bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure S3 from Evaluation of Somatic Mutations in Urine Samples as a Noninvasive Method for the Detection and Molecular Classification of Endometrial Cancer
Authors: Costas Laura , Onieva Irene , Pelegrina Beatriz , Marin Fátima , Carmona Álvaro , López-Querol Marta , Frias-Gomez Jon , Peremiquel-Trillas Paula , Martínez José Manuel , Dorca Eduard , Brunet Joan , Pineda Marta , Ponce Jordi , Matias-Guiu Xavier , de Sanjosé Silvia , Bosch Francesc Xavier , Alemany Laia , Paytubi Sonia
Published: August 2023

Variant allele frequency of all variants in supernatant urine from cases and controls and in tumor samples from cases
Supplementary Figure S1 from Evaluation of Somatic Mutations in Urine Samples as a Noninvasive Method for the Detection and Molecular Classification of Endometrial Cancer
Authors: Costas Laura , Onieva Irene , Pelegrina Beatriz , Marin Fátima , Carmona Álvaro , López-Querol Marta , Frias-Gomez Jon , Peremiquel-Trillas Paula , Martínez José Manuel , Dorca Eduard , Brunet Joan , Pineda Marta , Ponce Jordi , Matias-Guiu Xavier , de Sanjosé Silvia , Bosch Francesc Xavier , Alemany Laia , Paytubi Sonia
Published: August 2023

This graph shows a summary of the study
Data from Functional Homologous Recombination Assay on FFPE Specimens of Advanced High-Grade Serous Ovarian Cancer Predicts Clinical Outcomes
Authors: Pikkusaari Sanna , Tumiati Manuela , Virtanen Anni , Oikkonen Jaana , Li Yilin , Perez-Villatoro Fernando , Muranen Taru , Salko Matilda , Huhtinen Kaisa , Kanerva Anna , Koskela Heidi , Tapper Johanna , Koivisto-Korander Riitta , Joutsiniemi Titta , Haltia Ulla-Maija , Lassus Heini , Hautaniemi Sampsa , Färkkilä Anniina , Hynninen Johanna , Hietanen Sakari , Carpén Olli , Kauppi Liisa
Published: August 2023

AbstractPurpose:
Deficiency in homologous recombination (HR) repair of DNA damage is characteristic of many high-grade serous ovarian cancers (HGSC). It is imperative to identify patients with homologous recombination–deficient (HRD) tumors as they are most likely to benefit from platinum-based chemotherapy and PARP inhibitors (PARPi). Existing methods measure historical, not necessarily current HRD and/or require high tumor cell content, which is not achievable for many patients. We set out to develop a clinically feasible assay for identifying functionally HRD tumors that can predict clinical outcomes.
Experimental Design:
We quantified RAD51, a key HR protein, in immunostained formalin-fixed, paraffin-embedded (FFPE) tumor samples obtained from chemotherapy-naïve and neoadjuvant chemotherapy (NACT)-treated HGSC patients. We defined cutoffs for functional HRD separately for these sample types, classified the patients accordingly as HRD or HR-proficient, and analyzed correlations with clinical outcomes. From the same specimens, genomics-based HRD estimates (HR gene mutations, genomic signatures, and genomic scars) were also determined, and compared with functional HR (fHR) status.
Results:
fHR status significantly predicted several clinical outcomes, including progression-free survival (PFS) and overall survival (OS), when determined from chemo-naïve (PFS, P < 0.0001; OS, P < 0.0001) as well as NACT-treated (PFS, P < 0.0001; OS, P = 0.0033) tumor specimens. The fHR test also identified as HRD those PARPi-at-recurrence–treated patients with longer OS (P = 0.0188).
Conclusions:
We developed an fHR assay performed on routine FFPE specimens, obtained from either chemo-naïve or NACT-treated HGSC patients, that can significantly predict real-world platinum-based chemotherapy and PARPi response.

See related commentary by Garg and Oza, p. 2957
Data from Osimertinib and Selpercatinib Efficacy, Safety, and Resistance in a Multicenter, Prospectively Treated Cohort of EGFR-Mutant and RET Fusion-Positive Lung Cancers
Authors: Rotow Julia , Patel Jyoti D. , Hanley Matthew P. , Yu Helena , Awad Mark , Goldman Jonathan W. , Nechushtan Hovav , Scheffler Matthias , Kuo Chih-Hsi S. , Rajappa Senthil , Harada Guilherme , Clifford Sarah , Santucci Alison , Silva Laura , Tupper Rebecca , Oxnard Geoffrey R. , Kherani Jennifer , Drilon Alexander
Published: August 2023

AbstractPurpose:
Acquired RET fusions have been reported at resistance to treatment with EGFR inhibitors in EGFR-mutant non–small cell lung cancer (NSCLC); however, a multicenter cohort of patients with EGFR-mutant lung cancers treated with osimertinib and selpercatinib for RET fusion–mediated osimertinib resistance has not previously been published.
Patients and Methods:
Patients who received selpercatinib in combination with osimertinib on a prospective expanded access clinical trial (NCT03906331) and single-patient compassionate use programs across five countries were centrally analyzed. All patients had advanced EGFR-mutant NSCLC with a RET fusion detected from tissue or plasma following osimertinib therapy. Clinicopathologic and outcomes data were collected.
Results:
Fourteen patients with EGFR-mutant and RET fusion–positive lung cancers who experienced prior progression on osimertinib received osimertinib and selpercatinib. EGFR exon 19 deletions (±T790M, 86%) and non-KIF5B fusions (CCDC6-RET 50%, NCOA4-RET 36%) predominated. Osimertinib 80 mg daily and selpercatinib 80 mg twice daily were the most commonly administered dosages. The response rate, disease control rate, and median treatment duration were 50% [95% confidence interval (CI), 25%–75%, n = 12], 83% (95% CI, 55%–95%), and 7.9 months (range, 0.8–25+), respectively. Resistance was complex, involving EGFR on-target (EGFR C797S), RET on-target (RET G810S), and off-target (EML4–ALK/STRN–ALK, KRAS G12S, BRAF V600E) mechanisms; RET fusion loss; or polyclonal mechanisms.
Conclusions:
For patients with EGFR-mutant NSCLC with an acquired RET fusion as a mechanism of EGFR inhibitor resistance, the addition of selpercatinib to osimertinib was feasible and safe and offered clinical benefit, supporting the prospective evaluation of this combination.

