tbuckley/cabot-search huggingface dataset:
Abstract 3929: Patient-derived pancreatic cancer organoids as in-vitro cancer models for personalizing therapy
Authors: Claire Alexandra Zhen Chew, Li Min Tay, Lissa Hooi, Edward Kai-Hua Chow, Glenn K. Bonney, Shing Leng Chan
Journal: Cancer Research (2020)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive solid tumor. Unfortunately, patients with this disease have not benefited from the advances in precision medicine seen in other malignancies. The lack of actionable mutations as well as predictive biomarkers has hampered progress in this area. Combination therapy remains the cornerstone of systemic treatment, with FOLFIRINOX being the most effective therapeutic regimen in PDAC. However, it is clear that only subset of patients are responsive, and the toxicities of this 4-drug combination are intolerable to many patients particularly in the adjuvant setting. There is a clear need for more personalized rational drug combinations that are optimized to maximize efficacy while minimizing toxicity. We have established a protocol for the generation of PDAC organoids from endoscopic ultrasound biopsies for personalizing systemic therapy based on the principle of phenotype driven oncology. Organoids generated are analyzed for KRAS and p53 mutations to confirm their tumor origin. By applying a phenotypic optimization platform (QPOP) on these organoids, we are able to identify optimized drug combinations from a pool of both FDA-approved and preclinical drugs. As expected, FOLFIRINOX did not always rank high by treatment efficacy suggesting that alternative treatment may be more beneficial for these patients. In addition, we identified that the efficacy of FOLFIRINOX was driven by two-drug synergistic combinations which varied between patients. This can potentially advise modifications to this regimen when toxicity arises. From a discovery perspective, our platform has the capability of deriving novel drug combinations. The combination of gemcitabine and Abraxane with a WEE1-inhibitor was found to be synergistic in selected PDAC patients. Furthermore, patients with similar drug response profiles can be studied together to identify predictive markers of sensitivity. To demonstrate that this platform can indeed be applied to prospectively recommend treatment strategies for patients with progressive disease on first-line chemotherapy, we are establishing a clinical trial to personalize second-line therapy, with the endpoint of overall response rate. Overall, by combining patient-derived organoids with rational optimized drug combinations, we aim to personalize therapy for patients with PDAC to improve overall survival. Citation Format: Claire Alexandra Zhen Chew, Li Min Tay, Lissa Hooi, Edward Kai-Hua Chow, Glenn K. Bonney, Shing Leng Chan. Patient-derived pancreatic cancer organoids as in-vitro cancer models for personalizing therapy [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 3929.
Abstract 3707: Transcriptional downregulation of microRNA 199a-1 in the tumor microenvironment confers chemoresistance and stemness in ovarian cancer cells
Authors: Ayon A. Hassan, Zhenyu Yang, Ho-Cheung Shum, Hung-Cheng Lai, Alice S. Wong
Journal: Cancer Research (2020)

Abstract The tumor microenvironment is actively involved in cancer progression and is becoming an attractive therapeutic target. It is increasingly clear that both biotic and abiotic factors in the microenvironment play a crucial role in disease progression. Using a three-dimensional microfluidic platform that mimics the peritoneum, we previously demonstrated that physiologically relevant shear-stress can induce chemoresistance and stemness in ovarian cancer cells. Importantly, this mechanical stimulus resulted in downregulation of microRNA (miR)199a-3p, suggesting a previously unknown mechanosensitive property of this miRNA. In testing other microenvironmental factors known to be involved in ovarian cancer progression in the regulation of miR-199a-3p, we found that hepatocyte growth factor (HGF), which is abundant in malignant ascites, could decrease miR-199a-3p expression in a similar manner to shear stress. Both shear stress and HGF induced this downregulation through a transcriptional regulation of primary mir-199a-1, but not primary mir-199a-2, via a PI3/Akt signaling pathway. Using metanalysis, there was also a decrease of miR-199a-3p in patients' tumor samples, and an increase of Akt in high-risk group. Moreover, ectopic overexpression of primary mir-199a-1 could sensitize ovarian cancer cells to cisplatin and reduce their ability to form multicellular spheroids, confirming a role for this miRNA in chemoresistance and stemness. Taken together, our findings suggest a causal involvement of downregulation of primary mir-199a-1, and ultimately its mature counterpart miR-199a-3p, in the tumor microenvironment mediated induction of stemness and chemoresistance, and represents a potential therapeutic target for the treatment of ovarian cancer (This work is supported by HMRF 05163536). Citation Format: Ayon A. Hassan, Zhenyu Yang, Ho-Cheung Shum, Hung-Cheng Lai, Alice S. Wong. Transcriptional downregulation of microRNA 199a-1 in the tumor microenvironment confers chemoresistance and stemness in ovarian cancer cells [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 3707.
Abstract 3757: Examination of the epidermal growth factor 3 (HER3) dysregulations in hepatocellular carcinoma
Authors: Sheung In Ming, Lo Kong Chan, Daniel W.H. Ho, Irene O.L. Ng
Journal: Cancer Research (2020)

