tbuckley/cabot-search huggingface dataset:
Abstract 1674: Correlation of the mutational pattern and gene expression data of patient-derived Non-Hodgkin lymphoma xenografts (PDX) with the response to targeted therapies
Authors: Bernadette Brzezicha, Theresia Conrad, Michael Becker, Aitomi Bittner, Martin Janz, Clemens A. Schmitt, Ulrich Keilholz, Jens Hoffmann
Journal: Cancer Research (2020)

Abstract Non-Hodgkin lymphomas (NHL) are lymphoid malignant neoplasms that represent a very heterogeneous group and still pose an important clinical challenge. In particular, the frequent development of resistance to the treatment with standard-of-care (SoC) drugs is associated with a high incidence of disease recurrence. Recent progress in molecular high-throughput profiling has helped to identify genetic drivers for many subtypes of B-cell lymphomas as well as T-cell lymphomas. Target validation and drug development depend on corresponding preclinical models representing the different subtypes. Therefore, we established and characterized a panel of patient-derived NHL xenografts. All lymphoma PDX were derived from peripheral blood, lymph node extirpations or core needle biopsies, respectively, and were routinely implanted subcutaneously into immunodeficient mice. For further characterization, established lymphoma PDX models were treated with SoC (e.g., cyclophosphamide, doxorubicine, vincristine, etoposide) and investigational drugs. To gain a deeper insight into the molecular biology of the lymphoma models, RNA sequencing was performed. More than 20 PDX models from different NHL entities have been successfully established and characterized. We observed heterogeneous individual responses to the SoC treatments as well as to target treatments such as rituximab or ibrutinib. Explorative analysis of RNA sequencing data confirmed the representation of the clinical lymphoma subgroups (e.g. DLBCL, Burkitt, AITL) in our panel of lymphoma models. Based on the RNA sequencing data, the individual Human Leukocyte Antigen (HLA) type of each lymphoma PDX was determined with the aim to enable personalized, HLA type-specific studies. Our lymphoma PDX portfolio provides an exceptional platform for the identification and validation of new targets and allows the preclinical screening of new combinations in translational research projects. Citation Format: Bernadette Brzezicha, Theresia Conrad, Michael Becker, Aitomi Bittner, Martin Janz, Clemens A. Schmitt, Ulrich Keilholz, Jens Hoffmann. Correlation of the mutational pattern and gene expression data of patient-derived Non-Hodgkin lymphoma xenografts (PDX) with the response to targeted therapies [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 1674.
Abstract 3758: Impact of ANXA7 I1 expression on PDGFRA and MET endosomal trafficking in glioblastoma
Authors: Zachary B. White, Centdrika Dates Hurt, Rajani Rajbhandari, Sindhu Nair, Susan Nozell, Markus Bredel
Journal: Cancer Research (2020)

Abstract Purpose/Objective(s): Glioblastomas (GBM) are highly malignant tumors that arise from astrocytes. GBMs rely on signaling through receptor tyrosine kinases (RTK) to ensure tumorigenicity. EGFR, PDGFRA and MET are distinct RTKs; each is capable of binding a ligand, which promotes receptor dimerization and kinase activation. Annexin A7 (ANXA7), a protein involved in membrane binding and vesicle trafficking, is spliced into 2 isoforms - isoforms 1 (I1) and isoform 2 (I2). A normal adult brain will express both isoforms, however, in GBM, I1 expression is prevented. We determined that I1, but not I2, is tumor suppressive, in part, because it promotes the endocytic degradation of EGFR. Because I1 is typically not expressed in GBM, EGFR signaling persists unabated and tumors thrive. Recently, we extended these observations and determined that I1 also impacts additional RTKs, including PDGFRA and MET. By understanding how ANXA7 I1 impacts PDGFRA and MET signaling, we hope to target multiple tumorigenic RTKs and improve therapy for patients with GBM. Materials/Methods: To understand how and when I1 downregulates PDGFRα and MET, U251-malignant glioma (MG) cells, which only express I2 (P), were modified to express I1. Cells were serum starved overnight, and then stimulated with PDGFAA and HGF(20 ng/ml), which activate the aforementioned receptors respectively. As a positive control, cells were stimulated with EGF to activate EGFR. Total protein was then collected and analyzed by western blot analyses. Next, we sought to determine whether I1 was competent to down-regulate several RTKs coincidentally. To do this, P and I1 cells were serum starved, stimulated with EGF, PDGFAA or both, and total protein levels were evaluated. Results: The levels of activated EGFR, PDGFRα and MET are dramatically reduced in those cells that express I1 as compared to cells expressing I2 (P). Upon activation with both PDGFAA and EGF, in cells expressing I1 (I1), levels of PDGFRα and EGFR were markedly reduced 30 minutes post-stimulation as compared to cells expressing I2. Conclusion: Our results suggest I1 may be a master regulator of RTK endocytosis and degradation. Further investigations of the impact of I1 on endocytic trafficking patterns using immunofluorescence and confocal microscopy are underway. Collectively, understanding how I1 functions and targets multiple tumorigenic RTKs will provide the foundation for future selective therapies that restore I1 expression in GBM and reduce tumorigenicity. Citation Format: Zachary B. White, Centdrika Dates Hurt, Rajani Rajbhandari, Sindhu Nair, Susan Nozell, Markus Bredel. Impact of ANXA7 I1 expression on PDGFRA and MET endosomal trafficking in glioblastoma [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 3758.