See related commentary by Krebs and Popat, p. 2951
Data from Frequent Overexpression of HER3 in Brain Metastases from Breast and Lung Cancer
Authors: Tomasich Erwin , Steindl Ariane , Paiato Christina , Hatziioannou Teresa , Kleinberger Markus , Berchtold Luzia , Puhr Rainer , Hainfellner Johannes A. , Müllauer Leonhard , Widhalm Georg , Eckert Franziska , Bartsch Rupert , Heller Gerwin , Preusser Matthias , Berghoff Anna Sophie
Published: August 2023

AbstractPurpose:
HER3 belongs to a family of receptor tyrosine kinases with oncogenic properties and is targeted by a variety of novel anticancer agents. There is a huge unmet medical need for systemic treatment options in patients with brain metastases (BM). Therefore, we aimed to investigate HER3 expression in BM of breast (BCa) and non–small cell lung cancer (NSCLC) as the basis for future clinical trial design.
Experimental Design:
We analyzed 180 BM samples of breast cancer or NSCLC and 47 corresponding NSCLC extracranial tissue. IHC was performed to evaluate protein expression of HER3, and immune cells based on CD3, CD8, and CD68. To identify dysregulated pathways based on differential DNA methylation patterns, we used Infinium MethylationEPIC microarrays.
Results:
A total of 99/132 (75.0%) of BCa-BM and 35/48 (72.9%) of NSCLC-BM presented with HER3 expression. Among breast cancer, HER2-positive and HER2-low BM showed significantly higher rates of HER3 coexpression than HER2-negative BM (87.1%/85.7% vs. 61.0%, P = 0.004). Among NSCLC, HER3 was more abundantly expressed in BM than in matched extracranial samples (72.9% vs. 41.3%, P = 0.003). No correlation of HER3 expression and intratumoral immune cell density was observed. HER3 expression did not correlate with overall survival from BM diagnosis. Methylation signatures differed according to HER3 status in BCa-BM samples. Pathway analysis revealed subtype-specific differences, such as TrkB and Wnt signaling pathways dysregulated in HER2-positive and triple-negative breast cancer BM, respectively.
Conclusions:
HER3 is highly abundant in BM of breast cancer and NSCLC. Given the promising results of antibody–drug conjugates in extracranial disease, BM-specific trials that target HER3 are warranted.

See related commentary by Kabraji and Lin, p. 2961
Data from Targeting BCL2 Overcomes Resistance and Augments Response to Aurora Kinase B Inhibition by AZD2811 in Small Cell Lung Cancer
Authors: Ramkumar Kavya , Tanimoto Azusa , Della Corte Carminia M. , Stewart C. Allison , Wang Qi , Shen Li , Cardnell Robert J. , Wang Jing , Polanska Urszula M. , Andersen Courtney , Saeh Jamal , Pease J. Elizabeth , Travers Jon , Fabbri Giulia , Gay Carl M. , Urosevic Jelena , Byers Lauren A.
Published: August 2023

AbstractPurpose:
Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers of response. Aurora kinase B (AURKB) inhibition exploits an inherent genomic vulnerability in SCLC and is a promising therapeutic approach. Here, we identify biomarkers of response and develop rational combinations with AURKB inhibition to improve treatment efficacy.
Experimental Design:
Selective AURKB inhibitor AZD2811 was profiled in a large panel of SCLC cell lines (n = 57) and patient-derived xenograft (PDX) models. Proteomic and transcriptomic profiles were analyzed to identify candidate biomarkers of response and resistance. Effects on polyploidy, DNA damage, and apoptosis were measured by flow cytometry and Western blotting. Rational drug combinations were validated in SCLC cell lines and PDX models.
Results:
AZD2811 showed potent growth inhibitory activity in a subset of SCLC, often characterized by, but not limited to, high cMYC expression. Importantly, high BCL2 expression predicted resistance to AURKB inhibitor response in SCLC, independent of cMYC status. AZD2811-induced DNA damage and apoptosis were suppressed by high BCL2 levels, while combining AZD2811 with a BCL2 inhibitor significantly sensitized resistant models. In vivo, sustained tumor growth reduction and regression was achieved even with intermittent dosing of AZD2811 and venetoclax, an FDA-approved BCL2 inhibitor.
Conclusions:
BCL2 inhibition overcomes intrinsic resistance and enhances sensitivity to AURKB inhibition in SCLC preclinical models.
Data from Evaluation of Somatic Mutations in Urine Samples as a Noninvasive Method for the Detection and Molecular Classification of Endometrial Cancer
Authors: Costas Laura , Onieva Irene , Pelegrina Beatriz , Marin Fátima , Carmona Álvaro , López-Querol Marta , Frias-Gomez Jon , Peremiquel-Trillas Paula , Martínez José Manuel , Dorca Eduard , Brunet Joan , Pineda Marta , Ponce Jordi , Matias-Guiu Xavier , de Sanjosé Silvia , Bosch Francesc Xavier , Alemany Laia , Paytubi Sonia
Published: August 2023

