bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Table S9 from Spatial Gene-Expression Profiling Unveils Immuno-oncogenic Programs of NF1-Associated Peripheral Nerve Sheath Tumor Progression
Authors: Mitchell Dana K. , Burgess Breanne , White Emily E. , Smith Abbi E. , Sierra Potchanant Elizabeth A. , Mang Henry , Hickey Brooke E. , Lu Qingbo , Qian Shaomin , Bessler Waylan , Li Xiaohong , Jiang Li , Brewster Kylee , Temm Constance , Horvai Andrew , Albright Eric A. , Fishel Melissa L. , Pratilas Christine A. , Angus Steven P. , Clapp D. Wade , Rhodes Steven D.
Published: March 2024

PathView normalized signature scores for biological pathways relevant to tumor progression, immune response and tumor microenvironment for each sample.
Supplementary Table S8 from Spatial Gene-Expression Profiling Unveils Immuno-oncogenic Programs of NF1-Associated Peripheral Nerve Sheath Tumor Progression
Authors: Mitchell Dana K. , Burgess Breanne , White Emily E. , Smith Abbi E. , Sierra Potchanant Elizabeth A. , Mang Henry , Hickey Brooke E. , Lu Qingbo , Qian Shaomin , Bessler Waylan , Li Xiaohong , Jiang Li , Brewster Kylee , Temm Constance , Horvai Andrew , Albright Eric A. , Fishel Melissa L. , Pratilas Christine A. , Angus Steven P. , Clapp D. Wade , Rhodes Steven D.
Published: March 2024

Pairwise differential gene expression analysis comparing Cluster 1 (n=14), Cluster 2 (n=10), and Cluster 3 (n=11) tumors.
Supplementary Table S5 from Spatial Gene-Expression Profiling Unveils Immuno-oncogenic Programs of NF1-Associated Peripheral Nerve Sheath Tumor Progression
Authors: Mitchell Dana K. , Burgess Breanne , White Emily E. , Smith Abbi E. , Sierra Potchanant Elizabeth A. , Mang Henry , Hickey Brooke E. , Lu Qingbo , Qian Shaomin , Bessler Waylan , Li Xiaohong , Jiang Li , Brewster Kylee , Temm Constance , Horvai Andrew , Albright Eric A. , Fishel Melissa L. , Pratilas Christine A. , Angus Steven P. , Clapp D. Wade , Rhodes Steven D.
Published: March 2024

Normalized count matrix. Probes with raw counts below threshold were excluded.
Supplementary Table S4 from Spatial Gene-Expression Profiling Unveils Immuno-oncogenic Programs of NF1-Associated Peripheral Nerve Sheath Tumor Progression
Authors: Mitchell Dana K. , Burgess Breanne , White Emily E. , Smith Abbi E. , Sierra Potchanant Elizabeth A. , Mang Henry , Hickey Brooke E. , Lu Qingbo , Qian Shaomin , Bessler Waylan , Li Xiaohong , Jiang Li , Brewster Kylee , Temm Constance , Horvai Andrew , Albright Eric A. , Fishel Melissa L. , Pratilas Christine A. , Angus Steven P. , Clapp D. Wade , Rhodes Steven D.
Published: March 2024

Housekeeping genes selected for normalization by geNorm based on their variance across the data set.
Supplementary Figure S3 from Spatial Gene-Expression Profiling Unveils Immuno-oncogenic Programs of NF1-Associated Peripheral Nerve Sheath Tumor Progression
Authors: Mitchell Dana K. , Burgess Breanne , White Emily E. , Smith Abbi E. , Sierra Potchanant Elizabeth A. , Mang Henry , Hickey Brooke E. , Lu Qingbo , Qian Shaomin , Bessler Waylan , Li Xiaohong , Jiang Li , Brewster Kylee , Temm Constance , Horvai Andrew , Albright Eric A. , Fishel Melissa L. , Pratilas Christine A. , Angus Steven P. , Clapp D. Wade , Rhodes Steven D.
Published: March 2024

Supplemental Figure 3.  PNF, ANNUBP, and MPNST exhibit distinct global gene expression programs.
Supplementary Figure S11 from Spatial Gene-Expression Profiling Unveils Immuno-oncogenic Programs of NF1-Associated Peripheral Nerve Sheath Tumor Progression
Authors: Mitchell Dana K. , Burgess Breanne , White Emily E. , Smith Abbi E. , Sierra Potchanant Elizabeth A. , Mang Henry , Hickey Brooke E. , Lu Qingbo , Qian Shaomin , Bessler Waylan , Li Xiaohong , Jiang Li , Brewster Kylee , Temm Constance , Horvai Andrew , Albright Eric A. , Fishel Melissa L. , Pratilas Christine A. , Angus Steven P. , Clapp D. Wade , Rhodes Steven D.
Published: March 2024

Supplemental Figure 11. Diagnostic performance of a three gene signature (CXCL8, HLA-DQB1 and IL6) to identify neurofibromas contiguous with MPNST.
Table S6 from CD46-Targeted Theranostics for PET and 225Ac-Radiopharmaceutical Therapy of Multiple Myeloma
Authors: Wadhwa Anju , Wang Sinan , Patiño-Escobar Bonell , Bidkar Anil P. , Bobba Kondapa Naidu , Chan Emily , Meher Niranjan , Bidlingmaier Scott , Su Yang , Dhrona Suchi , Geng Huimin , Sarin Vishesh , VanBrocklin Henry F. , Wilson David M. , He Jiang , Zhang Li , Steri Veronica , Wong Sandy W. , Martin Thomas G. , Seo Youngho , Liu Bin , Wiita Arun P. , Flavell Robert R.
Published: March 2024

Table S6: %IA/Organ of [89Zr]Zr-DFO-IgG (non-specific) in subcutaneous MM.1S tumor model.
Table S5 from CD46-Targeted Theranostics for PET and 225Ac-Radiopharmaceutical Therapy of Multiple Myeloma
Authors: Wadhwa Anju , Wang Sinan , Patiño-Escobar Bonell , Bidkar Anil P. , Bobba Kondapa Naidu , Chan Emily , Meher Niranjan , Bidlingmaier Scott , Su Yang , Dhrona Suchi , Geng Huimin , Sarin Vishesh , VanBrocklin Henry F. , Wilson David M. , He Jiang , Zhang Li , Steri Veronica , Wong Sandy W. , Martin Thomas G. , Seo Youngho , Liu Bin , Wiita Arun P. , Flavell Robert R.
Published: March 2024

