tbuckley/cabot-search huggingface dataset:
Abstract 2947: Towards advanced precision oncology assays - Selection of immunohistochemistry chromogen impacts microdissection and downstream molecular analysis of archival specimens
Authors: Sarah Laun, Adam Roberge, Robert Weigman, Aubrey Lewis, Valarie Greisman, Meeiyueh Liu, Owen Stephens, Erich Peterson, Ikjae Shin, Michael Emmert-Buck, Michael Tangrea, Donald J. Johann
Journal: Cancer Research (2020)

Abstract Introduction: Precision medicine promises to improve patient treatment outcomes based on the application of molecular profiling methodologies to pathological specimens. This approach enables the development of rationally derived therapy assignments for each individual patient's tumor (versus categorical treatment assignments). Since tumors are composed of heterogeneous cells forming clusters of subtypes, dissimilar molecular profiles may emerge depending on which region is sampled and analyzed. Additionally, a manual slide scrape may result in a reduced or nearly absent molecular signal (i.e. key driver). Clearly, for cancer there is a need for an efficient, upfront enrichment method to specifically isolate specific tumor cell populations. Immuno-Laser Capture Microdissection (immuno-LCM) is a technology based on immunohistochemistry (IHC) that can isolate specific cell types from a heterogeneous cellular population. We sought to determine the impact of various IHC chromogens on the efficacy of microdissection and downstream molecular analysis from immuno-LCM samples. Methods: Histological tissue specimens (clinical colorectal and lung cancer PDX) were processed using traditional IHC methods with a variety of chromogens, including: Vector Black, Impact Vector Red, 3-amino-9-ethylcarbazole (AEC), and 3,3'-diaminobenzidine (DAB). These chromogens were evaluated for staining quality, microdissection efficiency, biomolecular extraction, and evaluation of specific molecular targets. Results: Interestingly, DAB, the most commonly used chromogen, demonstrated a negative impact on the retrieval of biomolecules from immuno-LCM samples. However, chromogens such as Vector Black and Impact Vector Red showed much improved biomolecule extraction compared to DAB even though the yield of microdissected material was comparable. While other chromogens, such as AEC, demonstrated a greater efficiency of biomolecule extraction but showed incomplete immuno-LCM of specific IHC-stained cells. Conclusions: The data indicate that traditional IHC chromogens should be carefully considered when using immuno-LCM to analyze biomolecules. Citation Format: Sarah Laun, Adam Roberge, Robert Weigman, Aubrey Lewis, Valarie Greisman, Meeiyueh Liu, Owen Stephens, Erich Peterson, Ikjae Shin, Michael Emmert-Buck, Michael Tangrea, Donald J. Johann. Towards advanced precision oncology assays - Selection of immunohistochemistry chromogen impacts microdissection and downstream molecular analysis of archival specimens [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2947.
Immune surveillance of the liver by T cells
Authors: Xenia Ficht, Matteo Iannacone
Journal: Science Immunology (2020)

The liver is the target of several infectious, inflammatory, and neoplastic diseases, which affect hundreds of millions of people worldwide and cause an estimated death toll of more than 2 million people each year. Dysregulation of T cell responses has been implicated in the pathogenesis of these diseases; hence, it is critically important to understand the function and fate of T cells in the liver. Here, we provide an overview of the current knowledge on liver immune surveillance by conventional and invariant T cells and explore the complex cross-talk between immune cell subsets that determines the balance between hepatic immunity and tolerance.
Abstract 4286: TGF-β signature is a therapeutic biomarker for combination immunotherapy for hepatocellular carcinoma
Authors: Jian Chen, Xiaoping Su
Journal: Cancer Research (2020)