AbstractPurpose:
Current diagnostic methods for endometrial cancer lack specificity, leading to many women undergoing invasive procedures. The aim of this study was to evaluate somatic mutations in urine to accurately discriminate patients with endometrial cancer from controls.
Experimental Design:
Overall, 72 samples were analyzed using next-generation sequencing (NGS) with molecular identifiers targeting 47 genes. We evaluated urine supernatant samples from women with endometrial cancer (n = 19) and age-matched controls (n = 20). Cell pellets from urine and plasma samples from seven cases were sequenced; further, we also evaluated paired tumor samples from all cases. Finally, immunohistochemical markers for molecular profiling were evaluated in all tumor samples.
Results:
Overall, we were able to identify mutations in DNA from urine supernatant samples in 100% of endometrial cancers. In contrast, only one control (5%) showed variants at a variant allele frequency (VAF) ≥ 2% in the urine supernatant samples. The molecular classification obtained by using tumor samples and urine samples showed good agreement. Analyses in paired samples revealed a higher number of mutations and VAF in urine supernatants than in urine cell pellets and blood samples.
Conclusions:
Evaluation of somatic mutations using urine samples may offer a user-friendly and reliable tool for endometrial cancer detection and molecular classification. The diagnostic performance for endometrial cancer detection was very high, and cases could be molecularly classified using these noninvasive and self-collected samples. Additional multicenter evaluations using larger sample sizes are needed to validate the results and understand the potential of urine samples for the early detection and prognosis of endometrial cancer.
Abstract A013: Tumor-specific immunity generated by a personalized neoantigen vaccination incorporating locally delivered ipilimumab in renal cell carcinoma
Authors: Braun David A. , Keskin Derin B. , Shukla Sachet A. , McGregor Bradley A. , Schindler Nicholas R. , Blass Eryn , Klaeger Susan , Pomerance Lucas , Sarkizova Siranush , Li Shuqiang , Southard Jackson , Moranzoni Giorgia , Pedersen Christina B. , Liu Yiwen , Chang Steven L. , Hirsch Michelle S. , LeBoeuf Nicole R. , Mossanen Matthew , Chea Vipheaviny , Carulli Isabel , Olive Oriol , Mehndiratta Ambica , Greenslade Haley , Oliveira Giacomo , Iorgulescu J. Bryan , Signoretti Sabina , Aster Jon C. , Elagina Liudmila , Leshchiner Ignaty , Getz Gad , Harden Maegan , Gabriel Stacey , Olsen Lars R. , Neuberg Donna S. , Fritsch Edward F. , Hacohen Nir , Livak Kenneth J. , Carr Steven , Ott Patrick A. , Wu Catherine J. , Choueiri Toni K.
Published: August 2023

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR015) of the Conference Program/Proceedings.

Citation Format: David A. Braun, Derin B. Keskin, Sachet A. Shukla, Bradley A. McGregor, Nicholas R. Schindler, Eryn Blass, Susan Klaeger, Lucas Pomerance, Siranush Sarkizova, Shuqiang Li, Jackson Southard, Giorgia Moranzoni, Christina B. Pedersen, Yiwen Liu, Steven L. Chang, Michelle S. Hirsch, Nicole R. LeBoeuf, Matthew Mossanen, Vipheaviny Chea, Isabel Carulli, Oriol Olive, Ambica Mehndiratta, Haley Greenslade, Giacomo Oliveira, J. Bryan Iorgulescu, Sabina Signoretti, Jon C. Aster, Liudmila Elagina, Ignaty Leshchiner, Gad Getz, Maegan Harden, Stacey Gabriel, Lars R. Olsen, Donna S. Neuberg, Edward F. Fritsch, Nir Hacohen, Kenneth J. Livak, Steven Carr, Patrick A. Ott, Catherine J. Wu, Toni K. Choueiri. Tumor-specific immunity generated by a personalized neoantigen vaccination incorporating locally delivered ipilimumab in renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A013.
Abstract A014: Modeling recurrent chromosomal alterations in renal cell carcinoma evolution
Authors: Dahiya Rashmi , Ly Peter
Published: August 2023

The loss of one copy of chromosome 3p represents an early truncal genetic event in the majority of clear cell renal cell carcinoma (ccRCC) tumors. Chromosome 3p loss can be initiated by chromothripsis, a process in which mis-segregated chromosomes entrapped within abnormal nuclear structures called micronuclei become pulverized into small genomic fragments. These fragments are then re-stitched together to form complex rearrangements that are accompanied by extensive segmental deletions that inactivate critical tumor suppressor genes located on chromosome 3p. Despite being a driver of ccRCC development, the mechanism(s) that initiate chromosome 3p chromothripsis followed by pressures that select for specific rearrangement patterns are poorly understood. To recapitulate early genetic events arising throughout ccRCC evolution, here we developed chromosome 3p-specific micronuclei models in non-transformed human renal proximal tubule epithelial cells (RPTECs) to interrogate recurrent patterns of chromosomal alterations that promote renal cell tumorigenesis. To do so, we used CRISPR/Cas9 to induce a DNA double-strand break on chromosome 3p, which generates chromosome 3p-specific micronuclei when the acentric arm is left unrepaired into the subsequent mitosis. DNA fluorescence in situ hybridization revealed that mis-segregation of chromosome 3p into micronuclei induces chromosome pulverization and rearrangements. Notably, these alterations are sufficient to provide a selective advantage by enabling anchorage-independent growth in vitro. Cytogenetic characterization of partially transformed RPTECs revealed enrichment of chromosome 3p rearrangements, which were gradually lost upon propagation as conventional monolayer cultures. These results provide mechanistic insight into the origins of chromosome 3p alterations in ccRCC and further highlight the role of selection pressure in shaping genome evolution.

