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  • American Association for Cancer Research (AACR)  (14)
  • 1
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    Online Resource
    Abstract A43: Loss of Keap1 promotes KRAS-driven lung cancer and results in genotype-specific vulnerabilities
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 10_Supplement ( 2018-05-15), p. A43-A43
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 10_Supplement ( 2018-05-15), p. A43-A43
    Abstract: Treating KRAS mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein1. One approach to addressing this challenge is to define frequently co-occurring mutations with KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS mutant LUAD tumors carry loss-of-function (LOF) mutations in Kelch-like ECH-associated protein 1 (KEAP1)2-4, a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response5-10. The high frequency of mutations in KEAP1, which would be predicted to result in activation of the NRF2 pathway, suggests an important role for the oxidative stress response in lung tumorigenesis. To test this directly, we used a CRISPR/Cas9-based approach in a mouse model of Kras-driven LUAD to examine the effects of loss of KEAP1 function in lung cancer progression. We show that loss of KEAP1 hyper-activates Nrf2 and promotes Kras-driven LUAD. Combining CRISPR/Cas9-based genetic screening and metabolomic analyses, we also show that KEAP1/NRF2 mutant cancers are dependent on increased glutaminolysis, and this property can be therapeutically exploited through the pharmacologic inhibition of glutaminase. Finally, we provide a rationale for sub-stratification of human lung cancer patients with KRAS-KEAP1 or -NRF2 mutant tumors as likely to respond to glutaminase inhibition. Citation Format: Rodrigo Romero, Volkan I. Sayin, Davidson M. Shawn, Matthew Bauer, Simranjit X. Singh, Sarah LeBoeuf, Triantafyllia R. Karakousi, Donald C. Ellis, Arjun Bhutkar, Francisco Sanchez-Rivera, Lakshmipriya Subbaraj, Britney Martinez, Roderick T. Bronson, Justin R. Prigge, Edward E. Schmidt, Craig J. Thomas, Angela Davies, Igor Dolgalev, Adriana Heguy, Viola Allaj, John T. Piorier, Andre L. Moreira, Charles M. Rudin, Harvey I. Pass, Matthew G. Vander Heiden, Tyler Jacks, Thales Papagiannakopoulos. Loss of Keap1 promotes KRAS-driven lung cancer and results in genotype-specific vulnerabilities [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A43.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.MOUSEMODELS17-A43
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
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    PD-1 Blockade Induces Reactivation of Nonproductive T-Cell Responses Characterized by NF-κB Signaling in Patients with Pancreatic Cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research ( 2023-10-05), p. OF1-OF12
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), ( 2023-10-05), p. OF1-OF12
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) trials have evaluated CTLA-4 and/or PD-(L)1 blockade in patients with advanced disease in which bulky tumor burden and limited time to develop antitumor T cells may have contributed to poor clinical efficacy. Here, we evaluated peripheral blood and tumor T cells from patients with PDAC receiving neoadjuvant chemoradiation plus anti–PD-1 (pembrolizumab) versus chemoradiation alone. We analyzed whether PD-1 blockade successfully reactivated T cells in the blood and/or tumor to determine whether lack of clinical benefit could be explained by lack of reactivated T cells versus other factors. Experimental Design: We used single-cell transcriptional profiling and TCR clonotype tracking to identify TCR clonotypes from blood that match clonotypes in the tumor. Results: PD-1 blockade increases the flux of TCR clonotypes entering cell cycle and induces an IFNγ signature like that seen in patients with other GI malignancies who respond to PD-1 blockade. However, these reactivated T cells have a robust signature of NF-κB signaling not seen in cases of PD-1 antibody response. Among paired samples between blood and tumor, several of the newly cycling clonotypes matched activated T-cell clonotypes observed in the tumor. Conclusions: Cytotoxic T cells in the blood of patients with PDAC remain sensitive to reinvigoration by PD-1 blockade, and some have tumor-recognizing potential. Although these T cells proliferate and have a signature of IFN exposure, they also upregulate NF-κB signaling, which potentially counteracts the beneficial effects of anti–PD-1 reinvigoration and marks these T cells as non-productive contributors to antitumor immunity.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-23-1444
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 3
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    Proapoptotic Activity of Bortezomib in Gastrointestinal Stromal Tumor Cells
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 1 ( 2010-01-01), p. 150-159