Table S5: Biodistribution analysis %IA/g of [89Zr]Zr-DFO-IgG (non-specific) in subcutaneous MM.1S tumor model.
Table S34 from CD46-Targeted Theranostics for PET and 225Ac-Radiopharmaceutical Therapy of Multiple Myeloma
Authors: Wadhwa Anju , Wang Sinan , Patiño-Escobar Bonell , Bidkar Anil P. , Bobba Kondapa Naidu , Chan Emily , Meher Niranjan , Bidlingmaier Scott , Su Yang , Dhrona Suchi , Geng Huimin , Sarin Vishesh , VanBrocklin Henry F. , Wilson David M. , He Jiang , Zhang Li , Steri Veronica , Wong Sandy W. , Martin Thomas G. , Seo Youngho , Liu Bin , Wiita Arun P. , Flavell Robert R.
Published: March 2024

Table S34: %IA/Organ of [89Zr]Zr-DFO-IgG in systemic MM.1S tumor model.
Table S29 from CD46-Targeted Theranostics for PET and 225Ac-Radiopharmaceutical Therapy of Multiple Myeloma
Authors: Wadhwa Anju , Wang Sinan , Patiño-Escobar Bonell , Bidkar Anil P. , Bobba Kondapa Naidu , Chan Emily , Meher Niranjan , Bidlingmaier Scott , Su Yang , Dhrona Suchi , Geng Huimin , Sarin Vishesh , VanBrocklin Henry F. , Wilson David M. , He Jiang , Zhang Li , Steri Veronica , Wong Sandy W. , Martin Thomas G. , Seo Youngho , Liu Bin , Wiita Arun P. , Flavell Robert R.
Published: March 2024

Table S29: [89Zr]Zr-DFO-YS5 %IA/g in the RPMI8266 systemic tumor model.
Table S2 from CD46-Targeted Theranostics for PET and 225Ac-Radiopharmaceutical Therapy of Multiple Myeloma
Authors: Wadhwa Anju , Wang Sinan , Patiño-Escobar Bonell , Bidkar Anil P. , Bobba Kondapa Naidu , Chan Emily , Meher Niranjan , Bidlingmaier Scott , Su Yang , Dhrona Suchi , Geng Huimin , Sarin Vishesh , VanBrocklin Henry F. , Wilson David M. , He Jiang , Zhang Li , Steri Veronica , Wong Sandy W. , Martin Thomas G. , Seo Youngho , Liu Bin , Wiita Arun P. , Flavell Robert R.
Published: March 2024

Table S2: %IA/Organ of [89Zr]Zr-DFO-YS5 in subcutaneous MM.1S tumor model.
Table S1 from CD46-Targeted Theranostics for PET and 225Ac-Radiopharmaceutical Therapy of Multiple Myeloma
Authors: Wadhwa Anju , Wang Sinan , Patiño-Escobar Bonell , Bidkar Anil P. , Bobba Kondapa Naidu , Chan Emily , Meher Niranjan , Bidlingmaier Scott , Su Yang , Dhrona Suchi , Geng Huimin , Sarin Vishesh , VanBrocklin Henry F. , Wilson David M. , He Jiang , Zhang Li , Steri Veronica , Wong Sandy W. , Martin Thomas G. , Seo Youngho , Liu Bin , Wiita Arun P. , Flavell Robert R.
Published: March 2024

Table S1: Biodistribution analysis %IA/g of [89Zr]Zr-DFO-YS5 in subcutaneous MM.1S tumor model.
Figure S6 from CD46-Targeted Theranostics for PET and 225Ac-Radiopharmaceutical Therapy of Multiple Myeloma
Authors: Wadhwa Anju , Wang Sinan , Patiño-Escobar Bonell , Bidkar Anil P. , Bobba Kondapa Naidu , Chan Emily , Meher Niranjan , Bidlingmaier Scott , Su Yang , Dhrona Suchi , Geng Huimin , Sarin Vishesh , VanBrocklin Henry F. , Wilson David M. , He Jiang , Zhang Li , Steri Veronica , Wong Sandy W. , Martin Thomas G. , Seo Youngho , Liu Bin , Wiita Arun P. , Flavell Robert R.
Published: March 2024

Figure S6: [89Zr]Zr-DFO-IgG PET imaging in the MM.1S systemic model demonstrates high nonspecific uptake in the bone marrow.
Figure S10 from CD46-Targeted Theranostics for PET and 225Ac-Radiopharmaceutical Therapy of Multiple Myeloma
Authors: Wadhwa Anju , Wang Sinan , Patiño-Escobar Bonell , Bidkar Anil P. , Bobba Kondapa Naidu , Chan Emily , Meher Niranjan , Bidlingmaier Scott , Su Yang , Dhrona Suchi , Geng Huimin , Sarin Vishesh , VanBrocklin Henry F. , Wilson David M. , He Jiang , Zhang Li , Steri Veronica , Wong Sandy W. , Martin Thomas G. , Seo Youngho , Liu Bin , Wiita Arun P. , Flavell Robert R.
Published: March 2024

Figure S10: Histological analysis of organs of a mouse injected with a fractionated dose of 0.125 µCi of [225Ac]Ac-DOTA-YS5 showed no sign of toxicity.
Supplementary Table S3 from Phase I Trial of First-line Bintrafusp Alfa in Patients with Locally Advanced or Persistent/Recurrent/Metastatic Cervical Cancer
Authors: Oaknin Ana , Ghamande Sharad A. , Kasamatsu Yuka , Gil-Martin Marta , Grau-Bejar Juan Francisco , Garcia-Duran Carmen , Sato Masashi , Siddiqui Abdul , Chaudhary Surendra Pal , Vugmeyster Yulia , Hasegawa Kosei
Published: March 2024

