tbuckley/cabot-search huggingface dataset:
Abstract LB-356: Deep immune profiling of de novo and recurrent glioblastoma
Authors: Cécile Alanio, Zev A. Binder, Donald M. O'Rourke, E. John Wherry
Journal: Cancer Research (2020)

Abstract To understand potential immune system alterations in glioblastoma patients and provide a foundation for immunotherapy, we profiled intra tumoral leucocytes from newly diagnosed de novo patients as well as patients with recurrent tumor using high dimensional CyTOF. All recurrent patients underwent standard-of-care therapy, including surgical resection, concurrent temozolomide and radiotherapy, and adjuvant temozolomide. We used two immune profiling panels: a broad profiling panel that includes 45 phenotypic markers that together permit the identification and enumeration of the main innate and adaptive immune cell subsets in humans, and a deep profiling panel that includes 45 features focused on T cell phenotype and biology. We report in both de novo and recurrent tumors a predominant infiltration by CD11b+CD14+ monocytes (43.6±13%. of CD45+ cells). These monocytes displayed an immunomodulatory M2 profile (CD163+HLA-DR-/+CD80-CD86-/+). The adaptive compartment was sparse and dominated by alpha beta T cells, although some mucosal associated invariant T cells and gamma delta T cells were also present. T cells were both conventional T cells and regulatory T cells. The latter tended to be more abundant in the de novo as compared to recurrent tumors (22.8±17.9% of CD4+ T cells in de novo vs 12.9±12.5% in recurrent tumors, P=0.09). Conventional T cells were mostly CD27-CD45RA- effectors, with high expression of PD1 (69.9±17.6% of CD8+ T cells). Using high dimensional approaches, we confirmed that this high expression of PD1 reflects T cell exhaustion, as defined by co-expression of other inhibitory receptors such as Tim3, CTLA-4 and LAG-3. Exhausted T cells typically co-expressed PD1 and CD39 in the de novo tumors, and this pattern was less often observed in recurrent tumors (63.4±22.84% of CD8+ T cells in de novo vs 46.3±14.5% in recurrent tumors, P=0.03). Together, our results highlight the potential issue of a substandard T cell compartment at the time of GBM diagnosis. We are now investigating the mechanisms underlying these observations, as well as their impact on T cell immunity of the patients, as well as current immunotherapy strategies. Our studies should provide a foundation for improving therapy in glioblastoma patients. Citation Format: Cécile Alanio, Zev A. Binder, Donald M. O'Rourke, E. John Wherry. Deep immune profiling of de novo and recurrent 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 LB-356.
Accuracy of Substituted Judgments in Patients with Terminal Diagnoses
Authors: Kevin O'Rourke
Journal: Annals of Internal Medicine (1998)

Letters15 December 1998Accuracy of Substituted Judgments in Patients with Terminal DiagnosesKevin O'Rourke, OP, JCD, STMKevin O'Rourke, OP, JCD, STMSaint Louis University; St. Louis, MO 63049Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-129-12-199812150-00040 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:The fundamental assumption of Dr. Sulmasy's recent article on substituted judgments [1], namely, that an “accurate” decision of a surrogate will also be an ethical decision, is open to question. To be ethical, the decision of the surrogate need not be a repetition of the patient's decision when he or she was still competent. The decision of the surrogate should be based on accurate medical knowledge of the patient's condition and a prognosis of benefit and burden that might result from the therapy. The surrogate is not bound to ask for futile or unreasonable treatment simply because ...References1. Sulmasy DP, Terry PB, Weisman CS, Miller DJ, Stallings RY, Vettese MA, et al. The accuracy of substituted judgments in patients with terminal diagnoses. Ann Intern Med. 1998; 128:621-9. Google Scholar Author, Article, and Disclosure InformationAuthors: Kevin O'Rourke, OP, JCD, STMAffiliations: Saint Louis University; St. Louis, MO 63049 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 15 December 1998Volume 129, Issue 12Page: 1082-1083KeywordsComaDecision makingKidneysLife expectancyMedical dialysis ePublished: 15 August 2000 Issue Published: 15 December 1998 Copyright & PermissionsCopyright © 1998 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Abstract 1855: Statins decrease the expression of c myc in cancer cell lines
Authors: U.S. Rao, Randy Mullins, Prema Rao
Journal: Cancer Research (2020)

