bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 482: Rapid highly multiplexed immunoprofiling of human fixed tissues by Orion imaging
Authors: Lin Jia-Ren , Campton Daniel E. , Cooper Jeremy , Chen Yu-An , McCarty Erin F. , Ligon Keith L. , Kaldjian Eric P. , Teplitz Kyla , Reese Steve , Santagata Sandro , Sorger Peter K. 
Published: July 2021

Abstract
The dramatic impact of immune checkpoint inhibitors (ICIs) has focused interest in investigating immune-tumor cell interactions to understand mechanisms of ICI sensitivity and resistance, to identify patients that are responsive to specific treatments, and to develop new therapies. Multiplexed tissue imaging is a highly promising approach to immunoprofile tumors; it can assess many cell types and states within the context of preserved tumor architecture. However, the promise of highly multiplexed tissue imaging remains largely unfulfilled by current methods which are not compatible with pathology workflows. Here we present the development and implementation of Orion™ technology that permits whole-slide rapid single-pass imaging of up to 21 markers from formalin fixed paraffin embedded (FFPE) tissues. This method measures spectra for specific fluorophores to optimally sample the emitted light spectrum and distinguish multiple fluorescence excitation and emission channels across the spectral range of optical microscopes (~400-900 nm). To establish the utility of the Orion™ platform for immuno-phenotyping and immune checkpoint protein detection, we created an immunoprofiling panel of 21 qualified antibodies and labelled with fluorophores to subdivide the available emission spectrum in the 438-893 nm range. The panel includes markers that define subsets of T cells and macrophages. FFPE sections of human tonsil and matched primary and brain metastatic lung adenocarcinoma were stained and imaged in a single pass demonstrating staining patterns consistent with known micro-anatomic compartments and cell types in tonsil and identifying immune cell subtypes and heterogeneous checkpoint protein expression in tumor samples. An unexpected benefit of imaging with the Orion platform is the reduction of autofluorescence which is highly advantageous for the detection of proteins, like PD-L1, that function at very low levels. Orion imaging promises to accelerate discovery of predictive and prognostic biomarkers, enable pharmacodynamics study of immuno-oncology drugs undergoing clinical trials and ultimately provide clinically actionable diagnostic tests.
Citation Format: Jia-Ren Lin, Daniel E. Campton, Jeremy Cooper, Yu-An Chen, Erin F. McCarty, Keith L. Ligon, Eric P. Kaldjian, Kyla Teplitz, Steve Reese, Sandro Santagata, Peter K. Sorger. Rapid highly multiplexed immunoprofiling of human fixed tissues by Orion imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 482.
Abstract 520: Potential role of serum proteome in predicting immune-related adverse events from immunotherapy in non-small cell lung cancer
Authors: Nam Myungwoo , Kim Leeseul , Cheng William , Bae William H. , Hwang Jin Young , Choi Yoonhee , Lee Yeun Ho , Hur Won Kyung , Jung Chan Mi , Cho Heayoon S. , Chae Young Kwang 
Published: July 2021

Abstract
Early recognition of immune-related adverse events (irAEs) of immunotherapy is important. Circulating proteome reflects host response to diseases and is being explored as a marker for response to immunotherapy. We used a serum-based proteomics test, Primary Immune Response (PIR), to explore the associations between developing irAEs and immunotherapy in non-small cell lung cancer (NSCLC) patients.
