bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-05-13: Crosstalk of post-translational modifications upon ERalpha activation
Authors: Chang Kai-Hsiung , Wen Hui-Chin , Tsai Sin-Yin 
Published: March 2020

Abstract
Breast cancer risk correlates highly with sustained estrogen receptor (ER) activities. Estrogen antagonists (e.g. anti-estrogens) and estrogen synthesis blockers (e.g. aromatase inhibitors) are frontline treatment to hinder disease progression in patients with breast cancer because most malignant breast tumors exhibit ERalpha positive expression signature. ERalpha harbors several post-translational modifications such as phosphorylation, acetylation, methylation, ubiquitination, sumoylation, palmitoylation, and others. Dysregulation of such PTMs on ERalpha enables abnormal tumor cell proliferation and promote malignancy. Although individual PTM on ERalpha is extensively deciphered, it remains relatively unclear how PTMs interact with each other to coordinate and execute 1) the recruitment of co-activators and RNA polymerase machinery to chromatin and 2) promoter clearance after transcription activation. Here, we report a novel PTM crosstalk between transcription-coupled phosphorylation and an ubiquitination-like modification on ERalpha. We also reveal its potential roles in regulating ER transcriptional activation and its future application in managing ER positive breast cancer.
Citation Format: Kai-Hsiung Chang, Hui-Chin Wen, Sin-Yin Tsai. Crosstalk of post-translational modifications upon ERalpha activation [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-05-13.
Abstract P6-10-13: Associated ductal carcinoma in situ in primary operated TNBC is associated with a longer time to distant event
Authors: Ardui Jan , Wildiers Hans , Floris Giuseppe , Izci Hava , Punie Kevin , Geukens Tatjana , Van Nieuwenhuysen Els , Han Sileny , Berteloot Patrick , Laenen Annouschka , Janssens Hilde , Smeets Ann , Weltens Caroline , Vergote Ignace , Neven Patrick 
Published: March 2020

Abstract
Purpose We studied presence of accompanying ductal adenoma in situ (accom-DCIS) in a consecutive series of primary operated TNBC for distant time-to-event outcome. Methods A retrospective cohort study (diagnosis 1/1/2000 - 31/12/2017) of prospectively registered primary operated TNBC patients in UZ Leuven. Only TNBC of no special type were included. We compared patient (age, BMI, symptomatic/screening-detected) and tumor related factors (Nottingham Prognostic Index (NPI), Lymphovascular Involvement (LVI)) for accom-DCIS and analyzed the effect of accom-DCIS on distant time to event outcome using the Cox proportional hazards model. Multivariate models were used to correct for possible confounders. Results We included 524 patients. Median follow-up was 102 months. Mean age of patient was 57.3 [26-90] years and 361 had accom-DCIS (68,9 %); demographics, clinical-pathological characteristics and postoperative chemo- and radiotherapy were similar in patients with and without accom-DCIS; only LVI was significantly more likely to be present in accom-DCIS cases (p=&lt;0.001). There were no differences in distant relapse rate (16.6% in accom-DCIS group vs 12.9% in no DCIS group [HR = 1.350, 95% CI (0.817;2.248) p=0.239]. Time to distant event was later if accom-DCIS was present: Mean time to distant event was 2.72yrs in the accom-DCIS group and 1.61yrs in the group with absent DCIS. In accom-DCIS 20/63 (31.8%) distant relapses occurred after 3 years while only 1/21 distant relapse (4.8%) occurred after 3 years in the non-DCIS group [HR =6.667, 95% CI (0.952-46.705) p=0,029]. Conclusion In our series of TNBCs, patients with and without accom-DCIS had similar distant relapse rates. Significantly more distant relapse occurred after 3 years in patients with accom-DCIS compared to patients without accom-DCIS.
Citation Format: Jan Ardui, Hans Wildiers, Giuseppe Floris, Hava Izci, Kevin Punie, Tatjana Geukens, Els Van Nieuwenhuysen, Sileny Han, Patrick Berteloot, Annouschka Laenen, Hilde Janssens, Ann Smeets, Caroline Weltens, Ignace Vergote, Patrick Neven. Associated ductal carcinoma in situ in primary operated TNBC is associated with a longer time to distant event [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-13.
Abstract P6-16-08: Evaluation of cytochrome P450 4A11 overexpression in breast cancer cells in vitro and in vivo
Authors: Ali Sehar , Borin Thaiz , Arbab Ali 
Published: March 2020

