bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Comparative Analysis of the Humoral Immune Response to the EBV Proteome across EBV-Related Malignancies
Authors: Argirion Ilona , Pfeiffer Ruth M. , Proietti Carla , Coghill Anna E. , Yu Kelly J. , Middeldorp Jaap M. , Sarathkumara Yomani D. , Hsu Wan-Lun , Chien Yin-Chu , Lou Pei-Jen , Wang Cheng-Ping , Rothman Nathaniel , Lan Qing , Chen Chien-Jen , Mbulaiteye Sam M. , Jarrett Ruth F. , Glimelius Ingrid , Smedby Karin E. , Hjalgrim Henrik , Hildesheim Allan , Doolan Denise L. , Liu Zhiwei
Published: May 2023

AbstractBackground:
Epstein–Barr virus (EBV) is linked to multiple cancers, including classical Hodgkin lymphoma (cHL), endemic Burkitt lymphoma (eBL), nasopharyngeal carcinoma (NPC), and extranodal natural killer/T-cell lymphoma (NKTCL).
Methods:
Anti-EBV IgG and IgA antibody responses targeting 202 sequences from 86 EBV proteins were measured using the same EBV whole proteome array across four case–control studies investigating EBV-positive cHL, eBL, NPC, and NKTCL (407 cases/620 controls). We grouped EBV-targeted antibodies into pathways by immunoglobulin type (IgA and IgG) and life-cycle stage (latent, immediate early lytic, early lytic, late lytic, and glycoprotein) and evaluated their association with each cancer type. In an additional analysis, we focused on the subset of 46 individual antibodies representing the top candidates for each cancer and compared their associations across the four cancer types using multivariable linear regression models.
Results:
IgA antibody responses targeting all EBV life-cycle stages were associated with NPC but limited to anti-early lytic stage for cHL. NPC and eBL were associated with IgG antibodies across the viral life cycle; cHL with antibodies in the early lytic, late lytic and glycoprotein stages; and NKTCL with antibodies in the latent, immediate early lytic and early lytic phases. EBNA3A, BBLF1, BDLF4, and BLRF2 IgG antibodies were associated with all cancer types.
Conclusions:
Our observed similarities and differences across four EBV-associated cancers may inform EBV-related oncogenesis.
Impact:
Understanding the comparative humoral immune response across EBV-related cancers may aid in identifying shared etiologic roles of EBV proteins and inform unique pathogenic processes for each cancer.
Data from Rural, Large Town, and Urban Differences in Optimal Subspecialty Follow-up and Survivorship Care Plan Documentation among Childhood Cancer Survivors
Authors: Noyd David H. , Janitz Amanda E. , Baker Ashley A. , Beasley William H. , Etzold Nancy C. , Kendrick David C. , Oeffinger Kevin C.
Published: May 2023

AbstractBackground:
Children with cancer from rural and nonurban areas face unique challenges. Health equity for this population requires attention to geographic disparities in optimal survivorship-focused care.
Methods:
The Oklahoma Childhood Cancer Survivor Cohort was based on all patients reported to the institutional cancer registry and ≤ 18 years old at diagnosis between January 1, 2005, and September 24, 2014. Suboptimal follow-up was defined as no completed oncology-related clinic visit five to 7 years after their initial diagnosis (survivors were 7–25 years old at end of the follow-up period). The primary predictor of interest was rurality.
Results:
Ninety-four (21%) of the 449 eligible survivors received suboptimal follow-up. There were significant differences (P = 0.01) as 36% of survivors from large towns (n = 28/78) compared with 21% (n = 20/95) and 17% (n = 46/276) of survivors from small town/isolated rural and urban areas received suboptimal follow-up, respectively. Forty-five percent of adolescents at diagnosis were not seen in the clinic compared with 17% of non-adolescents (P < 0.01). An adjusted risk ratio of 2.2 (95% confidence interval, 1.5, 3.2) was observed for suboptimal follow-up among survivors from large towns, compared with survivors from urban areas. Seventy-three percent of survivors (n = 271/369) had a documented survivorship care plan with similar trends by rurality.
Conclusions:
Survivors from large towns and those who were adolescents at the time of diagnosis were more likely to receive suboptimal follow-up care compared with survivors from urban areas and those diagnosed younger than thirteen.
Impact:
Observed geographic disparities in survivorship care will inform interventions to promote equitable care for survivors from nonurban areas.
The Imperative for Population-based Cancer Registration of All Metastatic Cancers
Authors: Stopsack Konrad H. , Plym Anna , Mucci Lorelei A.
Published: May 2023

Metastases are the main cause of morbidity and mortality from solid tumors. Surprisingly, population-based cancer registries in various countries, including the National Cancer Institute's Surveillance, Epidemiology, and End Results program in the United States, only capture data on individuals diagnosed with cancers that are metastatic at diagnosis (M1). Metastatic recurrences of previously diagnosed, initially nonmetastatic tumors are missed. Devasia and colleagues specify an illness-death model for chronic disease and estimate that in prostate cancer, which has a large pool of primary disease that may or may not progress to metastases, about half of all metastatic cancers arise as recurrences from initially nonmetastatic disease. Capturing all incident metastatic cancer cases across all tumor types in population-based cancer registries, not only based on initial stage at diagnosis, would be critical to better understand the disparities in metastatic disease burden and the effectiveness of primary prevention, screening, and therapies for primary and metastatic disease.

See related article by Devasia et al., p. 659
Supplementary Figure S4 from Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial
Authors: Landen Charles N. , Molinero Luciana , Hamidi Habib , Sehouli Jalid , Miller Austin , Moore Kathleen N. , Taskiran Cagatay , Bookman Michael , Lindemann Kristina , Anderson Charles , Berger Regina , Myers Tashanna , Beiner Mario , Reid Thomas , Van Nieuwenhuysen Els , Green Andrew , Okamoto Aikou , Aghajanian Carol , Thaker Premal H. , Blank Stephanie V. , Khor Victor K. , Chang Ching-Wei , Lin Yvonne G. , Pignata Sandro
Published: May 2023