Data of 38 consented NSCLC patients with baseline PIR test done within one week prior to the start of immunotherapy were collected. Samples were grouped into either sensitive or intermediate/resistant (not sensitive) by PIR classification. We analyzed the durations from the immunotherapy initiation to the first episode of irAE, each individual irAE, and each irAE above grade 1 using log-rank test. IrAEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Among the 38 NSCLC patients, 21 patients (55%) experienced one or more irAEs. The total number of irAEs was 33 with the majority classified as either grade 1 (n=18, 55%) or grade 2 (n=11, 33%) (Table 1). PIR-sensitive group showed longer irAE free period with the median ‘Time to first irAE' being 54 weeks compared to 9.5 weeks in PIR-not sensitive (p=0.22, HR=0.56, 95% CI=0.24-1.34). The median ‘Time to each irAE' were 45 weeks and 12 weeks in PIR-sensitive and PIR-not sensitive, respectively (p=0.1, HR=0.55, 95% CI=0.28-1.1). The median ‘Time to each irAE above grade 1' demonstrated similar results with less differences between the two groups with median values of 54 weeks and 30 weeks in PIR-sensitive and PIR-not sensitive, respectively (p=0.28, HR=0.57, 95% CI=0.21-1.56).
Our results demonstrated a trend that PIR-sensitive patients are more likely to tolerate immunotherapy longer without developing irAEs. It implies the potential value of the baseline PIR test in predicting the development of irAEs and selecting subsets of patients who need close monitoring with immunotherapy.
Distribution of irAEs by PIR classificationVariablesSensitiveNot-sensitiveTotal number of patients, n1325Patients without irAE, n (%)7 (54%)10 (40%)Patients with irAE, n (%)6 (46%)15 (60%)Total number of irAEs, n1023Grade 1, n (%)5 (50%)13 (57%)Grade 2, n (%)5 (50%)6 (26%)Grade 3, n (%)02 (8%)Grade 4, n (%)01 (4%)Grade 5, n (%)01 (4%)
Citation Format: Myungwoo Nam, Leeseul Kim, William Cheng, William H. Bae, Jin Young Hwang, Yoonhee Choi, Yeun Ho Lee, Won Kyung Hur, Chan Mi Jung, Heayoon S. Cho, Young Kwang Chae. Potential role of serum proteome in predicting immune-related adverse events from immunotherapy in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 520.
Abstract 735: hPG80 (circulating progastrin), a novel blood-based biomarker for detection of poorly differentiated neuroendocrine carcinoma and well differentiated neuroendocrine tumors
Authors: Chauhan Aman , Prieur Alexandre , Kolesar Jill , Arnold Susanne , Cousin Thierry , Payen Lea , Mahi Younes , Sanders Madison , Evers B. Mark , Joubert Dominique , Anthony Lowell 
Published: July 2021

Abstract
Background: Current blood-based biomarkers for neuroendocrine neoplasms (NENs) lack both sensitivity and specificity. This is especially true for high-grade NENs (small and large cell neuroendocrine carcinomas). Human circulating progastrin (hPG80) is a novel biomarker for NENs and is easily measured in plasma using an ELISA test. This study is the first to explore hPG80 in NENs.
Methods: Progastrin concentrations were quantified in plasma from 95 patients with stage IV NEN using DxPG80 technology (ECS Progastrin, Switzerland) and compared with hPG80 concentrations in 50-80-year-old healthy donors (n=252) as well as a subgroup comprised of only the 18-25-year-olds (n=137).
Results: The median hPG80 in NENs patients was 5.54 pM as compared to 1.5 pM for patients in the 50-80-year-old control group and 0.29 pM for patients in the 18-25-year-old cohort (p&lt;0.0001, one-tailed Mann-Whitney U-test). A subgroup analysis of NENs revealed a median hPG80 of 3.54 pM in neuroendocrine carcinoma (NEC n=25) vs 5.8 pM in neuroendocrine tumor (NET n=70). Interestingly small cell lung cancer sub cohort (n=13) also showed significant elevation of hPG80 (9.09 pM). All the above-mentioned differences were statistically significant as compared to healthy controls.
Conclusions: Plasma hPG80 in NENs suggests hPG80 may be a diagnostic blood biomarker for both low- and high-grade NENs and further study is warranted. A prospective trial is ongoing in small cell lung cancer to evaluate its role in monitoring of disease (NCT03958045) and further prospective studies in low-grade neuroendocrine tumors are underway.
