tbuckley/cabot-search huggingface dataset:
Heterologous and cross-species tropism of cancer-derived extracellular vesicles
Authors: Mariangela Garofalo, Alessandro Villa, Daniela Crescenti, Monica Marzagalli, Lukasz Kuryk, Patrizia Limonta, Vincenzo Mazzaferro, Paolo Ciana
Journal: Theranostics (2019)

Extracellular vesicles (EVs) are naturally occurring cargo delivery vesicles that have recently received considerable attention for their roles in intercellular communication in many physiological and pathological processes, including tumourigenesis. EVs generated by different tissues demonstrated specific homing: in particular, cancer-derived EVs showed a selective tropism for the tumor tissue from which the vesicles originated. For this property, EVs have been proposed as drug delivery tools for anti-cancer therapies, although the limited knowledge about their in vivo tropism hinders their therapeutic applications. The current study aimed to characterize the targeting properties of cancer-derived EVs in vitro and their biodistribution in vivo, by using an imaging approach. Methods: EVs were generated from: i) murine lung (LL/2) and colon (MC-38) cancer lines, ii) human lung cancer cell line (A549) and iii) human liver biopsy samples from healthy individuals. EVs were loaded with fluorescent dyes alone or in combination with a biopharmaceutical agent, the oncolytic adenovirus (OV), characterized for charge and size and tested for their activity in cancer cell lines. Finally, optical imaging was extensively applied to study in vivo and ex vivo the biodistribution of EVs originated from different sources in different mouse models of cancer, including xenograft, syngeneic graft and the MMTV-NeuT genetically modified animal. Results: We initially demonstrated that even loading EVs even with a large biopharmaceutical oncolytic viruses (OVs) did not significantly change their charge and dimension properties, while increasing their anti-neoplastic activity compared to the virus or EVs alone. Interestingly, this activity was observed even if the EVs derived from lung cancer were applied to colon carcinoma cell lines and vice versa, suggesting that the EV uptake occurred in vitro without any specificity for the cancer cells from which the vesicles originated. When administered i.v (intravenously) to the mouse models of cancer, the tumour-derived EVs, but not the EVs derived from a healthy tissue, demonstrated a selective accumulation of the fluorescence at the tumour site 24 h after injection; adding OVs to the formulation did not change the tumour-specific tropism of the EVs also in vivo. Most interestingly, the in vivo experiments confirmed the in vitro observation of the generalized tropism of tumour-derived EVs for any neoplastic tissue, independent of the tumour type or even the species originating the vesicles. Conclusions: Taken together, our in vitro and in vivo data demonstrate for the first time a heterologous, cross-species tumour-tropism for cancer-derived EVs. This finding challenges our current view on the homing properties of EVs and opens new avenues for the selective delivery of diagnostic/therapeutic agents to solid tumours.
Multi-omics profiling reveals key signaling pathways in ovarian cancer controlled by STAT3
Authors: Tiangong Lu, Armand Bankhead, Mats Ljungman, Nouri Neamati
Journal: Theranostics (2019)

Inhibiting STAT3 signaling reduces tumor progression, metastasis and chemoresistance, however the precise molecular mechanism has not been fully delineated in ovarian cancer.In this study, we generated STAT3 knockout (KO) ovarian cancer cell lines. Effects of STAT3 KO on cell proliferation, migration and spheroid formation were assessed in vitro and effects on in vivo tumor growth were tested using several tumor xenograft models. We used multi-omic genome-wide profiling to identify multi-level (Bru-Seq, RNA-Seq, and MS Proteomic) expression signatures of STAT3 KO ovarian cancer cells.We observed that deletion of STAT3 blocked cell proliferation and migration in vitro and suppressed tumor growth in mice. Deletion of STAT3 transcriptionally suppressed key genes involved in EMT, cell cycle progression, E2F signaling, and altered stemness markers. Notably, KO of STAT3 resulted in modulation of the expression of other STAT family members.Our study presents a rich, multi-faceted summary of the molecular mechanisms impacted by STAT3 deletion and provides new insight for STAT3's potential as a therapeutic target in ovarian cancer.
ERBB3 and IGF1R Signaling Are Required for Nrf2-Dependent Growth in KEAP1-Mutant Lung Cancer
Authors: Steffan Vartanian, James Lee, Christiaan Klijn, Florian Gnad, Maria Bagniewska, Gabriele Schaefer, Donglu Zhang, Jenille Tan, Sara A. Watson, Liling Liu, Honglin Chen, Yuxin Liang, Colin Watanabe, Trinna Cuellar, David Kan, Ryan J. Hartmaier, Ted Lau, Michael R. Costa, Scott E. Martin, Mark Merchant, Benjamin Haley, David Stokoe
Journal: Cancer Research (2019)

