tbuckley/cabot-search huggingface dataset:
Abstract 1551: <i>GULP1</i> is an epigenetically altered and functional tumor suppressor in urothelial carcinoma through regulation of Nrf2-Keap1 signaling axis
Authors: Masamichi Hayashi, Elisa Guida, Rachel Goldberg, Yoshikuni Inokawa, Leonardo Reis, Akira Oki, Evgeny Izumchenko, Leonel Maldonado, Luigi Marchionni, Mariana Brait, Trinity Bivalacqua, Alexander Baras, George J. Netto, Wayne Koch, David Sidransky, Mohammad O. Hoque
Journal: Cancer Research (2017)

Abstract We identified GULP1 as a novel tumor suppressor gene (TSG) selectively silenced during urothelial cancer (UC) progression through promoter hypermethylation (PH) analyzed by quantitative methylation specific PCR (QMSP) and novel methylation specific digital droplet PCR (ddPCR) assay. Numerous cell based assays revealed that GULP1 silencing confers growth advantage to tumor cells. Correspondently, in vivo tumorigenicity after xenotransplantation of GULP1 knockdown T24 cells was significantly higher than control cells. Further mechanistic analysis revealed that GULP1 has a crucial role in the regulation of Nrf2-Keap1 axis, maintaining actin cytoskeleton architecture and helping Keap1 to scaffold Nrf2 in the cytoplasm. Moreover, GULP1 silencing induces constitutive activation of Nrf2 target signature, responsible for chemoresistance of UCs. Additionally, we analyzed GULP1 PH and expression in cisplatin-based therapy responsive and resistant primary UC samples, and in isogenic cisplatin sensitive and resistant T24 cell lines. Interestingly, GULP1 expression at transcription level was lower in both resistant primary UC samples and resistant T24 cell line. Cell lines with lower expressions of GULP1 (SW780 and UM-UC-3) also showed higher resistance to cisplatin than those with higher expression (T24 and BFTC905). Altogether, our findings determined that GULP1 is an epigenetically silenced potential TSG in UC and GULP1 expression and/or PH may guide in selecting candidate patients for cisplatin based neo-adjuvant therapy. Citation Format: Masamichi Hayashi, Elisa Guida, Rachel Goldberg, Yoshikuni Inokawa, Leonardo Reis, Akira Oki, Evgeny Izumchenko, Leonel Maldonado, Luigi Marchionni, Mariana Brait, Trinity Bivalacqua, Alexander Baras, George J. Netto, Wayne Koch, David Sidransky, Mohammad O. Hoque. GULP1 is an epigenetically altered and functional tumor suppressor in urothelial carcinoma through regulation of Nrf2-Keap1 signaling axis [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 1551. doi:10.1158/1538-7445.AM2017-1551
The effect of a topical COX-2 inhibitor on the expression of C-Met in a rabbit model of uveal melanoma
Authors: Silvin Bakalian, Jean Claude Marshall, Emilia Antecka, Sebastian Di Cesare, Dana Faingold, Claudia Martins, Bruno Fernandes, Miguel Burnier
Journal: Cancer Research (2008)

2313  Purpose: Expression of C-Met was significantly associated with melanoma specific mortality in uveal melanoma patients. On the other hand, the expression of cyclooxygenase-2 (COX-2) has been reported as an indicator of poor prognosis in a wide variety of tumors including uveal melanoma. COX-2 inhibitors have shown promise in controlling the malignant characteristics of several types of tumors. Previous work has demonstrated that a COX-2 inhibitor (Nepafenac) has delayed the progression of uveal melanoma as well as the development of metastatic disease in a rabbit model. The aim of this study is to investigate the immunostaining levels of C-Met in the intraocular tumors of non-treated and Nepafenac treated animals. In addition, evaluate the expression levels of C-Met mRNA in non-treated and treated human uveal melanoma cell lines.  Methods: The animals were divided into two groups of 14 animals each. The control group received drops that contained only the vehicle, while the experimental group received drops containing 0.3% Nepafenac solution. Each group was given two drops, twice daily. The duration of the experiment was 12 week. Twenty-eight cases of paraffin-embedded specimens of uveal melanomas of non-treated and treated rabbits were immuno-stained with C-Met monoclonal antibody using the standard ABC technique. The immunostaining was evaluated in semi-quantitative fashion based on their extent and intensity. The expression levels of C-Met mRNA were assessed in five human uveal melanoma cell lines (92.1, OCM-1, SP6.5, MKT-BR, and UW-1) before and after treatment with Amfenac, the active metabolite of Nepafenac using quantitative Real-time PCR.  Results: All intraocular tumors showed varying degrees of immunostaining for C-Met. The immunostaining was cytoplasmic in all samples. The intensity of immunostaining was significantly higher in the primary tumors of all non-treated group of rabbits as apposed to the primary tumors of all treated group. All five human uveal melanoma cell lines expressed different amounts of C-Met mRNA. The expression levels of C-Met mRNA were always higher in non-treated cell lines compared to treated cell lines. There was up to four-fold decrease in the expression levels of C-Met mRNA after treatment with Amfenac.  Conclusion: This is the first study to show that the inhibition of COX-2 causes a down regulation of C-Met in uveal melanoma. Therefore, anti-COX-2 topical medication might be a useful strategy for an adjuvant therapy in uveal melanoma patients. Further studies detailing the pathway of this down regulation are underway.
Abstract 5021: Semaphorin signal via MICAL3 induces symmetrical cell division of cancer stem-like cells to confer aggressiveness in breast cancer
Authors: Kana Tominaga, Masao Yano, Kei-ichiro Tada, Arinobu Tojo, Noriko Gotoh
Journal: Cancer Research (2017)