Citation Format: Rashmi Dahiya, Peter Ly. Modeling recurrent chromosomal alterations in renal cell carcinoma evolution [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A014.
Abstract A024: Development of potent and selective nicotinamide N-methyltransferase inhibitors for kidney cancer
Authors: Huang Rong , Iyamu Iredia
Published: August 2023

Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that regulates energy balance and methylation potential through the methylation of nicotinamide using S-adenosylmethionine (SAM) as the cofactor. NNMT has emerged as a novel target for both primary and metastatic ccRCC, as its high expression in ccRCC tumor tissues is linked with low survival. Meanwhile, NNMT depletion or inhibition efficiently suppresses the growth and metastasis of ccRCC in cellular and animal studies. Here, we report rational design and synthesize cell-potent and selective NNMT inhibitors with cellular IC50 values of 140 nM, representing the most cell-potent inhibitors to date. Furthermore, our NNMT inhibitors suppress renal cancer 786O and Caki-1 cell growth with a GI50 value of 9.3 and 7.3 µM, respectively. Moreover, our NNMT inhibitors reduced the migration of renal cancer cells through wound healing assay. In summary, our inhibitors would serve as valuable chemical probes to investigate the catalytical function of NNMT and evaluate the therapeutic potential of NNMT for kidney cancer.

Citation Format: Rong Huang, Iredia Iyamu. Development of potent and selective nicotinamide N-methyltransferase inhibitors for kidney cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A024.
Abstract B008: Activation of the bile acid pathway promotes tumorigenesis in clear cell renal cell carcinoma
Authors: Riscal Romain , Gardner Sarah , Carens Madeleine , Mesaros Clementina , Xu Jimmy , Coffey Nate , Davis Leah , Vogt Austin , Olia Adam , Finan Jennifer , Godfrey Jason , Blair Ian , Keith Brian , Marmorstein Ronen , Skuli Nicolas , Simon Celeste
Published: August 2023

Clear cell renal cell carcinoma (ccRCC) incidence has risen steadily over the last decade. We and others have demonstrated that elevated lipid uptake and storage is required for ccRCC cell viability; however, the role of stored cholesterol, the most abundant component in ccRCC intracellular lipid droplets, remains unclear. We recently demonstrated that ccRCC cells acquire exogenous cholesterol through the HDL receptor SCARB1, inhibition or suppression of which induces apoptosis. Here, we show that elevated expression of 3 beta-hydroxy steroid dehydrogenase type 7 (HSD3B7), which metabolizes cholesterol-derived oxysterols in the bile acid biosynthetic pathway, is essential for ccRCC cell survival. Repressing HSD3B7 expression genetically, or treating ccRCC cells with a newly identified HSD3B7 inhibitor, resulted in toxic oxysterol accumulation, impaired proliferation, and increased apoptosis in vitro and in vivo. These data demonstrate that bile acid synthesis regulates cholesterol homeostasis in ccRCC and identifies HSD3B7 as a plausible therapeutic target.

Citation Format: Romain Riscal, Sarah Gardner, Madeleine Carens, Clementina Mesaros, Jimmy Xu, Nate Coffey, Leah Davis, Austin Vogt, Adam Olia, Jennifer Finan, Jason Godfrey, Ian Blair, Brian Keith, Ronen Marmorstein, Nicolas Skuli, Celeste Simon. Activation of the bile acid pathway promotes tumorigenesis in clear cell renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B008.
Abstract B011: An atlas of cellular heterogeneity in primary and metastatic renal cell carcinomas
Authors: Madrigal Ariel , Kim Minjun , Osakwe Adrien , Lu Tianyuan , Mehrjoo Zohreh , Moslemi Elham , Farouni Rick , Morales-Soto Larisa , Wang Yu Chang , Dankner Matthew , Djambazian Haig , Petrecca Kevin , Spicer Jonathan , Brimo Fadi , Siegel Peter , Park Morag , Ragoussis Jiannis , Tanguay Simon , Riazalhosseini Yasser , Najafabadi Hamed S.
Published: August 2023

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR005) of the Conference Program/Proceedings.

Citation Format: Ariel Madrigal, Minjun Kim, Adrien Osakwe, Tianyuan Lu, Zohreh Mehrjoo, Elham Moslemi, Rick Farouni, Larisa Morales-Soto, Yu Chang Wang, Matthew Dankner, Haig Djambazian, Kevin Petrecca, Jonathan Spicer, Fadi Brimo, Peter Siegel, Morag Park, Jiannis Ragoussis, Simon Tanguay, Yasser Riazalhosseini, Hamed S. Najafabadi. An atlas of cellular heterogeneity in primary and metastatic renal cell carcinomas [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B011.
Abstract IA004: Identification of potential new therapeutic targets in kidney cancer
Authors: Zhang Qing
Published: August 2023

VHL is the most important tumor suppressor in clear cell renal cell carcinoma (ccRCC). In the majority of ccRCC, as a result of VHL loss, HIF2a stabilization is sufficient and necessary for promoting ccRCC tumor growth. Despite the development of HIF2a specific inhibitors, the intrinsic and extrinsic resistance do exist, highlighting the importance of identifying additional therapeutic vulnerabilities in ccRCC. We have recently performed some genome-wide screening and identified new signaling pathways regulated by VHL, including ZHX2 and SFMBT1 that play important roles in ccRCC. In addition, we also identified some synthetic lethality binding partners for VHL loss in kidney cancer, including TBK1. However, it is challenging to target TBK1 in clinical practice due to lack of selectivity for TBK1 inhibitors and its role involved in innate immune signaling. To overcome this difficulty, one approach would be to identify a critical upstream regulator of TBK1 that can be targeted therapeutically, especially in ccRCC displaying hyper-activated TBK1 activity due to VHL loss. We have performed a kinome-wide screening and identified Doublecortin like kinase 2 (DCLK2), an enigmatic kinase involved in neuronal survival and growth cone regeneration upon injury, as a novel TBK1 regulator in ccRCC. Our functional assays demonstrate that DCLK2 is necessary and sufficient to promote ccRCC tumorigenesis through activating TBK1. In addition, we also characterized a DCLK2 short isoform (DCLK2203) that play a predominant role in ccRCC tumorigenesis. Our work suggests that DCLK2 is a novel TBK1 activator and potential therapeutic target in ccRCC.

