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25 results on '"Sheeno Thyparambil"'

1. Targeted multiplex validation of CSF proteomic biomarkers: implications for differentiation of PCNSL from tumor-free controls and other brain tumors

Author

Jingjing Ma, Zhiguang Lin, Yaqi Zhang, Yun Ding, Qiming Tang, Yufeng Qian, Bo Jin, Ruben Y. Luo, Wei-Li Liao, Sheeno Thyparambil, Zhi Han, C. James Chou, James Schilling, Qing Li, Mengxue Zhang, Yunan Lin, Yan Ma, Karl G. Sylvester, Seema Nagpal, Doff B. McElhinney, Xuefeng B. Ling, and Bobin Chen

Subjects
primary central nervous system lymphoma (PCNSL), diffuse large B-cell lymphoma (DLBCL), cerebrospinal fluid (CSF), targeted proteomics, liquid chromatography tandem-mass spectrometry (LC-MS/MS), Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionPrimary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin’s lymphoma that affects brain parenchyma, eyes, cerebrospinal fluid, and spinal cord. Diagnosing PCNSL can be challenging because imaging studies often show similar patterns as other brain tumors, and stereotactic brain lesion biopsy conformation is invasive and not always possible. This study aimed to validate a previous proteomic profiling (PMID: 32610669) of cerebrospinal fluid (CSF) and develop a CSF-based proteomic panel for accurate PCNSL diagnosis and differentiation.MethodsCSF samples were collected from patients of 30 PCNSL, 30 other brain tumors, and 31 tumor-free/benign controls. Liquid chromatography tandem-mass spectrometry targeted proteomics analysis was used to establish CSF-based proteomic panels.ResultsFinal proteomic panels were selected and optimized to diagnose PCNSL from tumor-free controls or other brain tumor lesions with an area under the curve (AUC) of 0.873 (95%CI: 0.723-0.948) and 0.937 (95%CI: 0.807- 0.985), respectively. Pathways analysis showed diagnosis panel features were significantly enriched in pathways related to extracellular matrices-receptor interaction, focal adhesion, and PI3K-Akt signaling, while prion disease, mineral absorption and HIF-1 signaling were significantly enriched with differentiation panel features.DiscussionThis study suggests an accurate clinical test panel for PCNSL diagnosis and differentiation with CSF-based proteomic signatures, which may help overcome the challenges of current diagnostic methods and improve patient outcomes.

Published
2024
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2. Altered expression of the L-arginine/nitric oxide pathway in ovarian cancer: metabolic biomarkers and biological implications

Author

Linfeng Chen, Qiming Tang, Keying Zhang, Qianyang Huang, Yun Ding, Bo Jin, Szumam Liu, KuoYuan Hwa, C. James Chou, Yani Zhang, Sheeno Thyparambil, Weili Liao, Zhi Han, Richard Mortensen, James Schilling, Zhen Li, Robert Heaton, Lu Tian, Harvey J. Cohen, Karl G. Sylvester, Rebecca C. Arent, Xinyang Zhao, Doff B. McElhinney, Yumei Wu, Wenpei Bai, and Xuefeng B. Ling

Subjects
Arginase (ARG), Nitric oxide synthase (NOS), Dimethylarginine dimethylaminohydrolase (DDAH), Protein arginine methyltransferases (PRMT), Asymmetric dimethylarginine (ADMA), Symmetric dimethylarginine (SDMA), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Motivation Ovarian cancer (OC) is a highly lethal gynecological malignancy. Extensive research has shown that OC cells undergo significant metabolic alterations during tumorigenesis. In this study, we aim to leverage these metabolic changes as potential biomarkers for assessing ovarian cancer. Methods A functional module-based approach was utilized to identify key gene expression pathways that distinguish different stages of ovarian cancer (OC) within a tissue biopsy cohort. This cohort consisted of control samples (n = 79), stage I/II samples (n = 280), and stage III/IV samples (n = 1016). To further explore these altered molecular pathways, minimal spanning tree (MST) analysis was applied, leading to the formulation of metabolic biomarker hypotheses for OC liquid biopsy. To validate, a multiple reaction monitoring (MRM) based quantitative LCMS/MS method was developed. This method allowed for the precise quantification of targeted metabolite biomarkers using an OC blood cohort comprising control samples (n = 464), benign samples (n = 3), and OC samples (n = 13). Results Eleven functional modules were identified as significant differentiators (false discovery rate, FDR