PFS by treatment arm according to TMB status (stratified by treatment approach, disease stage, and ECOG PS). A, TMB-low population. B, TMB-high population. CPB, paclitaxel, carboplatin, and bevacizumab.
Study protocol S1 from Integrating Tumor-Intrinsic and Immunologic Factors to Identify Immunogenic Breast Cancers from a Low-Risk Cohort: Results from the Randomized SweBCG91RT Trial
Authors: Stenmark Tullberg Axel , Sjöström Martin , Niméus Emma , Killander Fredrika , Chang S. Laura , Feng Felix Y. , Speers Corey W. , Pierce Lori J. , Kovács Anikó , Lundstedt Dan , Holmberg Erik , Karlsson Per
Published: May 2023

Protocol for original SweBCG91RT trial
Supplementary Figure S1 from Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial
Authors: Landen Charles N. , Molinero Luciana , Hamidi Habib , Sehouli Jalid , Miller Austin , Moore Kathleen N. , Taskiran Cagatay , Bookman Michael , Lindemann Kristina , Anderson Charles , Berger Regina , Myers Tashanna , Beiner Mario , Reid Thomas , Van Nieuwenhuysen Els , Green Andrew , Okamoto Aikou , Aghajanian Carol , Thaker Premal H. , Blank Stephanie V. , Khor Victor K. , Chang Ching-Wei , Lin Yvonne G. , Pignata Sandro
Published: May 2023

CCNE1 amplifications are mutually exclusive with BRCA1 and BRCA2 mutations.
Supplementary Materials S1 from BRD9 Degradation Disrupts Ribosome Biogenesis in Multiple Myeloma
Authors: Kurata Keiji , Samur Mehmet K. , Liow Priscilla , Wen Kenneth , Yamamoto Leona , Liu Jiye , Morelli Eugenio , Gulla Annamaria , Tai Yu-Tzu , Qi Jun , Hideshima Teru , Anderson Kenneth C.
Published: May 2023

Supplementary Materials
Supplementary Figure S4 from BRD9 Degradation Disrupts Ribosome Biogenesis in Multiple Myeloma
Authors: Kurata Keiji , Samur Mehmet K. , Liow Priscilla , Wen Kenneth , Yamamoto Leona , Liu Jiye , Morelli Eugenio , Gulla Annamaria , Tai Yu-Tzu , Qi Jun , Hideshima Teru , Anderson Kenneth C.
Published: May 2023

BRD9 occupies promoter regions of target gene.
Supplementary Figure S3 from BRD9 Degradation Disrupts Ribosome Biogenesis in Multiple Myeloma
Authors: Kurata Keiji , Samur Mehmet K. , Liow Priscilla , Wen Kenneth , Yamamoto Leona , Liu Jiye , Morelli Eugenio , Gulla Annamaria , Tai Yu-Tzu , Qi Jun , Hideshima Teru , Anderson Kenneth C.
Published: May 2023

BRD9 depletion downregulates expression of ribosome biogenesis genes.
Supplementary Data S2 from BRD9 Degradation Disrupts Ribosome Biogenesis in Multiple Myeloma
Authors: Kurata Keiji , Samur Mehmet K. , Liow Priscilla , Wen Kenneth , Yamamoto Leona , Liu Jiye , Morelli Eugenio , Gulla Annamaria , Tai Yu-Tzu , Qi Jun , Hideshima Teru , Anderson Kenneth C.
Published: May 2023

DifferentialExpression_RNAseq
Figure S8 from Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases
Authors: Von Roemeling Christina A. , Doonan Bently P. , Klippel Kelena , Schultz Daniel , Hoang-Minh Lan , Trivedi Vrunda , Li Chenglong , Russell Rylynn A. , Kanumuri Raju S. , Sharma Abhisheak , Tun Han W. , Mitchell Duane A.
Published: May 2023

Supplemental Figure 8. (a) Representative IHC for Ki67 proliferative marker (pink pseudocolor) in B16F10 MBM tumors isolated on day 7 of treatment (day 12 of study) with vehicle control or CA-4948 (100 mg/kg). GFAP (astrocytes, green pseudocolor), CD45 (red pseudocolor), and DAPI nuclear stain (blue pseudocolor) included, scale bar = 100μm. (b) Quantitative comparison of Ki67 tissue expression shown in panel f between vehicle control (n=5) and CA-4948 (n=5), measured as the % of Ki67 positive cells within total cell population defined by DAPI nuclear count within the tumor area. P-value determined by unpaired t test.
Figure S2 from Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases
Authors: Von Roemeling Christina A. , Doonan Bently P. , Klippel Kelena , Schultz Daniel , Hoang-Minh Lan , Trivedi Vrunda , Li Chenglong , Russell Rylynn A. , Kanumuri Raju S. , Sharma Abhisheak , Tun Han W. , Mitchell Duane A.
Published: May 2023

Supplemental Figure 2. CA-4948 affinity for murine IRAK-4.
Supplementary Table S6 from Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma
Authors: Schoen Robert E. , Boardman Lisa A. , Cruz-Correa Marcia , Bansal Ajay , Kastenberg David , Hur Chin , Dzubinski Lynda , Kaufman Sharon F. , Rodriguez Luz M. , Richmond Ellen , Umar Asad , Szabo Eva , Salazar Andres , McKolanis John , Beatty Pamela , Pai Reetesh K. , Singhi Aatur D. , Jacqueline Camille M. , Bao Riyue , Diergaarde Brenda , McMurray Ryan P. , Strand Carrie , Foster Nathan R. , Zahrieh David M. , Limburg Paul J. , Finn Olivera J.
Published: May 2023

Background Information on Advanced Adenoma
Supplementary Table S4 from Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma
Authors: Schoen Robert E. , Boardman Lisa A. , Cruz-Correa Marcia , Bansal Ajay , Kastenberg David , Hur Chin , Dzubinski Lynda , Kaufman Sharon F. , Rodriguez Luz M. , Richmond Ellen , Umar Asad , Szabo Eva , Salazar Andres , McKolanis John , Beatty Pamela , Pai Reetesh K. , Singhi Aatur D. , Jacqueline Camille M. , Bao Riyue , Diergaarde Brenda , McMurray Ryan P. , Strand Carrie , Foster Nathan R. , Zahrieh David M. , Limburg Paul J. , Finn Olivera J.
Published: May 2023

Adverse Events: Grade 2
Supplementary Table S3 from Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma
Authors: Schoen Robert E. , Boardman Lisa A. , Cruz-Correa Marcia , Bansal Ajay , Kastenberg David , Hur Chin , Dzubinski Lynda , Kaufman Sharon F. , Rodriguez Luz M. , Richmond Ellen , Umar Asad , Szabo Eva , Salazar Andres , McKolanis John , Beatty Pamela , Pai Reetesh K. , Singhi Aatur D. , Jacqueline Camille M. , Bao Riyue , Diergaarde Brenda , McMurray Ryan P. , Strand Carrie , Foster Nathan R. , Zahrieh David M. , Limburg Paul J. , Finn Olivera J.
Published: May 2023