Abstract Background: Several immune checkpoint inhibitors have recently shown promising results in patients with advanced hepatocellular carcinoma (HCC). However, tumor response rates ranged from 14% to 17%. Thus, there remains a large unmet medical need for novel and effective immunotherapeutic strategies against HCC. Dysregulated signaling in the transforming growth factor (TGF)-β pathway plays a central role in immunomodulation, inflammation, and fibrogenesis in the HCC microenvironment. We therefore used The Cancer Genome Atlas database to analyze potential therapeutic approaches combining TGF-β inhibition and immunotherapies for HCC. Methods: Transcriptomic analyses were performed in 193 HCC cases. Pathway analyses were performed by correlating 70 published signatures with TGF-β signatures. Results: 1. Unsupervised hierarchical clustering of TGF-β genes in HCC revealed four distinct clusters with unique TGF-β signatures: highly activated (14.5%), activated (45.0%), normal (30.6%), and inactivated (9.9%). 2. Highly activated TGF-β signatures were significantly associated with fibrosis and activated stromal signatures. 3. TGF-β signature subtypes were significantly associated with immune cell infiltration, T cell exhaustion, and checkpoint blockade response subclasses. 4. Potentially targetable genes were associated with specific TGF-β signatures. 5. TGF-β signatures provide potential combination therapeutic options for HCC. Conclusion: We demonstrated a specific immunosuppressive role of TGF-β in mediating immunotherapy resistance in HCC, highlighting the TGF-β signature as a potential biomarker in individualized immunotherapeutic approaches in HCC. Citation Format: Jian Chen, Xiaoping Su. TGF-β signature is a therapeutic biomarker for combination immunotherapy for hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4286.
cGAS-STING pathway in cancer biotherapy
Authors: Yang Wang, Jingwen Luo, Aqu Alu, Xuejiao Han, Yuquan Wei, Xiawei Wei
Journal: Molecular Cancer (2020)

The activation of the cGAS-STING pathway has tremendous potential to improve anti-tumor immunity by generating type I interferons. In recent decades, we have witnessed that producing dsDNA upon various stimuli is an initiative factor, triggering the cGAS-SING pathway for a defensive host. The understanding of both intracellular cascade reaction and the changes of molecular components gains insight into type I IFNs and adaptive immunity. Based on the immunological study, the STING-cGAS pathway is coupled to cancer biotherapy. The most challenging problem is the limited therapeutic effect. Therefore, people view 5, 6-dimethylxanthenone-4-acetic acid, cyclic dinucleotides and various derivative as cGAS-STING pathway agonists. Even so, these agonists have flaws in decreasing biotherapeutic efficacy. Subsequently, we exploited agonist delivery systems (nanocarriers, microparticles and hydrogels). The article will discuss the activation of the cGAS-STING pathway and underlying mechanisms, with an introduction of cGAS-STING agonists, related clinical trials and agonist delivery systems.
Abstract 3003: MET mediates entrectinib resistance in ROS1 gene fusion positiveNSCLC
Authors: Logan Tyler, Anh Le, Hala Nijmeh, Robert Doebele
Journal: Cancer Research (2020)