Abstract
Metastatic breast cancer (BC) is a highly invasive form of cancer that contributes greatly to patient mortality. Due to the complex mechanisms underlying cancer growth and metastasis, novel therapeutic targets must be found to increase patient survival. One such target is the cytochrome P450 4 (CYP4) metabolic pathway leading to the production of 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE is a lipid signaling molecule that promotes both tumor cell proliferation and neovascularization in tumors by inducing the proliferation and migration of endothelial cells, therefore promoting BC tumor survival. N-hydroxy-N’-(4-butyl-2 methyl phenyl) formamidine (HET0016) is a selective inhibitor of 20-HETE synthesis, thus impairing tumor growth and neovascularization. This study aims to investigate changes in BC (MDAMB231 and MCF7) cell lines overexpressing CYP4A11, a human CYP4 enzyme, with and without HET0016 treatment. To accomplish this, cells that overexpressed CYP4A11 were produced using lentivirus infection and confirmed via western blot. Tumor cell aggressiveness was assessed in vitro using migration and proliferation assays. Tumor growth with and without CYP4A11 overexpression was also measured in vivo using athymic nude mice. The results demonstrated that cells overexpressing CYP4A11 showed protein levels 4 times higher than the non-modified cells. MDAMB231 is a triple-negative BC (TNBC) that, when overexpressing CYP4A11, demonstrated increased proliferation capacity and significant increased tumor growth compared to non-modified cells. TNBC cells overexpressing CYP4A11 also showed increased motility. However, modified MCF7 cells did not show significant alterations when compared to non-modified MCF7 cells. Additionally, all cells treated with HET0016 showed decreased migration in the first 24 hours. In conclusion, these results demonstrate that the overexpression of CYP4A11 in TNBC cells increased tumor aggressiveness, proving this pathway to be an important target for therapeutic inhibition.
Citation Format: Sehar Ali, Thaiz Borin, Ali Arbab. Evaluation of cytochrome P450 4A11 overexpression in breast cancer cells in vitro and in vivo [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-16-08.
Abstract TS1-3: Proteogenomics and Clinical Translation
Authors: Ellis MJ 
Published: March 2020

Abstract
Improvements in breast cancer treatment are being achieved at an increasing pace in all three clinical subsets of the disease, namely ER+ HER2- (luminal), HER2+ (HER2-driven) and ER- PgR- and HER2- (triple negative). While these disease groupings served as useful approximations of the immense diversity of breast cancer when only endocrine therapy, chemotherapy and trastuzumab were available, the inadequacy of this disease classification is readily evident when set against the sophistication of our growing therapeutic armamentarium. What is on the horizon to replace our simple immunohistochemistry-based subtyping approaches to avoid misdiagnosis and consequent mismanagement? In this lecture I will make the argument that the advent of efficient and accurate protein mass spectrometry provides the “missing link” in ‘omics analysis that integrates information derived from next generation DNA and RNA analysis to create a more secure diagnostic conclusion. The new field of “clinical proteogenomics” validates proposed disease drivers, dissects complex amplicons, monitors signaling perturbations in response to targeted treatments and determines the activity of the immune microenvironment. The advent of cloud computing promotes the efficient delivery of individualized proteogenomic therapeutic road maps as a near-term possibility.
Citation Format: MJ Ellis. Proteogenomics and Clinical Translation [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr TS1-3.
Abstract A13: Leveraging Zika virus and the immune system to treat glioblastoma
Authors: Jash Arijita , Govero Jennifer , Nair Sharmila , Diamond Michael S. , Chheda Milan G. 
Published: March 2020