Abstract The widely used statin drugs for the prevention of cardiovascular diseases are envisioned to have the potential to control cancer. Repurposing these cardiovascular drugs for cancer prevention and/or treatment is an attractive proposition as these drugs are commonly prescribed in the clinic. However, there was no clinical evidence for statins being used as chemopreventive agents and the reasons for this are unclear. To further establish the effectiveness of statins as chemopreventive agents, we investigated the effects of three most common statins, simvastatin, atorvastatin and lovastatin on six different cancer cell lines including an ovarian cancer cell line that overexpresses P-glycoprotein, an ABCB1 gene product. Incubation of cells with statins (at both 12.5 microM and 25 microM) resulted in decreased cell growth in a time-dependent manner. The decreased cell growth could be correlated with decreased cellular NADPH levels. Measurement of viable and dead cells in statin treatments indicated that statins induced cell proliferation arrest without inducing cell death. Removal of statins from culture medium resulted in robust cell growth, identical to that observed in controls. Further, cell cycle analysis clearly indicated that statins induced cell cycle arrest at G0/G1 phase without inducing apoptosis. Analysis of the mechanism of statins in these cancer cells indicated that these drugs inhibit HMG CoA reductase, without affecting the transcript of the HMGCR. The HMG CoA reductase inhibition could be relieved with mevalonate. Analysis of key target proteins important for cancer cell proliferation identified that exposure of cancer cells to statins significantly decreased c-Myc protein without affecting its transcription. Importantly, removal of statins reversed the c-Myc expression to the normal level. Finally, incubation of cells with statins increased phosphorylation of H2AX, suggesting that statins promote cellular senescence. These data together suggested that statins are cytostatic, and eliminate c-Myc expression. These observations are consistently observed in the multidrug-resistant cells as well. These data lend strong support that statins could serve as excellent agents for cancer chemoprevention. Citation Format: U.S. Rao, Randy Mullins, Prema Rao. Statins decrease the expression of c myc in cancer cell lines [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 1855.
Abstract 978: Monocyte-derived macrophages contribute to the inflammation-induced survival of experimental micrometastases in the lung
Authors: Arif A. Arif, Spencer A. Freeman, Jawairia Atif, Pamela Dean, Megan Gilmour, Marie-Renee Blanchet, Kimberly Wiegand, Kelly M. McNagny, Michael Underhill, Michael Gold, Pauline Johnson, Calvin D. Roskelley
Journal: Cancer Research (2020)

Abstract Circulating tumor cells become fully metastatic if they are able to extravasate from the microvasculature and move into microenvironmental niches that facilitate their survival within distant site organs. To determine if inflammation promotes this process in the lungs, inflammatory asthma, hypersensitivity pneumonitis, or bleomycin-induced injury were initiated prior to the intravenous introduction of low malignant potential B16F0 melanoma cells. All three conditions increased end-stage metastatic burden without increasing the initial tumor cell extravasation from the lung microvasculature. There was, however, an increase in the number and size of early micrometastatic lesions within the lung interstitia that were visible 96 hr after melanoma cell introduction. There was also an increase in tumor cell survival within these early lesions located in the inflamed lungs that was associated with the presence of nearby newly recruited CD11c+CD11b+ monocyte-derived macrophages (MoDM). Adoptive transfer experiments indicated that these MoDM cells facilitated B16F0 cell metastasis in the absence of inflammation. Additionally, a factor, or factors, secreted by MoDM promoted B16F0 cell survival under stress-inducing condition. Taken together, these findings demonstrate that inflammation-induced monocyte-derived macrophages act as a modifier of the post-extravasation microenvironment that appears to facilitate the early emergence of distant site metastasis. Citation Format: Arif A. Arif, Spencer A. Freeman, Jawairia Atif, Pamela Dean, Megan Gilmour, Marie-Renee Blanchet, Kimberly Wiegand, Kelly M. McNagny, Michael Underhill, Michael Gold, Pauline Johnson, Calvin D. Roskelley. Monocyte-derived macrophages contribute to the inflammation-induced survival of experimental micrometastases in the lung [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 978.
Abstract 2697: Single cell RNA sequencing and tumor cell heterogeneity in metastatic triple-negative breast cancer
Authors: Dongbo Yang, Christopher Dann, Sebastian Pott, Marsha Rosner
Journal: Cancer Research (2020)