Table S3. Serious treatment-related adverse events. Bleeding events: a One patient had two consecutive hematuria events, and another patient also had two events, the first episode related to bevacizumab, the second episode due to bintrafusp alfa. All hematuria events resolved within 4-6 weeks. b One patient treated with blood transfusion and vaginal tamponade, resolved within 2 days; other patient required blood transfusion and event resolved within 3 weeks. c Patient presented with bloody diarrhea and stomach discomfort, assessed as being caused by late radiation therapy and a rectal ulcer due to bevacizumab use; resolved with fasting and fluid replacement within 2 weeks. d Mucosal bleeding assessed as being caused by bintrafusp alfa and bevacizumab use; resolved with blood transfusion. e One event resolved with tumor compression by gauze and blood transfusion within a few days. f Bleeding in the duodenum resolved with standard gastrointestinal medication and fluid replacement within one week. g Rectal bleeding along with urinary tract infection; patient treated in emergency room with antibiotics and discontinuation of heparin for prior thrombosis, symptoms resolved within 2 weeks. AE, adverse event; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2.
Data from GATA-3–dependent Gene Transcription is Impaired upon HDAC Inhibition
Authors: Geng Xiangrong , Wang Chenguang , Abdelrahman Suhaib , Perera Thilini , Saed Badeia , Hu Ying S. , Wolfe Ashley , Reneau John , Murga-Zamalloa Carlos , Wilcox Ryan A.
Published: March 2024

AbstractPurpose:
Many peripheral and cutaneous T-cell lymphoma (CTCL) subtypes are poorly responsive to conventional chemotherapeutic agents and associated with dismal outcomes. The zinc finger transcription factor GATA-3 and the transcriptional program it instigates are oncogenic and highly expressed in various T-cell neoplasms. Posttranslational acetylation regulates GATA-3 DNA binding and target gene expression. Given the widespread use of histone deacetylase inhibitors (HDACi) in relapsed/refractory CTCL, we sought to examine the extent to which these agents attenuate the transcriptional landscape in these lymphomas.
Experimental Design:
Integrated GATA-3 chromatin immunoprecipitation sequencing and RNA sequencing analyses were performed in complementary cell line models and primary CTCL specimens treated with clinically available HDACi.
Results:
We observed that exposure to clinically available HDACi led to significant transcriptional reprogramming and increased GATA-3 acetylation. HDACi-dependent GATA-3 acetylation significantly impaired both its ability to bind DNA and transcriptionally regulate its target genes, thus leading to significant transcriptional reprogramming in HDACi-treated CTCL.
Conclusions:
Beyond shedding new light on the mechanism of action associated with HDACi in CTCL, these findings have significant implications for their use, both as single agents and in combination with other novel agents, in GATA-3–driven lymphoproliferative neoplasms.
Data from CD46-Targeted Theranostics for PET and 225Ac-Radiopharmaceutical Therapy of Multiple Myeloma
Authors: Wadhwa Anju , Wang Sinan , Patiño-Escobar Bonell , Bidkar Anil P. , Bobba Kondapa Naidu , Chan Emily , Meher Niranjan , Bidlingmaier Scott , Su Yang , Dhrona Suchi , Geng Huimin , Sarin Vishesh , VanBrocklin Henry F. , Wilson David M. , He Jiang , Zhang Li , Steri Veronica , Wong Sandy W. , Martin Thomas G. , Seo Youngho , Liu Bin , Wiita Arun P. , Flavell Robert R.
Published: March 2024

AbstractPurpose:
Multiple myeloma is a plasma cell malignancy with an unmet clinical need for improved imaging methods and therapeutics. Recently, we identified CD46 as an overexpressed therapeutic target in multiple myeloma and developed the antibody YS5, which targets a cancer-specific epitope on this protein. We further developed the CD46-targeting PET probe [89Zr]Zr-DFO-YS5 for imaging and [225Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of prostate cancer. These prior studies suggested the feasibility of the CD46 antigen as a theranostic target in multiple myeloma. Herein, we validate [89Zr]Zr-DFO-YS5 for immunoPET imaging and [225Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of multiple myeloma in murine models.
Experimental Design:
In vitro saturation binding was performed using the CD46 expressing MM.1S multiple myeloma cell line. ImmunoPET imaging using [89Zr]Zr-DFO-YS5 was performed in immunodeficient (NSG) mice bearing subcutaneous and systemic multiple myeloma xenografts. For radioligand therapy, [225Ac]Ac-DOTA-YS5 was prepared, and both dose escalation and fractionated dose treatment studies were performed in mice bearing MM1.S-Luc systemic xenografts. Tumor burden was analyzed using BLI, and body weight and overall survival were recorded to assess antitumor effect and toxicity.
Results:
[89Zr]Zr-DFO-YS5 demonstrated high affinity for CD46 expressing MM.1S multiple myeloma cells (Kd = 16.3 nmol/L). In vitro assays in multiple myeloma cell lines demonstrated high binding, and bioinformatics analysis of human multiple myeloma samples revealed high CD46 expression. [89Zr]Zr-DFO-YS5 PET/CT specifically detected multiple myeloma lesions in a variety of models, with low uptake in controls, including CD46 knockout (KO) mice or multiple myeloma mice using a nontargeted antibody. In the MM.1S systemic model, localization of uptake on PET imaging correlated well with the luciferase expression from tumor cells. A treatment study using [225Ac]Ac-DOTA-YS5 in the MM.1S systemic model demonstrated a clear tumor volume and survival benefit in the treated groups.
Conclusions:
Our study showed that the CD46-targeted probe [89Zr]Zr-DFO-YS5 can successfully image CD46-expressing multiple myeloma xenografts in murine models, and [225Ac]Ac-DOTA-YS5 can effectively inhibit the growth of multiple myeloma. These results demonstrate that CD46 is a promising theranostic target for multiple myeloma, with the potential for clinical translation.
Supplementary Video 2B from Mitochondria Transfer by Platelet-Derived Microparticles Regulates Breast Cancer Bioenergetic States and Malignant Features
Authors: Veilleux Vanessa , Pichaud Nicolas , Boudreau Luc H. , Robichaud Gilles A.
Published: March 2024

Supplementary Video 2B displays the intracellular localization of internalized fluorescent mitochondria provided by microparticles in MCF7 cells using 3D confocal zStacks imaging.
Supplementary Video 1C from Mitochondria Transfer by Platelet-Derived Microparticles Regulates Breast Cancer Bioenergetic States and Malignant Features
Authors: Veilleux Vanessa , Pichaud Nicolas , Boudreau Luc H. , Robichaud Gilles A.
Published: March 2024

