tbuckley/cabot-search huggingface dataset:
Abstract 1426: Blinding the CYCLOPS - Cancer vulnerabilities unveiled by genomic loss
Authors: Alica Torkov, Kai-Oliver Henrich, Chunxuan Shao, Moritz Gartlgruber, Frank Westermann
Journal: Cancer Research (2017)

Abstract Background: Heterozygous deletions within distal 1p are observed in 30% of neuroblastomas. So far, several potential 1p tumor suppressor genes have been identified. However, in this study we are focussing on 1p genes whose inactivation is not necessarily linked to tumor development but which mediate cell-essential functions, rendering cells with copy number loss vulnerable to further impairment. These genes are candidate therapeutic targets according to the concept of CYCLOPS (copy number alterations yielding cancer liabilities owing to partial loss). Methods: To identify a subset of 1p genes for which heterozygous loss may be tolerated but further reduction leads to cell death, we performed siRNA screens mediating the systematic knock-down of distal 1p genes in five 1p-deleted versus five non-1p-deleted neuroblastoma cell lines. We used 3 different siRNAs per gene in a liquid forward approach. After 96h Hoechst stained nuclei were count. Among others, a neuron-related candidate gene has been identified as a potential CYCLOPS. The candidate gene was validated by viability assays, immunocytochemistry and cell cycle analysis via FACS. Results: We identified many potential CYCLOPS genes mapping on the distal end of chromosome arm 1p. One of these genes is involved in neuronal and embryonic development and has been further validated. Knock-down of the gene impaired cell viability in 1p-deleted cell lines but did not in 1p-non-deleted cells. G1/G0 phase arrest with corresponding S phase decrease was observed in both 1p-deleted and 1p-non-deleted cells. Additionally, neurite-like outgrowth could be observed in 1p-non-deleted cells indicating an induction of differentiation. Conclusion: This study identified a candidate CYCLOPS gene in neuroblastoma. Heterozygous deletions of chromosome arm 1p are also frequently observed in other cancers including melanoma, colorectal and breast cancer. We hypothesize that this proof-of-principle opens a new therapeutic window for tumors harbouring a heterozygous deletion of our candidate gene or other cell essential genes on chromosome arm 1p. Citation Format: Alica Torkov, Kai-Oliver Henrich, Chunxuan Shao, Moritz Gartlgruber, Frank Westermann. Blinding the CYCLOPS - Cancer vulnerabilities unveiled by genomic loss [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1426. doi:10.1158/1538-7445.AM2017-1426
Abstract 5744: The role of atypical protein kinase C in colorectal cancer cell growth and proliferation
Authors: S M Anisul Islam, Mildred Acevedo Duncan
Journal: Cancer Research (2017)

Abstract Colorectal cancer (CRC) is the second most common cancer in the world and death from colorectal cancer accounts for 8% of all cancer deaths both in men and women in the United States. CRC is life threatening disease due to therapy resistant cancerous cells. The exact mechanisms of cell growth, survival, metastasis and inter &amp; intracellular signaling pathways involved in colon cancer are still a major challenge for scientists. Hence, investigating the signaling pathways that lead to colon carcinogenesis may give insight into the therapeutic target. In this study, the role of atypical Protein kinase C (aPKC) on colon cancer was identified by using four inhibitors of that particular protein class: 1) ACPD (2-acetyl-1,3-cyclopentanedione and 2) DNDA (3,4-diamino-2,7 naphthalenedisulfonic acid) are non-specific inhibitors of aPKCs; 3) ζ-Stat (8-hydroxy-1, 3, 6-naphthalenetrisulfonic acid) is a specific inhibitor of PKC-ζ; and 4) ICA-I (4, 5-amino-4-carbamoylimidazol-1-yl-2, 3-dihydroxycyclopentyl) methyl dihydrogen phosphate) is a specific inhibitor of PKC-ι. The cell lines tested were HT-29 colon cancer and CCD18CO normal colon epithelial. Although PKC-ι is an oncogene in many cancers, we found that the PKC-ζ was responsible for the abnormal growth and proliferation in HT-29 colon cancer cells. Additionally, the inhibition of aPKCs did not bring any significant toxicity on CCD18CO normal colon cell line. These results suggest the potentiality of utilizing aPKC-ζ inhibitors to block colon cancer cell growth and proliferation. Citation Format: S M Anisul Islam, Mildred Acevedo Duncan. The role of atypical protein kinase C in colorectal cancer cell growth and proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5744. doi:10.1158/1538-7445.AM2017-5744