Mutations in KEAP1 and NFE2L2 (encoding the protein Nrf2) are prevalent in both adeno and squamous subtypes of non-small cell lung cancer, as well as additional tumor indications. The consequence of these mutations is stabilized Nrf2 and chronic induction of a battery of Nrf2 target genes. We show that knockdown of Nrf2 caused modest growth inhibition of cells growing in two-dimension, which was more pronounced in cell lines expressing mutant KEAP1. In contrast, Nrf2 knockdown caused almost complete regression of established KEAP1-mutant tumors in mice, with little effect on wild-type (WT) KEAP1 tumors. The strong dependency on Nrf2 could be recapitulated in certain anchorage-independent growth environments and was not prevented by excess extracellular glutathione. A CRISPR screen was used to investigate the mechanism(s) underlying this dependence. We identified alternative pathways critical for Nrf2-dependent growth in KEAP1-mutant cell lines, including the redox proteins thioredoxin and peroxiredoxin, as well as the growth factor receptors IGF1R and ERBB3. IGF1R inhibition was effective in KEAP1-mutant cells compared with WT, especially under conditions of anchorage-independent growth. These results point to addiction of KEAP1-mutant tumor cells to Nrf2 and suggest that inhibition of Nrf2 or discrete druggable Nrf2 target genes such as IGF1R could be an effective therapeutic strategy for disabling these tumors. SIGNIFICANCE: This study identifies pathways activated by Nrf2 that are important for the proliferation and tumorigenicity of KEAP1-mutant non-small cell lung cancer.
Continuous intravenous infusion (CIVI) topotecan may be safely combined with tipifarnib
Authors: D. Hills, L. Liebes, F. Muggia, J. Wright, A. Pavlick, M. Buckley, D. Fry, K. Farrell, H. Hochster
Journal: Journal of Clinical Oncology (2006)

2064 Background: Dose limiting (DL) myelosuppression occurred when topotecan 1.0 mg/m 2 /d × 5d was combined with tipifarnib (Proc ASCO, 2001, abst 321). We now report on a 3+3 cohort design to determine the safety and pharmacokinetics (PK) of this combination with topotecan given as CIVI in patients (pts) with refractory solid tumors. Methods: Pts were treated with escalating dose levels of topotecan (0.2–0.4 mg/m 2 /d) given as 21-day infusion in combination with tipifarnib 200 mg PO bid for 21 d every 28 d. Blood was drawn for topotecan PK and intracellular (PBMC) toposisomerase I on d 1 (baseline) and d 5 (tipifarnib omitted d1, cycle 1), and weekly × 8 for ras-farnesylation (membrane bound fraction). Plasma levels of the closed form of topotecan were determined by SPE and HPLC with fluorometric detection. Topoisomerase I in PBMCs was detected by Western blot. Results: 14 patients were accrued at 3 dose levels: topotecan 0.2 mg/m 2 /d (3 pts), 0.3 mg/m 2 /d (3), and 0.4 mg/m 2 /d (8), combined with tipifarnib. Median age was 50 years (33–62). 32 cycles (median 2) were given. Grade 1–3 fatigue, nausea, thrombocytopenia, neutropenia and anemia were common, and at dose level 3, two heavily-pretreated patients had DL myelosuppression. Six others had no significant toxicity over prolonged times. Of nine evaluable for response, a mucinous peritoneal cancer had a minor response for 5 m, an ovarian granulosa cell tumor had a mixed response in lung metastases for 15 m, and a PNET of bone had a minor response for 17 m; six had progression. Mean steady state (± SD) levels of topotecan for dose levels I, II and III were, respectively, 0.48 ± 08 (N = 3), 1.26 ± 0.32 (N = 3) and 1.47 ± 0.1 (N = 5) ng/ml, and were linear with respect to topotecan dose (r = 0.95). By the end of the 21 d infusion, 90% of baseline topoisomerase I signal was depleted in PBMCs. Conclusions: In contrast with bolus topotecan, CIVI topotecan may be combined at known effective doses with tipifarnib. Recommended phase II doses are 0.4 mg/m 2 /d × 21 days and 200 mg bid daily for those with limited prior therapy. Phase II studies in gynecologic and breast tumors are planned. Supported by UO1- 76642; CA 16087. [Table: see text]
Gain-of-function mutant of p53 initiates a positive feedback loop involving EGFR, ERK1/2 and transcription factor EGR-1 in prostate cancer cells
Authors: Veronique Baron, Lysann Sauer, Cassandra Vo
Journal: Cancer Research (2008)