Abstract Tumor cell heterogeneity has been strongly implicated in metastatic progression of solid tumors such as breast cancer, leading to resistance and recurrence. We hypothesize that inhibiting metastasis will reduce tumor cell heterogeneity and thereby increase therapeutic sensitivity. To test this hypothesis, we expressed the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP or PEBP1) in triple-negative breast cancer (TNBC) cells as a means of comparing the variation in gene expression between individual cells in metastatic versus non-metastatic tumors. Xenograft tumors with or without exogenous RKIP expression were dissociated into single cell suspensions. We removed mouse as well as dead cells, and the remaining cells were loaded onto a microfluidic device (Fluidigm C1) for separation and library preparation. For each condition we performed three independent experiments yielding a total of 1569 cells. Initially, we performed controls to ensure that differences were not due to batch effects, cell cycle stage or sample quality. Clustering of single cells across all samples indicated that gene expression profiles are similar, confirming reproducibility. Gene ontology analysis of differentially expressed genes between cells with and without RKIP overexpression reveals gene sets that are important in tumor cell transitions from metastatic to non-metastatic states. These data will allow us to specifically test whether metastatic tumors are more heterogeneous than non-metastatic tumors in TNBC. Citation Format: Dongbo Yang, Christopher Dann, Sebastian Pott, Marsha Rosner. Single cell RNA sequencing and tumor cell heterogeneity in metastatic triple-negative breast 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 2697.
Abstract 5443: Modulating plasticity in aggressive variant prostate cancers
Authors: Rama Soundararajan, Petra den Hollander, Peter Shepherd, Nora Navone, Daniele Lorenzini, Caddie Laberiano-Fernandez, Wei Lu, Jianling Zhou, Jingjing Liu, Jianhua Zhang, Luisa Maren Solis-Soto, Sendurai A. Mani, Ana Aparicio
Journal: Cancer Research (2020)