Abstract 1745: Multifocal prostate cancer has high degree of genomic heterogeneity
Authors: Marthe Løvf, Sen Zhao, Ulrika Axcrona, Bjarne Johannesen, Andreas M. Hoff, Anne Cathrine Bakken, Kristina Totland Carm, Ola Myklebost, Leonardo A. Meza-Zepeda, Agnes K. Lie, Karol Axcrona, Ragnhild A. Lothe, Rolf I. Skotheim
Journal: Cancer Research (2017)

Abstract Prostate cancer is the most common cancer type among men in the Western world. Most prostate cancers are multifocal with individual tumors harboring different aggressiveness. In recent genomics studies, the multifocal nature of prostate cancer has been investigated only in small sample cohorts. Here we have investigated the intra-organ mutational spectra of multiple tumors from a large cohort of prostate cancer patients. From radical prostatectomies performed between 2010 and 2012 at Oslo University Hospital, 43 prostatectomy specimens with multiple and clearly separated tumors were identified based on histology. From each of these prostatectomy specimens, DNA from frozen samples from 2-3 different tumor foci and corresponding normal tissue samples were analyzed by high-coverage whole-exome sequencing, adding up to a total of 159 samples. We identified 3093 somatic substitutions, insertions and deletions, with an average of 27 alterations per tumor sample. Both known and novel significantly mutated genes were identified and their distribution among different tumor foci from the same prostate was examined. Mutations in genes such as SPOP, MED12, and FOXA1 have previously been identified in prostate cancer and were also found to be frequently mutated in this cohort. However, the same mutations were rarely found in multiple tumor foci within the same prostate. In fact, for 13 out of the 43 examined patients there were no common mutations among tumors from the same prostate. For 12 patients, we found only one overlapping mutation among tumor foci. Whereas the overall list of mutated genes (n = 2101) overlap significantly with the 594 genes of the Cancer Gene Census (100/594; p=9.6e-06), this was not the case for 142 genes with overlapping mutations among different tumor foci (2/594; p=0.63). This indicates that the overlapping mutations are not typical cancer driving genes. To conclude, results from exome sequencing of multifocal prostate cancer show a large degree of heterogeneity in genomic alterations between different tumor foci within the same prostate. With very few common inter-foci mutations, an implementation of genome-based personalized prostate cancer medicine will require sampling of all tumor foci to tailor optimal treatment. Citation Format: Marthe Løvf, Sen Zhao, Ulrika Axcrona, Bjarne Johannesen, Andreas M. Hoff, Anne Cathrine Bakken, Kristina Totland Carm, Ola Myklebost, Leonardo A. Meza-Zepeda, Agnes K. Lie, Karol Axcrona, Ragnhild A. Lothe, Rolf I. Skotheim. Multifocal prostate cancer has high degree of genomic heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1745. doi:10.1158/1538-7445.AM2017-1745
Abstract 1602: Generation of anti-IL-17B antibodies neutralizing IL-17B-mediated alterations of the immune microenvironment, promotion of tumor cell initiating capacity and chemoresistance
Authors: Emilie Laprevotte, Aurélie Docquier, Jeremy Bastid, Cécile Déjou, Marion Lapierre, Gilles Alberici, Armand Bensussan, Jean-François Eliaou, Nathalie Bonnefoy
Journal: Cancer Research (2017)

Abstract Interleukin 17B (IL-17B) is a pro-inflammatory cytokine that belongs to a family encompassing 6 interleukins (IL-17A to F) and binds to the IL-17 receptor B (IL-17RB). Recently, amplified IL-17B/IL-17RB signaling was found critical for breast and pancreatic tumorigenesis and elevated expression of IL-17RB has been associated with the shortest survival rates in patients with breast or pancreatic cancer. Using IL-17B knock-out (IL-17B KO) mice we demonstrate here that melanoma, fibrosarcoma and breast cancer cell tumorigenicity is strongly impaired in immunocompetent IL-17B KO mice compared to WT littermates, including a large number of tumor free mice. Reduced tumor incidence in IL-17B KO mice is associated with alterations of the immune tumor microenvironment especially within innate lymphocyte and myeloid sub-populations. We further demonstrate that IL-17B is a key cytokine shaping the tumor initiating cancer cell niche. Indeed, MDA-MB-468 human breast cancer cells overexpressing IL-17B exhibit 10 times higher frequency of tumor initiating cells when xenografted at a serial limiting dilution in nude mice. Tumor progression is, again, associated with alterations