Abstract 1144: Novel prostate cancer mouse models for testing targeted chemopreventive potential of pterostilbene
Authors: Rutu Hemani, Ninad Inamdar, Avinash Kumar, Virginia Donovan, Anait S. Levenson
Journal: Cancer Research (2020)

Abstract Metastasis-associated protein 1 (MTA1) plays role in prostate cancer progression and metastasis. We have previously reported on the MTA1-targeted chemopreventive and therapeutic efficacy of pterostilbene (Pter) in the prostate-specific Pten heterozygous (Pten+/f; Pb-Cre+) and Pten null (Ptenf/f; Pb-Cre+) mice. To investigate the exact role of MTA1 in prostate cancer tumorigenesis and its early stages, we developed appropriate mouse models, namely prostate-specific MTA1-knocked in (MTA1-tg) and MTA1-tg on the background of prostate-specific Pten heterozygosity (MTA+/+, Pten+/f; Pb-Cre+). In the current project, we asked three major questions: 1) whether prostate MTA1 overexpression in the context of Pten loss promotes an earlier onset, greater total incidence and accelerated PIN or tumor growth rate; 2) what MTA1-associated molecules are involved in prostate cancer progression; and 3) whether Pter supplemented diet can provide beneficial effects. Identified from our ChIP-Seq data MTA1-associated molecules included CyclinD1, Notch2, and two neuroendocrine markers, namely CHGA and SYP. Using two prostate cancer cell lines, DU145 and PC3M and their corresponding MTA1 knockdown (shMTA1) clones, we validated the direct link between MTA1 and these markers on mRNA and protein levels. Further, we generated 28 prostate-specific MTA1+/+; Pten+/f; Pb-Cre+ mice and randomized them into two major groups: 1) mice on control diet (Ctrl-Diet) and 2) mice on Pter-Diet. After 5 months of feeding with corresponding diets (AIN-76A phytoestrogen free diets supplemented or not with Pter at 100 mg/kg/diet), mice were sacrificed and prostate tissues were isolated for histological, immunochemical and molecular analysis. Results demonstrated the contribution of MTA1 in more aggressive histological phenotype (Ki67, PCNA, p27, SMA, CK8), increased levels of oncogenic MTA1-guided molecules (CyclinD1, Notch2, CHGA, SYP, AR) and the potential for Pter in prostate cancer chemoprevention. Citation Format: Rutu Hemani, Ninad Inamdar, Avinash Kumar, Virginia Donovan, Anait S. Levenson. Novel prostate cancer mouse models for testing targeted chemopreventive potential of pterostilbene [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 1144.
