and paclitaxel, however new therapies are needed. We previously identified proteotoxic and replication stress as RMC cellular hallmarks. The neddylation pathway protects cells from proteotoxic and replication stress. We hypothesized that neddylation inhibition with pevonedistat will synergistically enhance carboplatin antitumor effects in RMC. METHODS: We evaluated the IC50 concentrations of the neddylation activating enzyme inhibitor pevonedistat in vitro using platinum-naïve RMC2C and platinum experienced RMC219 cell lines and 2 other SMARCB1(-) cell lines. To determine synergy, growth inhibition was measured after treating with varying concentrations of pevonedistat (0-0.5μM) and carboplatin (0-80μM). Bliss synergy scores were calculated using the SynergyFinder app. Scores >10 indicate synergy between pevonedistat and carboplatin. We evaluated proteins involved in DNA damage repair using western blot. Lastly, we evaluated tumor inhibition combining pevonedistat with carboplatin + paclitaxel using 2 patient derived xenograft models (RMC2X and RMC32X). RESULTS: The 2 RMC cell lines demonstrated IC50 concentrations below the maximum tolerated dose in humans (Fig 1A). When combined with carboplatin, pevonedistat demonstrated a significant synergistic effect with Bliss scores >10 in both RMC2C (score 22.91) and RMC219 (score 15.15) cell lines (Fig 1B). Pevonedistat caused down regulation of nucleotide excision repair (NER) pathway proteins including FANCD2 and activated ATR (p-ATR), and increased expression of p53 (known to suppress FANCD2). Pevonedistat with carboplatin suppressed p-CDK1(Tyr-15), which inhibits cell cycle progression (Fig 1C). Lastly, pevonedistat with carboplatin+paclitaxel significantly inhibited PDX tumor growth (Fig 1D). CONCLUSIONS: Pevonedistat synergizes with carboplatin to inhibit cell and tumor growth, likely through NER pathway inhibition. This pathway repairs carboplatin-induced DNA interstrand crosslinks. This study supports developing a clinical trial combining pevonedistat with platinum-based chemotherapy for RMC. Source of Funding: DOD Concept Award (W81XWH1810570) © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e701 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daniel Shapiro More articles by this author Niki Millward Zacharias More articles by this author Durga Tripathi More articles by this author Jean-Philippe Bertocchio More articles by this author Melinda Soeung More articles by this author Rong He More articles by this author Jianjun Gao More articles by this author Priya Rao More articles by this author Truong Lam More articles by this author Luigi Perelli More articles by this author Alessandro Carugo More articles by this author Timothy Heffernan More articles by this author Cheryl Walker More articles by this author Giannicola Genovese More articles by this author Nizar Tannir More articles by this author Christopher Wood More articles by this author Jose Karam More articles by this author Pavlos Msaouel More articles by this author Expand All Advertisement PDF DownloadLoading ...

Present embodiment is a study of evaluation of antioxidant property of bis-adamantylated resorcinol [4, 6- bis(1-adamantyl) resorcinol] 1b on nylon-12 as base polymer using differential scanning calorimetry (DSC) via oxidation induction time (OIT) studies. The DSC curves of 0.5% 1b mixed nylon-12 showed unusual pattern as it showed initially a hint of onset of oxidation but no prominent exotherm subsequently, thereby indicating no further oxidation of material. This behaviour showed that the 1b can be used as an antioxidant for variety of polymers. In this study, 1b has been functionalized to corresponding diamines 1bb which can be used for synthesis of bis-imides. 1b can itself be used as a precursor material for other polymers and active pharmaceutical ingredients.

Ultra-high molecular weight polyethylene (UHMWPE) is an exceedingly strong and lightweight polymer owing to its extremely long-chain molecules and a very high average molecular weight. Consequently, it is the material of choice for lightweight high-performance fibers. In this study, the tensile strength of single UHMWPE fibers, i.e., undrawn, drawn and Dyneema® SK75, has been determined experimentally as well as through simulation using finite element analysis (FEA) via von Mises stress criterion to study the effect of fiber drawing on tensile properties. The requisite material properties of UHMWPE were fed in the simulation software (SolidWorks and ANSYS), and the tensile properties were extracted using linear elastic isotropic model. The simulation results agree with the experimental results and illustrate that the percentage error between the simulated and experimentally determined results reduces with the extent of fiber drawing which can be ascribed to the better alignment and close packing of polymer chains during fiber drawing. This observation has been complemented by relative crystallinity through X-ray diffraction studies and also through morphological studies of the fiber specimens examined through scanning electron microscopy.

