bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Table S1 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

HRR gene mutations found in WGS/WES or clinical BRCA1/2 mutational testing.
Supplementary Table S2: Summary of Crowdsourcing Sumbissions Received from FDA Oncology Center of Excellence Crowdsourcing Initiative: Outreach to the Scientific Community to Identify Research Questions for Pooled Analyses of Oncology Clinical Trial Data
Authors: Schneider Julie A. , Eckstein Julia , Goldberg Kirsten B. , Ascione Mark C. , Bailey Thamar , Taylor Kimberly , Coffey Aisha M. , Satchi Darshini , Philips Howard , Sridhara Rajeshwari , Nair Abhilasha , Pazdur Richard , Theoret Marc R.
Published: August 2023

Summary of Crowdsourcing Submissions Received
Supplementary Figure S4 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

Comparisons of fHR scores obtained from different anatomical locations.
Supplementary Table S5 from DNA-Methylome–Based Tumor Hypoxia Classifier Identifies HPV-Negative Head and Neck Cancer Patients at Risk for Locoregional Recurrence after Primary Radiochemotherapy
Authors: Tawk Bouchra , Rein Katrin , Schwager Christian , Knoll Maximilian , Wirkner Ute , Hörner-Rieber Juliane , Liermann Jakob , Kurth Ina , Balermpas Panagiotis , Rödel Claus , Linge Annett , Löck Steffen , Lohaus Fabian , Tinhofer Ingeborg , Krause Mechtild , Stuschke Martin , Grosu Anca Ligia , Zips Daniel , Combs Stephanie E. , Belka Claus , Stenzinger Albrecht , Herold-Mende Christel , Baumann Michael , Schirmacher Peter , Debus Jürgen , Abdollahi Amir
Published: August 2023

Supplementary Table S5. Distribution of clinical and biomarker-related characteristics between Methylation Hypoxia High vs Low in the validation cohort (DKTK-ROG)
Supplementary Figure S1 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

The effects of long time-to-fixation on DNA damage markers
Figure 4 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

fHRD status indicates longer survival in patients treated with PARPi maintenance therapy at recurrence. A, In Kaplan–Meier survival analysis, time-to-progression from PARPi treatment start did not significantly differ between fHRD and fHRP patients. B, OS of patients in the fHRD group was significantly longer than in the fHRP group. (Log-rank, Mantel–Cox test).
Supplementary Figures S2 from DNA-Methylome–Based Tumor Hypoxia Classifier Identifies HPV-Negative Head and Neck Cancer Patients at Risk for Locoregional Recurrence after Primary Radiochemotherapy
Authors: Tawk Bouchra , Rein Katrin , Schwager Christian , Knoll Maximilian , Wirkner Ute , Hörner-Rieber Juliane , Liermann Jakob , Kurth Ina , Balermpas Panagiotis , Rödel Claus , Linge Annett , Löck Steffen , Lohaus Fabian , Tinhofer Ingeborg , Krause Mechtild , Stuschke Martin , Grosu Anca Ligia , Zips Daniel , Combs Stephanie E. , Belka Claus , Stenzinger Albrecht , Herold-Mende Christel , Baumann Michael , Schirmacher Peter , Debus Jürgen , Abdollahi Amir
Published: August 2023

Supplementary Figure S2. (Top) Hypoxia-M V2 is prognostic in the DKTK-ROG cohort. Patients predicted to have higher tumor hypoxia by Hypoxia-M V2 had higher rates of death (p=0.0097), local recurrence (p=0.0037), distant metastasis (p=0.027) and disease progression (p=0.00096). (Bottom) Hypoxia-M V2 remains an independent prognosticator of OS, LR and disease progression after adjusting for age, smoking status, GTV and anatomical site. Additionally, there is a trend towards higher rates of distant metastasis (HR=2.33, p=0.13)
Supplementary Figures S1 from DNA-Methylome–Based Tumor Hypoxia Classifier Identifies HPV-Negative Head and Neck Cancer Patients at Risk for Locoregional Recurrence after Primary Radiochemotherapy
Authors: Tawk Bouchra , Rein Katrin , Schwager Christian , Knoll Maximilian , Wirkner Ute , Hörner-Rieber Juliane , Liermann Jakob , Kurth Ina , Balermpas Panagiotis , Rödel Claus , Linge Annett , Löck Steffen , Lohaus Fabian , Tinhofer Ingeborg , Krause Mechtild , Stuschke Martin , Grosu Anca Ligia , Zips Daniel , Combs Stephanie E. , Belka Claus , Stenzinger Albrecht , Herold-Mende Christel , Baumann Michael , Schirmacher Peter , Debus Jürgen , Abdollahi Amir
Published: August 2023

Supplementary Figure 1. (Top) Venn Diagram showing the intersect between Hypoxia-M V2 significant DMPs (n=3397) and Hypoxia-M V1 significant DMPs (n=5129) 2551 (66%) of significant DMPs identified based on the 85th percentile of standard deviation are also included in the selection criteria of Hypoxia-M V1. (middle) Hypoxia-M V2 is prognostic in the TCGA HNSCC cohort (p=0.041) and the prognostic effect remained independent on multivariate analysis. (bottom) Multivariate Analysis revealed that patients predicted to have high Hypoxia by Hypoxia-M V2 had worsened OS outcomes (HR=1.59, p<0.026). Additionally, increasing age and pN2 nodal status were negatively prognostic of OS (p<0.05)
Supplementary Data 1 from Preclinical Characterization and Phase I Trial Results of INBRX-109, A Third-Generation, Recombinant, Humanized, Death Receptor 5 Agonist Antibody, in Chondrosarcoma
Authors: Subbiah Vivek , Chawla Sant P. , Conley Anthony P. , Wilky Breelyn A. , Tolcher Anthony , Lakhani Nehal J. , Berz David , Andrianov Vasily , Crago William , Holcomb Monica , Hussain Abrahim , Veldstra Carson , Kalabus James , O’Neill Brianne , Senne Lane , Rowell Emily , Heidt Analeah B. , Willis Katelyn M. , Eckelman Brendan P.
Published: August 2023