Supplementary Video 1C displays the intracellular localization of internalized fluorescent microparticles in MCF10A cells using 3D confocal zStacks imaging.
Supplementary Video 1A from Mitochondria Transfer by Platelet-Derived Microparticles Regulates Breast Cancer Bioenergetic States and Malignant Features
Authors: Veilleux Vanessa , Pichaud Nicolas , Boudreau Luc H. , Robichaud Gilles A.
Published: March 2024

Supplementary Video 1A displays the intracellular localization of internalized fluorescent microparticles in MB231 cells using 3D confocal zStacks imaging.
Supplementary Figure 6 from Mitochondria Transfer by Platelet-Derived Microparticles Regulates Breast Cancer Bioenergetic States and Malignant Features
Authors: Veilleux Vanessa , Pichaud Nicolas , Boudreau Luc H. , Robichaud Gilles A.
Published: March 2024

Figure S6 demonstrates the impact of microparticle freezing treatments have on mitochondrial function. Frozen microparticles have complete disruption of mitochondrial activities.
Supplementary Figure 2 from Single-Cell Transcriptomics Reveals Pre-existing COVID-19 Vulnerability Factors in Lung Cancer Patients
Authors: Liu Wendao , Li Wenbo , Zhao Zhongming
Published: March 2024

Supplementary Figure 2. ACE2 expression in alveolar and airway epithelial cells from COVID-19 and lung cancers.
Figure S4 from TNFRSF19 within the 13q12.12 Risk Locus Functions as a Lung Cancer Suppressor by Binding Wnt3a to Inhibit Wnt/β-Catenin Signaling
Authors: Zuo Xianglin , Wang Xuchun , Ma Tingzheng , Chen Shuhan , Cao Pingping , Cheng He , Yang Nan , Han Xiao , Gao Wei , Liu Xiaoyu , Sun Yujie
Published: March 2024

A diagram of the construction of fluorescent vectors for the FRET experiments.
Figure S3 from TNFRSF19 within the 13q12.12 Risk Locus Functions as a Lung Cancer Suppressor by Binding Wnt3a to Inhibit Wnt/β-Catenin Signaling
Authors: Zuo Xianglin , Wang Xuchun , Ma Tingzheng , Chen Shuhan , Cao Pingping , Cheng He , Yang Nan , Han Xiao , Gao Wei , Liu Xiaoyu , Sun Yujie
Published: March 2024

Correlation analysis of the TNFRSF19 and the Wnt/β-catenin signaling pathway target gene expression levels in smoker non-small cell lung cancer patients based on GEO database.
Supplemental Figure S2 from Modeling Molecular Pathogenesis of Idiopathic Pulmonary Fibrosis-Associated Lung Cancer in Mice
Authors: Barravecchia Ivana , Lee Jennifer M. , Manassa Jason , Magnuson Brian , Ferris Sarah F. , Cavanaugh Sophia , Steele Nina G. , Espinoza Carlos E. , Galban Craig J. , Ramnath Nithya , Frankel Timothy L. , Pasca di Magliano Marina , Galban Stefanie
Published: March 2024

Supplemental Figure S2. Expression of immune cell surface markers by CyTOF.
Supplementary Table 3 from Single-Cell RNA-Seq Analysis of Patient Myeloid-Derived Suppressor Cells and the Response to Inhibition of Bruton's Tyrosine Kinase
Authors: Savardekar Himanshu , Allen Carter , Jeon Hyeongseon , Li Jianying , Quiroga Dionisia , Schwarz Emily , Wu Richard C. , Zelinskas Sara , Lapurga Gabriella , Abreo Alexander , Stiff Andrew , Shaffer Jami , Blaser Bradley W. , Old Matthew , Wesolowski Robert , Xin Gang , Kendra Kari L. , Chung Dongjun , Carson William E.
Published: March 2024

Head & Neck baseline MDSC gene expression.
Supplementary Table 2 from Single-Cell RNA-Seq Analysis of Patient Myeloid-Derived Suppressor Cells and the Response to Inhibition of Bruton's Tyrosine Kinase
Authors: Savardekar Himanshu , Allen Carter , Jeon Hyeongseon , Li Jianying , Quiroga Dionisia , Schwarz Emily , Wu Richard C. , Zelinskas Sara , Lapurga Gabriella , Abreo Alexander , Stiff Andrew , Shaffer Jami , Blaser Bradley W. , Old Matthew , Wesolowski Robert , Xin Gang , Kendra Kari L. , Chung Dongjun , Carson William E.
Published: March 2024

Table listing patient characteristics of 5 patients from which 7 MDSC samples were processed for single cell RNA-seq.
Supplementary Table 6 from LINC00869 Promotes Hepatocellular Carcinoma Metastasis via Protrusion Formation
Authors: Shao Xiaowen , Dang Yamei , Zhang Tingting , Bai Nan , Huang Jianing , Guo Mengya , Sun Li , Li Minghe , Sun Xiao , Zhang Xinran , Han Feng , Zhang Ning , Zhuang Hao , Li Yongmei
Published: March 2024

Table of key reagents and resources.
Supplementary Figure 4 from Single-Cell RNA-Seq Analysis of Patient Myeloid-Derived Suppressor Cells and the Response to Inhibition of Bruton's Tyrosine Kinase
Authors: Savardekar Himanshu , Allen Carter , Jeon Hyeongseon , Li Jianying , Quiroga Dionisia , Schwarz Emily , Wu Richard C. , Zelinskas Sara , Lapurga Gabriella , Abreo Alexander , Stiff Andrew , Shaffer Jami , Blaser Bradley W. , Old Matthew , Wesolowski Robert , Xin Gang , Kendra Kari L. , Chung Dongjun , Carson William E.
Published: March 2024

Individual UMAP plots melanoma MDSC treated with DMSO control or 5 µM ibrutinib for 4h.
Supplementary Figure 8 from LINC00869 Promotes Hepatocellular Carcinoma Metastasis via Protrusion Formation
Authors: Shao Xiaowen , Dang Yamei , Zhang Tingting , Bai Nan , Huang Jianing , Guo Mengya , Sun Li , Li Minghe , Sun Xiao , Zhang Xinran , Han Feng , Zhang Ning , Zhuang Hao , Li Yongmei
Published: March 2024