Adverse Events: Grade 1
Supplementary Table S2 from Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma
Authors: Schoen Robert E. , Boardman Lisa A. , Cruz-Correa Marcia , Bansal Ajay , Kastenberg David , Hur Chin , Dzubinski Lynda , Kaufman Sharon F. , Rodriguez Luz M. , Richmond Ellen , Umar Asad , Szabo Eva , Salazar Andres , McKolanis John , Beatty Pamela , Pai Reetesh K. , Singhi Aatur D. , Jacqueline Camille M. , Bao Riyue , Diergaarde Brenda , McMurray Ryan P. , Strand Carrie , Foster Nathan R. , Zahrieh David M. , Limburg Paul J. , Finn Olivera J.
Published: May 2023

MDSC Values by Vaccine Immune Response vs. Non-Response
Supplementary Methods S2 from Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma
Authors: Schoen Robert E. , Boardman Lisa A. , Cruz-Correa Marcia , Bansal Ajay , Kastenberg David , Hur Chin , Dzubinski Lynda , Kaufman Sharon F. , Rodriguez Luz M. , Richmond Ellen , Umar Asad , Szabo Eva , Salazar Andres , McKolanis John , Beatty Pamela , Pai Reetesh K. , Singhi Aatur D. , Jacqueline Camille M. , Bao Riyue , Diergaarde Brenda , McMurray Ryan P. , Strand Carrie , Foster Nathan R. , Zahrieh David M. , Limburg Paul J. , Finn Olivera J.
Published: May 2023

supplementary methods: Detailed laboratory methods
Supplementary Figure S2 from Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma
Authors: Schoen Robert E. , Boardman Lisa A. , Cruz-Correa Marcia , Bansal Ajay , Kastenberg David , Hur Chin , Dzubinski Lynda , Kaufman Sharon F. , Rodriguez Luz M. , Richmond Ellen , Umar Asad , Szabo Eva , Salazar Andres , McKolanis John , Beatty Pamela , Pai Reetesh K. , Singhi Aatur D. , Jacqueline Camille M. , Bao Riyue , Diergaarde Brenda , McMurray Ryan P. , Strand Carrie , Foster Nathan R. , Zahrieh David M. , Limburg Paul J. , Finn Olivera J.
Published: May 2023

MUC1 expression and immune infiltrate in baseline and recurrent adenoma pairs
Supplementary Figure S1 from Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma
Authors: Schoen Robert E. , Boardman Lisa A. , Cruz-Correa Marcia , Bansal Ajay , Kastenberg David , Hur Chin , Dzubinski Lynda , Kaufman Sharon F. , Rodriguez Luz M. , Richmond Ellen , Umar Asad , Szabo Eva , Salazar Andres , McKolanis John , Beatty Pamela , Pai Reetesh K. , Singhi Aatur D. , Jacqueline Camille M. , Bao Riyue , Diergaarde Brenda , McMurray Ryan P. , Strand Carrie , Foster Nathan R. , Zahrieh David M. , Limburg Paul J. , Finn Olivera J.
Published: May 2023

Endpoint titers of plasma antibodies at week 12 amongst vaccine responders
Supplementary Tables S1-7 from CEACAM1 Marks Highly Suppressive Intratumoral Regulatory T Cells for Targeted Depletion Therapy
Authors: Jeon Seung Hyuck , Kang Minyong , Jeon Minwoo , Chung Youseung , Kim A Reum , Lee Yong Joon , Kim Eui-Soon , Nam Heejin , Park Junsik , Lee Jung-Yun , Shin Eui-Cheol , Seo Seong Il , Park Su-Hyung
Published: May 2023

Supplementary Tables S1-7
Supplementary Figures S1-11 from CEACAM1 Marks Highly Suppressive Intratumoral Regulatory T Cells for Targeted Depletion Therapy
Authors: Jeon Seung Hyuck , Kang Minyong , Jeon Minwoo , Chung Youseung , Kim A Reum , Lee Yong Joon , Kim Eui-Soon , Nam Heejin , Park Junsik , Lee Jung-Yun , Shin Eui-Cheol , Seo Seong Il , Park Su-Hyung
Published: May 2023

Supplementary Figures S1-11
Supplementary Table 3 from Genomic Complexity Predicts Resistance to Endocrine Therapy and CDK4/6 Inhibition in Hormone Receptor–Positive (HR+)/HER2-Negative Metastatic Breast Cancer
Authors: Davis Andrew A. , Luo Jingqin , Zheng Tiantian , Dai Chao , Dong Xiaoxi , Tan Lu , Suresh Rama , Ademuyiwa Foluso O. , Rigden Caron , Rearden Timothy P. , Clifton Katherine , Weilbaecher Katherine , Frith Ashley , Tandra Pavan K. , Summa Tracy , Haas Brittney , Thomas Shana , Hernandez-Aya Leonel F. , Peterson Lindsay L. , Wang Xiaohong , Luo Shujun J. , Zhou Kemin , Du Pan , Jia Shidong , King Bonnie L. , Krishnamurthy Jairam , Ma Cynthia X.
Published: May 2023

Gene alterations associated with shorter PFS.
Supplementary Table 1 from Genomic Complexity Predicts Resistance to Endocrine Therapy and CDK4/6 Inhibition in Hormone Receptor–Positive (HR+)/HER2-Negative Metastatic Breast Cancer
Authors: Davis Andrew A. , Luo Jingqin , Zheng Tiantian , Dai Chao , Dong Xiaoxi , Tan Lu , Suresh Rama , Ademuyiwa Foluso O. , Rigden Caron , Rearden Timothy P. , Clifton Katherine , Weilbaecher Katherine , Frith Ashley , Tandra Pavan K. , Summa Tracy , Haas Brittney , Thomas Shana , Hernandez-Aya Leonel F. , Peterson Lindsay L. , Wang Xiaohong , Luo Shujun J. , Zhou Kemin , Du Pan , Jia Shidong , King Bonnie L. , Krishnamurthy Jairam , Ma Cynthia X.
Published: May 2023