of NK cells within the tumor microenvironment and with increased percentages of CD44hi/CD24lo tumor cells, a phenotype associated with breast cancer stem cells (CSC). This is associated with resistance to conventional chemotherapeutic agents such as taxol, an effect that is totally abrogated by disrupting IL-17B-IL-17RB signaling with a neutralizing antibody. Altogether our results point out the key role of IL-17B in regulating the immune microenvironment as well as cardinal features of CSC, one of the alleged causes of resistance to therapy and tumor relapse. Thereby, IL-17B and its receptor appear as potential therapeutic targets for cancer immunotherapy. Collectively, these data support the ongoing development of IL-17B neutralizing antibodies. Citation Format: Emilie Laprevotte, Aurélie Docquier, Jeremy Bastid, Cécile Déjou, Marion Lapierre, Gilles Alberici, Armand Bensussan, Jean-François Eliaou, Nathalie Bonnefoy. Generation of anti-IL-17B antibodies neutralizing IL-17B-mediated alterations of the immune microenvironment, promotion of tumor cell initiating capacity and chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1602. doi:10.1158/1538-7445.AM2017-1602
Abstract 4986: Pancreatic cancers develop metabolic resistance pathways to glutaminase inhibition
Authors: Joseph D. Mancias, Douglas E. Biancur, Joao A. Paulo, Maria Quiles Del Rey, Cristovão M. Sousa, Xiaoxu Wang, Gerald C. Chu, Steven P. Gygi, J. Wade Harper, Alec C. Kimmelman
Journal: Cancer Research (2017)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease with poor prognosis. Therefore, novel treatment options are essential to combat this highly refractory disease. Oncogenic Kras can promote a metabolic rewiring of pancreatic cancers, including the non-canonical use of glutamine to support growth and proliferation through redox homeostasis. Indeed, inhibition of downstream components of glutamine metabolism leads to a decrease in tumor growth. The first step in glutamine metabolism is mediated by the enzyme glutaminase (GLS) which catalyzes the conversion of glutamine to glutamate in the mitochondria where, in PDAC, glutamine-derived glutamate is metabolized ultimately resulting in increased reducing potential in the form of increased NADPH and GSH. An outstanding question in pancreatic cancer is whether GLS inhibition is a viable therapeutic strategy given it is the most proximal enzyme in the PDAC-specific glutamine metabolism pathway, and how this may differ from targeting distal parts of the pathway. Using a combination of in vitro and in vivo models of pancreatic cancer, we tested whether recently developed highly potent inhibitors of GLS are an effective therapy for PDAC. We demonstrate that despite dramatic early effects on in vitro proliferation caused by GLS inhibition, pancreatic cancer cells have adaptive metabolic networks that allow them to sustain proliferation in vitro and in vivo. Through an integrated proteomic and metabolomic analysis, we identify multiple compensatory pathways that may explain the resistance to GLS inhibition and show as proof of concept that combining inhibitors to these pathways with GLS inhibitors may have therapeutic utility. Citation Format: Joseph D. Mancias, Douglas E. Biancur, Joao A. Paulo, Maria Quiles Del Rey, Cristovão M. Sousa, Xiaoxu Wang, Gerald C. Chu, Steven P. Gygi, J. Wade Harper, Alec C. Kimmelman. Pancreatic cancers develop metabolic resistance pathways to glutaminase inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4986. doi:10.1158/1538-7445.AM2017-4986
Abstract 3904: Inhibition of the ERK5 pathway as a novel approach to target human chronic myeloid leukemia stem cells
Authors: Ignazia Tusa, Giulia Cheloni, Nathanael Gray, Antonella Gozzini, Persio Dello Sbarba, Elisabetta Rovida
Journal: Cancer Research (2017)

Abstract Tyrosine kinase inhibitors (TKi) targeting BCR/ABL are very effective for the treatment of Chronic Myeloid Leukaemia (CML). However, resistance mechanisms or their inefficacy on CML leukaemia stem cells (LSC) may lead to relapse. Therefore, there is urgent need to identify new molecular targets. The Extracellular signal-Regulated Kinase 5 (ERK5) is a Mitogen-Activated Protein Kinase involved in cancer. Our aim was to study a possible role of the ERK5 pathway in CML LSC. Cells used were: human CML cell lines K562 and KCL22 that express constitutively active ERK5; CML patient-derived cells and CD34+ cells from heathy donors (after informed consent had been obtained). Cells were incubated in normoxic (routine) or hypoxic (0.2% O2) primary cultures (LC1) in the presence or