WASp promotes cell migration and invasion in HCC cells.
Supplementary Figure 4 from LINC00869 Promotes Hepatocellular Carcinoma Metastasis via Protrusion Formation
Authors: Shao Xiaowen , Dang Yamei , Zhang Tingting , Bai Nan , Huang Jianing , Guo Mengya , Sun Li , Li Minghe , Sun Xiao , Zhang Xinran , Han Feng , Zhang Ning , Zhuang Hao , Li Yongmei
Published: March 2024

LINC00869 promotes actin polymerization and protrusion formation.
Abstract A002: In-silico screening of race-specific endometrial cancer methylation markers using machine learning techniques
Authors: Asif Huma , Foley Grace , Kim Julie
Published: March 2024

Targeted molecular therapy is a promising strategy for cancer treatment. Despite the benefits of these therapies, racial disparities in cancer therapy efficacy persist. To close this racial gap, there is a need to find race-specific biomarkers at the molecular level. Since abnormal DNA methylation has been linked with cancer and has a great potential to transform the diagnosis and treatment of cancer, the main objective of this study was to combine differential DNA methylation and machine learning techniques to identify race-specific methylation signature biomarkers in endometrial tumor samples from White and Black women. We performed genome wide Differentially Methylated CpG (DMCs) analysis in tumors from White patients (TWP) samples compared to tumors from Black patients (TBP) samples using Endometrial Carcinoma (EC) methylation and clinical data from The Cancer Genome Atlas (TCGA). We used supervised and unsupervised machine learning techniques to filter and select signature biomarkers. To evaluate the prognostic capacity of these genes, we performed univariate and multivariate survival analyses using Cox proportional hazards regression model from survival R package. By combining differential methylation CpGs and machine learning techniques, we reduced 704 differentially methylated CpGs to reliable race-specific epigenetic signature genes (ESGs) and Core- epigenetic signature genes (core-ESGs). An area under the curve (AUC) of 0.98 was achieved based on these signature genes. We further found that ESGs showed statistically significant overall survival differences between two racial groups. In addition, comparison of the mutational landscape showed differences in mutation frequencies in the ESGs between the two groups. By combining differential methylation analysis and machine learning techniques, we identified novel race-specific epigenetic signature genes in Black and White women with endometrial cancer. We further showed the potential of these gene in predicting survival differences, mutation, and transcriptomic differences in Black and White women. We propose that combined methylation and somatic mutation profiling of these novel race-specific signature genes can be used to develop potential therapeutic targets for diagnosis and treating endometrial cancer.

Citation Format: Huma Asif, Grace Foley, Julie Kim. In-silico screening of race-specific endometrial cancer methylation markers using machine learning techniques [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A002.
Abstract A012: Genomic landscape of somatic alterations identified in endometrial cancer using liquid biopsy
Authors: Drusbosky Leylah , Haynes Ginger , Grant Brooke , Sobernis Pamela , Lheureux Stephanie
Published: March 2024

Background: With advances in understanding the biology of endometrial cancer, molecular sub-groups have been defined to assess prognosis and guide treatment decisions. This classification is based on surrogate markers in archival paraffin-embedded tissues. The landscape of somatic alterations as detected by liquid biopsy has not been well described in advanced endometrial cancer. Methods: A retrospective analysis was performed using de-identified genomic data collected from patients with advanced endometrial cancer who underwent liquid biopsy testing with a 74-83 gene panel as part of clinical care (Guardant360, Guardant Health, Inc.). Results: 1,988 females with a median age of 68 [range 23-95] years were included in the analysis. 45% of patients were tested at diagnosis of advanced disease; 43% were tested at time of disease progression. 91.6% of patients had ≥1 somatic alteration detected and 12% of patients were MSI-High. The most frequently altered genes included TP53 (65%), PIK3CA (31%), PTEN (27%), ARID1A (24%), like prior reports of genomic alterations detected in tissue samples. CCNE1 amplifications were enriched in 11% of samples with TP53 alterations (p<0.0001; q<0.0001) and EGFR amplifications were enriched in samples without TP53 alterations (p<0.0001; q<0.0001). MSI-H samples were enriched for alterations in ARID1A, PTEN, PIK3CA, ATM, MSH6 and others, while samples without MSI were enriched for alterations in TP53 and CCNE1 (p<0.0001; q<0.0001). Oncogenic fusions were rare in this cohort (0.2%) and included FGFR1 and FGFR3 rearrangements. Activating, druggable alterations were identified in PIK3CA, KRAS, ERBB2, and BRCA1/2. Putative pathogenic germline alterations were detected in 61 (3%) patients and included ATM (18%), BRCA1 (33%), BRCA2 (21%), and lower frequencies of CHEK2, FANCA, MLH1, MSH2, MSH6, and PALB2. Conclusions: While descriptive in nature, this analysis is the largest cohort of advanced endometrial cancer analyzed using a clinically available liquid biopsy assay and demonstrates the feasibility of somatic alteration detection. This report paves the way for using liquid biopsy as a potential tool for guiding targeted chemotherapeutic strategies.

Citation Format: Leylah Drusbosky, Ginger Haynes, Brooke Grant, Pamela Sobernis, Stephanie Lheureux. Genomic landscape of somatic alterations identified in endometrial cancer using liquid biopsy [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A012.
Abstract A019: Autologous patient-derived organoid-immune cell co-culture platform for therapeutics discovery in high-grade endometrial cancer
Authors: Chung Charlie , Nizam Aaron , Yueh Brian , Subhash Santhilal , Frimer Marina , Goldberg Gary L. , Beyaz Semir
Published: March 2024