Abstract
Glioblastoma (GBM) kills most adults within 2 years. One reason for inevitable recurrence is that GBM stem cells (GSCs) are resistant to existing therapies. Additionally, GBM is the hallmark example of an immunotherapy-resistant tumor. Since GSCs share properties with neural stem cells, we investigated whether the natural honing and lytic activity of Zika virus (ZIKV) could be harnessed to target and kill GSCs. We published the first use of ZIKV to kill GSCs: ZIKV kills GSCs in tumors removed from patients, with minimal impact on non-GSC tumor cells and importantly, normal human brain cells were not affected by ZIKV. In vivo, ZIKV more than doubled median survival in immunocompetent mice bearing orthotopic gliomas, and in 40-50% of cases, mice were cured. In new unpublished work, we assessed brains of mice treated with ZIKV and found that treatment induces a robust inflammatory response. Using MHC-I tetramers presenting ZIKV envelope (E) protein or luciferase peptides (expressed in the tumor cells), we found that CD8+ T cells in the region of the tumor respond to both ZIKV and tumor, and anti-tumor CD8+ T cells are increased after ZIKV infection compared to vehicle. Additionally, cured mice were protected against tumor rechallenge, suggesting ZIKV induces immunologic memory that can surveil against recurrence. Using blocking antibodies, we discovered that CD8+ T cells are required for the efficacy of ZIKV, and CD8+ T cells are required for long-term protection. Our findings suggest that ZIKV may be an effective therapy for GBM for two reasons: its direct targeting of treatment-resistant tumor cells in turn produces an antitumor inflammatory response. Such a response may now be further leveraged by immunotherapies.
Citation Format: Arijita Jash, Jennifer Govero, Sharmila Nair, Michael S. Diamond, Milan G. Chheda. Leveraging Zika virus and the immune system to treat glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A13.
Abstract A2: Identify biomarkers associated with immunotoxicities using single-cell RNAseq
Authors: Chen Jiamin , Pflieger Lance , Sathe Anuja , Grimes Sue , Brems Michael , Pattison Tabitha , Christensen Bryce , Rhodes Terence , Ji Hanlee 
Published: March 2020

Abstract
Recent advancements in immunotherapy are revolutionizing the landscape of clinical immuno-oncology and have significantly increased patient survival in a range of cancers. Notably, immune checkpoint blockade therapies have induced durable responses and provided tremendous clinical benefits to previously untreatable patients. However, unleashing immune system against cancer also disrupts the immunologic homeostasis and induces inflammatory responses, resulting in immune-related adverse events. The precise mechanisms underlying immune-related adverse events remain unknown. Furthermore, it is unclear why immune checkpoint blockade therapies only induce inflammatory side effects in some patients but not others. In this study, we identify biomarkers associated with adverse events in cancer immunotherapy. Leveraging high-throughput single-cell RNA sequencing (scRNAseq), we systematically characterize the functional impacts of immune checkpoint blockade on the patient immune system at single-cell resolution. The peripheral blood mononuclear cells (PBMCs) from six cancer patients with melanoma or non-small cell lung cancer (NSCLC) before (T0) and after (T1, T2) receiving immune checkpoint blockade therapies, i.e., anti-PD-1 and anti-CTLA4, were collected and sequenced thus far. The longitudinal study of PBMCs provides an opportunity to elucidate the dynamics of immune responses. In total, we sequenced more than 70,000 cells from 18 PBMC libraries. Notably, when PBMCs from T1 and T2 were compared to T0, we observed sustained immune activation in a variety of cell populations after checkpoint blockade. Furthermore, we found distinct pathway activations associated with specific checkpoint blockade. Currently, we are performing comprehensive analysis to identify specific immune subpopulations and cytokines associated with immune-related adverse events, e.g., colitis and pneumonitis. Ultimately, our study will identify clinically actionable biomarkers for response prediction and side effects alleviation in patients receiving immunotherapy in the era of precision medicine.
Citation Format: Jiamin Chen, Lance Pflieger, Anuja Sathe, Sue Grimes, Michael Brems, Tabitha Pattison, Bryce Christensen, Terence Rhodes, Hanlee Ji. Identify biomarkers associated with immunotoxicities using single-cell RNAseq [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A2.
Abstract A56: Releasing the brake on T-cell activation through inhibition of HPK1
Authors: Grimster Neil , Drew Lisa , Fawell Stephen , Mele Deanna A , Bommakanti Gayathri , Shen Minhui , Xu Kevin , Song Kun , Ziegler Rob , Kettle Jason , Mfuh Adelphe , Sheilds Jason 
Published: March 2020