Citation Format: Qing Zhang. Identification of potential new therapeutic targets in kidney cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA004.
Abstract IA009: Development of HIF2 inhibitors: Bench to bedside and back
Authors: Brugarolas James
Published: August 2023

Arguably the most important driver of clear cell renal cell carcinoma (ccRCC), HIF2a was traditionally regarded as undruggable. However, structural analyses at UT Southwestern Medical Center found a vulnerability leading to the identification of small molecule inhibitors, and eventually the development of highly related PT drugs by Peloton Therapeutics (PT2385 and PT2977, also called belzutifan). PT drugs bind to HIF2a and induce a conformational change that triggers its dissociation from HIF1b, thereby inhibiting DNA binding and gene transactivation. PT drugs have shown activity in patients, but resistance develops over time. Resistance mutations have been identified, initially in preclinical models, and subsequently in patients. This has spurred the development of second-generation inhibitors, including siRNA-based therapeutics. Recently, we reported a tumor-directed HIF2a-targeting siRNA drug (siHIF2) developed by Arrowhead Pharmaceuticals that effectively depleted both wild-type and mutant HIF2a. siHIF2 showed activity against ccRCC in preclinical models and in patients. Overall, these studies establish HIF2a as a core dependency and therapeutic target, and set a paradigm for tumor-directed RNA-based therapeutics in cancer.

Citation Format: James Brugarolas. Development of HIF2 inhibitors: Bench to bedside and back [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA009.
Abstract IA013: A zebrafish model for VHL and hypoxia signaling
Authors: van Rooijien Ellen , Schulte-Merker Stefan , Logister Ive , Voest Emile , Giles Rachel
Published: August 2023

he von Hippel-Lindau (VHL) tumor suppressor gene encodes an adaptor protein that regulates an array of transcription-dependent and -independent cellular and physiological processes. Mutations in this gene cause VHL disease, congenital polycythemia, renal cell carcinoma (RCC), and several other sporadic tumor types. Although different animal models for VHL disease have been adapted, the zebrafish VHL model offers distinct opportunities. Zebrafish vhl mutants develop key aspects of the human disease condition, including activation of the hypoxia-inducible factor (HIF) signaling pathway, polycythemia, excessive neovascularization, macular edema, and pronephric abnormalities resembling early stages of RCC. The zebrafish vhl model offers a platform for the identification of genetic pathways, modifiers, and interactors involved in the development of VHL-associated neoplasms. Vhl mutants represent a unique and clinically relevant in vivo model for studying genotype-phenotype correlations and the identification of prognostic biomarkers. The amenability of zebrafish for chemical genetic screens will not only be helpful to identify novel therapeutic agents but may also reveal novel processes that require regulation by VHL.

Citation Format: Ellen van Rooijien, Stefan Schulte-Merker, Ive Logister, Emile Voest, Rachel Giles. A zebrafish model for VHL and hypoxia signaling [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA013.
Abstract IA019: Metabolic adaptations in renal cell carcinoma
Authors: Rathmell W. Kimryn
Published: August 2023

Clear cell renal cell carcinoma (ccRCC) is characterized by deregulated hypoxic signaling, metabolic defects, and a complex tumor microenvironment (TME) highly enriched in both lymphoid and myeloid immune subsets. Loss of the oxygen sensing gene, von Hippel Lindau (VHL), is a critical early event in ccRCC pathogenesis and promotes stabilization of hypoxia inducible (transcription) factors (HIF) that upregulate pro-growth signaling pathways, including angiogenesis and aerobic glycolysis. However, whether Vhl loss in cancer cells impacts the frequency, energetic requirements, or other functional properties of immune subsets in the TME remains unclear. Here, using Vhl WT and Vhl KO in vivo murine kidney cancer models, we found that Vhl KO tumors across multiple clones were slower growing and promoted increased immune cell infiltration in the TME. Enhanced proinflammatory signatures in tumor associated macrophage (TAM) subsets from Vhl deficient tumors were also observed, and these features were rescued when Vhl was reintroduced to the cancer cells. Moreover, in vivo quantification of the PET tracer and glucose analog, [18F]fluorodeoxyglucose (FDG), revealed that both myeloid derived suppressor cells (MDSC) and TAM populations from Vhl KO tumors consume more glucose than myeloid subsets from Vhl intact tumors. Notably, Vhl loss did not confer increased glucose uptake in cancer cells or lymphoid subsets in vivo. Overall, these data are consistent with enhanced metabolism and proinflammatory properties observed in the myeloid compartment of human ccRCC and highlight cancer cell intrinsic mechanisms driving environmental reprograming as a means of shaping the immune landscape in ccRCC.

Citation Format: W. Kimryn Rathmell. Metabolic adaptations in renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA019.
Abstract PR003: PBRM1-deficient PBAF complexes target aberrant genomic loci to activate NF-κB pathway in clear cell renal cell carcinoma
Authors: Yao Xiaosai , Hong Jing Han , Nargund Amrita , Ng Michelle S.W. , Teh Bin Tean
Published: August 2023

PBRM1 encodes an accessory subunit of the PBAF subclass of the SWI/SNF chromatin remodeler and the inactivation of PBRM1 is the second most frequent mutational event in kidney cancer. However, the impact of PBRM1 loss on chromatin remodeling, especially pertaining to kidney tumorigenesis, has not been well examined. Here we show that in VHL-deficient renal tumors, PBRM1 deficiency results in ectopic PBAF complexes that localize to de novo genomic loci and activate the pro-tumorigenic NF-κB pathway. PBRM1-deficient PBAF complexes, despite retaining the association between SMARCA4 and ARID2, have loosely tethered BRD7. The PBAF complexes redistribute from promoter proximal regions to distal enhancers containing NF-κB motifs; subsequently, PBRM1-deficient cells display heightened NF-κB activity in multiple models and clinical samples. The ATPase function of SMARCA4 maintains chromatin occupancy of both pre-existing and newly acquired RELA specific to PBRM1 loss, and activates downstream target gene expression. Proteasome inhibitor bortezomib abrogates RELA occupancy, suppresses NF-κB activation and delays growth of PBRM1-deficient tumors. In conclusion, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-tumorigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes.