Endometrial cancer is the most common gynecologic malignancy with increasing incidence and mortality rates. Recurrent endometrial cancers, which are mostly from high-grade endometrial cancers (HGEC), have limited treatment options and display extremely poor response rate upon chemotherapies, thus showing very poor prognosis. Immunotherapy revolutionized the field of cancer medicine, but lack of scalable and sustainable pre-clinical models for HGEC poses a significant challenge in studying critical immunological aspects of HGEC. We therefore established a comprehensive endometrial cancer biobank comprising primary tissues, patient-derived organoids (PDO), and their matching immune cells from all existing HGEC types, enabling us to establish an autologous interaction between cancer and immune cells in vitro. Inactivation of antigen processing and presentation (APP) pathways is one of the major mechanisms for immune evasion in many cancer types including HGEC. Using a subset of our biobank, we performed bulk RNA-seq on 11 normal-cancer PDO pairs and found that genes involved in APP pathways, MHC-II in particular, are downregulated in HGEC organoids. We found that dampened MHC expression can be reverted by external stimuli such as IFNγ and Tazemetostat. We then assessed the effects of enhanced MHC-I and -II expression mediated by the two molecules on cancer-immune cell interactions by setting up organoid-immune cell co-cultures using autologous PBMC, CD4, and CD8 T cells. Our results suggest that cell signaling and epigenetic manipulations on HGEC can be exploited to enhance immune cell-mediated apoptosis. Using our co-culture platform, we next evaluated the efficacy of different immunotherapeutic modalities such as NK cell transfer, bi-specific T-cell engagers, and CAR-T cells on HGEC. Our proof-of-principle experiments demonstrate the utility of our co-culture system in studying the autologous cancer-immune cell interactions from the same patient ex vivo. Our sustainable and scalable testing platform could be used to assess the safety and efficacy of current therapeutics or to identify new therapeutics that enhance immune responses against advanced cancers lacking effective treatment options such as HGEC.

Citation Format: Charlie Chung, Aaron Nizam, Brian Yueh, Santhilal Subhash, Marina Frimer, Gary L. Goldberg, Semir Beyaz. Autologous patient-derived organoid-immune cell co-culture platform for therapeutics discovery in high-grade endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A019.
Abstract A022: Detecting cardiovascular disease risk in early-stage endometrial cancer survivors: preliminary evidence of pulse wave velocity and social vulnerability index
Authors: Bates-Fraser Lauren C. , Bae-Jump Victoria , Stoner Lee , Hanson Erik D.
Published: March 2024

BACKGROUND: Endometrial cancer survivors (ECS) experience high rates of cardiovascular disease (CVD) likely due to lifestyle and social-environmental factors, including high obesity rates up to 60%. Early detection of CVD is crucial in order to intervene; however, strategies to identify ECS most at risk for CVD are currently lacking. The gold-standard methodology to non-invasively measure CVD is pulse wave velocity (PWV), and one way to identify social-environmental susceptibility is the Centers for Disease Control social vulnerability index (SVI). PURPOSE: Therefore, the purpose of this study is to investigate (1) CVD risk in stage 1 ECS using PWV and (2) the social-environmental influence on CVD risk using SVI. METHODS: Stage 1 ECS who were 1-12 months post-treatment, with a BMI ≥ 25.0 kg/m2, age 50-80 years, and English speaking were recruited in the gynecology-oncology clinic. Oscillometric PWV was measured in a supine position via Mobil-O-Graph. Body composition [body fat percentage (%)] was measured via Bioelectrical Impedance Analysis. Participant zip code was used to determine SVI of their county of residence. SVI is defined as low-medium (0.00-0.49), medium-high (0.50-0.69), and high (0.70-1.00). Linear regression was used to compare PWV and SVI. RESULTS: Seventeen ECS (65% White, 25% Black, 5% Asian, 5% American Indian, 64 ± 7 years old, 6 ± 4 months post-treatment, 44 ± 6% body fat) participated in the study. Participants resided in counties with low-medium (18%), medium-high (24%), and high (58%) SVI and PWV was measured as 8.2 ± 0.8 m/s, 9.1 ± 0.8 m/s, and 9.7 ± 1.0 m/s respectively. The overall regression was not statistically significant (R=0.38, R2=0.14, F=1.15, p=0.34). DISCUSSION: Overall, PWV was elevated in ECS residing in counties with medium-high and high SVI categories compared to normative data. PWV can be used to non-invasively measure CVD risk in clinic in early-stage ECS. Despite failing to reach statistical significance, a 1.0 m/s change is considered to be a clinically meaningful difference in PWV. Therefore, ECS residing in counties with high SVI may be at greater CVD risk compared to those living in less vulnerable communities. Further research is needed, including a larger sample size, to identify successful interventions to reduce CVD in ECS most at risk.

Citation Format: Lauren C. Bates-Fraser, Victoria Bae-Jump, Lee Stoner, Erik D. Hanson. Detecting cardiovascular disease risk in early-stage endometrial cancer survivors: preliminary evidence of pulse wave velocity and social vulnerability index [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A022.
Abstract A023: Assessing the reproducibility crisis in vaginal microbiome studies for clinical applications in endometrial cancer
Authors: Dodani Dollina D. , Talhouk Aline
Published: March 2024

Recent associations between vaginal microbiota and gynecological cancer have led to high-throughput sequencing datasets identifying diagnostic biomarkers for Endometrial Cancer (EC). However, lack of bioinformatics standards results in inconsistent independent studies with poor reproducibility, making them clinically inapplicable. This study leverages publicly available amplicon sequence data to address the reproducibility of EC microbiome studies. We implemented bioinformatics pipelines from five studies to reproduce and measure the replicability of published results across cohorts using metrics such as alpha diversity, beta diversity and differentially expressed taxa. We further evaluated separability between benign and cancer patients at different taxonomic levels (phylum, class, order, family, and genus) within and across datasets using boosted tree classifiers and Area Under the Curve (AUC) as the performance metric. While we reproduced the general trend of observing higher microbial diversity in EC compared to healthy controls, we found irregularities in two cohorts. Using beta diversity distance metrics, we identified that histology alone explains less than 3% of the variance in all cohorts. Three microbiome differential abundance methods were used in the five studies. While they all agree on a decrease in the Lactobacillus genus in EC patients, there is no consensus on other taxa associated with EC. We also found that separability between benign and cancerous conditions is highest at the class level, having an AUC score of 0.86. In subsequent steps, we will perform an integrative analysis to identify an EC vaginal microbiome predictive signature that is preserved across all five cohorts, benefiting screening programs.

Citation Format: Dollina D. Dodani, Aline Talhouk. Assessing the reproducibility crisis in vaginal microbiome studies for clinical applications in endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A023.
Abstract IA015: Epigenetic approaches for endometrial cancer
Authors: Zhang Rugang
Published: March 2024

The past decade has brought unprecedented progress in understanding the genetics of endometrial cancer, but cures remain elusive due to the lack of insights into mechanisms that can be leveraged to develop new therapies. Endometrial cancer is genetically heterogeneous and, therefore, it is imperative that therapeutic strategies become personalized by targeting distinct molecular subsets of endometrial cancer. Despite the importance of epigenetic regulators in endometrial cancer, the mechanism of action for these epigenetic regulators and the associated vulnerabilities exposed by their dysregulations have remained elusive for most of them. Here we will discuss our recent work on how to leverage epigenetic mechanisms to address unmet clinical needs in endometrial cancer through integrated approaches.