Citation Format: Aman Chauhan, Alexandre Prieur, Jill Kolesar, Susanne Arnold, Thierry Cousin, Lea Payen, Younes Mahi, Madison Sanders, B. Mark Evers, Dominique Joubert, Lowell Anthony. hPG80 (circulating progastrin), a novel blood-based biomarker for detection of poorly differentiated neuroendocrine carcinoma and well differentiated neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 735.
Abstract 932: Discovery of D-1553, a novel and selective KRas-G12C Inhibitor with potent anti-tumor activity in a broad spectrum of tumor cell lines and xenograft models
Authors: Shi Zhe , Weng Jifang , Fan Xiaochong , Wang Emma , Zhu Qingqing , Tao Liangshan , Han Zixing , Wang Zhenwu , Niu Haotao , Jiang Yueheng , Zhang Ling , Dai Xing , Wang Yaolin 
Published: July 2021

Abstract
KRas mutations are frequently seen in solid tumors such as lung (~25%), colorectal (~40%) and pancreatic (~90%) cancers. The G12C mutation accounts for ~50% of all KRas mutations in lung cancer and to a lower percentage in other tumor types. Recently, selective inhibitors targeting the KRas-G12C mutation through covalent link to the cysteine of the mutated protein have been advanced to early clinical development and exhibited encouraging response in patients with lung cancer. Here, we present a novel small molecule compound that specifically inhibits KRas-G12C in vitro (cell lines) and in vivo (cell line-derived xenograft tumor models). The anti-tumor activity of D-1553 is evaluated across a panel of cancer cell lines including lung, pancreatic and colorectal cancers and shown to be active only in cancer cells with KRas-G12C mutation. In addition, D-1553 is highly potent in vivo in various cell line-derived xenograft tumor models with KRas-G12C mutation as a single agent. When D-1553 is combined with MEK inhibitor, SHP2 inhibitor or cytotoxic agents, further tumor growth inhibition or regression was observed in tumor xenograft models. These data suggest that D-1553 has anti-tumor activity in a broad spectrum of cancers and is suitable for tissue-agnostic clinical development targeting cancers with KRas-G12C mutation. D-1553 is currently in a Phase 1/2 clinical trial evaluating safety, tolerability, PK and efficacy in patients with advanced solid tumors harboring KRasG12C mutation (NCT04585035).
Citation Format: Zhe Shi, Jifang Weng, Xiaochong Fan, Emma Wang, Qingqing Zhu, Liangshan Tao, Zixing Han, Zhenwu Wang, Haotao Niu, Yueheng Jiang, Ling Zhang, Xing Dai, Yaolin Wang. Discovery of D-1553, a novel and selective KRas-G12C Inhibitor with potent anti-tumor activity in a broad spectrum of tumor cell lines and xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 932.
Abstract 978: Magnolol induces apoptosis and inhibits metastasis via suppression of NF-κB activation in human bladder cancer
Authors: Lee Sin-Rong , Tan Zhao-Lin , Chang Yuan , Chiang I-Tsang , Hsu Fei-Ting 
Published: July 2021

Abstract
Magnolol is a phenolic compound extracted from magnolia officinalis, and known as a common Chinese medicinal material used in the treatment of strokes, colds, etc. Magnolol has also recognized as an anti-inflammation agent which can downregulate several inflammation signals transduction. Several reports suggested that magnolol may also have anti-tumor potential in liver and colon cancer. Nevertheless, the regulatory mechanism of magnolol on apoptosis and NF-κB signaling in human bladder cancer has not been elucidated. Thus, the purpose of the study was to investigate the mechanism and therapeutic efficacy on bladder cancer. First of all, we used MTT assay to investigate the cytotoxicity induction after magnolol treatment in bladder cancer. Then, we used NF-κB translocation assay to evaluate whether the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was decreased after magnolol treatment. We also detected the apoptosis induction ability of magnolol on extrinsic/intrinsic apoptosis pathway. This study demonstrated that magnolol significantly triggered the accumulation at the sub-G1 phase, the loss of mitochondrial membrane potential, and the activation of cleaved caspase-3, -8 and -9. Further verify the effect of magnolol on the expression of anti-apoptotic related proteins, we performed Western blotting. Magnolol inhibited migration and invasion ability of bladder cancer were investigated by wound healing and invasion assay. Then, we performed Western blotting to detect whether magnolol may inhibit NF-κB-mediated downstream signaling that involving in anti-apoptosis and metastasis such as MCL-1 and MMP9 protein expression. Moreover, the reduction of Cyclin D1 protein expression was used to evaluate the inhibition of cell proliferation by magnolol. In sum, our result demonstrated that magnolol induced extrinsic and intrinsic apoptosis mechanism and inhibit invasion/migration ability of bladder cancer was associated with the inactivation of NF-κB.