Abstract
Introduction: Loss of immune surveillance is required for cancer cell growth and metastasis; tumors co-opt suppressive mechanisms to evade detection by the immune system. The immune system is equipped with multiple feedback mechanisms to limit inflammation to prevent autoimmunity; tumors activate these pathways to escape immunity. HPK1 (hematopoietic progenitor kinase 1) is a negative regulator of T-cell activation; the kinase activity limits T-cell signaling and tumoricidal cytokine production. Recent literature has shown that inactivation of the kinase function of HPK1 prevents tumor progression in murine tumor models (1).
Experimental Procedures: We used lentiviral delivered shRNAs and CRISPR/Cas9 technology to delete HPK1 in Jurkat cells and primary human T cells, respectively. Jurkat T cells (wt/KO) were activated with anti-CD3 antibody and cell lysates were assessed by Western blot to examine signaling events downstream of the T-cell receptor (TCR). Primary human T cells or CRISPR/Cas9 KO T cells were activated in vitro using anti-CD3/anti-CD28 antibodies in the presence or absence of prostaglandin E2 (PGE2). Cytokines were quantified by ELISA.
Results: We present novel findings demonstrating that the role of HPK1 is conserved in human Jurkat cells as well as in primary human T cells. Loss of HPK1 enhanced T-cell receptor signaling in Jurkat cells. In CRISPR/Cas9 KO HPK1 primary human T cells, TCR activation resulted in enhanced cytokine secretion and proliferation concomitant to a decrease in pSLP76, the target molecule phosphorylated by HPK1. In addition, HPK1 KO cells were rescued from PGE2-mediated suppression. A screening and assessment of HPK-1 inhibitor compounds that enhance T-cell function is ongoing.
Conclusions: In summary, HPK1 function is conserved in human T cells and inhibitors of HPK1 could enhance antitumor immunity through increased T-cell function, overcoming suppressive signals in the tumor microenvironment and broadening the response to check point inhibitors for cancer immunotherapy.
Reference
1. Hernandez S, Qing J et al. The kinase activity of hematopoietic progenitor kinase 1 is essential for the regulation of T cell function. Cell Rep 2018;25:80-94.
Citation Format: Neil Grimster, Lisa Drew, Stephen Fawell, Deanna A Mele, Gayathri Bommakanti, Minhui Shen, Kevin Xu, Kun Song, Rob Ziegler, Jason Kettle, Adelphe Mfuh, Jason Sheilds. Releasing the brake on T-cell activation through inhibition of HPK1 [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A56.
Abstract A60: GM-CSF modulation restricts the secretion of main cytokines associated with CAR T-cell induced cytokine release syndrome
Authors: Sachdeva Mohit , Aranda-Orgilles Beatriz , Duchateau Philippe , Poirot Laurent , Valton Julien 
Published: March 2020

Abstract
Emerging CAR T-cell therapies have shown high remission rates in patients with hematologic malignancies. Despite the success of these novel immunotherapies, multiple adverse effects are associated with CAR T-cell infusions. Cytokine release syndrome (CRS) is one of the most common CAR T cell-associated toxicities and results from the rapid elevation of inflammatory cytokines, which can be life threatening. CRS is commonly managed in the clinic with anti-IL-6R antibodies and glucocorticoids. While efficacious, these treatments address CRS only after it has initiated; therefore, alternative therapeutic strategies preventing CRS onset remain an urgent need. Using cytokine profiling arrays, we identified that secreted granulocyte macrophage colony stimulating factor (GM-CSF) contributes to CRS, since elevated GM-CSF levels promote macrophage-dependent secretion of key CRS biomarkers including MCP-1, IL-6, and IL-8. Modulation of GM-CSF levels either via genetic engineering of CAR T-cells using TALEN® technology or via neutralizing-antibodies resulted in a marked reduction of macrophage-dependent release of CRS-associated cytokines, while preserving antitumor activity. Our work proposes a novel therapeutic strategy to improve the overall safety of CAR T-cell therapies in cancer patients by using GM-CSF knockout CAR T cells.
Citation Format: Mohit Sachdeva, Beatriz Aranda-Orgilles, Philippe Duchateau, Laurent Poirot, Julien Valton. GM-CSF modulation restricts the secretion of main cytokines associated with CAR T-cell induced cytokine release syndrome [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A60.
Abstract A70: Bridging nonclinical studies to clinical design using quantitative systems pharmacology model of T cell-engaging bispecifics
Authors: Lin Lin , Wille Lucia , Betts Alison , Hua Fei , Hagen David , Park Jennifer , Apgar Josh , Burke John 
Published: March 2020