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 1 ( 2010-01-01), p. 150-159
    Abstract: Gastrointestinal stromal tumors (GIST) are caused by activating mutations in the KIT or PDGFRA receptor tyrosine kinase genes. Although & gt;85% of GIST patients treated with the small-molecule inhibitor imatinib mesylate (Gleevec) achieve disease stabilization, complete remissions are rare and a substantial proportion of patients develop resistance to imatinib over time. Upregulation of soluble, non–chromatin-bound histone H2AX has an important role in imatinib-induced apoptosis of GIST cells. Additionally, H2AX levels in untreated GIST are maintained at low levels by a pathway that involves KIT, phosphoinositide 3-kinase, and the ubiquitin-proteasome system. In this study, we asked whether bortezomib-mediated inhibition of the ubiquitin-proteasome machinery could lead to upregulation of histone H2AX and GIST cell death. We show that bortezomib rapidly triggers apoptosis in GIST cells through a combination of mechanisms involving H2AX upregulation and loss of KIT protein expression. Downregulation of KIT transcription was an underlying mechanism for bortezomib-mediated inhibition of KIT expression. In contrast, the nuclear factor-κB signaling pathway did not seem to play a major role in bortezomib-induced GIST cell death. Significantly, we found that bortezomib would induce apoptosis in two imatinib-resistant GIST cell lines as well as a short-term culture established from a primary imatinib-resistant GIST. Collectively, our results provide a rationale to test the efficacy of bortezomib in GIST patients with imatinib-sensitive or -resistant tumors. Cancer Res; 70(1); 150–9
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-09-1449
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
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    Online Resource
    CD47 Blockade as an Adjuvant Immunotherapy for Resectable Pancreatic Cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Clinical Cancer Research Vol. 24, No. 6 ( 2018-03-15), p. 1415-1425
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 6 ( 2018-03-15), p. 1415-1425
    Abstract: Purpose: Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and adjuvant chemotherapy have an expected survival of only 2 years due to disease recurrence, frequently in the liver. We investigated the role of liver macrophages in progression of PDAC micrometastases to identify adjuvant treatment strategies that could prolong survival. Experimental Design: A murine splenic injection model of hepatic micrometastatic PDAC was used with five patient-derived PDAC tumors. The impact of liver macrophages on tumor growth was assessed by (i) depleting mouse macrophages in nude mice with liposomal clodronate injection, and (ii) injecting tumor cells into nude versus NOD-scid-gamma mice. Immunohistochemistry and flow cytometry were used to measure CD47 (“don't eat me signal”) expression on tumor cells and characterize macrophages in the tumor microenvironment. In vitro engulfment assays and mouse experiments were performed with CD47-blocking antibodies to assess macrophage engulfment of tumor cells, progression of micrometastases in the liver and mouse survival. Results: In vivo clodronate depletion experiments and NOD-scid-gamma mouse experiments demonstrated that liver macrophages suppress the progression of PDAC micrometastases. Five patient-derived PDAC cell lines expressed variable levels of CD47. In in vitro engulfment assays, CD47-blocking antibodies increased the efficiency of PDAC cell clearance by macrophages in a manner which correlated with CD47 receptor surface density. Treatment of mice with CD47-blocking antibodies resulted in increased time-to-progression of metastatic tumors and prolonged survival. Conclusions: These findings suggest that following surgical resection of PDAC, adjuvant immunotherapy with anti-CD47 antibody could lead to substantially improved outcomes for patients. Clin Cancer Res; 24(6); 1415–25. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-17-2283
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 1225457-5
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  • 5
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    Abstract C087: Phase 1 study of DCC-3014, an oral inhibitor of CSF1R, to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with advanced solid tumors, including diffuse-type tenosynovial giant cell tumor
    American Association for Cancer Research (AACR) ; 2019
    In:  Molecular Cancer Therapeutics Vol. 18, No. 12_Supplement ( 2019-12-01), p. C087-C087
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 18, No. 12_Supplement ( 2019-12-01), p. C087-C087