Supplementary Tables, Figures, and References
Supplementary Appendix S1 from DNA-Methylome–Based Tumor Hypoxia Classifier Identifies HPV-Negative Head and Neck Cancer Patients at Risk for Locoregional Recurrence after Primary Radiochemotherapy
Authors: Tawk Bouchra , Rein Katrin , Schwager Christian , Knoll Maximilian , Wirkner Ute , Hörner-Rieber Juliane , Liermann Jakob , Kurth Ina , Balermpas Panagiotis , Rödel Claus , Linge Annett , Löck Steffen , Lohaus Fabian , Tinhofer Ingeborg , Krause Mechtild , Stuschke Martin , Grosu Anca Ligia , Zips Daniel , Combs Stephanie E. , Belka Claus , Stenzinger Albrecht , Herold-Mende Christel , Baumann Michael , Schirmacher Peter , Debus Jürgen , Abdollahi Amir
Published: August 2023

Statistical Output
Supplementary Figure S3 from The DRD2 Antagonist Haloperidol Mediates Autophagy-Induced Ferroptosis to Increase Temozolomide Sensitivity by Promoting Endoplasmic Reticulum Stress in Glioblastoma
Authors: Shi Linyong , Chen Hanning , Chen Kunxiang , Zhong Chengzong , Song Chong , Huang Yifeng , Wang Tong , Chen Lei , Li Chiyang , Huang Annie , Qi Songtao , Li Hong , Lu Yuntao
Published: August 2023

Fig. S3. HP radiosensitive GBM cells.
Supplementary Figure S1 from The DRD2 Antagonist Haloperidol Mediates Autophagy-Induced Ferroptosis to Increase Temozolomide Sensitivity by Promoting Endoplasmic Reticulum Stress in Glioblastoma
Authors: Shi Linyong , Chen Hanning , Chen Kunxiang , Zhong Chengzong , Song Chong , Huang Yifeng , Wang Tong , Chen Lei , Li Chiyang , Huang Annie , Qi Songtao , Li Hong , Lu Yuntao
Published: August 2023

Fig. S1. HP does not trigger apoptosis in GBM cells.
Supplementary Fig. 2 from Discovery and Targeting of a Noncanonical Mechanism of Sarcoma Resistance to ADI-PEG20 Mediated by the Microenvironment
Authors: Rogers Leonard C. , Kremer Jeff C. , Brashears Caitlyn B. , Lin Zongtao , Hu Zhixian , Bastos Alliny C.S. , Baker Adriana , Fettig Nicole , Zhou Dong , Shoghi Kooresh I. , Dehner Carina A. , Chrisinger John S.A. , Bomalaski John S. , Garcia Benjamin A. , Oyama Toshinao , White Eileen P. , Van Tine Brian A.
Published: August 2023

Supplemental Figure 2. ASS1 expression in spontaneous murine sarcoma cell lines and growth of Ass1 KO tumors in vivo.
Supplementary Data 1 from Genetic Alterations Detected by Circulating Tumor DNA in HER2-Low Metastatic Breast Cancer
Authors: Hensing Whitney L. , Gerratana Lorenzo , Clifton Katherine , Medford Arielle J. , Velimirovic Marko , Shah Ami N. , D'Amico Paolo , Reduzzi Carolina , Zhang Qiang , Dai Charles S. , Denault Elyssa N. , Bagegni Nusayba A. , Opyrchal Mateusz , Ademuyiwa Foluso O. , Bose Ron , Behdad Amir , Ma Cynthia X. , Bardia Aditya , Cristofanilli Massimo , Davis Andrew A.
Published: August 2023

HER2 subtype and genomic alterations for all patients
Supplemental Figure 3 from Genetic Alterations Detected by Circulating Tumor DNA in HER2-Low Metastatic Breast Cancer
Authors: Hensing Whitney L. , Gerratana Lorenzo , Clifton Katherine , Medford Arielle J. , Velimirovic Marko , Shah Ami N. , D'Amico Paolo , Reduzzi Carolina , Zhang Qiang , Dai Charles S. , Denault Elyssa N. , Bagegni Nusayba A. , Opyrchal Mateusz , Ademuyiwa Foluso O. , Bose Ron , Behdad Amir , Ma Cynthia X. , Bardia Aditya , Cristofanilli Massimo , Davis Andrew A.
Published: August 2023

Supplemental Figure 3. Interaction between HER2-positive status and oncogenic pathways on overall survival.
Supplementary Table S3 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

Differentially methylated CpG sites in HER3+ vs HER3- breast cancer samples (HER2+ cohort)
Supplemental Figure 1 from Genetic Alterations Detected by Circulating Tumor DNA in HER2-Low Metastatic Breast Cancer
Authors: Hensing Whitney L. , Gerratana Lorenzo , Clifton Katherine , Medford Arielle J. , Velimirovic Marko , Shah Ami N. , D'Amico Paolo , Reduzzi Carolina , Zhang Qiang , Dai Charles S. , Denault Elyssa N. , Bagegni Nusayba A. , Opyrchal Mateusz , Ademuyiwa Foluso O. , Bose Ron , Behdad Amir , Ma Cynthia X. , Bardia Aditya , Cristofanilli Massimo , Davis Andrew A.
Published: August 2023