Abstract Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide with a particularly high mortality rate. Treatment options for HCC are limited. Curative treatments including surgical resection and liver transplantation are only applicable to early diagnosed patients. For advanced HCC patients, the currently available first-line molecularly targeted medications are suffering from low rates of response and high inter-patients variability providing limited survival benefits. Receptor tyrosine kinases (RTKs) are plasma membrane-associated protein kinases which control the activation of intracellular signal transductions in response to the extracellular stimuli. Activation of specific RTKs has been implicated in various kinds of human cancers, and pharmacological inhibition of cancer associated RTKs is one of the key strategies of modern targeted therapy. However, a comprehensive and systematic assessment of the RTKs dysregulations in terms of expression and mutation in HCC is still much awaited. In this study, RNA-sequencing analysis was performed in paired HCC tissues to examine the expression profiles of 58 RTKs. Also, the mutational status of these RTKs in HCC tissues was examined by targeted DNA-sequencing analysis. Our systemic analyses have revealed that Epidermal Growth Factor Receptor 3 (HER3) was significantly upregulated and recurrently mutated in HCC. Independent qPCR analysis for HER3 in 101 paired HBV-associated HCC tumor and non-tumorous samples validated that HER3 was upregulated in HCC. More importantly, upregulation of HER3 was found to be significantly correlated with the presence of metastatic features of HCC including tumor microsatellite formation (p=0.015) and venous invasion (p=0.001). Neuregulin-1 (NRG-1) is the best-known ligand for HER3. Stimulation of HER3 activation by the ligand NRG-1 could induce HER3 phosphorylation, and activate the downstream PI3K/AKT and MAPK signaling pathways, and signficantly promoted the proliferation and migration of HCC cells. Conversely, CRISPR/Cas9-mediated HER3 knockout in Huh7 and PLC cells significantly reduced the NRG-1 induced functional changes. Consistently, our preliminary results demonstrated that HER3 knockout Huh7 cells forms relatively smaller tumors in a subcutaneous tumor xenograft model in vivo. Together, our results demonstrated that HER3 dysregulation plays a supporting role in HCC development. Targeting HER3 may potentially derive new therapeutic strategy for treatment of HCC. Citation Format: Sheung In Ming, Lo Kong Chan, Daniel W.H. Ho, Irene O.L. Ng. Examination of the epidermal growth factor 3 (HER3) dysregulations in 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 3757.
Abstract 3755: PDGF-induced tumor cell growth despite VEGF/EGF inhibition and absence of PDGF receptor expression in colon cancer
Authors: Romana Moench, Martin Gasser, Karol Nawalaniec, Tanja Grimmig, Minghua Cao, Yueming Luo, Li-Li Hsiao, Ana Maria Waaga-Gasser
Journal: Cancer Research (2020)