Citation Format: Sin-Rong Lee, Zhao-Lin Tan, Yuan Chang, I-Tsang Chiang, Fei-Ting Hsu. Magnolol induces apoptosis and inhibits metastasis via suppression of NF-κB activation in human bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 978.
Abstract CT153: Correlation of CDKN2A genomic alterations with tumor response to palbociclib given before chemoradiation therapy to patients with human papillomavirus-unrelated, locally advanced head and neck squamous-cell carcinoma
Authors: Oppelt Peter , Ley Jessica , Palka Kevin , Paniello Randal C. , Puram Sidharth V. , Rich Jason , Jackson Ryan , Pipkorn Patrik , Gay Hiram , Liu Jingxia , Thorstad Wade , Zevallos Jose , Adkins Douglas R. 
Published: July 2021

Abstract
The primary aims of this single-arm, phase 2 trial were to determine the objective response rate (ORR) of human papillomavirus (HPV)-unrelated, locally advanced head and neck squamous-cell carcinoma (LA-HNSCC) to palbociclib monotherapy, and to correlate responses to somatic genomic alterations in CDKN2A. HPV-unrelated disease was defined as 1) SCC of the larynx, hypopharynx or oral cavity, or 2) SCC of the oropharynx with &lt;70% of tumor cells expressing p16 by immunohistochemistry and/or absence of high-risk HPV-RNA by in situ hybridization. Genome sequencing (FoundationOne CDx or Tempus xT) was performed on tumor tissue obtained before treatment. Patients received palbociclib 125 mg/d orally on days 1-21 of each 28-day cycle. Tumor response was assessed using RECIST 1.1 on CT scans performed before and after two cycles of palbociclib. After palbociclib, patients received chemoradiation therapy. A sample size of 24 patients yielded an 80% power if the ORR was &gt;38% (alternative hypothesis), using an exact binomial test of one sample proportion comparison with an upper one-sided nominal significance level of 0.05 and null ORR of &lt;17%. To date, 12 patients have enrolled and completed two cycles of palbociclib: primary site (larynx-7; hypopharynx-2; oropharynx-2, oral cavity-1), stage (III-3; IV-9), and smoking history (yes-11; no-1). The ORR to palbociclib monotherapy was 33%: CR (1 patient), PR (3), SD (7), and PD (1). CDKN2A alterations were identified in 6 patients (50%), and included loss-of-function mutations (4) or deletions (2). Tumor responses to palbociclib occurred in 4 of 6 patients (67%) with CDKN2A alterations versus 0 of 6 patients (0%) without CDKN2A alterations (p=0.06, Fisher's Exact Test). These preliminary results suggest that palbociclib may be an effective treatment for CDKN2A-altered, HPV-unrelated, LA-HNSCC, but not in disease that lacks CDKN2A alterations.
Citation Format: Peter Oppelt, Jessica Ley, Kevin Palka, Randal C. Paniello, Sidharth V. Puram, Jason Rich, Ryan Jackson, Patrik Pipkorn, Hiram Gay, Jingxia Liu, Wade Thorstad, Jose Zevallos, Douglas R. Adkins. Correlation of CDKN2A genomic alterations with tumor response to palbociclib given before chemoradiation therapy to patients with human papillomavirus-unrelated, locally advanced head and neck squamous-cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT153.