1740  Genetic alteration of p53 is the most common event in human cancer. In prostate cancer, mutations of p53 are rare in primary tumors but frequent in advanced cancer. Their incidence is associated with prostate cancer progression, metastasis and hormone independence. In some instances, mutation of p53 results in gain of function when the mutant protein still binds to DNA and exhibits transcriptional activity. Gain-of-function mutations are associated with cell transformation and accelerated carcinogenesis.  We show here that gain-of-function mutation of p53 results in transactivation of Egr-1 (early growth response-1) in prostate cancer cells, leading to high expression of the protein. Thus, prostate cancer cells containing aberrant p53 activity highly expressed Egr-1, which was abolished upon pharmacological inhibition or RNAi silencing of p53. Interestingly, p53-induced transcription of Egr-1 was mediated by the EGFR/ERK1/2 signaling pathway, as indicated by the observation that pharmacological inhibitors of EGFR or ERK1/2 eliminated constitutive Egr-1 expression.  Several evidences pointed to p53-induced autocrine activation of the EGFR (epidermal growth factor receptor): (i) EGFR was constitutively activated, as assessed by unstimulated autophosphorylation and phosphorylation of AKT and ERK1/2; (ii) cells secreted at least one soluble growth factor that stimulated EGFR activity, ERK1/2 phosphorylation and Egr-1 transcription when added to other cell lines.  Finally, we observed that p53 and Egr-1 cooperate to induce EGFR transcription, thus contributing to EGFR over-expression. It should be noted that the promoter of the EGFR gene contains binding sequences for both p53 and Egr-1 and both transcription factors were found to bind the promoter in chromatin immunoprecipitation experiments.  We conclude that a gain-of function mutant of p53 initiates a positive feedback loop that involves autocrine activation of the EGFR and ERK1/2, transactivation of Egr-1, and leads to overexpression of both EGFR and Egr-1. Increased EGFR expression is frequent in prostate cancer and correlates with tumor progression and poor prognosis. The EGFR contributes to the malignant phenotype by promoting cell proliferation, survival, and migration. There are also indications that Egr-1 promotes the growth of prostate cancer. For example, lack of Egr-1 delayed tumor progression in mice models of prostate cancer. Silencing of Egr-1 in mouse cancer cells inhibited cell proliferation and injection of Egr-1 antisense delayed tumor growth in the TRAMP mouse.  Thus, activation of the EGFR-ERK1/2-Egr1 axis constitutes one possible mechanism by which gain-of-function mutants of p53 accelerate prostate cancer progression.
Fremanezumab versus placebo for migraine prevention in patients with documented failure to up to four migraine preventive medication classes (FOCUS): a randomised, double-blind, placebo-controlled, phase 3b trial
Authors: Michel D Ferrari, Hans Christoph Diener, Xiaoping Ning, Maja Galic, Joshua M Cohen, Ronghua Yang, Matthias Mueller, Andrew H Ahn, Yael Carmeli Schwartz, Melissa Grozinski-Wolff, Lindsay Janka, Messoud Ashina
Journal: The Lancet (2019)
Tumor-activated endothelial mannose receptors contribute to regional immune tolerance during experimental colon carcinoma hepatic metastasis
Authors: Beatriz Arteta-Ruiz, Nerea Lasuen, Bard Smedsrod, Fernando Vidal-Vanaclocha
Journal: Cancer Research (2006)