Published
2023
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3. High-throughput quantitation of amino acids and acylcarnitine in cerebrospinal fluid: identification of PCNSL biomarkers and potential metabolic messengers

Author

Jingjing Ma, Kun Chen, Yun Ding, Xiao Li, Qiming Tang, Bo Jin, Ruben Y. Luo, Sheeno Thyparambil, Zhi Han, C. James Chou, Ashlee Zhou, James Schilling, Zhiguang Lin, Yan Ma, Qing Li, Mengxue Zhang, Karl G. Sylvester, Seema Nagpal, Doff B. McElhinney, Xuefeng B. Ling, and Bobin Chen

Subjects
PCNSL, cerebrospinal fluid, amino acid, acylcarnitine, UHPLC-MS/MS, Biology (General), QH301-705.5
Abstract

Background: Due to the poor prognosis and rising occurrence, there is a crucial need to improve the diagnosis of Primary Central Nervous System Lymphoma (PCNSL), which is a rare type of non-Hodgkin’s lymphoma. This study utilized targeted metabolomics of cerebrospinal fluid (CSF) to identify biomarker panels for the improved diagnosis or differential diagnosis of primary central nervous system lymphoma (PCNSL).Methods: In this study, a cohort of 68 individuals, including patients with primary central nervous system lymphoma (PCNSL), non-malignant disease controls, and patients with other brain tumors, was recruited. Their cerebrospinal fluid samples were analyzed using the Ultra-high performance liquid chromatography - tandem mass spectrometer (UHPLC-MS/MS) technique for targeted metabolomics analysis. Multivariate statistical analysis and logistic regression modeling were employed to identify biomarkers for both diagnosis (Dx) and differential diagnosis (Diff) purposes. The Dx and Diff models were further validated using a separate cohort of 34 subjects through logistic regression modeling.Results: A targeted analysis of 45 metabolites was conducted using UHPLC-MS/MS on cerebrospinal fluid (CSF) samples from a cohort of 68 individuals, including PCNSL patients, non-malignant disease controls, and patients with other brain tumors. Five metabolic features were identified as biomarkers for PCNSL diagnosis, while nine metabolic features were found to be biomarkers for differential diagnosis. Logistic regression modeling was employed to validate the Dx and Diff models using an independent cohort of 34 subjects. The logistic model demonstrated excellent performance, with an AUC of 0.83 for PCNSL vs. non-malignant disease controls and 0.86 for PCNSL vs. other brain tumor patients.Conclusion: Our study has successfully developed two logistic regression models utilizing metabolic markers in cerebrospinal fluid (CSF) for the diagnosis and differential diagnosis of PCNSL. These models provide valuable insights and hold promise for the future development of a non-invasive and reliable diagnostic tool for PCNSL.

Published
2023
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4. Serological Phenotyping Analysis Uncovers a Unique Metabolomic Pattern Associated With Early Onset of Type 2 Diabetes Mellitus

Author

Linmin Zhu, Qianyang Huang, Xiao Li, Bo Jin, Yun Ding, C. James Chou, Kuo-Jung Su, Yani Zhang, Xingguo Chen, Kuo Yuan Hwa, Sheeno Thyparambil, Weili Liao, Zhi Han, Richard Mortensen, Yi Jin, Zhen Li, James Schilling, Karl G. Sylvester, Xuguo Sun, and Xuefeng B. Ling

Subjects
metabolomics, type 2 diabetes mellitus, biomarker, early detection, serum, Biology (General), QH301-705.5
Abstract