Supplemental Figure 1. Mutation distribution for the PIK3CA gene in the overall study population divided by HER2 status.
Supplementary Table S2 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

Baseline characteristics of patients used for genome-wide DNA-methlyation analysis, stratified into HER3-positive and HER3-negative
Supplementary Table S1 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

Protocols used for IHC stainings on the Ventana Benchmark ULTRA device
Supplementary Tables 1 from A Multiparameter Molecular Classifier to Predict Response to Neoadjuvant Lapatinib plus Trastuzumab without Chemotherapy in HER2+ Breast Cancer
Authors: Veeraraghavan Jamunarani , Gutierrez Carolina , De Angelis Carmine , Davis Robert , Wang Tao , Pascual Tomas , Selenica Pier , Sanchez Katherine , Nitta Hiroaki , Kapadia Monesh , Pavlick Anne C. , Galvan Patricia , Rexer Brent , Forero-Torres Andres , Nanda Rita , Storniolo Anna M. , Krop Ian E. , Goetz Matthew P. , Nangia Julie R. , Wolff Antonio C. , Weigelt Britta , Reis-Filho Jorge S. , Hilsenbeck Susan G. , Prat Aleix , Osborne C. Kent , Schiff Rachel , Rimawi Mothaffar F.
Published: August 2023

Supplementary Tables
Figure S5 from A Multiparameter Molecular Classifier to Predict Response to Neoadjuvant Lapatinib plus Trastuzumab without Chemotherapy in HER2+ Breast Cancer
Authors: Veeraraghavan Jamunarani , Gutierrez Carolina , De Angelis Carmine , Davis Robert , Wang Tao , Pascual Tomas , Selenica Pier , Sanchez Katherine , Nitta Hiroaki , Kapadia Monesh , Pavlick Anne C. , Galvan Patricia , Rexer Brent , Forero-Torres Andres , Nanda Rita , Storniolo Anna M. , Krop Ian E. , Goetz Matthew P. , Nangia Julie R. , Wolff Antonio C. , Weigelt Britta , Reis-Filho Jorge S. , Hilsenbeck Susan G. , Prat Aleix , Osborne C. Kent , Schiff Rachel , Rimawi Mothaffar F.
Published: August 2023

Supplementary Figure S5. Decision tree algorithm to construct the multiparameter classifier of response in PAMELA.
Figure S2 from A Multiparameter Molecular Classifier to Predict Response to Neoadjuvant Lapatinib plus Trastuzumab without Chemotherapy in HER2+ Breast Cancer
Authors: Veeraraghavan Jamunarani , Gutierrez Carolina , De Angelis Carmine , Davis Robert , Wang Tao , Pascual Tomas , Selenica Pier , Sanchez Katherine , Nitta Hiroaki , Kapadia Monesh , Pavlick Anne C. , Galvan Patricia , Rexer Brent , Forero-Torres Andres , Nanda Rita , Storniolo Anna M. , Krop Ian E. , Goetz Matthew P. , Nangia Julie R. , Wolff Antonio C. , Weigelt Britta , Reis-Filho Jorge S. , Hilsenbeck Susan G. , Prat Aleix , Osborne C. Kent , Schiff Rachel , Rimawi Mothaffar F.
Published: August 2023

Supplementary Figure S2. Distribution of HER2 gene ratio and protein in the two neoadjuvant cohorts.
Supplementary Data 1 from Bavituximab Decreases Immunosuppressive Myeloid-Derived Suppressor Cells in Newly Diagnosed Glioblastoma Patients
Authors: Ly K. Ina , Richardson Leland G. , Liu Mofei , Muzikansky Alona , Cardona Jonathan , Lou Kevin , Beers Andrew L. , Chang Ken , Brown James M. , Ma Xiaoyue , Reardon David A. , Arrillaga-Romany Isabel C. , Forst Deborah A. , Jordan Justin T. , Lee Eudocia Q. , Dietrich Jorg , Nayak Lakshmi , Wen Patrick Y. , Chukwueke Ugonma , Giobbie-Hurder Anita , Choi Bryan D. , Batchelor Tracy T. , Kalpathy-Cramer Jayashree , Curry William T. , Gerstner Elizabeth R.
Published: August 2023

Supplemental Data
Supplementary Table S3 from Association of Antifolate Response Signature Status and Clinical Activity of Pemetrexed-Platinum Chemotherapy in Non–Small Cell Lung Cancer: The Piedmont Study
Authors: Eisner Joel R. , Mayhew Gregory M. , Davison James M. , Beebe Kirk D. , Shibata Yoichiro , Guo Yuelong , Farhangfar Carol , Farhangfar Farhang , Uronis Joshua M. , Conroy Jeffrey M. , Milburn Michael V. , Hayes David Neil , Mileham Kathryn F.
Published: August 2023

Relationship of the expression of individual genes (ATIC, GART, DHFR, MTHFD1L or TYMS) with survival.
Supplementary Fig. 3 from MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling
Authors: Ghukasyan Razmik , Liang Keke , Chau Kevin , Li Luyi , Chan Charlotte , Abt Evan R. , Le Thuc , Park Joon Y. , Wu Nanping , Premji Alykhan , Damoiseaux Robert , Luu Tony , Labora Amanda , Rashid Khalid , Link Jason M. , Radu Caius G. , Donahue Timothy R.
Published: August 2023