PredicineATLAS gene panel.
Supplementary Methods S1 from Genomic Complexity Predicts Resistance to Endocrine Therapy and CDK4/6 Inhibition in Hormone Receptor–Positive (HR+)/HER2-Negative Metastatic Breast Cancer
Authors: Davis Andrew A. , Luo Jingqin , Zheng Tiantian , Dai Chao , Dong Xiaoxi , Tan Lu , Suresh Rama , Ademuyiwa Foluso O. , Rigden Caron , Rearden Timothy P. , Clifton Katherine , Weilbaecher Katherine , Frith Ashley , Tandra Pavan K. , Summa Tracy , Haas Brittney , Thomas Shana , Hernandez-Aya Leonel F. , Peterson Lindsay L. , Wang Xiaohong , Luo Shujun J. , Zhou Kemin , Du Pan , Jia Shidong , King Bonnie L. , Krishnamurthy Jairam , Ma Cynthia X.
Published: May 2023

Supplementary Methods
Supplementary Data S1 from Genomic Complexity Predicts Resistance to Endocrine Therapy and CDK4/6 Inhibition in Hormone Receptor–Positive (HR+)/HER2-Negative Metastatic Breast Cancer
Authors: Davis Andrew A. , Luo Jingqin , Zheng Tiantian , Dai Chao , Dong Xiaoxi , Tan Lu , Suresh Rama , Ademuyiwa Foluso O. , Rigden Caron , Rearden Timothy P. , Clifton Katherine , Weilbaecher Katherine , Frith Ashley , Tandra Pavan K. , Summa Tracy , Haas Brittney , Thomas Shana , Hernandez-Aya Leonel F. , Peterson Lindsay L. , Wang Xiaohong , Luo Shujun J. , Zhou Kemin , Du Pan , Jia Shidong , King Bonnie L. , Krishnamurthy Jairam , Ma Cynthia X.
Published: May 2023

DNA sequencing data summary.
Supplementary Tables S1-S10 from NPY Methylated ctDNA is a Promising Biomarker for Treatment Response Monitoring in Metastatic Colorectal Cancer
Authors: Janssens Katleen , Vanhoutte Greetje , Lybaert Willem , Demey Wim , Decaestecker Jochen , Hendrickx Koen , Rezaei Kalantari Hassan , Zwaenepoel Karen , Pauwels Patrick , Fransen Erik , Op de Beeck Ken , Van Camp Guy , Rolfo Christian , Peeters Marc
Published: May 2023

Table S1. Negative control samples used for LOB determination; Table S2. Quality of sequencing of BRAF and RAS genes; Table S3. REMARK checklist; Table S4. Patient characteristics; Table S5. Safety profiles; Table S6. Adverse event data; Table S7. Association of detectable ctDNA at baseline and patient characteristics; Table S8. Response in the LctDNA and HctDNA group; Table S9. BRAF V600E mutation analysis in patient 13; Table S10. Clinical trials comparing anti-EGFR and anti-VEGF in first-line therapy of RAS WT mCRC.
Supplementary Materials and Methods S1 from NPY Methylated ctDNA is a Promising Biomarker for Treatment Response Monitoring in Metastatic Colorectal Cancer
Authors: Janssens Katleen , Vanhoutte Greetje , Lybaert Willem , Demey Wim , Decaestecker Jochen , Hendrickx Koen , Rezaei Kalantari Hassan , Zwaenepoel Karen , Pauwels Patrick , Fransen Erik , Op de Beeck Ken , Van Camp Guy , Rolfo Christian , Peeters Marc
Published: May 2023

1. Eligibility criteria - Inclusion criteria, Exclusion criteria; 2. ddPCR methodology
Supplementary Figure S7 from NPY Methylated ctDNA is a Promising Biomarker for Treatment Response Monitoring in Metastatic Colorectal Cancer
Authors: Janssens Katleen , Vanhoutte Greetje , Lybaert Willem , Demey Wim , Decaestecker Jochen , Hendrickx Koen , Rezaei Kalantari Hassan , Zwaenepoel Karen , Pauwels Patrick , Fransen Erik , Op de Beeck Ken , Van Camp Guy , Rolfo Christian , Peeters Marc
Published: May 2023

Copy number alteration (CNA) profile of patient 24 based on shallow whole-genome sequencing (sWGS) of the baseline cfDNA sample.
Supplementary Figure S5 from NPY Methylated ctDNA is a Promising Biomarker for Treatment Response Monitoring in Metastatic Colorectal Cancer
Authors: Janssens Katleen , Vanhoutte Greetje , Lybaert Willem , Demey Wim , Decaestecker Jochen , Hendrickx Koen , Rezaei Kalantari Hassan , Zwaenepoel Karen , Pauwels Patrick , Fransen Erik , Op de Beeck Ken , Van Camp Guy , Rolfo Christian , Peeters Marc
Published: May 2023

Normalized methylation ratio.
Supplementary Figure S3 from NPY Methylated ctDNA is a Promising Biomarker for Treatment Response Monitoring in Metastatic Colorectal Cancer
Authors: Janssens Katleen , Vanhoutte Greetje , Lybaert Willem , Demey Wim , Decaestecker Jochen , Hendrickx Koen , Rezaei Kalantari Hassan , Zwaenepoel Karen , Pauwels Patrick , Fransen Erik , Op de Beeck Ken , Van Camp Guy , Rolfo Christian , Peeters Marc
Published: May 2023

Kaplan Meier curve for overall survival.
Data from CEACAM1 Marks Highly Suppressive Intratumoral Regulatory T Cells for Targeted Depletion Therapy
Authors: Jeon Seung Hyuck , Kang Minyong , Jeon Minwoo , Chung Youseung , Kim A Reum , Lee Yong Joon , Kim Eui-Soon , Nam Heejin , Park Junsik , Lee Jung-Yun , Shin Eui-Cheol , Seo Seong Il , Park Su-Hyung
Published: May 2023