Background: Type 2 diabetes mellitus (T2DM) is a multifaceted disorder affecting epidemic proportion at global scope. Defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond effectively to insulin are the underlying biology of T2DM. However, circulating biomarkers indicative of early diabetic onset at the asymptomatic stage have not been well described. We hypothesized that global and targeted mass spectrometry (MS) based metabolomic discovery can identify novel serological metabolic biomarkers specifically associated with T2DM. We further hypothesized that these markers can have a unique pattern associated with latent or early asymptomatic stage, promising an effective liquid biopsy approach for population T2DM risk stratification and screening.Methods: Four independent cohorts were assembled for the study. The T2DM cohort included sera from 25 patients with T2DM and 25 healthy individuals for the biomarker discovery and sera from 15 patients with T2DM and 15 healthy controls for the testing. The Pre-T2DM cohort included sera from 76 with prediabetes and 62 healthy controls for the model training and sera from 35 patients with prediabetes and 27 healthy controls for the model testing. Both global and targeted (amino acid, acylcarnitine, and fatty acid) approaches were used to deep phenotype the serological metabolome by high performance liquid chromatography-high resolution mass spectrometry. Different machine learning approaches (Random Forest, XGBoost, and ElasticNet) were applied to model the unique T2DM/Pre-T2DM metabolic patterns and contrasted with their effectiness to differentiate T2DM/Pre-T2DM from controls.Results: The univariate analysis identified unique panel of metabolites (n = 22) significantly associated with T2DM. Global metabolomics and subsequent structure determination led to the identification of 8 T2DM biomarkers while targeted LCMS profiling discovered 14 T2DM biomarkers. Our panel can effectively differentiate T2DM (ROC AUC = 1.00) or Pre-T2DM (ROC AUC = 0.84) from the controls in the respective testing cohort.Conclusion: Our serological metabolite panel can be utilized to identifiy asymptomatic population at risk of T2DM, which may provide utility in identifying population at risk at an early stage of diabetic development to allow for clinical intervention. This early detection would guide ehanced levels of care and accelerate development of clinical strategies to prevent T2DM.

Published
2022
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5. Early-pregnancy prediction of risk for pre-eclampsia using maternal blood leptin/ceramide ratio: discovery and confirmation

Author

Gary M Shaw, Xin Zhou, David K Stevenson, Sheeno Thyparambil, Shiying Hao, Xuefeng B Ling, Doff B McElhinney, John C Whitin, Harvey J Cohen, Karl G Sylvester, Jin You, Xiaoming Yao, Lihong Mo, Subhashini Ladella, Ronald J Wong, Zhen Li, Qianyang Huang, James Schilling, Wei-Li Liao, Shantay R Davies-Balch, Hangyi Zhao, and David Fan

Subjects
Medicine
Abstract

Objective This study aimed to develop a blood test for the prediction of pre-eclampsia (PE) early in gestation. We hypothesised that the longitudinal measurements of circulating adipokines and sphingolipids in maternal serum over the course of pregnancy could identify novel prognostic biomarkers that are predictive of impending event of PE early in gestation.Study design Retrospective discovery and longitudinal confirmation.Setting Maternity units from two US hospitals.Participants Six previously published studies of placental tissue (78 PE and 95 non-PE) were compiled for genomic discovery, maternal sera from 15 women (7 non-PE and 8 PE) enrolled at ProMedDx were used for sphingolipidomic discovery, and maternal sera from 40 women (20 non-PE and 20 PE) enrolled at Stanford University were used for longitudinal observation.Outcome measures Biomarker candidates from discovery were longitudinally confirmed and compared in parallel to the ratio of placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) using the same cohort. The datasets were generated by enzyme-linked immunosorbent and liquid chromatography-tandem mass spectrometric assays.Results Our discovery integrating genomic and sphingolipidomic analysis identified leptin (Lep) and ceramide (Cer) (d18:1/25:0) as novel biomarkers for early gestational assessment of PE. Our longitudinal observation revealed a marked elevation of Lep/Cer (d18:1/25:0) ratio in maternal serum at a median of 23 weeks’ gestation among women with impending PE as compared with women with uncomplicated pregnancy. The Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting impending event of PE with superior sensitivity (85% vs 20%) and area under curve (0.92 vs 0.52) from 5 to 25 weeks of gestation.Conclusions Our study demonstrated the longitudinal measurement of maternal Lep/Cer (d18:1/25:0) ratio allows the non-invasive assessment of PE to identify pregnancy at high risk in early gestation, outperforming the established sFlt-1/PlGF ratio test.