Supplementary Fig. 3 MEK inhibition amplifies STING-induced transcription of IFNB1, IL-6, and TNFA in multiple PDAC cell lines.
Supplementary Fig. 2 from MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling
Authors: Ghukasyan Razmik , Liang Keke , Chau Kevin , Li Luyi , Chan Charlotte , Abt Evan R. , Le Thuc , Park Joon Y. , Wu Nanping , Premji Alykhan , Damoiseaux Robert , Luu Tony , Labora Amanda , Rashid Khalid , Link Jason M. , Radu Caius G. , Donahue Timothy R.
Published: August 2023

Supplementary Fig. 2 Tumor growth is inhibited by STING agonism and MEK inhibition in vivo.
Supplementary Data 3 from Clinical Activity of Combined Telomerase Vaccination and Pembrolizumab in Advanced Melanoma: Results from a Phase I Trial
Authors: Ellingsen Espen B. , O'Day Steven , Mezheyeuski Artur , Gromadka Agnieszka , Clancy Trevor , Kristedja Timothy S. , Milhem Mohammed , Zakharia Yousef
Published: August 2023

Figure S3
Supplementary Figure S5 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 illustrates the relationship between the number of interrogated genes and the sensitivity and specificity values.
Supplementary Figure S2 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

Heat map of mutations according to the highest variant allele frequency per gene in urine samples from cases and controls
Data from DNA-Methylome–Based Tumor Hypoxia Classifier Identifies HPV-Negative Head and Neck Cancer Patients at Risk for Locoregional Recurrence after Primary Radiochemotherapy
Authors: Tawk Bouchra , Rein Katrin , Schwager Christian , Knoll Maximilian , Wirkner Ute , Hörner-Rieber Juliane , Liermann Jakob , Kurth Ina , Balermpas Panagiotis , Rödel Claus , Linge Annett , Löck Steffen , Lohaus Fabian , Tinhofer Ingeborg , Krause Mechtild , Stuschke Martin , Grosu Anca Ligia , Zips Daniel , Combs Stephanie E. , Belka Claus , Stenzinger Albrecht , Herold-Mende Christel , Baumann Michael , Schirmacher Peter , Debus Jürgen , Abdollahi Amir
Published: August 2023

AbstractPurpose:
Tumor hypoxia is a paradigmatic negative prognosticator of treatment resistance in head and neck squamous cell carcinoma (HNSCC). The lack of robust and reliable hypoxia classifiers limits the adaptation of stratified therapies. We hypothesized that the tumor DNA methylation landscape might indicate epigenetic reprogramming induced by chronic intratumoral hypoxia.
Experimental Design:
A DNA-methylome–based tumor hypoxia classifier (Hypoxia-M) was trained in the TCGA (The Cancer Genome Atlas)-HNSCC cohort based on matched assignments using gene expression–based signatures of hypoxia (Hypoxia-GES). Hypoxia-M was validated in a multicenter DKTK-ROG trial consisting of human papillomavirus (HPV)–negative patients with HNSCC treated with primary radiochemotherapy (RCHT).
Results:
Although hypoxia-GES failed to stratify patients in the DKTK-ROG, Hypoxia-M was independently prognostic for local recurrence (HR, 4.3; P = 0.001) and overall survival (HR, 2.34; P = 0.03) but not distant metastasis after RCHT in both cohorts. Hypoxia-M status was inversely associated with CD8 T-cell infiltration in both cohorts. Hypoxia-M was further prognostic in the TCGA-PanCancer cohort (HR, 1.83; P = 0.04), underscoring the breadth of this classifier for predicting tumor hypoxia status.
Conclusions:
Our findings highlight an unexplored avenue for DNA methylation–based classifiers as biomarkers of tumoral hypoxia for identifying high-risk features in patients with HNSCC tumors.

See related commentary by Heft Neal and Brenner, p. 2954
Data from Association of Antifolate Response Signature Status and Clinical Activity of Pemetrexed-Platinum Chemotherapy in Non–Small Cell Lung Cancer: The Piedmont Study
Authors: Eisner Joel R. , Mayhew Gregory M. , Davison James M. , Beebe Kirk D. , Shibata Yoichiro , Guo Yuelong , Farhangfar Carol , Farhangfar Farhang , Uronis Joshua M. , Conroy Jeffrey M. , Milburn Michael V. , Hayes David Neil , Mileham Kathryn F.
Published: August 2023