AbstractPurpose:
Regulatory T cells (Tregs) exert immunosuppressive functions and hamper antitumor immune responses in the tumor microenvironment. Understanding the heterogeneity of intratumoral Tregs, and how it changes with tumor progression, will provide clues regarding novel target molecules of Treg-directed therapies.
Experimental Design:
From 42 patients with renal cell carcinoma and 5 patients with ovarian cancer, immune cells from tumor and peripheral blood were isolated. We performed multicolor flow cytometry and RNA-sequencing to characterize the phenotypes and heterogeneity of intratumoral Tregs. In vitro functional assays were performed to evaluate suppressive capacity of Tregs and effect of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1)-mediated depletion. The CT26 tumor model was used to evaluate the association between intratumoral Tregs and tumor growth, and examine the in vivo role of CEACAM1+ intratumoral Tregs on antitumor immunity.
Results:
We found that CEACAM1 was selectively expressed on intratumoral Tregs, whereas its expression on peripheral Tregs or other immune cells was low. The CEACAM1+ intratumoral Tregs accumulated with tumor progression, whereas the CEACAM1− subset did not. Notably, we found that CEACAM1 marked intratumoral Tregs that exhibited highly suppressive and activated phenotypes with substantial clonal expansion. Depletion of CEACAM1-expressing cells from tumor-infiltrating leukocytes led to increased effector functions of tumor-infiltrating T cells. Moreover, CEACAM1+ cell depletion further enhanced anti-PD-1–mediated reinvigoration of exhausted CD8+ T cells.
Conclusions:
CEACAM1 marks highly suppressive subset of intratumoral Tregs, and can be a target for selective depletion of intratumoral Tregs. These results may inform future studies on CEACAM1-mediated depletion in patients with cancer.
Efficacy of Nivolumab in Pediatric Cancers with High Mutation Burden and Mismatch Repair Deficiency
Authors: Das Anirban , Tabori Uri , Sambira Nahum Lauren C. , Collins Natalie B. , Deyell Rebecca , Dvir Rina , Faure-Conter Cecile , Hassall Timothy E. , Minturn Jane E. , Edwards Melissa , Brookes Elissa , Bianchi Vanessa , Levine Adrian , Stone Simone C. , Sudhaman Sumedha , Sanchez Ramirez Santiago , Ercan Ayse B. , Stengs Lucie , Chung Jill , Negm Logine , Getz Gad , Maruvka Yosef E. , Ertl-Wagner Birgit , Ohashi Pamela S. , Pugh Trevor , Hawkins Cynthia , Bouffet Eric , Morgenstern Daniel A.
Published: May 2023

Purpose:

Checkpoint inhibitors have limited efficacy for children with unselected solid and brain tumors. We report the first prospective pediatric trial (NCT02992964) using nivolumab exclusively for refractory nonhematologic cancers harboring tumor mutation burden (TMB) ≥5 mutations/megabase (mut/Mb) and/or mismatch repair deficiency (MMRD).

Patients and Methods:

Twenty patients were screened, and 10 were ultimately included in the response cohort of whom nine had TMB >10 mut/Mb (three initially eligible based on MMRD) and one patient had TMB between 5 and 10 mut/Mb.

Results:

Delayed immune responses contributed to best overall response of 50%, improving on initial objective responses (20%) and leading to 2-year overall survival (OS) of 50% [95% confidence interval (CI), 27–93]. Four children, including three with refractory malignant gliomas are in complete remission at a median follow-up of 37 months (range, 32.4–60), culminating in 2-year OS of 43% (95% CI, 18.2–100). Biomarker analyses confirmed benefit in children with germline MMRD, microsatellite instability, higher activated and lower regulatory circulating T cells. Stochastic mutation accumulation driven by underlying germline MMRD impacted the tumor microenvironment, contributing to delayed responses. No benefit was observed in the single patient with an MMR-proficient tumor and TMB 7.4 mut/Mb.

Conclusions:

Nivolumab resulted in durable responses and prolonged survival for the first time in a pediatric trial of refractory hypermutated cancers including malignant gliomas. Novel biomarkers identified here need to be translated rapidly to clinical care to identify children who can benefit from checkpoint inhibitors, including upfront management of cancer.

See related commentary by Mardis, p. 4701
Table S1 from Exosomal lincROR Promotes Docetaxel Resistance in Prostate Cancer through a β-catenin/HIF1α Positive Feedback Loop
Authors: Jiang Xingkang , Xu Yong , Liu Ranlu , Guo Shanqi
Published: May 2023

qPCR primers
Supplementary Figures 1 and 2 from Exosomal lincROR Promotes Docetaxel Resistance in Prostate Cancer through a β-catenin/HIF1α Positive Feedback Loop
Authors: Jiang Xingkang , Xu Yong , Liu Ranlu , Guo Shanqi
Published: May 2023

S1. A. CCK-8 assay was used to detect the cytotoxicity of DTX in DTX-resistant PCa cells (PC3/DR and DU145/DR) and their parental sensitive cells (PC3 and DU145). B. The list of hypoxia-related lncRNAs from Pubmed and the top 80 upregulated lncRNAs in PC3/DR cells from RNA-seq (Jiang X, et al. Front Oncol, 2022). The data are presented as the mean ± S.D. of at least three independent experiments. *P < 0.05.S2. A. The relative expression of lincROR was evaluated by qRT-PCR in PC3 and DU145 cells after being transfected with lincROR. B. DU145 cells were treated with different dosages of DTX (concentration of 0, 5, 10, 20, 40, and 80 nM) for 72 hours and cell viability was evaluated by a CCK-8 assay. C. The LDH release in the culture medium was detected in lincROR-transfected DU145 cells after DTX treatment. D. The expression of lincROR was evaluated in PC3/DR and DU145/DR cells after transfected with siROR #1 or #2. E. The cytotoxicity of DTX in DU145/DR cells was detected by CCK-8 assay after lincROR knockdown. F. The LDH release in culture medium was detected in lincROR-knockdown DU145/DR cells after DTX treatment. The data are presented as the mean ± S.D. of at least three independent experiments.
Supplementary Table S4 from BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification
Authors: Barnett Sarah E. , Kenyani Jenna , Tripari Martina , Butt Zohra , Grosman Rudi , Querques Francesca , Shaw Liam , Silva Luisa C. , Goate Zoe , Marciniak Stefan J. , Rassl Doris M. , Jackson Richard , Lian Lu-Yun , Szlosarek Peter W. , Sacco Joseph J. , Coulson Judy M.
Published: May 2023

Metabolomics MeT5A isogenics
Supplementary Table S2 from BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification
Authors: Barnett Sarah E. , Kenyani Jenna , Tripari Martina , Butt Zohra , Grosman Rudi , Querques Francesca , Shaw Liam , Silva Luisa C. , Goate Zoe , Marciniak Stefan J. , Rassl Doris M. , Jackson Richard , Lian Lu-Yun , Szlosarek Peter W. , Sacco Joseph J. , Coulson Judy M.
Published: May 2023