Published
2021
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6. Supplementary Figure 2 from EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer

Author

Sandra Misale, Alberto Bardelli, Federica Di Nicolantonio, Neal Rosen, Bob T. Li, Livio Trusolino, Andrea Bertotti, Salvatore Siena, Silvia Marsoni, Elisa de Stanchina, Hui-Yong Zhao, Sheeno Thyparambil, Anuja Bhalkikar, Wei-Li Liao, Nicola Valeri, Efsevia Vakiani, Yonina R. Murciano-Goroff, Marika Pinnelli, Adele Whaley, Yu Bian, Benedetta Mussolin, Monica Montone, Sabrina Arena, Annalisa Lorenzato, Simona Lamba, Carlotta Cancelliere, Pamela Arcella, Rona Yaeger, and Vito Amodio

Abstract

Supplementary Figure 2

Published
2023

7. Supplementary Fig 3 from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Supplementary Fig 3

Published
2023

8. Supplementary Fig 2 from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Supplementary Fig 2

Published
2023

9. Supplementary Figure 1 from EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer

Author

Sandra Misale, Alberto Bardelli, Federica Di Nicolantonio, Neal Rosen, Bob T. Li, Livio Trusolino, Andrea Bertotti, Salvatore Siena, Silvia Marsoni, Elisa de Stanchina, Hui-Yong Zhao, Sheeno Thyparambil, Anuja Bhalkikar, Wei-Li Liao, Nicola Valeri, Efsevia Vakiani, Yonina R. Murciano-Goroff, Marika Pinnelli, Adele Whaley, Yu Bian, Benedetta Mussolin, Monica Montone, Sabrina Arena, Annalisa Lorenzato, Simona Lamba, Carlotta Cancelliere, Pamela Arcella, Rona Yaeger, and Vito Amodio

Abstract

Supplementary Figure 1

Published
2023

10. Data from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody–drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy.Significance:T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.See related commentary by Rolfo and Russo, p. 643.This article is highlighted in the In This Issue feature, p. 627

Published
2023

11. Supplementary Fig 5 from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Supplementary Fig 5

Published
2023

12. Supplementary Figure 3 from EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer

Author

Sandra Misale, Alberto Bardelli, Federica Di Nicolantonio, Neal Rosen, Bob T. Li, Livio Trusolino, Andrea Bertotti, Salvatore Siena, Silvia Marsoni, Elisa de Stanchina, Hui-Yong Zhao, Sheeno Thyparambil, Anuja Bhalkikar, Wei-Li Liao, Nicola Valeri, Efsevia Vakiani, Yonina R. Murciano-Goroff, Marika Pinnelli, Adele Whaley, Yu Bian, Benedetta Mussolin, Monica Montone, Sabrina Arena, Annalisa Lorenzato, Simona Lamba, Carlotta Cancelliere, Pamela Arcella, Rona Yaeger, and Vito Amodio

Abstract

Supplementary Figure 3

Published
2023

13. Supplementary Table 3 from EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer

Author

Sandra Misale, Alberto Bardelli, Federica Di Nicolantonio, Neal Rosen, Bob T. Li, Livio Trusolino, Andrea Bertotti, Salvatore Siena, Silvia Marsoni, Elisa de Stanchina, Hui-Yong Zhao, Sheeno Thyparambil, Anuja Bhalkikar, Wei-Li Liao, Nicola Valeri, Efsevia Vakiani, Yonina R. Murciano-Goroff, Marika Pinnelli, Adele Whaley, Yu Bian, Benedetta Mussolin, Monica Montone, Sabrina Arena, Annalisa Lorenzato, Simona Lamba, Carlotta Cancelliere, Pamela Arcella, Rona Yaeger, and Vito Amodio