Abstract Aggressive Variant Prostate Cancers (AVPC) are a clinically and molecularly distinct subset of prostate cancers with a poor prognosis characterized by androgen-indifference, platinum-sensitivity and combined defects in Tp53, RB1 and PTEN, for which novel therapeutic approaches are urgently needed. Defects observed in these tumor suppressor pathways have been linked to lineage plasticity in genetically engineered mouse models. We hypothesized that this plasticity can be identified in human tumor samples, and can be modulated to serve as the foundation for effective combination therapies for the AVPC subset. We previously defined a gene expression signature derived from mouse embryonic day 6.5 that is representative of extensive cellular plasticity (PMID:26123483). We determined the plasticity scores in 12 patient-derived xenograft (PDX) models representative of the spectrum of prostate cancer biology (using available RNA sequencing profiles), and in 26 macrodissected tumor biopsies obtained from patients who received platinum-based chemotherapy for aggressive prostate cancer (using ALMAC Affymetrix gene expression microarray). As expected, the AVPC PDX models exhibited high plasticity scores as did 11 (42.3%) of the patient samples, associated with patient progression free- and overall survival. We next treated a well characterized AVPC PDX model (144-4) with the anti-EMT drug (p38MAPK inhibitor) SB203580 at 10mg/kg, and observed a decrease in stem-cell and EMT factors associated with plasticity. These data confirm the association between plasticity and AVPC in human tumor samples, and suggest that changes in plasticity can be measured in tumor samples to determine the value of its modulation in clinical trials. Acknowledgments: ALMAC Diagnostics Services, UK, and UTMDACC ATGC Core Lab (CCSG-CA016672-ATGC) for RNA sequencing services; UTMDACC Prostate Cancer SPORE (RS, SAM, AA), UTMDACC IRG (RS), and the UTMDACC Prostate Cancer Moonshot Program (AA) for financial support. Citation Format: Rama Soundararajan, Petra den Hollander, Peter Shepherd, Nora Navone, Daniele Lorenzini, Caddie Laberiano-Fernandez, Wei Lu, Jianling Zhou, Jingjing Liu, Jianhua Zhang, Luisa Maren Solis-Soto, Sendurai A. Mani, Ana Aparicio. Modulating plasticity in aggressive variant prostate cancers [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 5443.
Abstract 4968: Blockade of p38 kinase impedes the mobilization of myeloid populations that promote breast cancer metastasis
Authors: Justin Zonneville, Sean Colligan, Paul Wallace, Scott I. Abrams, Andrei V. Bakin
Journal: Cancer Research (2020)

Abstract Patients with metastatic breast cancer (MBC) have limited therapeutic options and novel treatments are critically needed. Prior studies demonstrated that the p38 kinase (p38) promotes MBC, while the mechanisms remained unknown. Here, we provide evidence for a novel mechanism by which p38 promotes metastasis. Using triple-negative breast cancer models, we showed that a selective inhibitor of p38 (p38i) significantly reduced tumor growth, angiogenesis, and lung metastasis. Importantly, p38i decreased the accumulation of myeloid populations, namely myeloid-derived suppressor cells (MDSCs) and CD163+ tumor-associated macrophages (TAMs). p38 controlled the expression of tumor-derived chemokines/cytokines that facilitated the recruitment of pro-tumor myeloid populations. Depletion of MDSCs was accompanied by reduced TAM infiltration and phenocopied the anti-metastatic effects of p38i. Reciprocally, p38i increased tumor infiltration by cytotoxic CD8+ T cells. Metadata showed that a reduced CD163+/CD8+ expression ratio correlates with metastasis-free survival in breast cancer, suggesting that targeting p38 may improve clinical outcomes. This study highlights a novel p38-driven mechanism as a therapeutic target in MBC. Citation Format: Justin Zonneville, Sean Colligan, Paul Wallace, Scott I. Abrams, Andrei V. Bakin. Blockade of p38 kinase impedes the mobilization of myeloid populations that promote breast cancer metastasis [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 4968.
Abstract 3934: UBXN2A inhibits tumor invasion and metastasis by targeting the mTORC2-VEGF pathway
Authors: Morgan Eikanger, Rekha Srinivasan, Sanam Sane, Khosrow Rezvani
Journal: Cancer Research (2020)