WGS MeT5A isogenics
Supplementary Table S1 from BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification
Authors: Barnett Sarah E. , Kenyani Jenna , Tripari Martina , Butt Zohra , Grosman Rudi , Querques Francesca , Shaw Liam , Silva Luisa C. , Goate Zoe , Marciniak Stefan J. , Rassl Doris M. , Jackson Richard , Lian Lu-Yun , Szlosarek Peter W. , Sacco Joseph J. , Coulson Judy M.
Published: May 2023

STR profiling MPM cell lines
Table S2 from Comparative Tumor Microenvironment Analysis of Primary and Recurrent Ovarian Granulosa Cell Tumors
Authors: Khlebus Eleonora , Vuttaradhi Veena K. , Welte Thomas , Khurana Namrata , Celestino Joseph , Beird Hannah C. , Gumbs Curtis , Little Latasha , Legarreta Alejandra Flores , Fellman Bryan M. , Nguyen Tri , Lawson Barrett , Ferri-Borgogno Sammy , Mok Samuel C. , Broaddus Russell R. , Gershenson David M. , Futreal P. Andrew , Hillman R. Tyler
Published: May 2023

Clinical Characteristics by Patient
Table S1 from Comparative Tumor Microenvironment Analysis of Primary and Recurrent Ovarian Granulosa Cell Tumors
Authors: Khlebus Eleonora , Vuttaradhi Veena K. , Welte Thomas , Khurana Namrata , Celestino Joseph , Beird Hannah C. , Gumbs Curtis , Little Latasha , Legarreta Alejandra Flores , Fellman Bryan M. , Nguyen Tri , Lawson Barrett , Ferri-Borgogno Sammy , Mok Samuel C. , Broaddus Russell R. , Gershenson David M. , Futreal P. Andrew , Hillman R. Tyler
Published: May 2023

RNA Sequencing QC Metrics
Figure S7 from Bone Marrow Mesenchymal Stem Cells Induce Metabolic Plasticity in Estrogen Receptor–Positive Breast Cancer
Authors: Buschhaus Johanna M. , Rajendran Shrila , Chen Siyi , Wharram Bryan L. , Bevoor Avinash S. , Cutter Alyssa C. , Humphries Brock A. , Robison Tanner H. , Farfel Alex P. , Luker Gary D.
Published: May 2023

Figure S7. Inhibition of monocarboxylate transporters regulates intracellular and extracellular lactate. Western blot shows expression of MCT4 in monocultures of MCF7, T47D, HS5, and HS27a cells. Images are from adjacent lanes on one gel and non-adjacent lanes from a second gel. We show β-actin as a loading control. B,C) Graphs show mean values ± standard deviation for relative concentrations of intracellular (B) and extracellular (C) lactate in monocultures of MCF7 cells or co-cultures of MCF7 and HS5 cells treated with 10 µM syrosingopine, an inhibitor of MCT1/4, or vehicle for 3 days. *** p<0.0001 using paired t tests for each comparison.
Figure S6 from Bone Marrow Mesenchymal Stem Cells Induce Metabolic Plasticity in Estrogen Receptor–Positive Breast Cancer
Authors: Buschhaus Johanna M. , Rajendran Shrila , Chen Siyi , Wharram Bryan L. , Bevoor Avinash S. , Cutter Alyssa C. , Humphries Brock A. , Robison Tanner H. , Farfel Alex P. , Luker Gary D.
Published: May 2023

Figure S6. Flow cytometry data for CSC stains. Cell type of interest is bolded in co-culture comparisons. A) Representative gating scheme for ALDH activity, CD24, and CD44 analyses. B-D) Flow cytometry data for MCF7 (B), T47D (C), and HCC1428 (HCC, D) cells in monoculture versus co-culture with MSCs stained for ALDH activity, CD24, and CD44. N > 10,000 cells.
Figure S1 from Bone Marrow Mesenchymal Stem Cells Induce Metabolic Plasticity in Estrogen Receptor–Positive Breast Cancer
Authors: Buschhaus Johanna M. , Rajendran Shrila , Chen Siyi , Wharram Bryan L. , Bevoor Avinash S. , Cutter Alyssa C. , Humphries Brock A. , Robison Tanner H. , Farfel Alex P. , Luker Gary D.
Published: May 2023

Figure S1. Representative images of NADH lifetimes for various experimental conditions. Cell type of interest is bolded in co-culture comparisons. Top row of images denotes cancer cells marked with nuclear mCherry. Pseudocolor scale depicts high (red) and low (blue) NADH lifetime. Scale bar = 50 µm. A) HS5 and HS27a MSCs in monoculture. B-C) MCF7 (B) or T47D (C) cells in monoculture or with conditioned media (CM) from listed MSCs. D) HCC1428 (HCC) cancer cells in monoculture, CM from MSCs, or direct co-culture with MSCs.
Figure S5 from The Elongin BC Complex Negatively Regulates AXL and Marks a Differentiated Phenotype in Melanoma
Authors: Schieven Sebastiaan M. , Traets Joleen J.H. , Vliet Alex v. , Baalen Martijn v. , Song Ji-Ying , Guimaraes Marcos Da Silva , Kuilman Thomas , Peeper Daniel S.
Published: May 2023

Extended data on Figure 5: Low expression of ELOB/C is associated with phenotype switching and EMT.
Figure S2 from The Elongin BC Complex Negatively Regulates AXL and Marks a Differentiated Phenotype in Melanoma
Authors: Schieven Sebastiaan M. , Traets Joleen J.H. , Vliet Alex v. , Baalen Martijn v. , Song Ji-Ying , Guimaraes Marcos Da Silva , Kuilman Thomas , Peeper Daniel S.
Published: May 2023

Extended data on Figure 2: Elongin BC complex members serve as keyAXL regulators.
Supplementary Tables 1-5 from Activation of the JAK/STAT Pathway Leads to BRAF Inhibitor Resistance in BRAFV600E Positive Thyroid Carcinoma
Authors: Limberg Jessica , Egan Caitlin E. , Gray Katherine D. , Singh Mandeep , Loewenstein Zachary , Yang Yanping , Riascos Maria Cristina , Al Asadi Hala , Safe Parima , El Eshaky Steve , Liang Heng , Ullmann Timothy M. , Wang Weibin , Li Wei , Zhang Tuo , Xiang Jenny , Stefanova Dessislava , Jin Moonsoo M. , Zarnegar Rasa , Fahey Thomas J. , Min Irene M.
Published: May 2023