the absence of drugs. Day-7 LC1 cells were transferred to drug-free, non-selective normoxic secondary cultures (LC2), to measure LC2 repopulation as a read-out of progenitor/stem cell potential (CRA assay). Compounds: XMD8-92 (ERK5 inhibitor) and BIX02189 (MEK5 inhibitor); imatinib (BCR/ABL inhibitor, IM). We previously showed that stem cell potential of CML LSC is maintained in severe hypoxia. In K562 and KCL22 cells and in primary cells derived from 9 CML patients, the treatment in hypoxic LC1 with XMD8-92 or BIX02189, but not with IM, impaired progenitor/stem cell potential. The same results were obtained by combined treatment of XMD892 with IM. Importantly, XMD8-92 did not affect progenitor/stem cell potential of CD34+ cells from heathy donors. In colony formation ability assays ERK5 inhibition decreased colony formation by human primary CML cells to a higher extent than that by normal human CD34+ hematopoietic cells. Interestingly, in hypoxia, combined treatment XMD8-92/IM decreased the expression of genes relevant for stem cell maintenance such as p21, nanog and c-myc and the expression of CD26, a CML LSC marker. Moreover, combined XMD8- 92/IM maintained low the expression of p27, another gene involved in stem cell maintenance, that is increased by either drug when administered alone. This indicate that the ERK5 pathway inhibitors impaired LSC maintenance of CML cell lines and primary CML cells. Citation Format: Ignazia Tusa, Giulia Cheloni, Nathanael Gray, Antonella Gozzini, Persio Dello Sbarba, Elisabetta Rovida. Inhibition of the ERK5 pathway as a novel approach to target human chronic myeloid leukemia stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3904. doi:10.1158/1538-7445.AM2017-3904
Abstract 2827: Establishing a mouse model to investigate GRB7-mediated signaling in development and triple-negative breast cancer
Authors: Kristopher A. Lofgren, David R. Meier, Steven E. Cash, Paraic A. Kenny
Journal: Cancer Research (2017)

Abstract Triple-negative breast cancer (TNBC) lacks expression of the estrogen and progesterone steroid receptors and HER2; thus TNBC patients cannot benefit from the recent successes of targeted therapies, and instead rely on cytotoxic chemotherapeutic combinations. As such, tumor recurrence is high and patient prognosis is poor. GRB7 is a cytoplasmic adaptor protein required for cell migration, invasion, and proliferation in TNBC. We have previously reported that a high GRB7 mRNA level was the strongest predictor of tumor recurrence in a cohort of 246 TNBC patients treated with doxorubicin. GRB7 was confirmed in a smaller, independent cohort as an indicator of poor prognosis. After the observation of both decreased doxorubicin sensitivity and elevated GRB7 expression levels in TNBC tumors, we hypothesized that GRB7 was mediating a signaling pathway critical for drug resistance and cell survival. To determine the role of GRB7 in mouse development and tumorigenesis, the current study focuses on the Grb7tm1a(EUCOMM)Wtsi knockout-first transgenic mouse, in which the insertion of the 1L2_Bact_P cassette upstream of the critical exons of GRB7 renders an effective knockout of GRB7, and the inclusion of loxP sites flanking critical exons of GRB7 facilitates the creation of tissue-specific, conditional GRB7 deletions. Herein, we investigate GRB7 expression in the homozygous Grb7tm1a mouse and derivative tissue-specific deletions, and evaluate their suitability for modeling GRB7-mediated events in mammary gland development and tumorigenesis in a TNBC model. Primary cell lines from the Grb7tm1a mouse and breast cancer cell lines will then be used to delineate the effects of altered GRB7 levels on the mechanism of developmental and TNBC cell signaling, respectively. Citation Format: Kristopher A. Lofgren, David R. Meier, Steven E. Cash, Paraic A. Kenny. Establishing a mouse model to investigate GRB7-mediated signaling in development and triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2827. doi:10.1158/1538-7445.AM2017-2827
Abstract 319: Cholesterol inhibition reduces Hh mediated chondrosarcoma
Authors: Qingxia Wei, Eyal Ramu, Mushriq AL-Jazrawe, Raymond Poon, Jay Wunder, Benjamin Alman
Journal: Cancer Research (2017)