Abstract ROS1 gene fusions are predominantly found in non-small cell lung cancer (NSCLC), and ROS1 gene fusion-positive (ROS1+) tumors comprise 1-2% of all diagnosed lung adenocarcinomas. Currently, there are two ROS1 tyrosine kinase inhibitors (TKIs) which are US FDA approved, crizotinib and entrectinib, both of which generate tumor response rates in excess of 70% and demonstrate prolonged disease control. However, acquired resistance to TKIs is inevitable, and has been reported in ROS1+ NSCLC tumors or cancer cell models by our group and others and include ROS1 kinase domain mutations (e.g., L1951R, S1986Y/F, F2004V, L2026M, and G2032R), activation of bypass signaling pathways (e.g., EGFR, RAS, or KIT), or phenotypic transformation (such as epithelial to mesenchymal transition). In order to better understand mechanisms of acquired TKI resistance in ROS1 NSCLC, our lab utilized primary, patient-derived cancer cell models harboring these rare oncogenic kinase rearrangements. Herein, using a patient-derived NSCLC cancer cell line (CUTO28) harboring a TPM3-ROS1 fusion, we derived an entrectinib-resistant cell line (CUTO28-ER) through in vitro culture under drug selection. In these CUTO28-ER cells, we identified: (1) MET-mediated bypass signaling as an acquired resistance mechanism to entrectinib, (2) upregulation of MET signaling is accomplished via MET gene amplification, and (3) resistance could be overcome by the dual ROS1/MET inhibitor crizotinib. To our knowledge, this is the first reported case of MET-mediated acquired resistance in a ROS1+ cancer. This cell line model finding was supported by another primary, patient-derived cell line (CUTO38) harboring a CD74-ROS1 fusion; this cell line was derived from a NSCLC patient following disease progression on entrectenib in the clinic. CUTO38 is resistant to entrectinib in vitro and displays elevated MET expression, MET activation with increased phosphorylation, and dependence on MET for cell proliferation and survival. Notably, MET activation in CUTO38 was not generated by gene amplification, MET exon 14 splicing, MET gene fusion, or autocrine HGF expression, suggesting alternate means of MET activation. These findings suggest that interrogation of MET gene amplification or other MET biomarkers should be performed in ROS1+ NSCLC patients who experience disease progression on entrectinib or other ROS1 TKIs that do not inhibit MET, since there are clinically available MET inhibitors, some of which are dual ROS1/MET inhibitors, that may overcome drug resistance in these patients. Citation Format: Logan Tyler, Anh Le, Hala Nijmeh, Robert Doebele. MET mediates entrectinib resistance in ROS1 gene fusion positiveNSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3003.
A Practical Guide for Using Myelofibrosis Prognostic Models in the Clinic
Authors: Joan How, Gabriela S. Hobbs
Journal: Journal of the National Comprehensive Cancer Network (2020)

Primary myelofibrosis (PMF) has the least favorable prognosis of the Philadelphia chromosome–negative myeloproliferative neoplasms, which also include essential thrombocythemia (ET) and polycythemia vera (PV). However, clinical presentations and outcomes of PMF vary widely, with median overall survival ranging from years to decades. Given the heterogeneity of PMF, there has been considerable effort to develop discriminatory prognostic models to help with management decisions, particularly for the consideration of hematopoietic stem cell transplantation in patients at higher risk. Although earlier models incorporated only clinical features in risk stratification, contemporary models increasingly use molecular and cytogenetic features, leading to more comprehensive prognostication. This article reviews the most widely adopted prognostic models used for PMF, including the International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS)/DIPSS+, mutation-enhanced IPSS for transplant-age patients (MIPSS70)/MIPSS70+/MIPSS70+ version 2.0, genetically inspired prognostic scoring system, and Myelofibrosis Secondary to PV and ET-Prognostic Model in patients with post-ET/PV myelofibrosis. We also discuss newly emerging prognostic models and provide a practical approach to risk stratification in patients with PMF and post-ET/PV myelofibrosis.
Abstract 6163: Integrated stress response contributes to triple negative breast cancer radioresistance by regulating glutathione biosynthesis
Authors: Xupeng Bai, Jie Ni, Yong Li, Julia Beretov
Journal: Cancer Research (2020)

Abstract Triple negative breast cancer (TNBC) is one of the most malignant gynecological cancer worldwide. Radiotherapy (RT) is an effective option for TNBC local control. However, TNBC tends to develop a radioresistant phenotype which results in a poor response of TNBC to following therapy. In this study, we identified integrated stress response (ISR) as the most activated signaling in radioresistant MDA-MB-231, MDA-MB-436, and MDA-MB-468 cells. We found that constitutive phosphorylation of eIF2α in radioresistant TNBC cells promoted the activation of activating transcription factor 4 (ATF4) via increasing its translational efficiency, which elicited the transcription of a set of genes implicated in GSH biosynthesis, including glutamate-cysteine ligase catalytic subunit (GCLC), solute carrier family 7 member 11 (SLC7A11), and cystathionine-γ-lyase (CTH), leading to a higher intracellular level of reduced glutathione (GSH) and an efficient reactive oxygen species (ROS) scavenging after irradiation (IR). Treating radiosensitive TNBC cells with salubrinal, a selective inhibitor of eIF2α dephosphorylation, can mimic the stress-resistant phenotypes of their radioresistant counterparts. In contrast, eIF2α dephosphorylation or ATF4 knockdown accelerated IR-induced ROS accumulation and increased IR-induced cell apoptosis in radioresistant TNBC cells in vitro. In combination with eIF2α dephosphorylation, IR significantly reduced the size and weight of radioresistant TNBC xenograft tumors in vivo. These data reveal ISR as an important mechanism underlying TNBC radioresistance and provide a rationale for exploring eIF2 signaling as a novel therapeutic target for TNBC treatment. Citation Format: Xupeng Bai, Jie Ni, Yong Li, Julia Beretov. Integrated stress response contributes to triple negative breast cancer radioresistance by regulating glutathione biosynthesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6163.
Abstract 1763: NEO2734, a novel dual bromodomain and histone acetyltransferase inhibitor, in the treatment of colorectal cancer
Authors: Chaoyuan Kuang, Manbo Cai, Denise Risnik, Francis Giles, Lin Zhang
Journal: Cancer Research (2020)