Abstract 6259: Exosomal formulation escalates cellular uptake of honokiol leading to enhanced antitumor efficacy in pancreatic cancer
Authors: Mohammad Aslam Khan, Rajashekhar Kanchanapally, Sachin Kumar Deshmukh, Sanjeev K. Srivastava, Seema Singh, Ajay P. Singh
Journal: Cancer Research (2020)

Abstract Pancreatic cancer (PC) is the third leading cause of cancer-related death in the United States. It is challenging to treat PC due to the existence of intrinsic and extrinsic chemoresistance mechanisms. We previously reported that honokiol, a phytochemical isolated from Magnolia plant, targets important signaling pathways involved in PC associated with survival, chemoresistance and stromal remodeling, and exhibits significant anti-tumor activity both in vitro and in vivo. However, considering poor bioavailability and tumor uptake as major hurdles in clinical translation, we made efforts to develop an exosomal nanoformulation of honokiol. Mesenchymal cell-derived exosomes are non-immunogenic and express surface markers that could support tumor-targeted delivery. Maximum entrapment of honokiol was achieved when it was used in 1:4 weight ratio with exosomes and subjected to 6 cycles of sonication. Data from dynamic light scattering suggested that key features of exosomes (size, polydispersity and integrity) remained intact post-honokiol encapsulation. The comparative half maximal inhibitory concentration (IC50) data suggested 4 to 5 times greater therapeutic efficacy of exosomal honokiol as compared to that of free honokiol. Similarly, exosomal-honokiol had significantly superior effect on cell cycle progression, apoptosis and expression of cell cycle- and survival-associated proteins than that observed in PC cells treated with equivalent doses of free honokiol. We also found that the cellular uptake of honokiol was significantly greater for exosomal-honokiol as compared to its free form. Together, our work is the first demonstration of exosomal encapsulation of honokiol and its improved anti-tumor efficacy against pancreatic cancer. Citation Format: Mohammad Aslam Khan, Rajashekhar Kanchanapally, Sachin Kumar Deshmukh, Sanjeev K. Srivastava, Seema Singh, Ajay P. Singh. Exosomal formulation escalates cellular uptake of honokiol leading to enhanced antitumor efficacy in pancreatic 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 6259.
Association of Continuity of Care With Outcomes in US Veterans With Inflammatory Bowel Disease
Authors: Shirley Cohen-Mekelburg, Sameer D. Saini, Sarah L. Krein, Timothy P. Hofer, Beth I. Wallace, John M. Hollingsworth, Julie P. W. Bynum, Wyndy Wiitala, Jennifer Burns, Peter D. R. Higgins, Akbar K. Waljee
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Health care fragmentation is associated with inefficiency and worse outcomes. Continuity of care (COC) models were developed to address fragmentation. <h3>Objective</h3> To examine COC and selected outcomes in US veterans with inflammatory bowel disease (IBD). <h3>Design, Setting, and Participants</h3> This retrospective cohort study used the Veterans Health Administration (VHA) Corporate Data Warehouse to identify veterans with IBD who received care in the VHA health care system between January 1, 2002, and December 31, 2014. Included patients were veterans with IBD who had a primary care physician and at least 4 outpatient visits with key physicians (gastroenterologist, primary care physician, and surgeon) within the first year after an index IBD encounter. Data were analyzed from November 2018 to May 2020. <h3>Exposures</h3> Care continuity was measured with the Bice-Boxerman COC index to define care density and dispersion within year 1 after the initial presentation. <h3>Main Outcomes and Measures</h3> A Cox proportional hazards regression model was used to quantify the association between a low level of COC in year 1 (defined as ≤0.25 on a 0 to 1 scale) and subsequent IBD-related outcomes in years 2 and 3 (outpatient flare, hospitalization, and surgical intervention). <h3>Results</h3> Among the 20 079 veterans with IBD who met the inclusion criteria, 18 632 were men (92.8%) and the median (interquartile range [IQR]) age was 59 (48-66) years. In the first year of follow-up, substantial variation in the dispersion of care was observed (median [IQR] COC, 0.24 [0.13-0.46]). In a Cox proportional hazards regression model, a low level of COC was associated with a higher likelihood of outpatient flares that required corticosteroids (adjusted hazard ratio [aHR], 1.11; 95% CI, 1.01-1.22), hospitalizations (aHR, 1.25; 95% CI, 1.06-1.47), and surgical interventions (aHR, 1.72; 95% CI, 1.43-2.07). <h3>Conclusions and Relevance</h3> Results of this cohort study showed a wide variation in dispersion of IBD care and an association between a lower level of COC and active IBD and worse outcomes. The findings suggest that investigating the barriers to COC in integrated systems that have invested in care coordination is key to not only better understanding COC but also identifying opportunities to improve care fragmentation.