Abstract Anti-Epithelial/Vascular Endothelial Growth Factor (EGF/VEGF)-targeted therapy plays important roles in advanced stage colorectal cancer (CRC) patients but fails to show clinical efficacy in specific subgroups which lack of clear underlying mechanisms. In vitro studies indicated that cross-talk or alternative receptor/ligand activities can bypass anti-growth factor signaling arrest and therefore may explain failure of monoclonal antibody (mAb) targeted therapy. In this study we analyzed effects of Platelet Derived Growth Factor (PDGF)-mediated bypassed signaling in CRC. We first investigated human UICC (Union for International Cancer Control ) stage I-IV tumors (n=46) from our Center and found increased PDGFRβ and VEGFR1/2 gene expression (p&amp;lt;0.01/p&amp;lt;0.001). Interestingly, further analysis on human HT29 colon cancer in vitro showed upregulated VEGFR1/2 expression upon VEGF stimulation. This was even more pronounced upon stimulation with PDGF. Inhibition of VEGFR2 and EGFR resulted in decreased HT29 cell proliferation, while additional treatment with VEGF and particularly PDGF attenuated the inhibiting effect and resulted in altered downstream signaling events. Treatment with the tyrosine kinase inhibitor Regorafenib alone, that blocks VEGFR/EGFR+PDGFR, prevented PDGF and VEGF-induced proliferation. This effect was not observed for either VEGFR2 mAb treatment with Ramucirumab or EGFR mAb therapy with Cetuximab. To conclude, PDGF-induced human colon cancer proliferation in the absence of PDGFR and simultaneously inhibited VEGFR2 and EGFR expression in HT29 colon cancer cells suggests bypassed alternative PDGF receptor partners for ligand binding on the tumor cell surface and subsequent intracellular signaling. This may explain failure of anti-VEGF/EGF-targeted monoclonal antibody therapies in CRC patient subgroups and underlines the necessity to effectively inhibit PDGF-mediated signaling events beside VEGF/EGF blockade in patients with increased PDGF expression within their tumors. Citation Format: Romana Moench, Martin Gasser, Karol Nawalaniec, Tanja Grimmig, Minghua Cao, Yueming Luo, Li-Li Hsiao, Ana Maria Waaga-Gasser. PDGF-induced tumor cell growth despite VEGF/EGF inhibition and absence of PDGF receptor expression in colon 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 3755.
Abstract 6621: A combined VHH and small molecule approach to modulate the antitumor immunity function of ERAP1
Authors: Nicolas Basse
Journal: Cancer Research (2020)

Abstract ERAP1 is a multifunctional enzyme trimming N-terminal amino acids of peptides. Its most characterised function is its role in generating peptide ligands in the endoplasmic reticulum for loading onto MHC class I (MHCI) molecules for presentation at the cell surface. Here it acts as an antigenic peptide editor influencing the peptide repertoire displayed at the cell surface to circulating CD8+ T cells and NK cells. ERAP1 modulates the immunopeptidome and could play a key role in tumor antigenicity. ERAP1 is a highly dynamic enzyme and its conformation is crucial for intracellular immuno-signals and also various extracellular functions. The precise molecular mechanisms behind the secretion and conformational status of ERAP1 remain unclear. To study ERAP1, we combined a VHH and a small molecule approach. After Lama immunization, the selected ERAP1 binders were filtered for functional activity. To measure ERAP1 activity with relevant substrates, we developed a mass spectrometry assay and a fluorogenic substrate mimicking ERAP1 peptidic substrates. Nanobodies modulators of ERAP1 activity are currently used for structural studies. In addition to the mechanistic studies, the team also developed ERAP1 small molecule modulators to induce or restore tumor immunogenicity. Herein, we report a chemical family of potent ERAP1 inhibitors that demonstrate structure activity relationship. The nanobodies and small molecule modulators we developed provide useful tools to better understand the biology of ERAP1 in immune responses. Citation Format: Nicolas Basse. A combined VHH and small molecule approach to modulate the antitumor immunity function of ERAP1 [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 6621.
Incremental Gains in the Battle against ALS
Authors: Michael Benatar, Michael P. McDermott
Journal: New England Journal of Medicine (2020)