Abstract Background: Oncogenic c-MYC activation is seen in a broad spectrum of cancers and is often associated with more aggressive disease and/or poor outcomes. c-MYC expression is often driven by transcriptional super-enhancers which depend on histone modifications to function. We report the results of our studies on the novel suppressor of histone reading and writing, NEO2734, and the effects on colorectal cancer cells. Methods: Commercially and publicly available colorectal cancer cell lines were used under standard culture conditions. All small molecule treatments were performed with DMSO as the primary solvent and dilutions made in aqueous solution. Commonly employed techniques such as MTS viability assays, immunofluorescent 2-D microscopy, siRNA knockdown, western blotting, and single-color flow cytometry were used. Results: NEO2734, a dual BET/bromodomain inhibitor and p300/CBP inhibitor, reduced cell growth more than the BET inhibitor OTX-015 and the p300/CBP inhibitor CPI-637. NEO2734 potently induced cell death and markers of apoptosis such as PUMA and TRAIL2/DR5. Inhibition of the caspase by zVAD-fmk eliminated the induction of cell death by NEO2734. Knockdown or knockout of the death proteins PUMA or DR5 additively reduced the amount of NEO2734-induced apoptosis. NEO2734 reduced the expression of downstream targets c-MYC, acetylated histone H3, and acetylated histone-H4. Strikingly, NEO2734 significantly upregulated the ER stress markers BiP and ATF3. NEO2734 also activated immunogenic cell death in vitro, as measured by HMGB1 release and membrane localization of calreticulin. Finally, examination of a panel of cell lines revealed SPOP mutant colorectal cancer cells to be exquisitely sensitive to growth inhibition by NEO2734. Conclusions: NEO2734 causes growth inhibition and apoptosis of colorectal cancer cells. NEO2734 is more potent than single-target BET inhibitors. Anticipated targets such as c-MYC and acetylated histone are confirmed. NEO2734 appears to trigger cell death through both PUMA and TRAIL mediated apoptosis. NEO2734 also activates ER stress and immunogenic cell death. Work is ongoing to confirm the mechanism of apoptosis and test rational drug combinations such as with chemotherapy and immunotherapy. Citation Format: Chaoyuan Kuang, Manbo Cai, Denise Risnik, Francis Giles, Lin Zhang. NEO2734, a novel dual bromodomain and histone acetyltransferase inhibitor, in the treatment of colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1763.
Abstract 3993: 'Educated' osteoblasts suppress osteoclastogenesis and bone resorption in a bone mimetic microenvironment
Authors: Alexus D. Kolb, Karen M. Bussard
Journal: Cancer Research (2020)