Gene discovery efforts in autism spectrum disorder have identified heterozygous defects in chromatin remodeller genes, the 'readers, writers and erasers' of methyl marks on chromatin, as major contributors to this disease. Despite this advance, a convergent aetiology between these defects and aberrant chromatin architecture or gene expression has remained elusive. Recently, data have begun to emerge that chromatin remodellers also function directly on the cytoskeleton. Strongly associated with autism spectrum disorder, the SETD2 histone methyltransferase for example, has now been shown to directly methylate microtubules of the mitotic spindle. However, whether microtubule methylation occurs in post-mitotic cells, for example on the neuronal cytoskeleton, is not known. We found the SETD2 α-tubulin lysine 40 trimethyl mark occurs on microtubules in the brain and in primary neurons in culture, and that the SETD2 C-terminal SRI domain is required for binding and methylation of α-tubulin. A CRISPR knock-in of a pathogenic SRI domain mutation (Setd2SRI) that disables microtubule methylation revealed at least one wild-type allele was required in mice for survival, and while viable, heterozygous Setd2SRI/wtmice exhibited an anxiety-like phenotype. Finally, whereas RNA-sequencing (RNA-seq) and chromatin immunoprecipitation-sequencing (ChIP-seq) showed no concomitant changes in chromatin methylation or gene expression in Setd2SRI/wtmice, primary neurons exhibited structural deficits in axon length and dendritic arborization. These data provide the first demonstration that microtubules of neurons are methylated, and reveals a heterozygous chromatin remodeller defect that specifically disables microtubule methylation is sufficient to drive an autism-associated phenotype.

Epigenetic effectors "read" marks "written" on chromatin to regulate function and fidelity of the genome. Here, we show that this coordinated read-write activity of the epigenetic machinery extends to the cytoskeleton, with PBRM1 in the PBAF chromatin remodeling complex reading microtubule methyl marks written by the SETD2 histone methyltransferase. PBRM1 binds SETD2 methyl marks via BAH domains, recruiting PBAF components to the mitotic spindle. This read-write activity was required for normal mitosis: Loss of SETD2 methylation or pathogenic BAH domain mutations disrupt PBRM1 microtubule binding and PBAF recruitment and cause genomic instability. These data reveal PBRM1 functions beyond chromatin remodeling with domains that allow it to integrate chromatin and cytoskeletal activity via its acetyl-binding BD and methyl-binding BAH domains, respectively. Conserved coordinated activity of the epigenetic machinery on the cytoskeleton opens a previously unknown window into how chromatin remodeler defects can drive disease via both epigenetic and cytoskeletal dysfunction.

Abstract The chromatin modifier SETD2 often mutated in clear cell renal cell carcinoma (ccRCC), was recently shown to be a dual-function methyltransferase that “writes” methyl marks on both chromatin and microtubules, revealing α-tubulin methylation as a new posttranslational modification of the mitotic spindle. Here, we report that the polybromo protein PBRM1, the 2nd most mutated gene in ccRCC, is a “reader” for this SETD2-dependent methyl mark on α-tubulin. PBRM1 is a component of the PBAF (Polybromo BRG1 associated factor) chromatin remodeler complex. Our western and immunocytochemistry data in multiple kidney-derived cell lines, including HEK293T, HKC and 786-O, revealed that PBRM1 binds to methylated α-tubulin and localizes to the mitotic spindle and spindle pole during cell division. PBRM1 has six bromo domains, two bromo-associated homology (BAH) domains and one HMG domain. While PBRM1 is known to bind acetylated histones via its bromo domains, our GST pull down assays showed that PBRM1 binds methylated α-tubulin via its two BAH domains. Additional western and immunocytochemical experiments following knockout or re-expression of PBRM1 revealed that PBRM1 recruits other PBAF components to the mitotic spindle to maintain genomic stability. Two clinically established ccRCC mutations (P1048R and C1233W) in PBRM1 BAH domains result in loss of microtubule binding, mislocalization of PBAF, and the inability of PBRM1 to maintain genomic stability, as assessed by increased lagging chromosomes, chromosome bridges, multipolar spindles and micronuclei count. A third pathogenic ccRCC mutation (T1202K) in the PBRM1 BAH domain did not affect microtubule binding and consequently was not associated with mitotic spindle defects or genomic instability. Mass spectrometry and RNASeq confirmed BAH domain mutant PBRM1 still assembled a transcriptionally competent PBAF complex, clearly distinguishing the cytoskeletal from the chromatin impact of these mutations. These data reveal a previously unknown function of PBRM1 beyond reading acetylated histones, and expand the repertoire of chromatin remodelers acting on the cytoskeleton to maintain genomic stability. Citation Format: Menuka Karki, Rahul Jangid, Ramakrishnan Anish, Riyad N. Seervai, Jean-Philippe Bertocchio, Takashi Hotta, Pavlos Msaouel, Sung Y. Jung, Sandra L. Grimm, Cristian Coarfa, Bernard E. Weissman, Ryoma Ohi, Kristen J. Verhey, Courtney H. Hodges, Ruhee Dere, In Young Park, B. V. Venkataram Prasad, W. Kimryn Rathmell, Cheryl L. Walker, Durga N. Tripathi. A cytoskeletal function for PBRM1: reading methylated microtubules to maintain genomic stability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2042.