    Abstract: Background: DCC-3014 is an orally administered kinase inhibitor targeting the switch pocket of colony-stimulating factor 1 receptor (CSF1R). DCC-3014 exhibits approximately 100-fold selectivity from kinases homologous to CSF1R, such as KIT, and greater selectivity against 300 other human kinases. Tumor-associated macrophages (TAMs) are dependent on CSF1R kinase activity for proliferation and maintenance of the immunosuppressive phenotype. TAMs are known to enable tumor cells escape from immune surveillance. DCC-3014 is designed to exhibit an antitumor effect by inhibition of immunosuppressive TAMs or other CSF1R signaling-dependent pro-tumor activities. In addition, tenosynovial giant cell tumor (TGCT) is a rare, monoarticular disease known to be caused by the translocation in the CSF1 gene leading to overexpression of CSF1. Anti-CSF1R therapies have shown clinical activity in diffuse TGCT. Methods: This study is a multicenter, first-in-human study of DCC-3014 to determine a recommended Phase 2 dose (RP2D) or maximally tolerated dose (MTD) with a 3+3 dose escalation design and evaluate the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of DCC-3014 in advanced solid tumors, including diffuse-type TGCT [NCT03069469]. Results: As of June 2, 2019, the study is ongoing in the dose escalation phase and has enrolled 32 patients with advanced solid tumors in 7 cohorts. The first cohort was initiated at 10 mg daily. Based on preliminary PK analysis from the first cohort, subsequent cohorts utilized a loading dose followed by a maintenance dosing schedule to achieve steady-state exposures more rapidly. The median age of patients was 61 years old and 69% were female with the median of 4 lines of prior anti-cancer treatment. No dose limiting toxicities (DLTs) have been seen in the assessed cohorts. Most commonly seen treatment-emergent adverse events (TEAEs & gt;20%) were constipation (38%), vomiting (34%), diarrhea (31%), nausea (31%), decreased appetite (25%), abdominal pain (22%), and dyspnea (22%) whereas diarrhea, nausea and fatigue were reported as treatment-related AEs seen in & gt;10% of all patients (13%). TEAEs were mostly Grade 1 or 2. Serious AEs (SAEs) were seen in 16 patients, none of which were related to DCC-3014. Exposure was approximately dose proportional. PD effects were seen for dose levels at 10 mg and above, and induction of the CSF1R ligand, CSF-1, was seen up to 148-fold from baseline. The RP2D or MTD has not been selected or reached. Conclusion: DCC-3014 in this study was generally well tolerated in patients with advanced solid tumors and showed approximately dose-proportional exposure and PD changes as expected. Further evaluation is ongoing to determine the RP2D or MTD. Data from the TGCT cohort will be presented at a future meeting. Citation Format: Matthew H Taylor, Stephen Leong, Ying Su, Cynthia B Leary, Xiaoyan Li, Keisuke Kuida, Rodrigo Ruiz-Soto, Todd Bauer. Phase 1 study of DCC-3014, an oral inhibitor of CSF1R, to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with advanced solid tumors, including diffuse-type tenosynovial giant cell tumor [abstract] . In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C087. doi:10.1158/1535-7163.TARG-19-C087
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-19-C087
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 6
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    Online Resource
    Abstract C19: The role of resident liver macrophages in suppressing the progression of hepatic micrometastases from pancreatic ductal adenocarcinoma
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 15_Supplement ( 2016-08-01), p. C19-C19
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 15_Supplement ( 2016-08-01), p. C19-C19
    Abstract: Background: The majority of patients with localized pancreatic ductal adenocarcinoma (PDAC) die from metastatic disease, typically of the liver, despite a margin-negative (R0) resection. Therefore, these patients likely harbor occult metastatic disease in the liver at the time of surgery. In this study, we evaluated the role of resident liver macrophages in suppressing the progression of hepatic micrometastases using a murine model of micrometastatic PDAC with patient-derived xenografts (PDXs). Methods and Results: Low-passage, patient-derived KRAS-mutant tumor cells expressing firefly luciferase were injected into the spleens of athymic nude mice resulting in liver metastases, followed by splenectomy to remove the primary tumor. Hepatic tumor burden and metastatic growth kinetics were evaluated by bioluminescent imaging on post-injection days 1, 2, 3, 7, and weekly thereafter. Each of the PDX tumors exhibited a decline in tumor burden over the initial days after injection followed by a period of quiescence with a reproducible, PDX-specific time to proliferative outgrowth ranging from 15 days to greater than 200 days. To assess the role of apoptosis in initial tumor cell clearance and suppression of outgrowth, mouse liver preparations were analyzed for expression of cleaved caspase-3 and cleaved PARP in tumor cells using flow cytometry. There was low expression of both apoptosis markers, suggesting that apoptosis is not a major cell-clearance mechanism. Athymic