In this issue of the Journal, Paganoni et al.1 describe the results of a well-designed, multicenter, phase 2 trial of a fixed-dose combination of 6 g per day of sodium phenylbutyrate and 2 g per day of taurursodiol, also known as tauroursodeoxycholic acid, in patients with definite amyotrophic lateral sclerosis (ALS) according to El Escorial criteria who were enrolled within 18 months after symptom onset. The trial showed a difference of 0.42 points per month between the active-drug group and the placebo group in the mean rate of change in the total score on the Amyotrophic Lateral Sclerosis Functional Rating . . .
Use of over-the-scope clips in the colon in clinical practice: results from a German administrative database
Authors: Dirk Horenkamp-Sonntag, Judith Liebentraut, Susanne Engel, Christoph Skupnik, David Albers, Brigitte Schumacher, Herbert Koop
Journal: Endoscopy (2020)

Abstract Background The efficacy and safety of over-the-scope (OTS) clips in the colon is limited. This study aimed to evaluate OTS clip use in the colon in routine colonoscopy. Methods Using administrative data from a large health insurance company, patients with OTS clip placement during colonoscopy were identified and analyzed by specific administrative codes. Indication for OTS clipping was analyzed, and follow-up was evaluated for surgical and repeat endoscopic interventions. Results In 505 patients, indications for OTS clips were iatrogenic perforations (n = 80; Group A), polypectomy (n = 315; Group B), colonic bleeding (n = 51; Group C), and various underlying diseases (n = 59; Group D). In 11 Group A patients (13.8 %), surgical interventions occurred, mostly within 24 hours after clipping (n = 9), predominantly overstitching (n = 8). OTS clipping during polypectomy (Group B) was for complications (e. g. bleeding in 27 %) or was applied prophylactically. Only five patients required early surgery, three of whom had colorectal cancer. In four Group C patients (7.8 %), surgical resections were performed (persistent bleeding n = 1, colorectal cancer n = 2), while six patients underwent early repeat colonoscopy for recurrent bleeding. During further follow-up (days 11–30), 17 patients underwent resection for colonic neoplasms (n = 12) or persistent bleeding (n = 4), but only one case could be directly traced back to local OTS clip complication. Conclusion Colonic OTS clipping appears safe and effective in selected indications and complications in clinical routine but must be anatomically and technically feasible, avoiding overuse.
Abstract 6452: Exosomal Let 7 and its downstream protein targets may serve as predictive biomarkers in peritoneal carcinomatosis
Authors: Mei Li M. Kwong, Paul A. Vallejos, Vola-Masoandro Andrianarijaona, Audrey Choi, Matthew J. Selleck, Tiantian Liu, Janviere Kabagwira, Charles Wang, William Langridge, Nathan R. Wall, Maheswari Senthil
Journal: Cancer Research (2020)