3503  Mannose receptor (ManR)-mediated liver sinusoidal endothelial cell (LSEC) endocytosis plays a primary role in circulating antigen clearance, antigen presentation and innate immunity, but its role on hepatic tumor development and anti-tumor immune response is unknown. Previously we reported that ManR ligands increase experimental hepatic metastasis occurrence via interleukin (IL)-1-dependent mechanism. Herein we studied ManR activity and expression during murine C26 colon carcinoma cell interaction with LSECs in vitro and in vivo, its regulation by IL-1 and cell adhesion molecules, and its immunological implications in the hepatic sinusoid microenvironment. ManR activity and IL-1beta production increased in LSECs co-cultured with C26 cells. Preincubation of LSEC with anti-murine IL-1 receptor type I antibody or IL-1beta converting enzyme inhibitor abrogated both ManR activity and IL-1beta production from tumor-activated LSECs. The same effects were obtained when C26 cells were pre-treated with celecoxib to inhibit COX-2 activity prior to interacting with LSECs. Consistent with in vitro data, the intrasplenic injection of C26 cells enhanced ManR expression and activity in vivo, and mouse treatment with recombinant IL-1 receptor antagonist prior to C26 cell injection abrogated tumor-dependent ManR up regulation. Blockade of ICAM-1 on LSECs or LFA-1 on C26 cells also abrogated ManR activation and IL-1beta production from tumor-activated LSECs in vitro. Endothelial cell production of soluble ICAM-1 (sICAM-1) also increased during LSEC co-culture with C26 cells via IL-1-dependent mechanism. In turn, sICAM-1-treated C26 cell-derived conditioned medium (CM), but not untreated C26 cell-CM, increased ManR activity and IL-1beta production in LSECs. This effect was abrogated by tumor-COX-2 inhibition. Addition of sICAM-1-treated C26-CM to LSECs prior to being co-cultured with freshly isolated intrahepatic lymphocytes decreased tumor cell cytolysis. However, suppression of both ManR activity with specific antibodies and ManR-stimulating activity in C26-CM with tumor COX-2 inhibition restored the cytotoxic potential of hepatic lymphocytes against C26 cells. In summary, C26 cells upregulated IL-1 production from LSECs via ICAM-1/LFA-1 interaction leading to ManR-mediated endocytosis upregulation. Tumor-activated LSECs produced sICAM-1 which in turn upregulated tumor release of ManR-stimulating factor(s) via COX-2-dependent mechanism. Tumor-induced ManR activation may contribute to regional immune tolerance during metastasis formation in the liver and its inhibition may restore anti-tumor response. These results suggest ManR as a novel molecular target whose direct or indirect blockade via IL-1 or COX-2 inhibition may restore regional immune competence in liver against metastatic cells.
Identification of a new mutation in the EGFR ligand-binding domain: Predictive factor for cetuximab antitumor activity in head and neck carcinoma?
Authors: Olivier Rixe, Li Ya-Qin, Trisha Wise-Draper, Li Deng, Jiang Wang, Colleen Marie Darnell, Mohamad Adham Salkeni, Keith Wilson, Susanne I Wells, Peter Stambrook, El Mustapha Bahassi
Journal: Journal of Clinical Oncology (2012)

e16017 Background: Cetuximab is an EGFR-blocking antibody that has been approved for the treatment of patients with head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer, but no predictive biomarkers of cetuximab activity have yet been identified. Methods: We report on a patient with HNSCC who had a complete tumor regression following treatment with cetuximab given as a single agent after initial surgery and radiation therapy. The EGFR protein expression level, gene copy number and sequence were assessed from both normal and tumor tissues from this patient. Results: Besides protein overexpression and gene amplification in the tumor tissue, sequencing of the EGFR gene from the patient revealed the presence of two somatic mutations, one in the kinase domain (R705G) and the other in the ligand binding domain (P546S). Cells that stably express these EGFR mutants were treated with cetuximab and their sensitivity to the drug was compared to cells expressing the wildtype gene. While the P546S mutation sensitized NIH-3T3 cells to cetuximab, R705G had a marginal effect. The double mutant (P546S/R705G) behaved the same as the P546S mutant, indicating that the mutation in the kinase domain does not contribute to the increased sensitivity to cetuximab. No mutations were found in K-RAS or B-RAF genes and there was no indication that the tumor was HPV-positive. Conclusions: Our results support a role for the P546S mutation in cetuximab sensitivity. To our knowledge, this is the first report of a somatic mutation in the EGFR ligand binding domain that may contribute to increased sensitivity to cetuximab. Other factors including EGFR copy number, EGFR over-expression and the immune response, as indicated by a very adverse side effect that correlated with the antitumor activity, may have also contributed to the observed response. It remains to be determined how frequently this mutation occurs in patients with HNSCCs and other cancers. Prospective evaluation of cetuximab anti-tumor activity in patients harboring P546S mutation needs to be clinically evaluated.
Associations of Physical Activity With Survival and Progression in Metastatic Colorectal Cancer: Results From Cancer and Leukemia Group B (Alliance)/SWOG 80405
Authors: Brendan J. Guercio, Sui Zhang, Fang-Shu Ou, Alan P. Venook, Donna Niedzwiecki, Heinz-Josef Lenz, Federico Innocenti, Bert H. O’Neil, James E. Shaw, Blase N. Polite, Howard S. Hochster, James N. Atkins, Richard M. Goldberg, Kaori Sato, Kimmie Ng, Erin Van Blarigan, Robert J. Mayer, Charles D. Blanke, Eileen M. O’Reilly, Charles S. Fuchs, Jeffrey A. Meyerhardt
Journal: Journal of Clinical Oncology (2019)