nude mice lack cell-mediated immunity but have functioning innate immunity. Because there is a large population of resident macrophages in the liver, we hypothesized that macrophages play an important role in the clearance and suppression of hepatic PDAC metastases. To test this, hepatic metastasis outgrowth was assessed following macrophage ablation with liposomal clodronate treatment of mice 48 hours prior to tumor cell injection. Following macrophage ablation, there was a trend toward less robust initial tumor cell clearance and a significantly decreased time to proliferative outgrowth compared with control (13 days vs 26 days, p=0.039). H & E sections demonstrated an abundance of hepatic macrophages surrounding tumor cells in the control group while this response was absent in the clodronate group. Splenic tumor cell injections were repeated using athymic nude mice vs NOD scid gamma (NSG) mice which lack both cell-mediated immunity as well as functional macrophages, dendritic cells, and NK cells. Initial tumor cell clearance was significantly reduced in the NSG mice vs nude mice (PDX 608: 35.6% vs 90.1% clearance at seven days, p & lt;0.001; PDX 366: 40.4% vs 76.3% clearance at seven days, p=0.024). Average relative hepatic bioluminescence at 21 days was significantly increased for PDX 608 in the NSG mice (14.7 vs 0.355, p=0.014) and there was a trend toward increase for PDX 366 (3.07 vs 0.025, p=0.065). Conclusions: In a preclinical model of hepatic micrometastatic PDAC, resident liver macrophages are implicated in the initial clearance and the suppression of proliferation of tumor cells. Further investigation of the interaction of resident hepatic macrophages and micrometastatic PDAC cells may lead to novel strategies for therapy. Citation Format: Alex D. Michaels, Timothy E. Newhook, James M. Lindberg, Sara J. Adair, Sarbajeet Nagdas, Matthew G. Mullen, Edward B. Stelow, J. Thomas Parsons, Todd W. Bauer. The role of resident liver macrophages in suppressing the progression of hepatic micrometastases from pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C19.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.TME16-C19
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    Online Resource
    Abstract A47: A patient-derived xenograft model of pancreatic cancer in mice to develop novel adjuvant therapies
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 7_Supplement ( 2016-04-01), p. A47-A47
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 7_Supplement ( 2016-04-01), p. A47-A47
    Abstract: Background: Eighty percent of patients with pancreatic ductal adenocarcinoma (PDAC) die from their disease within five years of surgical resection, likely due to presence of occult metastases at diagnosis. We have developed a patient-derived xenograft (PDX) model in mice to investigate the behavior of occult metastatic cells in the liver microenvironment and derive novel adjuvant therapies. Methods: Five PDAC tumors (215, 366, 608, 654 and 738) were resected from patients and implanted orthotopically in mice. Tumors were harvested, cell lines generated and transduced with luciferase, then injected into spleens of mice to generate microscopic liver metastases, then primary tumors removed via splenectomy. Bioluminescence imaging of mice and histologic analysis and flow cytometry of livers were utilized to characterize each tumor's distinct pattern of cell clearance and outgrowth kinetics. Affymetrix gene expression of tumors was performed. Mice were treated with adjuvant therapy following resection of primary tumors in the spleen and time-to-progression (TTP) and overall survival (OS) were measured. Results: Each PDX cell line demonstrated unique and reproducible clearance in the liver and outgrowth kinetics as measured by bioluminescence imaging. Distinct differences in gene expression were identified in tumors exhibiting rapid vs. delayed outgrowth. The MEK inhibitor trametinib (0.3 mg/kg oral daily) prolonged TTP and OS vs. control (OS - Tumor 608: 114 vs. 43 days, p & lt;0.001; Tumor 366: MS not achieved vs. 167 days, p=0.0488). In a randomized preclinical trial, sequential therapy with gemcitabine followed by trametinib provided a survival advantage and increased TTP when compared with control and single agent gemcitabine treatment. Conclusions: This PDX PDAC model of occult metastasis allows characterization of hepatic clearance of tumor cells and outgrowth kinetics. Metastatic outgrowth appears to be dependent upon distinguishable tumor cell-specific factors. Trametinib effectively inhibits KRAS-MEK-ERK signaling, delays outgrowth of occult metastases and prolongs survival of mice. Utilization of this model will help further define the complex interaction of PDAC cells and the metastatic microenvironment of the liver. Citation Format: Matthew G. Mullen, Timothy E. Newhook, James M. Lindberg, Sara J. Adair, Edik M. Blais, Alex D. Michaels, Edward B. Stelow, Jason A. Papin, J. Thomas Parsons, Todd W. Bauer. A patient-derived xenograft model of pancreatic cancer in mice to develop novel adjuvant therapies. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A47.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.TUMMET15-A47