AbstractPurpose:
The Piedmont study is a prospectively designed retrospective evaluation of a new 48-gene antifolate response signature (AF-PRS) in patients with locally advanced/metastatic nonsquamous (NS) non–small cell lung cancer (NSCLC) treated with pemetrexed-containing platinum doublet chemotherapy (PMX-PDC). The study tested the hypothesis that AF-PRS identifies patients with NS-NSCLC who have a higher likelihood of responding positively to PMX-PDC. The goal was to gather clinical evidence supporting AF-PRS as a potential diagnostic test.
Experimental Design:
Residual pretreatment FFPE tumor samples and clinical data were analyzed from 105 patients treated with first-line (1L) PMX-PDC. Ninety-five patients had sufficient RNA sequencing (RNA-seq) data quality and clinical annotation for inclusion in the analysis. Associations between AF-PRS status and associate genes and outcome measures including progression-free survival (PFS) and clinical response were evaluated.
Results:
Overall, 53% of patients were AF-PRS(+), which was associated with extended PFS, but not overall survival, versus AF-PRS(−) (16.6 months vs. 6.6 months; P = 0.025). In patients who were stage I to III patients at the time of treatment, PFS was further extended in AF-PRS(+) versus AF-PRS(−) (36.2 months vs. 9.3 months; P = 0.03). Complete response (CR) to therapy was noted in 14 of 95 patients. AF-PRS(+) preferentially selected a majority (79%) of CRs, which were evenly split between patients stage I to III (six of seven) and stage IV (five of seven) at the time of treatment.
Conclusions:
AF-PRS identified a significant population of patients with extended PFS and/or clinical response following PMX-PDC treatment. AF-PRS may be a useful diagnostic test for patients indicated for systemic chemotherapy, especially when determining the optimal PDC regimen for locally advanced disease.
Data from Patient-Reported Outcomes as Interradiographic Predictors of Response in Non–Small Cell Lung Cancer
Authors: Bhatt Ambika S. , Schabath Matthew B. , Hoogland Aasha I. , Jim Heather S.L. , Brady-Nicholls Renee
Published: August 2023

AbstractPurpose:
Minimally invasive biomarkers have been used as important indicators of treatment response and progression in cancers such as prostate and ovarian. Unfortunately, all biomarkers are not prognostic in all cancer types and are often not routinely collected. Patient-reported outcomes (PRO) provide a non-obtrusive, personalized measure of a patient's quality of life and symptomatology, reported directly from the patient, and are increasingly collected as part of routine care. Previous literature has shown correlations between specific PROs (i.e., insomnia, fatigue) and overall survival. Although promising, these studies often only consider single time points and ignore patient-specific dynamic changes in individual PROs, which might be early predictors of treatment response or progression.
Experimental Design:
In this study, PRO dynamics were analyzed to determine if they could be used as interradiographic predictors of tumor volume changes among 85 patients with non–small cell lung cancer undergoing immunotherapy. PRO questionnaires and tumor volume scans were completed biweekly and monthly, respectively. Correlation and predictive analysis were conducted to identify specific PROs that could accurately predict patient response.
Results:
Changes in tumor volume over time were significantly correlated with dizziness (P < 0.005), insomnia (P < 0.05), and fatigue (P < 0.05). In addition, cumulative changes in insomnia could predict progressive disease with a 77% accuracy, on average 45 days prior to the next imaging scan.
Conclusions:
This study presents the first time that patient-specific PRO dynamics have been considered to predict how individual patients will respond to treatment. This is an important first step in adapting treatment to improve response rates.
Abstract A012: Investigating the heterogeneity and clinical significance of tumor-associated macrophages in renal cell carcinoma milieu
Authors: Zavacky Evelyn M. , Kim Minjun , Madrigal Ariel , Mehrjoo Zohreh , Spicer Jonathon , Tanguay Simon , Brimo Fadi , Najafabadi Hamed , Riazalhosseini Yasser
Published: August 2023

Background: Tumor-associated macrophages (TAMs) exert a range of immunomodulatory functions in the tumor microenvironment (TME) and have been considered key regulators of tumor development. The interactions of TAMs with cancer and stromal cells in the TME have been shown to promote and sustain tumor progression; however, TAMs are largely phenotypically and functionally heterogeneous. Studies at a single-cell level are therefore necessary to understand biological and clinical relevance of heterogeneity of TAMs. Objective: To investigate the heterogeneity of TAM populations in renal cell carcinoma (RCC), the most common form of Kidney cancer, and to determine their connections to patient outcome. Methods and Results: We leverage single-cell RNA sequencing analysis of six primary RCC tumors and three Lung metastatic clear cell RCC (ccRCC) tumors, from which we identified eight TAM and two monocyte clusters shared across all nine patient tissue samples. Differential gene expression and pathway analyses revealed distinct subsets of upregulated genes and cellular pathways activated in each subpopulation. Survival analysis using gene signatures characteristic of each TAM population in datasets of ccRCC tumors (n=533) from TCGA revealed two subpopulations associated with poor patient outcome in ccRCC. Of these, one subpopulation, which we labelled as TAM-8, was characterized by upregulation of pro-inflammatory cytokines, chemokines, and growth factors such as CCL20, CXCL8, and IL1A/B. To our knowledge, this TAM population has not been described in RCC previously. We performed additional in silico functional analyses to further characterize the function of TAM-8 subpopulation, which indicated an active role in promoting immune cell infiltration and angiogenesis via various pro-inflammatory signaling pathways. Conclusion: This study provides new insight into the heterogeneity of TAM populations in RCC and defines CCL20/CXCL8/IL1High TAM-8 population as a potential driver of poor outcome and a candidate therapeutic target.

Citation Format: Evelyn M. Zavacky, Minjun Kim, Ariel Madrigal, Zohreh Mehrjoo, Jonathon Spicer, Simon Tanguay, Fadi Brimo, Hamed Najafabadi, Yasser Riazalhosseini. Investigating the heterogeneity and clinical significance of tumor-associated macrophages in renal cell carcinoma milieu [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 A012.
Abstract A015: Injury-associated transcriptional state transitions in early renal carcinogenesis
Authors: Hirosue Shoko , Ge Jianfeng , Castillon Leticia , Rodrigues Paulo , Bihary Dóra , Speed Alyson , Wesolowski Ludovic , Caraffini Veronica , Warren Anne Y. , Stewart Grant D. , Welsh Sarah J. , Mitchell Thomas J. , Matakidou Athena , Seyednasrollah Fatemeh S. , Samarajiwa Shamith A. , Vanharanta Sakari
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 (PR002) of the Conference Program/Proceedings.