Abstract Constitutive activation of Hh signaling is a common occurrence in chondrosarcoma(CSA). Gene profiling analysis showed that Gli transcription regulates genes that govern cholesterol homeostasis, which alters cholesterol accumulation in chondrocytes; a higher level of Gli-mediated transcription results in accumulation of intracellular cholesterol. Here we determined if targeting cholesterol-processing genes downstream of Hh signalling could be used as a novel treatment approach. With institutional review board approval, human CSA samples were obtained fresh from surgery. For in vitro studies, CSA explants of 2mmx2mm x2 mm cubic in size establihed as organ cultures. For in vivo studies, one million CSA cells were subcutanously injected into NSG mice. Cells from five CSAs were treated both in vitro and in vivo with a hedgehog inhibitor, Cur61414, a cholesterol inhibitor, Lovastatin, or both. In vitro, CSA explants were treated for 48 hrs at concentration of 20 μM of each drug. In vivo, mice were treated with 4.5mg/kg/day of Cur61414, Lovastatin, or both by intraperitoneal injection for 4 wks. At the end of treatment, the explants or xenografts were harvested and processed for further analysis. RT-PCR was used to meausre the expression of Hh and cholesterol target genes. Tumor size was meausred from the xenografts. Blockade of Hh signaling significantly decreased Gli1 gene expression by 30%, increased 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) expression for more than 300% indicating decreased intracellular cholesterol. Treatment with the cholesterol inhibitor Lovastatin increased expression of HMGCR for more than 500%. The combination of Hh and cholesterol blockage resulted in increased expression of HMGCR for more than 3400%. Analysis of chondrosarcoma xenografts in vivo showed a significnat decrease in tumor size with Lovastatin (32% decline), 3 folds reducation of Brdu(+) cells, and 2.4 fold increase of Caspase-3 + cells, treatment with Cur 61414 reduced the tumor growth by 5% with no significant reduction of Brdu(+) cells but 2.6 fold increase of Caspase-3 (+) cells . The combination treatment of lovastatin and Cur61414 on xenografts resulted in a significnat decrease in tumor size (32% decline), 3 fold reduction of Brdu (+) cells, but no significant changes of Caspase-3 (+) cells . These data suggest that cholesterol functions downstream of Hh signaling pathway in CSA. The more effective reduction in tumor growth with cholesterol inhibition compared to Hh blockade suggests cholesterol blockade is an effective therapeutic approach. Citation Format: Qingxia Wei, Eyal Ramu, Mushriq AL-Jazrawe, Raymond Poon, Jay Wunder, Benjamin Alman. Cholesterol inhibition reduces Hh mediated chondrosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 319. doi:10.1158/1538-7445.AM2017-319
Attenuated FOLFIRINOX (5-FU/LV, irinotecan and oxaliplatin) as second-line chemotherapy for the Koreans (Asian population) with gemcitabine-resistant or –refractory advanced pancreatic cancer.
Authors: Sang-Cheol Lee, Jung Hoon Kim, Sung Yong Oh, Kyoungha Kim, Seo-Young Song, Namsu Lee, Eun Mi Nam, Soonil Lee, In Gyu Hwang, Hyo Rak Lee, Jong-Ho Won, Kyu Taek Lee, Sang-Byung Bae, Hanjo Kim, Hyun Jung Kim, JoungSoon Jang, Do Hyoung Lim, Hyun Woo Lee, Jung Hun Kang
Journal: Journal of Clinical Oncology (2016)

e15731 Background: The PRODIGE trials showed superiority of FOLFIRINOX over gemcitabine. However, some of the grade 3/4 toxicity rates that were significantly greater in the FOLFIRINOX group than in the Gemcitabine group were 45.7% for neutropenia, 12.7% for diarrhea. 9.1% for thrombocytopenia, and 9.0% for sensory neuropathy. And so FOLFIRINOX may be more toxic in the salvage setting of advanced pancreatic cancer. We determine the efficacy and safety of attenuated FOLFIRNOX as 2nd-line chemotherapy for gemcitabine-resistant or –refractory advanced pancreatic cancer. Methods: Modified FOLFIRINOX consisted of oxaliplatin 65 mg/m2 i.v. on day 1, irinotecan 135 mg/m2 i.v. on day 1, leucovorin 400 mg/m2 i.v. on day 1 and 5-fluorouracil 2000 mg/m2i.v. continuous infusion over 46 hours on day 1-2. Each cycle is repeated every 2 weeks. Chemotherapy was administered until disease progression or unacceptable toxicity. Results: Thirty-nine patients were enrolled in the study from Oct. 2013 to Mar 2015. Median Age was 58.5 (range 42-75). Male and female were respectively 29 and 10. ECOG performance status was usually 0 to 1 except for 2 participants. Grade 3/4 toxicities included neutropenia(41%), thrombocytopenia(2.6%), nausea(10.3%), diarrhea(2.6%), pneumonia(2.6%). The median progression free survival was 3.93 months. The median overall survival was 8.5 months. One treatment related death occurred during this trials. Conclusions: This results suggest that the FOLFIRINOX would be an effective regimen as second-line chemotherapy for advanced pancreatic cancer. The potential of toxicity may need to be further studied.