Abstract

Supplementary Table 3

Published
2023

14. Supplementary Table 1 from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Supplementary Table 1

Published
2023

15. Supplementary Fig 6 from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Supplementary Fig 6

Published
2023

16. Supplementary Figure 4 from EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer

Author

Sandra Misale, Alberto Bardelli, Federica Di Nicolantonio, Neal Rosen, Bob T. Li, Livio Trusolino, Andrea Bertotti, Salvatore Siena, Silvia Marsoni, Elisa de Stanchina, Hui-Yong Zhao, Sheeno Thyparambil, Anuja Bhalkikar, Wei-Li Liao, Nicola Valeri, Efsevia Vakiani, Yonina R. Murciano-Goroff, Marika Pinnelli, Adele Whaley, Yu Bian, Benedetta Mussolin, Monica Montone, Sabrina Arena, Annalisa Lorenzato, Simona Lamba, Carlotta Cancelliere, Pamela Arcella, Rona Yaeger, and Vito Amodio

Abstract

Supplementary Figure 4

Published
2023

17. Supplementary Fig 4 from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Author

Maurizio Scaltriti, Charles M. Rudin, Neal Rosen, Elisa de Stanchina, Gary A. Ulaner, Junji Tsurutani, Ronglai Shen, John T. Poirier, Mark G. Kris, Maria E. Arcila, Pedram Razavi, Jorge S. Reis-Filho, Vicky Makker, Alan L. Ho, Darren J. Buonocore, Jason S. Lewis, David M. Hyman, Fabiola Cecchi, Anuja Bhalkikar, Wei-Li Liao, Sheeno Thyparambil, Helena A. Yu, David R. Jones, James M. Isbell, Michael Offin, Tony Ng, Paul R. Barber, Michael F. Berger, David B. Solit, Nancy U. Lin, Rachel A. Freedman, Irmina Diala, Alshad S. Lalani, Clare J. Wilhem, Gregory Weitsman, Besnik Qeriqi, Megan Little, Inna Khodos, Marissa Mattar, Chongrui Xu, Mackenzie L. Myers, Hai-Yan Tu, Sophie Shifman, Yanyan Cai, Laura Baldino, Emiliano Cocco, Sandra Misale, Flavia Michelini, and Bob T. Li

Abstract

Supplementary Fig 4

Published
2023

18. Supplementary Table 2 from EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer

Author

Sandra Misale, Alberto Bardelli, Federica Di Nicolantonio, Neal Rosen, Bob T. Li, Livio Trusolino, Andrea Bertotti, Salvatore Siena, Silvia Marsoni, Elisa de Stanchina, Hui-Yong Zhao, Sheeno Thyparambil, Anuja Bhalkikar, Wei-Li Liao, Nicola Valeri, Efsevia Vakiani, Yonina R. Murciano-Goroff, Marika Pinnelli, Adele Whaley, Yu Bian, Benedetta Mussolin, Monica Montone, Sabrina Arena, Annalisa Lorenzato, Simona Lamba, Carlotta Cancelliere, Pamela Arcella, Rona Yaeger, and Vito Amodio

Abstract

Supplementary Table 2

Published
2023

19. Supplementary Table 1 from EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer

Author

Sandra Misale, Alberto Bardelli, Federica Di Nicolantonio, Neal Rosen, Bob T. Li, Livio Trusolino, Andrea Bertotti, Salvatore Siena, Silvia Marsoni, Elisa de Stanchina, Hui-Yong Zhao, Sheeno Thyparambil, Anuja Bhalkikar, Wei-Li Liao, Nicola Valeri, Efsevia Vakiani, Yonina R. Murciano-Goroff, Marika Pinnelli, Adele Whaley, Yu Bian, Benedetta Mussolin, Monica Montone, Sabrina Arena, Annalisa Lorenzato, Simona Lamba, Carlotta Cancelliere, Pamela Arcella, Rona Yaeger, and Vito Amodio