Supplementary Table 1. Gene expression changes in 8505C after vemurafenib treatment.Supplementary Table 2. Gene expression changes in WRO after vemurafenib treatment.Supplementary Table 3. Gene expression changes in 8505C -Vem-Res 1 relative to parental 8505C.Supplementary Table 4. Gene expression changes in WRO -Vem-Res 6 relative to parental WRO.Supplementary Table 5. Clinical features of thyroid tumors used in Fig. 5.
Supplementary Figures 1-7 from Activation of the JAK/STAT Pathway Leads to BRAF Inhibitor Resistance in BRAFV600E Positive Thyroid Carcinoma
Authors: Limberg Jessica , Egan Caitlin E. , Gray Katherine D. , Singh Mandeep , Loewenstein Zachary , Yang Yanping , Riascos Maria Cristina , Al Asadi Hala , Safe Parima , El Eshaky Steve , Liang Heng , Ullmann Timothy M. , Wang Weibin , Li Wei , Zhang Tuo , Xiang Jenny , Stefanova Dessislava , Jin Moonsoo M. , Zarnegar Rasa , Fahey Thomas J. , Min Irene M.
Published: May 2023

S1. BRAFV600E mutation identified in thyroid cancer cell lines analyzed by RNA-seq.S2. STR analysis in thyroid cancer cell lines used in this study.S3. Gene expression of thyroid-specific genes in thyroid cancer cell lines analyzed by RNA-seq.S4. Dose-dependent toxicity of vemurafenib in BRAFV600E thyroidcancer cells.S5. Vemurafenib dose-dependent curves of vemurafenib-resistantBRAFV600E thyroid cancer cells.S6. Vemurafenib induces apoptosis in 8505C cells.S7. Predicted activators and inhibitors in Vem-resistant BRAF mutant thyroid cancer cells.
Data from BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification
Authors: Barnett Sarah E. , Kenyani Jenna , Tripari Martina , Butt Zohra , Grosman Rudi , Querques Francesca , Shaw Liam , Silva Luisa C. , Goate Zoe , Marciniak Stefan J. , Rassl Doris M. , Jackson Richard , Lian Lu-Yun , Szlosarek Peter W. , Sacco Joseph J. , Coulson Judy M.
Published: May 2023

Abstract
The nuclear deubiquitylase BRCA1-associated protein 1 (BAP1) is frequently inactivated in malignant pleural mesothelioma (MPM) and germline BAP1 mutation predisposes to cancers including MPM. To explore the influence on cell physiology and drug sensitivity, we sequentially edited a predisposition mutation (w-) and a promoter trap (KO) into human mesothelial cells. BAP1w-/KO MeT5A cells express less BAP1 protein and phenocopy key aspects of BAP1 loss in MPM. Stable isotope labeling with amino acids in cell culture–mass spectrometry revealed evidence of metabolic adaptation, with concomitant alteration of cellular metabolites. In MeT5A, BAP1 deficiency reduces glycolytic enzyme levels but increases enzymes involved in the tricarboxylic acid cycle and anaplerotic pathways. Notably both argininosuccinate synthase 1 (ASS1), essential for cellular synthesis of arginine, and its substrate aspartate, are elevated in BAP1w-/KO MeT5A cells. Likewise, ASS1 expression is higher in BAP1-altered MPM cell lines, and inversely correlates with BAP1 in The Cancer Genome Atlas MESO dataset. Elevated ASS1 is also evident by IHC staining in epithelioid MPM lacking nuclear BAP1 expression, with improved survival among patients with BAP1-negative/ASS1-expressing tumors. Alterations in arginine metabolism may sensitize cells to metabolic drugs and we find that BAP1-negative/ASS1-expressing MPM cell lines are more sensitive to ASS1 inhibition, although not to inhibition of purine synthesis by mizoribine. Importantly, BAP1w-/KO MeT5A become desensitized to arginine deprivation by pegylated arginine deiminase (ADI-PEG20), phenocopying BAP1-negative/ASS1-expressing MPM cell lines.
Implications:
Our data reveal an interrelationship between BAP1 and arginine metabolism, providing a potential means of identifying patients with epithelioid MPM likely to benefit from ADI-PEG20.
Data from The Elongin BC Complex Negatively Regulates AXL and Marks a Differentiated Phenotype in Melanoma
Authors: Schieven Sebastiaan M. , Traets Joleen J.H. , Vliet Alex v. , Baalen Martijn v. , Song Ji-Ying , Guimaraes Marcos Da Silva , Kuilman Thomas , Peeper Daniel S.
Published: May 2023

Abstract
High expression of the receptor tyrosine kinase AXL is implicated in epithelial-to-mesenchymal transition, cancer progression, and therapy resistance. For example, AXL is abundant in BRAF mutant melanomas progressing on targeted BRAF/MEK inhibition. Therefore, AXL is thought to represent an attractive therapeutic target. This notwithstanding, little is known about the mechanisms governing expression of AXL. Here, we describe a FACS-based whole-genome-wide CRISPR-Cas9 screen to uncover regulators of AXL expression. We identified several genes, inactivation of which led to increased AXL expression. Most remarkable was the identification of five components that associate with the Elongin BC heterodimer. Elongin B/C engage in multiple protein–protein interactions, including the transcription factor complex subunit Elongin A, the von Hippel-Lindau (VHL) tumor suppressor protein, and members of the SOCS-box protein family. The screen identified ELOB, ELOC, SOCS5, UBE2F, and RNF7, each of which we demonstrate to serve as an inhibitor of AXL expression. Although the AXL promoter contains hypoxia response elements and Elongin B/C are found in the VHL complex, Elongin B/C unexpectedly regulate AXL independently of hypoxia. Instead, we demonstrate that the Elongin BC complex interacts with AXL through ELOB, and contributes to proteasomal AXL turnover. RNA-sequencing and IHC analyses of melanoma patient-derived xenografts and clinical samples revealed a negative association between Elongin B/C and dedifferentiation. Together, the Elongin BC complex regulates AXL and marks a differentiated melanoma phenotype.
Implications:
This study identifies the Elongin BC complex as a key regulator of AXL expression and marker of melanoma differentiation.
Abstract A002: Early changes in circulating cell free KRAS G12C as a possible blood-based response biomarker for adagrasib in non-small cell lung cancer (NSCLC).