Abstract Breast cancer (BC) preferentially disseminates to bone. During BC progression in bone, BC cells communicate with osteoblasts (OBs), osteoclasts (OCs), and other stromal cells to shape the bone-tumor niche. Recently, our lab discovered two distinct subpopulations of OBs in the bone-tumor niche based on protein marker expression. One group ‘educated' osteoblasts (EOs) have engaged in crosstalk with disseminated BC cells, whereas another group, ‘uneducated' osteoblasts (UOBs) have not. We have new evidence that EOs suppress osteoclastogenesis and reduce bone resorption associated with BC cell metastatic progression in bone. Culture supernatant of EOs and OBs was analyzed for soluble protein expression of receptor activator of nuclear factor-kappa β ligand (RANKL) and osteoprotegerin (OPG) via ELISA. EOs were co-cultured with pre-osteoclasts to determine OC maturation and resorption. EOs and pre-osteoclasts were co-cultured on a mimetic bone matrix in the presence of soluble RANKL to assess for OC resorption and pit formation. In addition, pre-osteoclasts were tri-cultured with EOs plus either human metastatic triple negative or estrogen receptor positive (ER+) BC cells to assess the effect of BC cells on the formation of OCs. The culture supernatant of EOs expressed reduced amounts of RANKL and OPG soluble protein compared to UOB supernatant. OCs formed in the presence of EOs were approximately half the size of those formed in the presence of UOBs as visualized by TRAP stain. Furthermore, we found up to a 66% reduction in the number of OCs formed in the presence of EOs when compared to the number of OCs formed in the presence of UOBs. When pre-osteoclasts were co-cultured on a mimetic bone matrix, up to 45% reduction was observed in the number of resorptive pits formed upon co-culture with EOs versus UOBs. Moreover, the tri-cultures of pre-osteoclasts, EOs, and human metastatic BC cells yielded up to a 28% reduction in the number of mature, multi-nucleated OCs formed, as opposed to the number of mature, multi-nucleated OCs formed in tri-cultures of pre-osteoclasts, UOBs, plus human metastatic BC cells. Overall, these data suggest that EOs suppress osteoclastogenesis and reduce bone resorption on a bone mimetic surface. These data imply that EOs provide a protective effect against bone resorption during bone metastatic BC progression. These data underscore the importance of investigating EOs as mediators of bone remodeling during BC progression in bone. Supported by NIH R00 CA178177 and Commonwealth of Pennsylvania-Department of Health SAP 4100072566 for KMB. Citation Format: Alexus D. Kolb, Karen M. Bussard. 'Educated' osteoblasts suppress osteoclastogenesis and bone resorption in a bone mimetic microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3993.
Abstract 2028: Recent trends in use of adjuvant chemotherapy in elderly stage II-III non-small cell lung cancer
Authors: Takefumi Komiya, Emily Powell, Achuta Kumar Guddati
Journal: Cancer Research (2020)

Abstract Background: Although randomized trials demonstrated survival benefit of adjuvant chemotherapy, previous reports have suggested that its use in elderly populations for early stage non-small cell lung cancer (NSCLC) was infrequent. Oncologists often hesitate to offer adjuvant chemotherapy in resected early stage non-small cell lung cancer for elderly population. The status of adjuvant chemotherapy in this population is unknown for recent decades. Materials and Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database which represents about 28% of the US population, we examined the incidence of chemotherapy in resected stage II-III NSCLC between 2004 and 2015. Staging was determined according to the American Joint Committee on Cancer (AJCC) 6th version. Cases were grouped by age (20-69, 70-79, and 80+). Trends in use of chemotherapy by age group was assessed by univariate and multivariate analyses. Results: A total of 35,009 were selected as surgically resected stage II-III NSCLC. Use of chemotherapy was 66.9%, 48.2%, 25.0% in age 20-69, 70-79, 80+, respectively. Multivariate analysis demonstrated that younger age (20-69) and recent year (2010-2015) of diagnosis were associated with increased use of chemotherapy. Chemotherapy use increased from 2004 to 2015 by 11.0%, 18.3%, and 11.3% in age 20-69, 70-79, 80+, respectively. In the age 70-79 group, increased use of chemotherapy was greater in stage II (24.3%) than stage III (14.1%). Five-year overall survival in age 70-79 group mildly increased by 7.6% from 2004 to 2011. Conclusion: This study suggests that use of adjuvant chemotherapy in elderly population increased primarily in age 70-79. Few patients in age 80+ receive adjuvant chemotherapy even in recent years. This study not only informs oncologists of current status but also suggests further research on very elderly populations. Citation Format: Takefumi Komiya, Emily Powell, Achuta Kumar Guddati. Recent trends in use of adjuvant chemotherapy in elderly stage II-III non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2028.