Citation Format: Shoko Hirosue, Jianfeng Ge, Leticia Castillon, Paulo Rodrigues, Dóra Bihary, Alyson Speed, Ludovic Wesolowski, Veronica Caraffini, Anne Y. Warren, Grant D. Stewart, Sarah J. Welsh, Thomas J. Mitchell, Athena Matakidou, Fatemeh S. Seyednasrollah, Shamith A. Samarajiwa, Sakari Vanharanta. Injury-associated transcriptional state transitions in early renal carcinogenesis [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 A015.
Abstract B003: Increasing branched-chain amino acid metabolism reduces clear cell renal cell carcinoma growth
Authors: Coffey Nathan J. , Riscal Romain , Skuli Nicolas , Lesner Nicholas P. , Noji Michael , Jiang Christine , Kim Laura C. , Han Xu , Blair Megan C. , Keith Brian , Arany Zoltan , Simon M. Celeste
Published: August 2023

North America has the highest incidence of renal cancer in the world with the most common subtype being clear cell renal cell carcinoma (ccRCC). Metabolic dysfunction is a hallmark of ccRCC based on molecular analysis and its clear cell histologic appearance due to significant cytoplasmic accumulation of lipid droplets and glycogen. Using publicly available RNA-Seq and proteomic datasets, we identified reduced expression of branched-chain amino acid (BCAA) enzymes BCAA transaminase 2 (BCAT2) and the branched-chain ketoacid dehydrogenase complex (BCKDH) in ccRCC compared to healthy kidney tissue. We validated these results by confirming that BCAT2 and the BCKDH complex are decreased at the mRNA and protein level in ccRCC tumors and cell lines compared to pair-matched normal adjacent kidney tissue. The reduced expression of the BCKDH complex was reinforced at the genome level by copy number loss of BCKDH subunits DBT and BCKDHB, underscoring the selection for suppression of this pathway. Metabolomics analysis then showed that the abundance of BCAAs were decreased in ccRCC tumors. Additionally, public datasets revealed that ccRCC patients presenting low mRNA expression of any of the four BCKDH subunits DBT, BCKDHB, BCKDHA, and DLD have a worse overall survival compared to patients with higher expression. To test if reactivating the BCAA pathway would impact ccRCC growth, I inhibited BCKDK, a kinase that inactivates the BCKDH complex, pharmacologically with BT2 and genetically with shRNA. Multiple ccRCC cell lines demonstrated reduced proliferation due to apoptosis after being treated with shRNA targeting BCKDK. Cell viability could be rescued by the antioxidant N-acetyl cysteine, suggesting loss of BCKDK increased the production of reactive oxygen species (ROS). Flow cytometry showed that knocking down BCKDK increases cellular ROS. Our data reveal that BCAA catabolism is decreased in ccRCC and reactivating the pathway reduces ccRCC growth in vitro by inducing apoptosis through increased production of ROS. This suggests that BCKDK could be a therapeutic target in ccRCC.

Citation Format: Nathan J. Coffey, Romain Riscal, Nicolas Skuli, Nicholas P. Lesner, Michael Noji, Christine Jiang, Laura C. Kim, Xu Han, Megan C. Blair, Brian Keith, Zoltan Arany, M. Celeste Simon. Increasing branched-chain amino acid metabolism reduces clear cell renal cell carcinoma growth [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 B003.
Abstract B016: 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

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR012) of the Conference Program/Proceedings.

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 B016.
Abstract B026: Combined inhibition of mammalian target of rapamycin (mTOR) and survivin augments radiation therapy in renal cell carcinoma
Authors: Pal Krishnendu , Madamsetty Vijay S. , Rachamala Hari K. , Dutta Shamit K. , Wang Enfeng , Mukhopadhyay Debabrata
Published: August 2023

Purpose: Although renal cell carcinoma (RCC) is relatively more resistant to radiation therapy (RT) compared to other cancer indications, recent advances in single-fraction and multi-fraction stereotactic ablative radiotherapy (SABR) made it possible to achieve better outcome and reduce treatment related toxicities. In addition, with studies demonstrating that certain therapeutic agents including chemotherapies can act as radiosensitizers, the idea of combining radiotherapy with those agents are being actively pursued. Among them, mammalian target of rapamycin (mTOR) inhibitor everolimus (E) and survivin inhibitor YM155 (Y) are of special interest since they target multiple RT-resistance mechanisms simultaneously. Additionally, YM155 has been shown to help in overcoming resistance to mTOR inhibitors in various cancer including RCC. Hence, the present study aims to evaluate the efficacy of a tumor-targeted liposomal formulation combining everolimus and YM155 (EY-L) in sensitizing RCC tumors towards radiation. Experimental Design: Previously we developed a tumor-targeted liposomal formulation and used it successfully to deliver multiple drugs for the treatment of RCC in both immune-deficient and immune-competent mouse models. Here we developed a similar formulation combining everolimus and YM155 (EY-L) and assessed its efficacy in RCC cell lines in vitro and in RCC tumors in vivo. We further evaluated the efficacy of EY-L in sensitizing RCC cell lines and tumors towards radiation in vitro using clonogenic assay and in vivo in RCC xenografts in immunodeficient mice and murine RCC models in immunocompetent mice. Results: EY-L (2 mg/kg E, 1.4 mg/kg Y, twice a week intravenous administration) was better than E-L or Y-L, the corresponding single drug loaded formulations in containing the primary tumor growth and improving survival in an immunocompetent syngeneic mouse model of RCC. Furthermore, EY-L leads to significantly higher sensitization of RCC cells towards radiation in vitro than E-L or Y-L. Finally, EY-L was able to sensitize RCC tumors towards radiation therapy in both RCC xenograft and murine RCC model. Conclusion: Taken together, our study demonstrated the efficacy of a strategic combination therapy in sensitizing RCC to radiation therapy using in vitro clonogenic assay and in vivo radiosensitization studies in multiple RCC tumor models.