Citation Format: Rugang Zhang. Epigenetic approaches for endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA015.
Abstract IA017: Spontaneous humoral responses in endometrial cancer provide a rationale for novel tumor-penetrating therapeutic antibodies
Authors: Conejo-Garcia Jose R.
Published: March 2024

The role of humoral responses in endometrial cancer remains insufficiently investigated. Using a cohort of 107 patients with different histological subtypes of endometrial carcinoma, we found that concomitant accumulation of T, B, and plasma cells at tumor beds predicted better survival. However, only B cell markers corresponded with prolonged survival specifically in high-grade endometrioid type and serous tumors. Immune protection was associated with class-switched IgA and, to a lesser extent, IgG. Expression of polymeric immunoglobulin receptor (PIGR) by tumor cells allow dimeric IgA transcytosis. Taking advantage of tumor cell penetration, we demonstrated that mutation-specific dIgA, but not IgG, neutralized KRASG12D inside carcinoma cells and expelled this oncodriver (but not wild-type KRAS) outside tumor cells, abrogating tumor cell proliferation in an antigen-specific manner. Accordingly, KRASG12D-specific dIgA1, but not the same antibody on an IgG backbone, abrogated KRASG12D carcinoma growth in vivo, more effectively than small molecule KRASG12D inhibitors, including in syngeneic tumor-bearing immunocompetent mice. Because >6% of endometrial cancers exhibit KRAS mutations, our results provide a rationale for developing PIGR-targeting tumor cell-penetrating antibodies to effectively target intracellular oncogenes, which could be applicable to many aggressive and frequent human cancers.

Citation Format: Jose R. Conejo-Garcia. Spontaneous humoral responses in endometrial cancer provide a rationale for novel tumor-penetrating therapeutic antibodies [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA017.
Supplementary Table 2 from INX-315, a Selective CDK2 Inhibitor, Induces Cell Cycle Arrest and Senescence in Solid Tumors
Authors: Dietrich Catherine , Trub Alec , Ahn Antonio , Taylor Michael , Ambani Krutika , Chan Keefe T. , Lu Kun-Hui , Mahendra Christabella A. , Blyth Catherine , Coulson Rhiannon , Ramm Susanne , Watt April C. , Matsa Sunil Kumar , Bisi John , Strum Jay , Roberts Patrick , Goel Shom
Published: March 2024

LanthaScreen Eu Kinase Binding and Z’-Lyte Kinase Assay data for INX-315
Figure 6 from INX-315, a Selective CDK2 Inhibitor, Induces Cell Cycle Arrest and Senescence in Solid Tumors
Authors: Dietrich Catherine , Trub Alec , Ahn Antonio , Taylor Michael , Ambani Krutika , Chan Keefe T. , Lu Kun-Hui , Mahendra Christabella A. , Blyth Catherine , Coulson Rhiannon , Ramm Susanne , Watt April C. , Matsa Sunil Kumar , Bisi John , Strum Jay , Roberts Patrick , Goel Shom
Published: March 2024

INX-315 delays the onset of acquired CDK4/6i resistance. A, Representative images from a clonogenic assay in which MCF7 and T47D cells were treated with control vehicle, abemaciclib (500 nmol/L), INX-315 (300 nmol/L for MCF7, 100 nmol/L for T47D), or the combination. Six technical replicates per condition. B, Representative images (right) and quantification (left) after treating MCF7 cells as in A for 7 days followed by staining for beta-galactosidase (β-gal) activity (scale bar = 100 μm). Note that representative images for control and abemaciclib group are identical to those used in Fig. 5A. C, Representative images (right) and quantification of relative nuclear size (left) for cells treated as in B (scale bar = 100 μm). Note that representative images of control and abemaciclib group are identical to those used in Fig. 5B. D, Heat map showing z scores for individual E2F target genes (RNA-sequencing) in MCF7 and T47D cells treated with drugs shown for 7 days at concentrations as in A. Bar plot above shows mean z-score for all genes in each sample. Three technical replicates per condition. E, Tumor growth curves for MMTV-rtTA/tetO-HER2 tumors treated with control vehicle (n = 41 tumors in 5 mice), abemaciclib (n = 40 tumors in 5 mice), INX-315 (n = 39 tumors in 5 mice), or the combination (n = 29 tumors in 5 mice). Experiment was repeated twice. F, GSEA plots derived from RNA-sequencing performed on tumor tissue from experiment (E). Normalized enrichment score (NES) and q value (false discovery rate) were calculated as described in Methods. For B and C, P values calculated using unpaired t test; for E, error bars represent SEM; P values calculated using two-way ANOVA). G, Heat map showing z scores for individual E2F target genes (RNA-sequencing) in MMTV-rtTA/tetO-HER2 tumors from E. Bar plot above shows mean z-score for all genes in each sample. Five samples for vehicle, abemaciclib, and combination; four samples for INX-315.
Supplementary Table S5 from Cancer Mutations Converge on a Collection of Protein Assemblies to Predict Resistance to Replication Stress
Authors: Zhao Xiaoyu , Singhal Akshat , Park Sungjoon , Kong JungHo , Bachelder Robin , Ideker Trey
Published: March 2024

Table S5 Assembly predictive performance in cisplatin-treated cervical cancer.xlsx
Supplementary Figure S5 from Targeting DHX9 Triggers Tumor-Intrinsic Interferon Response and Replication Stress in Small Cell Lung Cancer
Authors: Murayama Takahiko , Nakayama Jun , Jiang Xinpei , Miyata Kenichi , Morris Alexander D. , Cai Kathy Q. , Prasad Rahul M. , Ma Xueying , Efimov Andrey , Belani Neel , Gerstein Emily R. , Tan Yinfei , Zhou Yan , Kim William , Maruyama Reo , Campbell Kerry S. , Chen Lu , Yang Yibin , Balachandran Siddharth , Cañadas Israel
Published: March 2024