Abstract

Supplementary Table 1

Published
2023

20. Data from EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer

Author

Sandra Misale, Alberto Bardelli, Federica Di Nicolantonio, Neal Rosen, Bob T. Li, Livio Trusolino, Andrea Bertotti, Salvatore Siena, Silvia Marsoni, Elisa de Stanchina, Hui-Yong Zhao, Sheeno Thyparambil, Anuja Bhalkikar, Wei-Li Liao, Nicola Valeri, Efsevia Vakiani, Yonina R. Murciano-Goroff, Marika Pinnelli, Adele Whaley, Yu Bian, Benedetta Mussolin, Monica Montone, Sabrina Arena, Annalisa Lorenzato, Simona Lamba, Carlotta Cancelliere, Pamela Arcella, Rona Yaeger, and Vito Amodio

Abstract

Most patients with KRASG12C–mutant non–small cell lung cancer (NSCLC) experience clinical benefit from selective KRASG12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRASG12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRASG12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRASG12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRASG12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRASG12C blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRASG12C inhibitors. The combinatorial targeting of EGFR and KRASG12C is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRASG12C colorectal cancer.Significance:The efficacy of KRASG12C inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRASG12C inhibition in colorectal cancer. EGFR and KRASG12C should be concomitantly inhibited to overcome resistance to KRASG12C blockade in colorectal tumors.See related commentary by Koleilat and Kwong, p. 1094.This article is highlighted in the In This Issue feature, p. 1079

Published
2023

21. Complete Remission of Widely Metastatic Human Epidermal Growth Factor Receptor 2–Amplified Pancreatic Adenocarcinoma After Precision Immune and Targeted Therapy With Description of Sequencing and Organoid Correlates

Author

Daniel A. King, Amber R. Smith, Gino Pineda, Michitaka Nakano, Flavia Michelini, S. Peter Goedegebuure, Sheeno Thyparambil, Wei-Li Liao, Aaron McCormick, Jihang Ju, Michele Cioffi, Xiuli Zhang, Jasreet Hundal, Malachi Griffith, Carla Grandori, Maddy Pollastro, Rachele Rosati, Astrid Margossian, Payel Chatterjee, Trevor Ainge, Marta Flory, Paolo Ocampo, Lee-may Chen, George A. Poultsides, Ari D. Baron, Daniel T. Chang, Joseph M. Herman, William E. Gillanders, Haeseong Park, William A. Hoos, Mike Nichols, George A. Fisher, and Calvin J. Kuo

Subjects
Cancer Research, Oncology
Published
2023

22. Complete remission in a patient with widely metastatic HER2-amplified pancreatic adenocarcinoma following multimodal therapy informed by tumor sequencing and organoid profiling

Author

Daniel A King, Amber R Smith, Gino Pineda, Michitaka Nakano, Flavia Michelini, S. Peter Goedegebuure, Sheeno Thyparambil, Wei-Li Liao, Aaron McCormick, Jihang Ju, Michele Cioffi, Xiuli Zhang, Jasreet Hundal, Malachi Griffith, Carla Grandori, Maddy Pollastro, Rachele Rosati, Astrid Margossian, Payel Chatterjee, Trevor Ainge, Marta Flory, Paolo Ocampo, Lee-may Chen, George A Poultsides, Ari D Baron, Daniel T Chang, Joseph M Herman, William E Gillanders, Haeseong Park, William A Hoos, Mike Nichols, George A Fisher, and Calvin J Kuo

Abstract

Here, we demonstrate a complete clinical response achieved in a patient with HER2+ metastatic pancreatic ductal adenocarcinoma to a coordinated barrage of anti-HER2, personalized vaccine and checkpoint inhibition immunotherapy, radiation, and chemotherapy. Comprehensive organoid profiling with drug sensitivity screening and drug testing suggested a vulnerability to anti-HER2 directed therapy, facilitating personalized treatment selection for our patient, which contributed to her clinical benefit. Immune response monitoring following personalized vaccine, radiation and checkpoint inhibition showed a sustained increase in neoantigen specific T cell response.