Abstract The prognosis for patients with colorectal cancer with peritoneal carcinomatosis (PC) is dismal. Current biomarkers and imaging studies lack sensitivity and specificity to identify PC at early stages. Predictive and diagnostic serum biomarkers that help diagnose PC at early stages is necessary to improve patient outcomes. In the rapidly evolving field of liquid biopsy, exosomes show significant promise. The objective of our study is to identify exosomal biomarkers that are differentially expressed in patients with PC compared to visceral metastases (VM). Proteomic and miRNA analysis were performed using mass spectrometry and next generation sequencing on plasma exosomes from ten patients with colorectal cancer VM and nine patients with PC. Multiple members of the Let-7 family had differential levels of expression between these two patient groups. Specifically, Let-7 isoforms (Let-7a, Let-7d, Let-7e, Let-7f, Let-7g, Let-7i) were upregulated in plasma exosomes of patients with PC compared to those with VM. In addition, 33 exosomal proteins that are downstream targets of Let-7 were also found to be differentially expressed. Correlative investigation was conducted using cell lines representative of PC, VM and control to investigate the possible origins for this exosomal profile. RT-PCR was performed on cell lysates taken from normal colon (CCD-33-CO) and colorectal cancer (SK-CO-1, SNU-C1, and T84) cell lines to further identify Let-7 isoforms in these samples. Let-7 isoforms (Let 7a, Let-7b, Let-7d, Let-7e, Let-7f, Let-7i) were identified at increased levels in the colorectal cancer PC cell line in comparison to cells lines of non-PC colorectal cancer and normal colon. In-vivo and in-vitro studies demonstrate plasma exosomal Let-7 and its downstream protein targets are differentially expressed in colorectal PC compared to VM. Let-7 has been previously implicated in cancer progression and chemoresistance. While this differential expression suggests possible mechanistic differences between colorectal PC and VM, it may also offer a potential liquid biopsy for predicting peritoneal metastasis at a much earlier and treatable time. Citation Format: Mei Li M. Kwong, Paul A. Vallejos, Vola-Masoandro Andrianarijaona, Audrey Choi, Matthew J. Selleck, Tiantian Liu, Janviere Kabagwira, Charles Wang, William Langridge, Nathan R. Wall, Maheswari Senthil. Exosomal Let 7 and its downstream protein targets may serve as predictive biomarkers in peritoneal carcinomatosis [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 6452.
Assigning Distal Genomic Enhancers to Cardiac Disease–Causing Genes
Authors: Chukwuemeka George Anene-Nzelu, Wilson Lek Wen Tan, Chang Jie Mick Lee, Zheng Wenhao, Arnaud Perrin, Albert Dashi, Zenia Tiang, Matias Ilmari Autio, Bram Lim, Eleanor Wong, Hui San Tan, Bangfen Pan, Michael P. Morley, Kenneth B. Margulies, Thomas P. Cappola, Roger S-Y. Foo
Journal: Circulation (2020)
Abstract 5430: Deep learning-based prognosis prediction in T3N1 nasopharyngeal carcinoma patients treated with induction chemotherapy followed by concurrent chemoradiotherapy
Authors: Lianzhen Zhong, Di Dong, Linglong Tang, Shuyan Han, Jie Tian
Journal: Cancer Research (2020)

Abstract Purpose: To estimate the value of deep learning on magnetic resonance (MR)-base radiomics for T3N1 nasopharyngeal carcinoma (NPC) patients receiving induction chemotherapy (ICT) followed by concurrent chemoradiotherapy (CCRT). Methods: A total of 672 NPC patients with T3N1 disease (training cohort: n = 470; test cohort: n = 202) were enrolled and underwent MRI scan prior to receiving ICT+CCRT. Primary endpoint was disease-free survival (DFS). From each of three sequences of MR images of the primary tumor at baseline, a survival model based on SE-ResNeXt was developed to predict DFS end-to-end. Incorporating three deep learning-based radiomic signatures, a radiomic model was built using multivariable Cox proportional hazard model. Harrell's concordance indices (C-index) were applied to evaluate the predictive power of radiomics nomogram. Results: Three deep learning-based radiomic signatures were significant associated with DFS in the training (C-index: 0.609-0.616) and test (C-index: 0.587-604) cohorts. The radiomic model had the best result for predicting DFS (train cohort: C-index, 0.647, 95% CI, 0.587-0.708, p &amp;lt; 0.001; test cohort: C-index, 0.647, 95% CI, 0.552-0.741, p = 0.002). In addition, the radiomic model also had a significant predictive value for secondary endpoints in the entire dataset (overall survival: C-index, 0.622, p &amp;lt; 0.001; distant metastasis-free survival: C-index, 0.578, p = 0.044; locoregional relapse-free survival: C-index, 0.648, p &amp;lt; 0.001). Conclusion: Deep learning MR-based radiomic signatures may serve as a powerful tool for prognosis prediction in T3N1 nasopharyngeal carcinoma patients receiving ICT + CCRT treatment. Citation Format: Lianzhen Zhong, Di Dong, Linglong Tang, Shuyan Han, Jie Tian. Deep learning-based prognosis prediction in T3N1 nasopharyngeal carcinoma patients treated with induction chemotherapy followed by concurrent chemoradiotherapy [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 5430.
Addressing the New Last-Mile Problem in Health Care With Home-Based Complex Diagnostics
Authors: Mintu P. Turakhia
Journal: JAMA Cardiology (2020)

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