Authors: Paweletz Cloud , Heavey Grace A. , Kuang Yanan , Kheoh Thian , Anderes Kenna , Christensen James , Jänne Pasi A.
Published: May 2023

Introduction: While tumor imaging has a fundamental role in drug development as a determinant of clinical response it may not always be a rapid measure of treatment effect. Changes in plasma ctDNA levels, on the other hand, has the potential to be a more readily available measure of response. Here we report on early plasma response measurements of KRAS G12C ctDNA by digital droplet PCR (ddPCR) in a Phase 2 trial of Adagrasib, a potent, orally available, small molecule covalent inhibitor of KRAS G12C, in patients with advanced non-small cell lung cancer with KRAS G12C mutation. Methods/Results: To study the timing of plasma response, we performed serial ddPCR on 60 KRAS G12C-mutant NSCLC patients that participated in cohort A of the KRYSTAL-1 phase 2 clinical trial. Cohort A evaluated adagrasib at 600 mg orally BID in patients with NSCLC previously treated with platinum-based chemotherapy. We analyzed the change in ctDNA levels at 2 specific intervals: between cycles 1 and 2 (i.e. initial change) and at start of cycles 4. Of 60 pts, 7 pts were excluded because of missing C1D1 draws, 13 pts were excluded for non-detectable KRAS G12C level at C1D1 and 1 patient was excluded because of a missing C2D1 draw leaving us with 39 evaluable patients for plasma response assessment. We found that most of the response in ctDNA could be seen during the initial 3-4 week treatment period, well before the first scan at 6-8 weeks. 38 pts (97.4%) showed any decrease in plasma levels from baseline levels. 35 patients (89.7%) show a decrease >90% and 33 pts (84.6%) achieved complete clearance at C2D1. Patients with complete ctDNA clearance at C2D1 showed improved ORR (60.6% vs 33.3%), while ctDNA clearance at C4 was associated with an improved survival (12.6 months vs 5.4 months) and PFS (HR 0.3). Conclusion: Our results support using early plasma response of KRAS G12C assessed at 2-3 weeks to inform the interpretation of initial imaging performed at 6-8 weeks

Citation Format: Cloud Paweletz, Grace A. Heavey, Yanan Kuang, Thian Kheoh, Kenna Anderes, James Christensen, Pasi A. Jänne. Early changes in circulating cell free KRAS G12C as a possible blood-based response biomarker for adagrasib in non-small cell lung cancer (NSCLC).
 [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A002.
Abstract A014: Inhibition of KrasG12D with a novel small molecule inhibitor alters the pancreatic cancer microenvironment
Authors: Kemp Samantha B. , Cheng Noah , Markosyan Nune , Sor Rina , Kim Il-Kyu , Hallin Jill , Shoush Jason , Quinones Liz , Brown Natalie , Bassett Jared B. , Joshi Nikhil , Yuan Salina , Smith Molly , Vostrejs William P. , Perez-Vale Kia Z. , Kahn Benjamin , Mo Feiyan , Donahue Timothy R. , Radu Caius G. , Clendenin Cynthia , Christensen James G. , Vonderheide Robert H. , Stanger Ben Z.
Published: May 2023

Approximately 90% of pancreatic ductal adenocarcinoma (PDAC) patients harbor an oncogenic KRAS mutation, with Gly-to-Asp mutations (KrasG12D) being most common. PDAC is characterized by a robust, immunosuppressive tumor microenvironment that is rich in myeloid-derived suppressor cells (MDSCs) and has a paucity of T cells. The majority of therapeutic interventions in PDAC are ineffective, in part, due to this immunosuppressive TME. We aimed to examine the efficacy of a small molecule KrasG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14d. MRTX1133 treatment additionally reduced metastatic burden after 7d of treatment. An increase in tumor cell death was identified after only 36h of treatment, with concomitant loss of tumor cell proliferation. Inhibition of KrasG12D led to marked shifts in the TME composition. MRTX1133-treated tumors had an increase in fibroblasts, collagen deposition, and blood vessel density. There was a robust increase in M1-like macrophages after MRTX1133 treatment. Further, there was a loss of MDSCs, along with an increase in cytotoxic T cells. Proteome profiling on tumor cells treated with MRTX1133 identified a loss of tumor cell-derived GM-CSF (a MDSC recruiter), as well as an increase in CCL2 (a macrophage recruiter), providing evidence that MRTX1133 alters the TME through tumor secreted factors. T cells were necessary for MRTX1133’s full anti-tumor effect, and T cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KrasG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies.

Citation Format: Samantha B. Kemp, Noah Cheng, Nune Markosyan, Rina Sor, Il-Kyu Kim, Jill Hallin, Jason Shoush, Liz Quinones, Natalie Brown, Jared B. Bassett, Nikhil Joshi, Salina Yuan, Molly Smith, William P. Vostrejs, Kia Z. Perez-Vale, Benjamin Kahn, Feiyan Mo, Timothy R. Donahue, Caius G. Radu, Cynthia Clendenin, James G. Christensen, Robert H. Vonderheide, Ben Z. Stanger. Inhibition of KrasG12D with a novel small molecule inhibitor alters the pancreatic cancer microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A014.
Abstract A031: KRAS (G12C) mediated mRNA translation program
Authors: Singh Kamini
Published: May 2023

KRAS-dependent activation of mRNA translation signaling is a common feature in cancer however, the KRAS-specific translation landscape and functional proteome are not fully characterized in a genome-wide manner. We show that mutant KRAS drives specific mechanisms of translational control to support cancer growth. We have utilized the technology of ribosome footprinting combined with advanced sequencing methodology to define the translation landscape affected by a specific inhibitor of KRAS, sotorasib that targets G12C mutant KRAS activity. We show that acute treatment of sotorasib inhibits the translation of key oncogenic proteins including MYC and MYC targets. KRAS (G12C) inhibition profoundly affects the translation of ribosomal proteins and translation elongation factors. G12C mutant KRAS remarkably affects the translation of proteins involved in the ROS and DNA repair pathways in cancer. Moreover, these translational changes are mediated through specific RNA motifs and RNA binding proteins. In summary, our study defines the KRAS (G12C) specific regulation of translation and provides the mechanism of KRAS (G12C) mediated regulation of cancer proteome.

Citation Format: Kamini Singh. KRAS (G12C) mediated mRNA translation program [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A031.