CDK9 inhibition rescues the DHX9 depletion effect on cell survival by reducing replication stress
Supplementary Figure S4 from Targeting DHX9 Triggers Tumor-Intrinsic Interferon Response and Replication Stress in Small Cell Lung Cancer
Authors: Murayama Takahiko , Nakayama Jun , Jiang Xinpei , Miyata Kenichi , Morris Alexander D. , Cai Kathy Q. , Prasad Rahul M. , Ma Xueying , Efimov Andrey , Belani Neel , Gerstein Emily R. , Tan Yinfei , Zhou Yan , Kim William , Maruyama Reo , Campbell Kerry S. , Chen Lu , Yang Yibin , Balachandran Siddharth , Cañadas Israel
Published: March 2024

DHX9 depletion decreases cell viability and induces dsRNA and dsDNA antiviral sensing pathways in SCLC cells
Supplementary Figure S3 from Targeting DHX9 Triggers Tumor-Intrinsic Interferon Response and Replication Stress in Small Cell Lung Cancer
Authors: Murayama Takahiko , Nakayama Jun , Jiang Xinpei , Miyata Kenichi , Morris Alexander D. , Cai Kathy Q. , Prasad Rahul M. , Ma Xueying , Efimov Andrey , Belani Neel , Gerstein Emily R. , Tan Yinfei , Zhou Yan , Kim William , Maruyama Reo , Campbell Kerry S. , Chen Lu , Yang Yibin , Balachandran Siddharth , Cañadas Israel
Published: March 2024

DNA damage and R-loop accumulation in DHX9 depleted SCLC cells
Supplementary Figures S1-S9 from Passenger Gene Coamplifications Create Collateral Therapeutic Vulnerabilities in Cancer
Authors: Bei Yi , Bramé Luca , Kirchner Marieluise , Fritsche-Guenther Raphaela , Kunz Severine , Bhattacharya Animesh , Rusu Mara-Camelia , Gürgen Dennis , Dubios Frank P.B. , Köppke Julia K.C. , Proba Jutta , Wittstruck Nadine , Sidorova Olga Alexandra , Chamorro González Rocío , Dorado Garcia Heathcliff , Brückner Lotte , Xu Robin , Giurgiu Mădălina , Rodriguez-Fos Elias , Yu Qinghao , Spanjaard Bastiaan , Koche Richard P. , Schmitt Clemens A. , Schulte Johannes H. , Eggert Angelika , Haase Kerstin , Kirwan Jennifer , Hagemann Anja I.H. , Mertins Philipp , Dörr Jan R. , Henssen Anton G.
Published: March 2024

Legends for supplementarytables and supplementary figures.
Supplementary Figure S1. Passenger genes are frequently co-amplified with oncogenes in cancers.
Supplementary Figure S2. DDX1 is highly expressed when co-amplified with MYCN.
Supplementary Figure S3. Neuroblastoma cell lines with DDX1-MYCN co-amplification depend on mTORC1.
Supplementary Figure S4. Ectopic DDX1 expression does not alter MYCN-driven tumorigenesis in zebrafish.
Supplementary Figure S5.DDX1 expression does not affect tumorigenic properties of cancer cell lines but induces changes in cell size.
Supplementary Figure S6. Aberrant DDX1 overexpression results in mTOCR1 pathway activation.
Supplementary Figure S7. DDX1 interacts with alpha-KGDH complex members and disruption of the DDX1:DLST interaction reduces mTORC1 pathway activation.
Supplementary Figure S8. High DDX1 expression is associated with -KG accumulation and OXPHOS reduction.
Supplementary Figure S9. Aberrant DDX1 expression is associated with increased sensitivity to KG and pharmacological mTORC1 inhibition.
Figure S3 from EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth
Authors: Kuhlmann-Hogan Alexandra , Cordes Thekla , Xu Ziyan , Kuna Ramya S. , Traina Kacie A. , Robles-Oteíza Camila , Ayeni Deborah , Kwong Elizabeth M. , Levy Stellar , Globig Anna-Maria , Nobari Matthew M. , Cheng George Z. , Leibel Sandra L. , Homer Robert J. , Shaw Reuben J. , Metallo Christian M. , Politi Katerina , Kaech Susan M.
Published: March 2024

Figure S3. Lipid import from myeloid cells in the TME.
Data from INX-315, a Selective CDK2 Inhibitor, Induces Cell Cycle Arrest and Senescence in Solid Tumors
Authors: Dietrich Catherine , Trub Alec , Ahn Antonio , Taylor Michael , Ambani Krutika , Chan Keefe T. , Lu Kun-Hui , Mahendra Christabella A. , Blyth Catherine , Coulson Rhiannon , Ramm Susanne , Watt April C. , Matsa Sunil Kumar , Bisi John , Strum Jay , Roberts Patrick , Goel Shom
Published: March 2024

Abstract
Cyclin-dependent kinase 2 (CDK2) is thought to play an important role in driving proliferation of certain cancers, including those harboring CCNE1 amplification and breast cancers that have acquired resistance to CDK4/6 inhibitors (CDK4/6i). The precise impact of pharmacologic inhibition of CDK2 is not known due to the lack of selective CDK2 inhibitors. Here we describe INX-315, a novel and potent CDK2 inhibitor with high selectivity over other CDK family members. Using cell-based assays, patient-derived xenografts (PDX), and transgenic mouse models, we show that INX-315 (i) promotes retinoblastoma protein hypophosphorylation and therapy-induced senescence (TIS) in CCNE1-amplified tumors, leading to durable control of tumor growth; (ii) overcomes breast cancer resistance to CDK4/6i, restoring cell cycle control while reinstating the chromatin architecture of CDK4/6i-induced TIS; and (iii) delays the onset of CDK4/6i resistance in breast cancer by driving deeper suppression of E2F targets. Our results support the clinical development of selective CDK2 inhibitors.
Significance:
INX-315 is a novel, selective inhibitor of CDK2. Our preclinical studies demonstrate activity for INX-315 in both CCNE1-amplified cancers and CDK4/6i–resistant breast cancer. In each case, CDK2 inhibition induces cell cycle arrest and a phenotype resembling cellular senescence. Our data support the development of selective CDK2 inhibitors in clinical trials.

See related commentary by Watts and Spencer, p. 386.

This article is featured in Selected Articles from This Issue, p. 384