Abstract LB031: Plasma based metabolic profiling in metastatic gastrointestinal stromal tumors (GIST)
Authors: Honrao Chandrashekhar , Rao Srihari Raghavendra , Teissier Nathalie , Call S. Greg , ODay Elizabeth M. , Janku Filip 
Published: July 2021

Abstract
Background: Discovery of oncogenic mutations as targets for cancer therapy revolutionized treatment of GIST and other cancers. However, nearly all patients ultimately progress, which emphasizes the need for development of new tools to assess cancer prognosis and factors associated with benefit of cancer therapies. Altered metabolism is a hallmark of cancer, enabling tumors to proliferate, survive and metastasize. By measuring the complete set of metabolites in an individual (metabolome) it is possible to identify biomarkers that correlate with disease status, prognosis, and therapeutic response. Methods: We performed untargeted NMR and MS-based machine learning metabolomic analysis (Olaris, Waltham, MA) of serial plasma samples collected at baseline and during experimental systemic therapies in 39 patients with advanced/metastatic GIST. Results were compared to clinical outcomes. Results: In serial plasma samples from 39 patients with advanced/metastatic GIST using untargeted NMR and MS-based machine learning (ML) metabolomic analysis, we identified metabolic signatures to build Biomarker-of-Response (BoR) ML models that could accurately differentiate patients with response, intrinsic and adaptive resistance to experimental systemic therapies. The BoR ML model also correlated with tumor growth or tumor reduction in patients with response, intrinsic and adaptive resistance. Finally, we identified metabolic pathways associated with response and resistance. Conclusions: Comprehensive metabolomic profiling of serially collected plasma is feasible and detects metabolic signatures associated with therapeutic response in advanced GIST.
Citation Format: Chandrashekhar Honrao, Srihari Raghavendra Rao, Nathalie Teissier, S. Greg Call, Elizabeth M. ODay, Filip Janku. Plasma based metabolic profiling in metastatic gastrointestinal stromal tumors (GIST) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB031.
Abstract LB175: APX601, a Potent TNFR2 Antagonist as a Novel and Promising Approach to Reverse Tumor Immune Suppression
Authors: Krishnan Sushma , Alvarado Ryan , Huang George , Yang Xiaodong , Filbert Erin L. 
Published: July 2021

Abstract
A key barrier to effective immunotherapy for cancer is the immunosuppressive tumor microenvironment (TME) characterized by infiltrating regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC). While depletion of immune-suppressive cells is a promising cancer immunotherapy strategy, current approaches are ineffective due to lack of specificity and safety concerns. Tumor Necrosis Factor Receptor 2 (TNFR2) is emerging as a novel, selective target to overcome immunosuppression in the TME. Here we present APX601 as a potent Treg and myeloid suppressive cell inhibitor. APX601 is a humanized IgG1 antibody to TNFR2 generated using APXiMAB™, Apexigen's proprietary antibody platform. APX601 selectively binds human and monkey TNFR2, blocks the binding of TNFR2 to TNF-α and depletes TNFR2-expressing Treg and tumor cells in vitro. In addition to depleting suppressive cells, APX601 can also reverse MDSC and Tregs mediated immune suppression. In human TNFR2 knock-in syngeneic mouse tumor models CT26 and MC38, treatment with APX601 results in significant tumor growth inhibition both as a single agent and in combination with anti-PD-1. Thus, APX601 is a potent antagonist antibody against TNFR2 with the ability to reverse immune suppression in TME and inhibit tumor growth. APX601 was evaluated in a repeat dose range finding toxicology study in monkeys and demonstrated a good safety profile when administered up to 100mg/kg. These data strongly support the development of APX601 as a novel therapeutic approach for reversing tumor immune suppression and for the treatment solid tumors.
Citation Format: Sushma Krishnan, Ryan Alvarado, George Huang, Xiaodong Yang, Erin L. Filbert. APX601, a Potent TNFR2 Antagonist as a Novel and Promising Approach to Reverse Tumor Immune Suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB175.