Abstract
Purpose: T cell-engaging bispecific molecules (TCEs) are protein therapeutics that can bind to both T cells, via CD3 interactions, and target cells through target specific/overexpressed molecules. The TCEs bring cytolytic T cells to kill tumor cells through the formation of the trimolecular complex (CD3:TCE:Target). While it offers a potentially very potent approach to treat cancer, it also has a complex relationship between binding potency, exposure, and efficacy. These complex relationships bring challenges to drug discovery and development such as identifying optimal Kds for the drug candidate, predicting efficacious dose, and selecting dosing regimen in clinical study.
Methods: A quantitative systems pharmacology model was developed for solitomab, a bispecific T-cell engager binding to CD3 and EpCAM. The model includes solitomab binding to both CD3 and EpCAM in both tumor and normal tissue, different E:T ratios for tumor and normal tissue, turnover of CD3 and EpCAM proteins, as well as pharmacokinetics (PK) and tissue distribution of the drug. Literature data such as binding Kds, in vitro cell killing, and PK were used to inform model development.
Results: Using the calibrated QSP model, we demonstrated that the trimolecular complex per T cells required for in vitro T-cell killing are ~200 molecules, which is similar to the number predicted at the maximal tolerated dose observed in the clinical study despite many differences between in vivo and in vitro conditions such as E:T ratios. The therapeutic index (TI) for solitomab was predicted to be close to 1 based on the trimolecular complex per T cells in tumor and in normal tissue. This result is consistent with clinical observation. Using the developed model, we explored the effects of varying binding Kds to EpCAM and CD3, varying half-life of the drug, and varying target expression levels on TI.
Conclusion: Current work demonstrated the possibility of using a QSP model integrating in vitro data, human PK, and target biology to predict efficacious dose and TI for treating cancer. The model also demonstrated the complex relationship between Kds, target expression level, drug half-life, and TI for TCEs. This model can be used to guide future drug candidate selection and clinical study design.
Citation Format: Lin Lin, Lucia Wille, Alison Betts, Fei Hua, David Hagen, Jennifer Park, Josh Apgar, John Burke. Bridging nonclinical studies to clinical design using quantitative systems pharmacology model of T cell-engaging bispecifics [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A70.
Abstract A83: Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade
Authors: Miller Brian C. , Sen Debattama R. , Abosy Rose Al , Bi Kevin , Virkud Yamini , LaFleur Martin W. , Yates Kathleen B. , Lako Ana , Felt Kristen , Naik Girish S. , Manos Michael , Gjini Evisa , Ishizuka Jeffrey J. , Hodi F. Stephen , Rodig Scott J. , Sharpe Arlene H. , Haining W. Nicholas 
Published: March 2020

Abstract
T-cell dysfunction in the tumor microenvironment (TME) is a hallmark of many cancers. Reinvigoration of T-cell function by PD-1 checkpoint blockade can result in striking clinical responses, but is only effective in a minority of patients. The mechanisms by which anti-PD-1 therapy acts on exhausted T cells are not fully understood. Here we show that anti-PD-1 therapy acts on a specific subpopulation of CD8+ tumor-infiltrating lymphocytes (TILs) in melanoma mouse models, which can also be found in patients with melanoma. Exhausted CD8+ TILs contain a subpopulation of “progenitor exhausted” T cells with critical functional attributes that are not shared by the majority “terminally exhausted” TILs: they retain more polyfunctionality, persist following transfer into tumor-bearing mice, and differentiate to repopulate terminally exhausted TILs in the TME. As a result, progenitor exhausted CD8+ TILs are better able to control tumor growth than terminally exhausted cells. Progenitor exhausted, but not terminally exhausted, CD8+ TILs can respond to anti-PD-1 therapy. Melanoma patients with a higher percentage of progenitor exhausted cells have a longer duration of response to checkpoint blockade therapy. Therefore, approaches to expand progenitor exhausted CD8+ T cells in the tumor microenvironment may be an important component of improving checkpoint blockade response.
Citation Format: Brian C. Miller, Debattama R. Sen, Rose Al Abosy, Kevin Bi, Yamini Virkud, Martin W. LaFleur, Kathleen B. Yates, Ana Lako, Kristen Felt, Girish S. Naik, Michael Manos, Evisa Gjini, Jeffrey J. Ishizuka, F. Stephen Hodi, Scott J. Rodig, Arlene H. Sharpe, W. Nicholas Haining. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A83.