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
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    Online Resource
    Abstract C054: Hypoxia promotes a durable epithelial-mesenchymal transition in pancreas cancer through a histone methylation-MAPK signaling axis
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 22_Supplement ( 2022-11-15), p. C054-C054
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 22_Supplement ( 2022-11-15), p. C054-C054
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) tumors are poorly vascularized and exhibit regions of hypoxia. Here, we demonstrate that this feature of the tumor microenvironment promotes epithelial-mesenchymal transition (EMT), which occurs early in PDAC and drives chemoresistance, and we identify the underlying signaling mechanism. Analysis of publicly-available human transcriptomics and proteomics demonstrated that PDAC cells or tumors enriched in mesenchymal markers were also enriched in markers of hypoxia or HIF activity. Furthermore, in lineage-traced autochthonous, orthotopic patient-derived xenograft, and orthotopic or subcutaneous implanted cell line models of PDAC, hypoxic tumor tissue regions were enriched for neoplastic cells that had undergone EMT. In cell culture experiments, PDAC cells from human and mouse tumors exhibited an ability to undergo EMT in response to 1% O2, with loss of membranous E-cadherin, increased vimentin protein expression, and transcriptional changes indicative of both hypoxia and EMT. Moreover, EMT in response to hypoxia was substantially more persistent than that observed in response to growth factors, and a hypoxia fate mapping system revealed that once-hypoxic cells could retain mesenchymal characteristics outside hypoxic tumor regions. To understand the mechanism for EMT in response to low oxygen tension, we constructed a multivariable linear regression model of the dependence of the hypoxic gene signature on different gene sets in PDAC ductal cells, which identified MAPK signaling as the most important feature. Consistent with the model inference, in both in vitro and in vivo settings, hypoxic cells showing evidence of EMT displayed elevated MAPK signaling. We further demonstrated that MAPK activation in hypoxia was potentiated by suppressed activity of a histone demethylase and concomitant loss of protein phosphatase expression, which reinforced the mechanism by stabilizing the expression of a histone methyltransferase. Thus, this study identifies a tumor microenvironment-initiated mechanism leading to EMT and nominates several potential drug targets whose antagonism may promote PDAC chemoresponse. Citation Format: Brooke A. Brown, Paul J. Myers, Sara J. Adair, Jason R. Pitarresi, Shiv Sah Teli, Peppi Karppinen, Ben Z. Stanger, Todd W. Bauer, Matthew J. Lazzara. Hypoxia promotes a durable epithelial-mesenchymal transition in pancreas cancer through a histone methylation-MAPK signaling axis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C054.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PANCA22-C054
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
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    Abstract CT220: A randomized multicenter phase Ib/II study to assess the safety and the immunological effect of chemoradiation therapy (CRT) in combination with Pembrolizumab (anti-PD1) to CRT alone in patients with resectable or borderline resectable pancreatic canc
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. CT220-CT220
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. CT220-CT220
    Abstract: Background: Immunotherapy has recently emerged as a promising modality in cancer treatment, but little is known about the application of this modality in pancreatic cancer (PC). Tumor-infiltrating lymphocytes (TILs) play a major role in anti-tumor immune responses, and their presence is correlated with survival in a variety of tumors. These TILs do not reach the PC cells in significant numbers due to the presence of stroma and a suppressive microenvironment. One of the leading causes for immune suppression is elevated expression of PD-L1 either by the tumor cells or the surrounding regulatory cells, resulting in dysfunction of TILs. Neoadjuvant chemoradiation therapy (CRT) has been advocated as a potential way to improve outcomes of patients with resectable or borderline resectable PC. More importantly, there is recent evidence to suggest that CRT can increase the presence of TILs in the PC microenvironment (PCME), leading to production of interferon-γ (IFN-γ), which could increase the expression of PD-L1 through a negative feedback loop. Accordingly, we hypothesize that blocking the PD-1 receptor will synergize with CRT to increase the density and