Citation Format: Xiaosai Yao, Jing Han Hong, Amrita Nargund, Michelle S.W. Ng, Bin Tean Teh. PBRM1-deficient PBAF complexes target aberrant genomic loci to activate NF-κB pathway in clear cell renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr PR003.
Abstract PR012: SETD2 safeguards the genome against isochromosome formation
Authors: Mason Frank M. , Tebeje Anteneh T. , Kounlavong Emily S. , Dahiya Rashmi , Vlach Logan , Guess Tiffany , Dere Ruhee , Ohi Ryoma , Ly Peter , Walker Cheryl L. , Rathmell W. Kimryn
Published: August 2023

Chromosome mis-segregation during cell division occurs in diverse tumor types, promoting aneuploidy and intratumoral genetic heterogeneity. While the mechanisms that govern chromosome segregation are well-established, how changes in the activities of tumor suppressors or oncogenes drive mitotic errors remain poorly understood. Loss of the tumor suppressor SETD2, the methyltransferase responsible for tri-methylation of histone 3 lysine 36 (H3K36me3), correlates with clear cell renal cell carcinoma (ccRCC) tumors exhibiting extensive intratumoral heterogeneity. Yet, how loss of H3K36me3 or SETD2 promotes heterogeneity is unknown. Here, we show that loss of SETD2 promotes chromosome mis-segregation during mitosis and interphase DNA bridges driven by the formation of dicentric chromosomes. Cytogenetic analyses revealed that these dicentrics loss were largely comprised of mirror-imaged isodicentric chromosomes that contain two active centromeres. In addition to isodicentrics, cells lacking SETD2 or H36K36me3 generated iso- and acentric chromosomes, however loss of SETD2 protein additionally caused chromosome instability. These data directly link loss of a tumor suppressor to these mutable chromatin structures that initiate intratumor heterogeneity by promoting gross chromosomal rearrangements.

Citation Format: Frank M. Mason, Anteneh T. Tebeje, Emily S. Kounlavong, Rashmi Dahiya, Logan Vlach, Tiffany Guess, Ruhee Dere, Ryoma Ohi, Peter Ly, Cheryl L. Walker, W. Kimryn Rathmell. SETD2 safeguards the genome against isochromosome formation [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr PR012.
Table S2 from Clinical benefit of autologous stem cell transplantation for multiple myeloma patients achieving undetectable minimal residual disease after induction treatment
Authors: Liu Jiahui , Yan Wenqiang , Fan Huishou , Xu Jingyu , Li Lingna , Du Chenxing , Mao Xuehan , Yan Yuting , Xu Yan , Sui Weiwei , Deng Shuhui , Yi Shuhua , Anderson Kenneth C. , Qiu Lugui , Zou Dehui , An Gang
Published: August 2023

The impact of ASCT on PFS and OS among all patients
Figure S5 from Clinical benefit of autologous stem cell transplantation for multiple myeloma patients achieving undetectable minimal residual disease after induction treatment
Authors: Liu Jiahui , Yan Wenqiang , Fan Huishou , Xu Jingyu , Li Lingna , Du Chenxing , Mao Xuehan , Yan Yuting , Xu Yan , Sui Weiwei , Deng Shuhui , Yi Shuhua , Anderson Kenneth C. , Qiu Lugui , Zou Dehui , An Gang
Published: August 2023

The impact of continued MRD-negative status (≥2 years) on PFS
Figure S3 from Clinical benefit of autologous stem cell transplantation for multiple myeloma patients achieving undetectable minimal residual disease after induction treatment
Authors: Liu Jiahui , Yan Wenqiang , Fan Huishou , Xu Jingyu , Li Lingna , Du Chenxing , Mao Xuehan , Yan Yuting , Xu Yan , Sui Weiwei , Deng Shuhui , Yi Shuhua , Anderson Kenneth C. , Qiu Lugui , Zou Dehui , An Gang
Published: August 2023

The prognostic impact of ASCT and early MRD status by molecular risk groups
Figure S1 from Clinical benefit of autologous stem cell transplantation for multiple myeloma patients achieving undetectable minimal residual disease after induction treatment
Authors: Liu Jiahui , Yan Wenqiang , Fan Huishou , Xu Jingyu , Li Lingna , Du Chenxing , Mao Xuehan , Yan Yuting , Xu Yan , Sui Weiwei , Deng Shuhui , Yi Shuhua , Anderson Kenneth C. , Qiu Lugui , Zou Dehui , An Gang
Published: August 2023

The workflow of patient selection in this study.
Supplementary Figure 7 from Kinase Inhibitor Pulldown Assay Identifies a Chemotherapy Response Signature in Triple-negative Breast Cancer Based on Purine-binding Proteins
Authors: Wang Junkai , Saltzman Alexander B. , Jaehnig Eric J. , Lei Jonathan T. , Malovannaya Anna , Holt Matthew V. , Young Meggie N. , Rimawi Mothaffar F. , Ademuyiwa Foluso O. , Anurag Meenakshi , Kim Beom-Jun , Ellis Matthew J.
Published: August 2023