Abstract 1236: <i>In vitro</i> association of chloroquine with alkylating and antimicrotubule agents in patient derived cell lines of glioblastoma
Authors: Franciele C. Kipper, Ajith Thomas, Guido Lenz
Journal: Cancer Research (2020)

Abstract Autophagy is an important mechanism for cell survival after chemotherapy treatment. Many preclinical and clinical trials have tried to achieve tumor remission combining alkylating agents with autophagy inhibition. Chloroquine (CQ) has a long record as an autophagy inhibitor. In previous studies it was administered in vitro with mixed effects on central nervous system cell lines: while high doses of CQ were cytotoxic, low doses were neuroprotective. Preclinical studies showed that CQ could be used to treat glioblastoma, tumors derived from glial cells in the brain. In a phase I/II clinical trial combining CQ with the standard alkylating agent (temozolomide) plus radiotherapy treating patients with glioblastoma, a dose-limiting toxicity was observed at high doses. Although the authors reported that autophagy inhibition could not be achieved, they did not describe if this mechanism was involved in tumor resistance in that cohort of patients. In order to clarify if CQ can be used to block autophagy, we performed long term treatment combining low doses of CQ with chemotherapeutic agents. We used patient derived cell lines (PDCL) from glioblastoma tumors and treated them with therapeutic agents, using the reported plasma concentration of each drug. We measured acidic organelles with acridine orange incorporation 3, 5 and 7 days after addition of the treatment with flow cytometry. Additionally, 7 days after treatment surviving cells were counted. We did not observe significant increase in autophagy levels or decrease in cell number after temozolomide treatment. On the contrary, paclitaxel induced autophagy and decreased cell survival. Interestingly the combination of procarbazine, lomustine and vincristine (PCV), induced a broad range of results, ranging from high autophagy to increased cell death. We decided to combine PCV with CQ and perform long term analysis in order to evaluate the ability of cells undergoing or escaping apoptosis, senescence or mitotic catastrophe. After 5 days nuclear morphometric analysis demonstrated that out of 6 PDCL tested, only one presented an increase in senescence. The same PDCL also presented a decrease in total number of cells and increase in p62, although combining CQ with PCV was not better than PCV alone. Our results in vitro, using low concentrations of CQ corroborate the finding in clinical trials that chloroquine does not eliminate malignant cells in glioblastoma and better autophagy inhibitors need to be developed to achieve this goal. Citation Format: Franciele C. Kipper, Ajith Thomas, Guido Lenz. In vitro association of chloroquine with alkylating and antimicrotubule agents in patient derived cell lines of glioblastoma [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 1236.
Depressive Symptoms in Danish Patients With Glioma and a Cancer-Free Comparison Group
Authors: Katrine Løppenthin, Christoffer Johansen, Matilde Bille Larsen, Birgitte Hysse Forchhammer, Jannick Brennum, Karin Piil, Neil Aaronson, Birthe Krogh Rasmussen, Pernille Bidstrup
Journal: Journal of the National Comprehensive Cancer Network (2020)

Background: It is well established that patients with glioma may experience adverse general (eg, headache) or focal symptoms (eg, personality changes) and neurocognitive deficits (eg, planning), but they may also experience severe emotional distress. We investigated the prevalence of depressive symptoms in patients with newly diagnosed glioma and in matched cancer-free persons. Methods: For this study, we recruited patients with glioma diagnosed within 12 months at all 4 neurosurgical clinics in Denmark. The cancer-free comparison group was identified through the Danish Central Person Register and matched on sex and age. Participants’ depressive symptoms were evaluated using the Center for Epidemiologic Studies Depression Scale (CES-D; score range, 0–60), with a cutoff score ≥16 indicating moderate-to-severe depressive symptoms. Results: In this study, 363 of 554 patients with glioma and 481 of 1,304 cancer-free persons participated. Mean age of all patients was 55 years and 60% of the population was male. Mean scores for depressive symptoms were statistically significantly higher among patients with glioma, with a mean CES-D score of 10.9 (95% CI, 10.1–11.8) compared with 5.3 (95% CI, 4.7–5.8) among cancer-free persons ( P &lt;.0001). Overall, 92 patients with glioma (25%) and 30 cancer-free persons (6%) had moderate-to-severe depressive symptoms. After adjustment for marital status, education level, and comorbidity, the prevalence of depressive symptoms was 5 times higher among patients with glioma compared with cancer-free persons. Conclusions: A substantially higher prevalence of moderate-to-severe depressive symptoms was identified in patients with glioma compared with cancer-free persons. This indicates the importance of programs to systematically identify and manage depressive symptoms in patients with glioma.