activation of TILs in the PCME. Methods: This is a prospective multicenter randomized trial which will accrue subjects with resectable or borderline resectable pancreatic cancer who had not received prior treatment for PC. The primary objectives of the study are: (1) to determine the safety of neoadjuvant CRT in combination with Pembrolizumab. (2) To estimate the difference in the number of TILs in pancreatic cancer subjects receiving neoadjuvant CRT in combination with Pembrolizumab to the number of TILs in subjects receiving neoadjuvant CRT alone. This study will also investigate the effect of CRT+/-anti-PD-1 on the other effector and suppressive immune cells and immune checkpoints in PCME. Eligible subjects will be randomized 2:1 to the investigational treatment (Arm A) to receive Pembrolizumab administered IV every 3 weeks on days 1, 22, and 43 during concurrent CRT with capecitabine (825 mg/m2 orally twice daily, Monday through Friday, on days of radiation only) and radiation (50.4 Gy in 28 fractions over 28 days) or Arm B to receive only concurrent CRT with capecitabine. In all subjects, restaging CT scan or MRI will be performed at 4-6 weeks after completion of neoadjuvant treatment to determine resectability. Patients without local or distant disease progression will be taken to the operative room for planned surgery (within 2 weeks of imaging). Postoperatively, resected patients will receive off study standard of care adjuvant gemcitabine (1000mg/kg IV weekly for 3 out of 4 weeks for 6 months). Post operatively resected patients will be followed for up for PFS and OS for up to 2 years. Citation Format: Matthew H.G Katz, Todd W. Bauer, Gauri Rajani Varadhachary, Reid B. Adams, Amy R. Lankford, Gina Petroni, Timothy N. Bullock, Craig L. Slingluff, Osama E. Rahma. A randomized multicenter phase Ib/II study to assess the safety and the immunological effect of chemoradiation therapy (CRT) in combination with Pembrolizumab (anti-PD1) to CRT alone in patients with resectable or borderline resectable pancreatic canc [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT220. doi:10.1158/1538-7445.AM2015-CT220
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-CT220
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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    BTU Cottbus
    Wissenschaftspark Albert Einstein
    EUV Frankfurt
    TH Wildau
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  • 10
    Online Resource
    Online Resource
    Phase 0 Clinical Chemoprevention Trial of the Akt Inhibitor SR13668
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Prevention Research Vol. 4, No. 3 ( 2011-03-01), p. 347-353
    Details
    In: Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 4, No. 3 ( 2011-03-01), p. 347-353
    Abstract: SR13668, an orally active Akt pathway inhibitor, has demonstrated cancer chemopreventive potential in preclinical studies. To accelerate the clinical development of this promising agent, we designed and conducted the first-ever phase 0 chemoprevention trial to evaluate and compare the effects of food and formulation on SR13668 bioavailability. Healthy adult volunteers were randomly assigned to receive a single, 38-mg oral dose of SR13668 in one of five different formulations, with or without food. On the basis of existing animal data, SR13668 in a PEG400/Labrasol oral solution was defined as the reference formulation. Blood samples were obtained pre- and post-agent administration for pharmacokinetic analyses. Area under the plasma concentration–time curve (AUC0–∞) was defined as the primary endpoint. Data were analyzed and compared using established statistical methods for phase 0 trials with a limited sample size. Participants (n = 20) were rapidly accrued over a 5-month period. Complete pharmacokinetic data were available for 18 randomized participants. AUC0–∞ values were highest in the fed state (range = 122–439 ng/mL × hours) and were statistically significantly different across formulations (P = 0.007), with Solutol HS15 providing the highest bioavailability. SR13668 time to peak plasma concentration (3 hours; range, 2–6 hours) and half-life were (11.2 ± 3.1 hours) were not formulation-dependent. Using a novel, highly efficient study design, we rapidly identified a lead formulation of SR13668 for further clinical testing. Our findings support application of the phase 0 trial paradigm to accelerate chemoprevention agent development. Cancer Prev Res; 4(3); 347–53. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1940-6207 , 1940-6215
    URL: Article
    DOI: 10.1158/1940-6207.CAPR-10-0313
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2422346-3
    Library Location Call Number Volume/Issue/Year Availability
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    Availability (electronic / print)
    BTU Cottbus
    Wissenschaftspark Albert Einstein
    EUV Frankfurt
    TH Wildau
    FH Potsdam
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