Supplementary Figure 7
Supplementary Figure 6 from Kinase Inhibitor Pulldown Assay Identifies a Chemotherapy Response Signature in Triple-negative Breast Cancer Based on Purine-binding Proteins
Authors: Wang Junkai , Saltzman Alexander B. , Jaehnig Eric J. , Lei Jonathan T. , Malovannaya Anna , Holt Matthew V. , Young Meggie N. , Rimawi Mothaffar F. , Ademuyiwa Foluso O. , Anurag Meenakshi , Kim Beom-Jun , Ellis Matthew J.
Published: August 2023

Supplementary Figure 6
Supplementary Figure 3 from Kinase Inhibitor Pulldown Assay Identifies a Chemotherapy Response Signature in Triple-negative Breast Cancer Based on Purine-binding Proteins
Authors: Wang Junkai , Saltzman Alexander B. , Jaehnig Eric J. , Lei Jonathan T. , Malovannaya Anna , Holt Matthew V. , Young Meggie N. , Rimawi Mothaffar F. , Ademuyiwa Foluso O. , Anurag Meenakshi , Kim Beom-Jun , Ellis Matthew J.
Published: August 2023

Supplementary Figure 3
Supplementary Figure 1 from Kinase Inhibitor Pulldown Assay Identifies a Chemotherapy Response Signature in Triple-negative Breast Cancer Based on Purine-binding Proteins
Authors: Wang Junkai , Saltzman Alexander B. , Jaehnig Eric J. , Lei Jonathan T. , Malovannaya Anna , Holt Matthew V. , Young Meggie N. , Rimawi Mothaffar F. , Ademuyiwa Foluso O. , Anurag Meenakshi , Kim Beom-Jun , Ellis Matthew J.
Published: August 2023

Supplementary Figure 1
FIGURE 6 from Kinase Inhibitor Pulldown Assay Identifies a Chemotherapy Response Signature in Triple-negative Breast Cancer Based on Purine-binding Proteins
Authors: Wang Junkai , Saltzman Alexander B. , Jaehnig Eric J. , Lei Jonathan T. , Malovannaya Anna , Holt Matthew V. , Young Meggie N. , Rimawi Mothaffar F. , Ademuyiwa Foluso O. , Anurag Meenakshi , Kim Beom-Jun , Ellis Matthew J.
Published: August 2023

The relationship between the KIPA-based PBP signature score, immune scores, and immune checkpoint levels. A, Scatter plot shows the correlation between the KIPA-based PBP signature score and mRNA-based immune scores (from ESTIMATE, Cibersort, and xCell). EST: ESTIMATE, CS: Cibersort, xC: xCell. B, Scatter plot shows the correlation between the KIPA-based PBP signature score and protein-based immune modulator stimulatory or inhibitory scores. C, Scatter plot shows the correlation between the KIPA-based PBP signature score and PD-L1 CPSs from IHC staining. D, Scatter plot shows the correlation between the KIPA-based PBP signature score and PD-L1 phosphoprotein levels.
FIGURE 4 from Kinase Inhibitor Pulldown Assay Identifies a Chemotherapy Response Signature in Triple-negative Breast Cancer Based on Purine-binding Proteins
Authors: Wang Junkai , Saltzman Alexander B. , Jaehnig Eric J. , Lei Jonathan T. , Malovannaya Anna , Holt Matthew V. , Young Meggie N. , Rimawi Mothaffar F. , Ademuyiwa Foluso O. , Anurag Meenakshi , Kim Beom-Jun , Ellis Matthew J.
Published: August 2023

Validation of candidates identified from the KIPA analysis in the BrighTNess dataset. A, The differential proteins from the KIPA analysis were examined in the BrighTNess dataset (Arm A + B) where patients with TNBC were treated with carboplatin and paclitaxel with or without veliparib. The 24,031 genes were ranked on the basis of signed −log10 of P values from Wilcoxon rank-sum tests comparing mRNA levels for pCR samples with RD samples. Positive values indicate higher expression in pCR samples, and negative values indicate higher expression in RD samples. The PBP signature genes were indicated as red dots, and other differential proteins from the KIPA analysis were indicated as either pink (higher in pCR samples) or light blue (higher in non-pCR samples) dots. B, The levels of mRNA-based PBP signature in pCR and RD samples. Boxplots show interquartile range (IQR) with median marked in center. Whiskers indicate 1.5x IQR. P value was determined by Wilcoxon rank-sum test between pCR and RD samples. C, ROC curve analysis to test the validity of mRNA-based PBP signature score and mRNA levels of individual signature genes in discriminating pCR and RD samples. ROC, receiver operating characteristic; AUC, area under the ROC curve.
FIGURE 2 from Kinase Inhibitor Pulldown Assay Identifies a Chemotherapy Response Signature in Triple-negative Breast Cancer Based on Purine-binding Proteins
Authors: Wang Junkai , Saltzman Alexander B. , Jaehnig Eric J. , Lei Jonathan T. , Malovannaya Anna , Holt Matthew V. , Young Meggie N. , Rimawi Mothaffar F. , Ademuyiwa Foluso O. , Anurag Meenakshi , Kim Beom-Jun , Ellis Matthew J.
Published: August 2023