Citation Format: Krishnendu Pal, Vijay S. Madamsetty, Hari K. Rachamala, Shamit K. Dutta, Enfeng Wang, Debabrata Mukhopadhyay. Combined inhibition of mammalian target of rapamycin (mTOR) and survivin augments radiation therapy 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 B026.
Abstract B028: Tipifarnib synergizes with axitinib in renal cell carcinoma models
Authors: Gatchalian Jovylyn , Kessler Linda , Patel Hetika Vora , Chan Stacia , Burrows Francis , Malik Shivani
Published: August 2023

Clear cell renal cell carcinoma (ccRCC) is a highly vascularized tumor type, primarily due to loss of the Von Hippel-Lindau (VHL) gene that stabilizes hypoxia-inducible factor alpha proteins (HIF1α and HIF2a), primary drivers of the angiogenic response in this cell type. This includes production of angiogenic factors, such as VEGFA, which promotes the formation of blood vessels that provide tumors oxygen, nutrients, and growth factors. Anti-angiogenic tyrosine kinase inhibitors (TKIs) such as the VEGFR1/2/3 inhibitor axitinib have demonstrated therapeutic benefit in RCC patients by exploiting the critical dependency of RCC tumors on their vasculature. However, resistance to TKIs is commonly observed, leading to clinical relapse. Here, we report that the farnesyltransferase inhibitor (FTI), tipifarnib synergizes with axitinib, resulting in tumor regressions in the VHL-mutant RCC cell line-derived xenograft (CDX) models, 786-O and A498, and stasis in VHL-wild type Caki1 CDX and KI-9310 PDX models, despite the modest antitumor activity of either drug as monotherapy. To investigate the mechanism underlying this synergism, we performed immunohistochemical analysis of angiogenic markers in 786-O tumors treated with tipifarnib, axitinib, or the combination. Consistent with its mechanism of action, axitinib alone decreased angiogenesis compared to vehicle, which was evident as reduced expression of endothelial cell (EC) markers in the tumors. The combination of tipifarnib and axitinib, however, led to a further two-fold reduction in EC staining, suggesting that tipifarnib is enhancing the anti-angiogenic effect of axitinib. Further in vitro and in vivo studies are underway to establish the scope and mechanistic underpinnings of the axitinib-tipifarnib effects in RCC.

Citation Format: Jovylyn Gatchalian, Linda Kessler, Hetika Vora Patel, Stacia Chan, Francis Burrows, Shivani Malik. Tipifarnib synergizes with axitinib in renal cell carcinoma models [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 B028.
Abstract IA001: Evidence for a ‘pathway tuning’ model of VHL-associated renal carcinoma
Authors: Ratcliffe Peter J.
Published: August 2023

In clear cell renal carcinoma (RCC), the hypoxia inducible factor (HIF) transcriptional response is unphysiologically activated by mutations that impair or inactivate the von Hippel-Lindau tumour suppressor, which normally acts as a ubiquitin E3 ligase promoting the oxygen dependent proteolysis of hypoxia inducible factor (HIF). The lecture will review evidence for pro- and anti-tumourigenic actions arising from different components of HIF pathway activation in the setting of VHL-associated RCC. This includes evidence from genome-wide association studies (GWAS) that demonstrate a striking association of GWAS signals with cis-acting sequences in the HIF transcriptional system. This supports a ‘pathway tuning’ model in which multiple small selective effects are important in enabling cancer progression in the face of unphysiological activation of very extensive biological pathways. To assess this hypothesis a new experimental model has been developed, which enables the precise tracking of Vhl-inactivated cells. Results on the temporal and spatial effects of Vhl inactivation in kidneys will be presented.

Citation Format: Peter J. Ratcliffe. Evidence for a ‘pathway tuning’ model of VHL-associated renal 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 IA001.
Abstract IA007: A novel strategy to trigger ferroptosis in kidney cancer
Authors: Koh Mei Yee
Published: August 2023

Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is typically initiated by inactivation of the von Hippel Lindau (VHL) gene resulting in constitutive activation of the hypoxia inducible factors, HIF-1α and HIF-2α. VHL loss and HIF activation promote lipid accumulation that increases the sensitivity of ccRCC cells to ferroptosis. Here, we reveal Iron Sulfur Cluster Assembly 2 (ISCA2) as a novel molecular target whose inhibition decreases HIF-1/2α levels and induces ferroptosis specifically in VHL-deficient cells. ISCA2 is a component of the late mitochondrial Iron Sulfur Cluster (L-ISC) assembly complex and ISCA2 inhibition either pharmacologically or using siRNA triggers the iron starvation response, resulting in iron/metals overload and death via ferroptosis. ISCA2 inhibition also decreases HIF-2α protein levels by blocking iron-responsive element (IRE)-dependent translation, and at higher concentrations, also decreases HIF-1α translation through unknown mechanisms. Strikingly, pharmacological inhibition of ISCA2 using a novel, orally available ISCA2 inhibitor significantly reduced ccRCC xenograft growth in vivo, decreased HIF-α levels and increased lipid peroxidation, suggesting increased ferroptosis in vivo. Thus, the targeting of ISCA2 may be a promising therapeutic strategy to inhibit HIF-1/2α and to induce ferroptosis in pVHL deficient cells.