Published
2021

23. Early-pregnancy prediction of risk for pre-eclampsia using maternal blood leptin/ceramide ratio: discovery and confirmation

Author

Doff B. McElhinney, Shantay R Davies-Balch, Gary M. Shaw, Qianyang Huang, Harvey J. Cohen, Ronald J. Wong, James Schilling, Subhashini Ladella, David Fan, Sheeno Thyparambil, Lihong Mo, Karl G. Sylvester, Xin Zhou, John C. Whitin, Shiying Hao, Jin You, Xuefeng B. Ling, Zhen Li, Xiaoming Yao, Hangyi Zhao, David K. Stevenson, and Wei-Li Liao

Subjects
Placental growth factor, Leptin, medicine.medical_specialty, Placenta, Adipokine, Ceramides, Pre-Eclampsia, Predictive Value of Tests, Pregnancy, Obstetrics and Gynaecology, Medicine, Blood test, Humans, Placenta Growth Factor, Retrospective Studies, Eclampsia, obstetrics, medicine.diagnostic_test, business.industry, Obstetrics, gynaecology, public health, General Medicine, medicine.disease, Cohort, Gestation, Biomarker (medicine), Female, business, Biomarkers
Abstract

ObjectiveThis study aimed to develop a blood test for the prediction of pre-eclampsia (PE) early in gestation. We hypothesised that the longitudinal measurements of circulating adipokines and sphingolipids in maternal serum over the course of pregnancy could identify novel prognostic biomarkers that are predictive of impending event of PE early in gestation.Study designRetrospective discovery and longitudinal confirmation.SettingMaternity units from two US hospitals.ParticipantsSix previously published studies of placental tissue (78 PE and 95 non-PE) were compiled for genomic discovery, maternal sera from 15 women (7 non-PE and 8 PE) enrolled at ProMedDx were used for sphingolipidomic discovery, and maternal sera from 40 women (20 non-PE and 20 PE) enrolled at Stanford University were used for longitudinal observation.Outcome measuresBiomarker candidates from discovery were longitudinally confirmed and compared in parallel to the ratio of placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) using the same cohort. The datasets were generated by enzyme-linked immunosorbent and liquid chromatography-tandem mass spectrometric assays.ResultsOur discovery integrating genomic and sphingolipidomic analysis identified leptin (Lep) and ceramide (Cer) (d18:1/25:0) as novel biomarkers for early gestational assessment of PE. Our longitudinal observation revealed a marked elevation of Lep/Cer (d18:1/25:0) ratio in maternal serum at a median of 23 weeks’ gestation among women with impending PE as compared with women with uncomplicated pregnancy. The Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting impending event of PE with superior sensitivity (85% vs 20%) and area under curve (0.92 vs 0.52) from 5 to 25 weeks of gestation.ConclusionsOur study demonstrated the longitudinal measurement of maternal Lep/Cer (d18:1/25:0) ratio allows the non-invasive assessment of PE to identify pregnancy at high risk in early gestation, outperforming the established sFlt-1/PlGF ratio test.

Published
2021

24. Abstract P3-02-05: Assessment of repeatability and uptake quantification of 68GaNOTA-anti-HER2 sdAb PET/CT in patients with locally advanced or metastatic breast cancer

Author

Odrade Gondry, Catarina Xavier, Wim Waelput, Omar Al Dabssi, Marian Vanhoeij, Sandrine Aspeslagh, Sofie Joris, Christel Fontaine, Guy Verfaillie, Jacques De Grève, Katrien Glorieus, Ine Luyten, Frederik Vandenbroucke, Sophie Bourgeois, Laurens Raes, Sheeno Thyparambil, Nick Devoogdt, Ilse Vaneycken, Julie Cousaert, Vicky Caveliers, Hendrik Everaert, Tony Lahoutte, and Marleen Keyaerts