PURPOSE Regular physical activity is associated with reduced risk of recurrence and mortality in patients with nonmetastatic colorectal cancer. Its influence on patients with advanced/metastatic colorectal cancer (mCRC) has been largely unexplored. PATIENTS AND METHODS We conducted a prospective cohort study nested in Cancer and Leukemia Group B (Alliance)/SWOG 80405 (ClinicalTrials.gov identifier: NCT00265850 ), a National Cancer Institute–sponsored phase III trial of systemic therapy for mCRC. Within 1 month after therapy initiation, patients were invited to complete a validated questionnaire that reported average physical activity over the previous 2 months. On the basis of responses, we calculated metabolic equivalent task (MET) hours per week to quantify physical activity. The primary end point of the clinical trial and this companion study was overall survival (OS). Secondary end points included progression-free survival (PFS) and first grade 3 or greater treatment-related adverse events. To minimize confounding by poor and declining health, we excluded patients who experienced progression or died within 60 days of activity assessment and used Cox proportional hazards regression analysis to adjust for known prognostic factors, comorbidities, and weight loss. RESULTS The final cohort included 1,218 patients. Compared with patients engaged in less than 3 MET hours per week of physical activity, patients engaged in 18 or more MET hours per week experienced an adjusted hazard ratio for OS of 0.85 (95% CI, 0.71 to 1.02; P Trend = .06) and for PFS of 0.83 (95% CI, 0.70 to 0.99; P Trend = .01). Compared with patients engaging in less than 9 MET hours per week, patients engaging in 9 or more MET hours per week experienced an adjusted hazard ratio for grade 3 or greater treatment-related adverse events of 0.73 (95% CI, 0.62 to 0.86; P Trend &lt; .001). CONCLUSION Among patients with mCRC in Cancer and Leukemia Group B (Alliance)/SWOG 80405, association of physical activity with OS was not statistically significant. Greater physical activity was associated with longer PFS and lower adjusted risk for first grade 3 or greater treatment-related adverse events.
Soluble glypican 3 inhibits the growth of hepatocellular carcinoma
Authors: Sandra Zittermann, Wen Shi, Jorge Filmus
Journal: Cancer Research (2008)

1516  Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver, and the third most common cause of cancer-related mortality. Currently, there are not effective treatments for HCCs that cannot be removed by surgery. Work from our laboratory and from other groups has demonstrated that glypican-3 (GPC3) is expressed by most HCCs (~ 75 %), while it is undetectable in hepatocytes from normal liver and benign liver disease. GPC3 is a member of the glypican family. Glypicans are heparan sulfate proteoglycans that are bound to the exocytoplasmic surface of the plasma membrane through a glycosyl-phosphatidylinositol anchor. Experimental evidence accumulated during the last few years indicates that glypicans regulate the activity of several signaling pathways, including those triggered by Wnts, Hedgehogs, BMPs and FGFs. This regulatory activity is based on the ability of glypicans to facilitate or inhibit the interaction of these ligands withtheir signaling receptors. Our laboratory has previously shown that GPC3 promotes the in vitro and in vivo growth of HCC cells by stimulating theWnt signaling pathway. Preliminary evidence suggests that GPC3 facilitates the interaction of Wnt with its receptor Frizzled. Because the growth stimulatory activity of GPC3 in HCC cells requires the attachment of GPC3 to the cell membrane, we havehypothesized that a mutated GPC3 lacking the GPI anchoring domain (soluble GPC3, sGPC3) will inhibit HCC growth. To investigate this hypothesis, Huh7, Li7 and Huh6 HCC cell lines were transduced with alentivirus containingsGPC3 or viruscontrol. We observed that sGPC3-expressing cells have a lower proliferation rate and form fewer colonies in agar than the controls. In addition, sGPC3 significantly inhibited the in vivo growth of HCC cells. Our results suggest that sGPC3 could be used as a therapeutic tool for HCC.