Citation Format: Mei Yee Koh. A novel strategy to trigger ferroptosis 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 IA007.
Abstract IA020: Exploiting cholesterol metabolism for treatment resistant ccRCC patients
Authors: Simon M. Celeste
Published: August 2023

Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets (LDs) comprised primarily of free and esterified cholesterol molecules; however, the functional significance of cholesterol accumulation in ccRCC cells was unknown. We demonstrated that, surprisingly, genes encoding cholesterol biosynthetic pathway enzymes are strongly repressed in ccRCC cells, making them auxotrophic for exogenous cholesterol. Intriguingly, Mendelian randomization analyses of over 31,000 human genomes indicate a causal link between elevated serum levels of high-density lipoprotein (HDL) cholesterol and ccRCC risk. Depriving ccRCC cells of either cholesterol or HDL compromises proliferation and survival in vitro and ccRCC tumor growth in vivo; in contrast, elevated dietary cholesterol promotes tumor growth. We showed that Scavenger Receptor B1 (SCARB1) is uniquely required for cholesterol import by ccRCC cells, and inhibiting SCARB1 expression or activity is sufficient to cause ccRCC cell cycle arrest and apoptosis accompanied by elevated intracellular reactive oxygen species (ROS) levels and decreased PI3K/AKT signaling. Collectively, our data reveal a previously unrecognized cholesterol dependency in ccRCC and implicate SCARB1 as a therapeutic target that may contribute to novel strategies for treating kidney cancer.

Citation Format: M. Celeste Simon. Exploiting cholesterol metabolism for treatment resistant ccRCC patients [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 IA020.
Abstract IA027: New advances in the pathogenesis of renal cell carcinoma in tuberous sclerosis and Birt-Hogg-Dubé syndrome
Authors: Henske Elizabeth
Published: August 2023

Tuberous Sclerosis Complex (TSC) is caused by either TSC1 or TSC2 mutations, resulting in tumors of the brain, heart, skin, and kidney with hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1). Renal cell carcinomas (RCC) in TSC have chromophobe-like histology features. In TSC2-deficient cells, mTORC1 activity toward its canonical (Raptor-dependent) substrates is increased, while the phosphorylation of non-canonical substrates such as TFEB is decreased, leading to nuclear localization and increased activity of TFEB. Remarkably, treatment with the mTORC1 inhibitor Rapamycin or downregulation of Rheb or Raptor shifts the balance of mTORC1 activity toward the non-canonical substrates in TSC2-deficient cells, leading to increased phosphorylation of TFEB and decreased TFEB activity. Knockout of Tfeb abolishes renal pathology in two mouse models of TSC, indicating that this substrate specificity is the critical mediator of renal disease in TSC. Together, our results indicate that the TSC protein complex controls a critical switch in mTORC1 substrate specificity upstream of Rheb and the Rags, and the effects of rapamycin in TSC are mediated by the paradoxical increased activity of mTORC1 towards the non-canonical target TFEB. These findings may shed light on the sporadic form of chromophobe RCC, which is derived from the renal intercalated cells and has several mysterious features including mitochondrial abundance, whole chromosome losses, and high levels of glutathione (50-100 times higher than matched normal kidney). We hypothesize that hyperactivation of TFEB and/or TFE3 may represent a “missing link” to chromophobe RCC, which highly express lysosomal genes and proteins, thereby connecting chromophobe RCC to TSC-associated and BHD-associated RCC and to translocation RCC.

Citation Format: Elizabeth Henske. New advances in the pathogenesis of renal cell carcinoma in tuberous sclerosis and Birt-Hogg-Dubé syndrome [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 IA027.
Abstract PR006: STING is a vulnerability in RCC independent of its innate immunity function
Authors: Liu Pengda , Zhu Zhichuan
Published: August 2023

STING is an innate immune sensor for immune surveillance of viral/bacterial infection and maintenance of an immune-friendly microenvironment to prevent tumorigenesis. However, if and how STING exerts innate immunity-independent function remains elusive. Recently, we find STING expression is increased in renal cell carcinoma (RCC) patients and governs tumor growth through non-canonical innate immune signaling involving mitochondrial ROS maintenance and calcium homeostasis. We identify mitochondrial voltage dependent anion channel VDAC2 as a new STING binding partner. STING depletion potentiates VDAC2/GRP75-mediated MERC (mitochondria-ER contact) formation to increase mitochondrial ROS/calcium levels, impairs mitochondria function and suppresses mTORC1/S6K signaling leading to RCC growth retardation. STING interaction with VDAC2 occurs through STING-C88/C91 palmitoylation and inhibiting STING palmitoyl-transferases ZDHHCs by 2-BP significantly impedes RCC cell growth alone or in combination with sorafenib. Together, our studies reveal an innate immunity-independent function of STING in regulating mitochondrial function and growth in RCC, providing a rationale to target the STING/VDAC2 interaction in treating RCC.

Citation Format: Pengda Liu, Zhichuan Zhu. STING is a vulnerability in RCC independent of its innate immunity function [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 PR006.