Subjects
Cancer Research, Oncology, skin and connective tissue diseases
Abstract

Background: Human epidermal growth factor receptor 2 (HER2) status is an important predictive biomarker in breast cancer (BC). Tumor heterogeneity has been described, with changes in HER2 expression levels between lesions and over the disease course. HER2 expression is assessed on tissue biopsies, at primary diagnosis and in metastatic lesions. A whole-body imaging technique such as PET/CT could help understand expression levels in different lesions. A 68Ga-labeled single domain antibody (sdAb) targeting the HER2 receptor has been developed and proven safe (Keyaerts et al., 2016). Imaging is performed at 90 min post-injection (pi). We report results of a phase II trial to assess the repeatability of the technique in 20 patients and the correlation of tracer uptake with HER2 tissue expression of the lesions present at the time of imaging. Methods: Twenty patients (pts) with a locally advanced or metastatic BC with at least one lesion of minimum 12 mm were included. Pts were injected intravenously with a typical protein mass of 100 µg and a radioactive dose ranging from 98-168 MBq 68GaNOTA-anti-HER2 sdAb. PET/CT images were obtained at 90 min pi. A second tracer injection followed by PET/CT was done with a maximal interval of 8 days. To assess repeatability, up to 5 lesions per pt were selected, with no more than 2 in a single organ. Peak Standard Uptake Values (SUVpeak) of the lesions were measured on both scans and compared with a t-test and Bland-Altman Plots. Images were compared to other available medical or imaging data and interpreted considering the subject’s disease course. Serum and plasma samples were collected before injection and between 60 and 365 days pi and stored for future detection of anti-drug antibodies (ADA) and liquid biopsies analysis for the presence of HER2 amplification. Tissue samples were assessed by central labs using mass spectrometry, immunohistochemistry and in fluorescence situ hybridization. Results: Twenty women with BC (6 HER2+, 14 HER2-) with a mean age of 58.6 y (37-81) were included. Three pts were scanned only once (2 due to withdrawal of consent, 1 due to covid pandemic). Repeatability of the technique was visually scored as excellent. For quantification, 50 lesions were compared on both scans in 17 pts without significant differences between the two measurements (p=0.40). The repeatability coefficient (RC) was 38.2%. The mean absolute percentage difference (MAPD) was 13.6%, comparable to repeat values reported for 18F-FDG. In 3 out of 6 HER2-positive (HER2+) patients, lesions showed high uptake, even better visible than using 18F-FDG in 2 of them. In 2 HER2+ subjects with a negative scan, lesions were confirmed to be true negatives: one patient did not relapse from BC but had tuberculosis; the other was confirmed to have a radiopneumonitis after radiotherapy and no relapse. In 1 HER2+ patient, the uptake was unexpectedly low. However, the HER2 status was also not reconfirmed in the metastatic setting for this subject. In 1 HER2-negative patient, the tumor HER2 status was changed from negative to positive based on a subsequent image-guided biopsy performed in this study. High tracer uptake was also seen in many of the patients presenting with HER2-low BC (IHC 1+ or 2+), indicating the potential of the tracer to detect low-level HER2 expression. Additional correlation to centrally performed tissue and blood analysis is ongoing. Conclusion: 68GaNOTA-Anti-HER2 PET/CT shows high uptake in HER2-expressing BC lesions but also in HER2-low lesions. The technique shows good repeatability and, in some cases, even better sensitivity than 18F-FDG PET/CT. Specificity was confirmed in relapse-free lesions such as tuberculosis and radiopneumonitis. Its sensitivity makes it a promising technique to assess HER2+ and HER2-low lesions in BC patients. Citation Format: Odrade Gondry, Catarina Xavier, Wim Waelput, Omar Al Dabssi, Marian Vanhoeij, Sandrine Aspeslagh, Sofie Joris, Christel Fontaine, Guy Verfaillie, Jacques De Grève, Katrien Glorieus, Ine Luyten, Frederik Vandenbroucke, Sophie Bourgeois, Laurens Raes, Sheeno Thyparambil, Nick Devoogdt, Ilse Vaneycken, Julie Cousaert, Vicky Caveliers, Hendrik Everaert, Tony Lahoutte, Marleen Keyaerts. Assessment of repeatability and uptake quantification of 68GaNOTA-anti-HER2 sdAb PET/CT in patients with locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-02-05.

Published
2022

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