Abstract Despite advances in treatment regimens, one-third of colorectal cancer (CRC) patients will die from this metastatic disease that can disseminate, or spread, throughout the body. Therefore, understanding the mechanisms underlying the multistep metastatic program of CRC cells is critical for the development of novel therapies that will improve the management of this advanced disease. Our preliminary data indicate that a ubiquitin-like protein, UBXN2A, function as mTORC2 inhibitor in colon cancer cell lines. Our flow cytometry and western blot experiments revealed that induction of UBXN2A with Doxycycline or enhancement of UBXN2A expression with a pharmacological tool, Veratridine, inhibits mTORC2 complex in primary and metastatic colon cancer cells. Based on these results, we hypothesized that increased expression of UBXN2A suppresses the vascular endothelial growth factor, or VEGF protein, which is a key factor in tumor angiogenesis. Our current results indicate that the induction of UBXN2A significantly reduces VEGF protein, a key component in tumor invasion and metastasis. Collectively, our results suggest UBXN2A is a potential key player in intercepting the angiogenesis pathway and downstream regulators of metastasis by suppressing VEGF protein. These findings provide an attractive and promising target for the treatment of metastatic CRC. Citation Format: Morgan Eikanger, Rekha Srinivasan, Sanam Sane, Khosrow Rezvani. UBXN2A inhibits tumor invasion and metastasis by targeting the mTORC2-VEGF pathway [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 3934.
Abstract 3016: Tucatinib inhibits CYP3A, CYP2C8 and P-gp-mediated elimination and is impacted by CYP2C8 inhibition in healthy volunteers
Authors: Ariel R. Topletz-Erickson, Anthony Lee, Hao Sun, JoAl Mayor, Luke Walker, Christopher J. Endres
Journal: Cancer Research (2020)

Abstract Background: Tucatinib is a potent, highly selective HER2 tyrosine kinase inhibitor in development for the treatment of patients with HER2+ metastatic breast cancer. In vitro metabolism studies suggest that drug metabolizing enzymes CYP2C8 and CYP3A play a role in tucatinib metabolism. Tucatinib exhibits competitive inhibition of CYP2C8, CYP2C9, CYP3A, and P-gp, and metabolism-dependent inactivation of CYP3A in vitro. ONT-380-012 was a clinical drug interaction study conducted to evaluate the magnitude of potential enzyme and transporter interactions for tucatinib (both as a victim and perpetrator), and the safety of healthy subjects when administered tucatinib doses at therapeutic levels (300 mg BID). Methods: Healthy volunteers (n=116) at multiple centers were enrolled in the study. Parts A-C evaluated the effects of a strong CYP2C8 inhibitor (gemfibrozil), a strong CYP3A inhibitor (itraconazole), and a CYP3A/CYP2C8 inducer (rifampin) on single-dose tucatinib (300 mg) PK. Parts D and E assessed the effects of steady-state tucatinib (300 mg BID) on single-dose PK of substrate probes for CYP2C8 (repaglinide), CYP2C9 (tolbutamide), CYP3A (midazolam), and P-gp (digoxin). Plasma samples were collected for PK analysis and drug concentrations were measured using validated LC-MS/MS methods. Results: A strong CYP3A inhibitor (itraconazole) increased tucatinib AUCinf and Cmax 1.3-fold. A CYP3A/CYP2C8 inducer (rifampin) decreased tucatinib AUCinf and Cmax 48% and 37%, respectively. A strong CYP2C8 inhibitor (gemfibrozil) increased tucatinib AUCinf and Cmax 3.1- and 1.6-fold, respectively. Tucatinib increased the AUCinf and Cmax of the CYP3A substrate (midazolam) 5.7- and 3.0-fold, respectively, the AUCinf and Cmax of the CYP2C8 substrate (repaglinide) 1.7-fold, and the AUCinf of the P-gp substrate (digoxin) 1.5-fold. Tucatinib had no impact on the PK of the CYP2C9 substrate (tolbutamide). Overall, tucatinib was well tolerated in healthy volunteers when administered 300 mg BID. Conclusions: Together, these data indicate tucatinib is metabolized primarily by CYP2C8 and to a lesser extent via CYP3A. Tucatinib was found to be a strong inhibitor of CYP3A, a weak inhibitor of CYP2C8 and P-gp, and had no impact on CYP2C9-mediated metabolism in vivo. Citation Format: Ariel R. Topletz-Erickson, Anthony Lee, Hao Sun, JoAl Mayor, Luke Walker, Christopher J. Endres. Tucatinib inhibits CYP3A, CYP2C8 and P-gp-mediated elimination and is impacted by CYP2C8 inhibition in healthy volunteers [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 3016.