TERT and DNMT1 expression predict sensitivity to decitabine in gliomas
Authors: Jong-Whi Park, Felix Sahm, Bianca Steffl, Isabel Arrillaga-Romany, Daniel Cahill, Michelle Monje, Christel Herold-Mende, Wolfgang Wick, Şevin Turcan
Journal: Neuro-Oncology (2020)

Decitabine (DAC) is an FDA-approved DNA methyltransferase (DNMT) inhibitor that is used in the treatment of patients with myelodysplastic syndromes. Previously, we showed that DAC marks antitumor activity against gliomas with isocitrate dehydrogenase 1 (IDH1) mutations. Based on promising preclinical results, a clinical trial has been launched to determine the effect of DAC in IDH-mutant gliomas. The next step is to comprehensively assess the efficacy and potential determinants of response to DAC in malignant gliomas.The expression and activity of telomerase reverse transcriptase (TERT) and DNMT1 were manipulated in patient-derived IDH1-mutant and -wildtype glioma lines, followed by assessment of cell proliferation with DAC treatment alone or in combination with telomerase inhibitors. RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and correlation analysis were performed.IDH1-mutant glioma tumorspheres with hemizygous codeletion of chromosome arms 1p/19q were particularly sensitive to DAC and showed significant inhibition of DNA replication genes. Our transcriptome analysis revealed that DAC induced expression of cyclin-dependent kinase inhibitor 1A/p21 (CDKN1A), along with downregulation of TERT. These molecular changes were also observed following doxorubicin treatment, supporting the importance of DAC-induced DNA damage in contributing to this effect. We demonstrated that knockdown of p21 led to TERT upregulation. Strikingly, TERT overexpression increased DNMT1 levels and DAC sensitivity via a telomerase-independent mechanism. Furthermore, RNA inhibition (RNAi) targeting of DNMT1 abrogated DAC response in TERT-proficient glioma cells.DAC downregulates TERT through p21 induction. Our data point to TERT and DNMT1 levels as potential determinants of response to DAC treatment.
Abstract 1873: Drivers of secondary resistance to anti-EGFR therapy in metastatic colorectal cancer
Authors: Soha Hussein Noseir, Stephan Hahn, Abdelouahid Maghnouj, Swetlana Ladigan
Journal: Cancer Research (2020)

Abstract Secondary Resistance (SR) evolves in virtually all metastatic colorectal cancers (mCRC) treated with anti-EGFR targeting drugs such as Cetuximab (Cmab). Yet, SR patient-derived xenograft (pdx) models are largely lacking. Here, we established eight SR pdx models through chronic Cmab treatment of drug-sensitive mCRC pdx. All pdx models were initially wild-type for KRAS, NRAS, PI3K and BRAF, as required for Cmab treatment. Post SR establishment, two models showed KRAS mutations and were excluded from further studies. Whole exome sequencing of the remaining six SR pdx models did not reveal any known driver mutations which could confer SR. However, global gene expression analyses identified widespread transcriptional reprograming with many genes able to activate KRAS and/or PI3K signaling pathways. Among the highly dysregulated genes, fibroblast growth factors FGF13, FGF19, FGF20, and insulin-like growth factor IGF2 stood out as potential drivers of SR through upregulation of RTK signaling. Functional molecular analyses of these factors were performed using lentiviral vector mediating gene transduction. Cell viability, proliferation assays and western blot (WB) analyses were applied to assess the molecular functionality of FGFs and IGF2-ligands in vitro. Finally, transgenic cell lines were injected into nude mice to test their therapeutic response towards Cmab treatment following upregulation or downregulation of the chosen candidates. Stable lentiviral overexpression of FGF13 and IGF2 in drug-sensitive cell lines and pdx models triggered SR both in vitro and in vivo. WB analyses showed that FGF13 and IGF2 overexpression induced phosphorylation of pAKT, pS6, and pERK. Conversely, knockdown of IGF2 in a cell line with high endogenous IGF2 expression improved Cmab sensitivity. Lastly, when subjecting a Cmab SR pdx model with high endogenous overexpression of FGF13 and FGF19 to a Pan-FGF inhibitor (LY2874455) in combination with Cmab, we observed a conversion of the SR into partial response. Taken together, these results support a role of IGF2 and FGFs as candidate proteins conferring SR in an autocrine fashion in the setting of KRAS wild-type mCRC under chronic anti-EGFR treatment. Importantly, these results also suggest that potential combination therapies of Cmab and an IGF2 or FGF inhibitor could prevent establishment of SR through these pathways and offer new treatment opportunities for patients with SR mCRC. Citation Format: Soha Hussein Noseir, Stephan Hahn, Abdelouahid Maghnouj, Swetlana Ladigan. Drivers of secondary resistance to anti-EGFR therapy in metastatic 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 1873.