Differential protein analysis between pCR and non-pCR samples. A, Volcano plot shows results from differential analysis between pCR and non-pCR samples with the KIPA. X-axis is the log10 fold change between median value of pCR and non-pCR samples for each protein. Y-axis is the −log10P-value from Wilcoxon rank-sum tests comparing protein levels in pCR samples to non-pCR samples. Red and blue points indicate the most significant (P < 0.01) proteins, and pink and light blue points indicate significant (0.01 < P < 0.05) proteins. B, Heat map shows the levels of seven PBP signature genes across 43 samples, arranged by RCB class (0, I, II, II) and the KIPA-based PBP signature score. The levels of seven genes were assessed at the level of KIPA (orange), protein (light blue), and mRNA (pink), and normalized across all samples by z-score. P values were determined by Wilcoxon rank-sum tests comparing gene levels for pCR samples to non-pCR samples. PBP signature, purine-binding protein signature.
FIGURE 1 from Kinase Inhibitor Pulldown Assay Identifies a Chemotherapy Response Signature in Triple-negative Breast Cancer Based on Purine-binding Proteins
Authors: Wang Junkai , Saltzman Alexander B. , Jaehnig Eric J. , Lei Jonathan T. , Malovannaya Anna , Holt Matthew V. , Young Meggie N. , Rimawi Mothaffar F. , Ademuyiwa Foluso O. , Anurag Meenakshi , Kim Beom-Jun , Ellis Matthew J.
Published: August 2023

The application of the KIPA in the CPTAC-TNBC samples. A, Overview of the 43 pretreatment biopsy samples used in this study (14 pCR samples and 29 non-pCR samples). The biopsy samples were accrued from patients with TNBC enrolled in two clinical trials (NCT02547987 and NCT02124902) who were treated with six cycles of docetaxel and carboplatin (14). pCR, RCB class, omics data availability, and molecular subtypes were obtained from previous publication (16) and are indicated via color-coded annotation tracks. B, The workflow of KIPA was similar as described previously (13). Native lysates from OCT-embedded biopsy samples were incubated with homemade kinobeads (9 inhibitor bead cocktail) for 1 hour, followed by multiple washing steps and in-solution digestion. Quantitative MS was used for accurate identification and quantification. C, Protein classes of total 2,641 proteins detected by KIPA in 43 biopsy samples. KI-L, lipid kinase; KI-P, protein kinase, KI-M, metabolic kinase, KI-X, uncategorized kinase. D, Top 20 molecular function terms of GO ORA with a total of 2,641 proteins detected by KIPA. The color of each dot represents the significance (P-value) of enrichment, and the size is proportional to the overlapping number between 2,641 proteins and each term (also indicated by the labeled number). The red text denotes kinase-associated function while green denotes nucleotide-associated functions.
Adalimumab-Induced Paradoxical Psoriasis Treated with Biologics Targeting the IL-17/IL-23 Axis in Patients with Hidradenitis Suppurativa
Authors: Tsiogka Aikaterini , Liakou Aikaterini I. , Agiasofitou Efthimia , Gregoriou Stamatis , Stratigos Alexander , Rigopoulos Dimitrios , Kontochristopoulos Georgios
Published: August 2023

Background: Paradoxical psoriasis (PP) has been mainly described in patients receiving tumor necrosis factor-α (TNFα) inhibitors for inflammatory bowel disease or psoriasis vulgaris, while such data in the context of hidradenitis suppurativa (HS) are scarce. The purpose of this study was to demonstrate the course of PP and the underlying HS upon switching from adalimumab to a biologic agent targeting the interleukin (IL)-17/IL-23 axis. Methods: The electronic medical database of the outpatient department for HS of a tertiary hospital for skin diseases was searched to identify patients with moderate-to-severe HS under treatment with adalimumab, who developed PP and were switched to biological therapy with an IL-17 or IL-23 inhibitor between February 2016 and January 2022. Disease assessment scores were evaluated at baseline, at time of PP development, as well as six and 12 months thereafter. Results: Among the 83 patients who received adalimumab for the treatment of HS between February 2016 and January 2022, 10 patients (12%) developed paradoxical psoriasiform skin reactions after a median time of seven (range, 2–48) months. There were four females (40%) and six males (60%) with a median age of 42.5 (range, 33–56) years. Five patients presented with plaque psoriasis and five with palmoplantar pustulosis, while four had intertriginous and three nail involvement. In most of the patients, HS responded well to adalimumab at onset of PP. Eight patients were changed to secukinumab, one to ustekinumab, and one to risankizumab. HS further improved in all but 2 patients, one receiving secukinumab and one receiving risankizumab. In addition, all patients achieved improvement of PP. Conclusion: Despite the small number of patients, this study provides support that patients with adalimumab-induced PP may benefit from biologics targeting the IL-17/IL-23 axis. Further studies are needed to establish the optimal therapeutic strategy of the anti-TNFα-induced PP in the context of HS.
High Osmol Gap Hyponatremia Caused by Icodextrin: A Case Series Report
Authors: de Fijter Caroline W. H. , Stachowska-Pietka Joanna , Waniewski Jacek , Lindholm Bengt
Published: August 2023

Recently, hyperosmolar hyponatremia following excessive off-label use of two exchanges of 2 L icodextrin daily during peritoneal dialysis (PD) was reported. We encountered a cluster of 3 cases of PD patients who developed hyperosmolar hyponatremia during on-label use of icodextrin. This appeared to be due to absorption of icodextrin since after stopping icodextrin, the serum sodium level and osmol gap returned to normal, while a rechallenge again resulted in hyperosmolar hyponatremia. We excluded higher than usual concentrations of specific fractions of dextrins in fresh icodextrin dialysis fluid (lot numbers of used batches were checked by manufacturer). We speculate that in our patients, either an exaggerated degradation of polysaccharide chains by α-amylase activity in dialysate, lymph, and interstitium and/or rapid hydrolysis of the absorbed larger degradation products in the circulation may have contributed to the hyperosmolality observed, with the concentration of oligosaccharides exceeding the capacity of intracellular enzymes (in particular maltase) to metabolize these products to glucose. Both hyponatremia and hyperosmolality are risk factors for poor outcomes in PD patients. Less conventional PD prescriptions such as off-label use of two exchanges of 2 L icodextrin might raise the risk of this threatening side effect. This brief report is intended to create awareness of a rare complication of on-label icodextrin use in a subset of PD patients and/or PD prescriptions.