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology II (PD49)1 Sep 2021PD49-11 COMBINING NEDDYLATION INHIBITION WITH CHEMOTHERAPY TO TREAT RENAL MEDULLARY CARCINOMA Daniel Shapiro, Niki Millward Zacharias, Durga Tripathi, Jean-Philippe Bertocchio, Melinda Soeung, Priya Rao, Cheryl Walker, Giannicola Genovese, Nizar Tannir, Christopher Wood, Jose Karam, and Pavlos Msaouel Daniel ShapiroDaniel Shapiro More articles by this author , Niki Millward ZachariasNiki Millward Zacharias More articles by this author , Durga TripathiDurga Tripathi More articles by this author , Jean-Philippe BertocchioJean-Philippe Bertocchio More articles by this author , Melinda SoeungMelinda Soeung More articles by this author , Priya RaoPriya Rao More articles by this author , Cheryl WalkerCheryl Walker More articles by this author , Giannicola GenoveseGiannicola Genovese More articles by this author , Nizar TannirNizar Tannir More articles by this author , Christopher WoodChristopher Wood More articles by this author , Jose KaramJose Karam More articles by this author , and Pavlos MsaouelPavlos Msaouel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002071.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Renal medullary carcinoma (RMC) is a rare and aggressive malignancy that primarily affects young patients of African descent with sickle cell trait. No targeted therapies are currently approved for patients with RMC. The current standard of care consists of platinum-based chemotherapy and new therapies are needed. We previously identified proteotoxic and replication stress as RMC hallmarks. The neddylation pathway protects cells from proteotoxic and replication stress. We hypothesized that inhibition of neddylation will produce antitumor responses in RMC. METHODS: We tested the efficacy of neddylation activating enzyme inhibitor pevonedistat (MLN4924) in vitro in the platinum-naïve RMC2C and the platinum-experienced RMC219 cell lines, as well as in vivo in the platinum-naïve RMC2X and the platinum-experienced RMC32X patient-derived xenograft (PDX) models. Cell viability was evaluated using MTT assays. To determine the effects of pevonedistat in combination with platinum-based cytotoxic chemotherapy (carboplatin+paclitaxel) in vivo, immunodeficient mice bearing subcutaneous RMC tumors were divided into 4 treatment arms (n=5-8 per arm) which consisted of vehicle control, pevonedistat (30mg/kg), carboplatin (80mg/kg)+paclitaxel (20mg/kg), and pevonedistat+carboplatin+paclitaxel. Synergy between pevonedistat and chemotherapy was determined based on the Bliss definition of drug independence. RESULTS: Pevonedistat showed in vitro antitumor efficacy against both RMC2C (IC50 0.199 μΜ) and RMC219 (IC50 0.551) cell lines. In the RMC2X in vivo model, mean tumor volumes were 2164±835mm3 for control, 433±250mm3 for pevonedistat, 339±44mm3 for chemotherapy, 75±46mm3 for pevonedistat+chemotherapy. The combination of pevonedistat with chemotherapy significantly reduced tumor volumes compared to vehicle control (p=0.02) and chemotherapy alone (p=0.008). A similar pattern was demonstrated with RMC32X tumor volumes, whereby pevonedistat combined with chemotherapy significantly reduced tumor volume compared to control (p=0.006) and chemotherapy alone (p=0.02). A significant synergistic therapeutic effect of pevonedistat combined with chemotherapy was found for both RMC2X (p=0.008) and RMC32X (p=0.002). CONCLUSIONS: Our results identify the neddylation pathway as a targetable vulnerability of RMC tumors, and provide preclinical rationale for a clinical trial testing the combination of pevonedistat with carboplatin+paclitaxel to improve the RMC outcomes. Source of Funding: Supported in part by the Cancer Center Support Grant to MDACC (grant P30CA016672) from the National Cancer Institute of the National Institutes of Health and by a Concept award (W81XWH1810570) from the United States Department of Defense © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e849-e849 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daniel Shapiro More articles by this author Niki Millward Zacharias More articles by this author Durga Tripathi More articles by this author Jean-Philippe Bertocchio More articles by this author Melinda Soeung More articles by this author Priya Rao More articles by this author Cheryl Walker More articles by this author Giannicola Genovese More articles by this author Nizar Tannir More articles by this author Christopher Wood More articles by this author Jose Karam More articles by this author Pavlos Msaouel More articles by this author Expand All Advertisement Loading ...