Abstract Breast cancer stem cells (BCSCs) are thought to be maintained in cancerous tissues by increased frequency of symmetric cell division at the expense of asymmetric cell divisionin the cancer tissues, although how this occurs it remain largely unknown. Here, we discovered that molecules interactinging with CasL 3 (MICAL3) contributed to tumor sphere formation in patient-derived breast cancer cells and tumor initiating activity in a patient-derived xenograft (PDX) model. Semaphorin (Sema)-stimulation induced complex formation involving MICAL3 and collapsin response mediator protein 2 (CRMP2), leading to stabilization of Numb in breast cancer cells. Neuropillin-1 (NP1), a receptor for Sema, and Numb were specifically expressed and colocalized at high levels in a BCSC-enriched population that induce tumor sphere formation. MICAL3 knockdown decreased symmetric cell division and increased asymmetric division of in NP1-high cancer stem-like cells that express high level of Numb at high levels. Thus, MICAL3/CRMP2/Numb pathway appears to play a critical role in the symmetric division of NP1-high cancer stem-like cells to expand the pool of BCSCs. Finally, we showed that breast cancer patients with higher expression levels of NP1 and Numb in cancer tissues show poor prognosis compared with those with lower expression levels of NP1 and Numb by using tissue microarray of breast cancer tissues. We provide a rationale for eradicating BCSC by blocking the symmetric division of BCSC by targeting molecules in Sema/NP1/MICAL3 pathway. Citation Format: Kana Tominaga, Masao Yano, Kei-ichiro Tada, Arinobu Tojo, Noriko Gotoh. Semaphorin signal via MICAL3 induces symmetrical cell division of cancer stem-like cells to confer aggressiveness in 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 5021. doi:10.1158/1538-7445.AM2017-5021
Abstract 3282: Common chronic medical conditions in pancreatic cancer: impact on overall survival
Authors: Ahmed O. Abousamra, David Fogelman, Vijayashri Rallapalli, Akram Shalaby, Milind Javle, Renato Lenzi, Linus Ho, Donghui Li, Manal Hassan
Journal: Cancer Research (2017)

Abstract Background: We aimed to categorize the most common comorbid medical conditions in pancreatic cancer (PC) patients and to determine whether these conditions have impact on the overall survival (OS). Methods: Between January 2000 and 2014, 2165 patients with pathologically confirmed adenocarcinoma of the pancreas consented to participate in a clinico-epidemiological study at the University of Texas MD Anderson Cancer Center. We reviewed the electronic medical records of all patients to identify the prevalence of four chronic medical conditions, including systemic hypertension, hyperlipidemia, type 2 diabetes, and altered morphology of the pancreas. Prevalence of each chronic disease was assessed and median survival was estimated by using the Kaplan-Meier product-limit method, and significant differences between the survival times were determined by using the log-rank test. Results: Among all patients, 950 (43.9%) had history of hypertension, 516 (23.8%) had hyperlipidemia, 585 (27%) had type 2 diabetes. Radiological and pathological records indicted presence of steatosis (0.4%), fibrosis (1.9%), and pancreatitis (9.9%). The prevalence of hyperlipidemia and diabetes was significantly higher in men (27.9%, 30.2%) than in women (18.2%, 22.8%) respectively; P value &amp;lt;.01. We found no significant variation in the prevalence of hypertension and altered pancreatic morphology between men and women. Hypertension was more frequent among African American patients while diabetes was more common among Hispanics and African Americans. No significant variations in the distribution of other conditions by ethnicity. Median survivals of PC patients by comorbidities are presented in table 1. Conclusion: Chronic medical conditions are commonly reported by PC patients and the prevalence of these conditions may vary by gender. However, the impact of these conditions may not significantly affect the survival of the patients. The interaction treatment choices with these conditions still needs to be elaborated in future studies. OS (months), 95%CI of PC patients by comorbiditiesComorbidityYesNoP valueHypertension10.9 (10-11.7)11.6 (10.7-12.4).09Hyperlipidemia12 (11.8-13.1)10.9 (10.2-11.6).4Diabetes Mellitus9.7 (8.4-11.1)11.4 (10.7-12.1).1 Note: This abstract was not presented at the meeting. Citation Format: Ahmed O. Abousamra, David Fogelman, Vijayashri Rallapalli, Akram Shalaby, Milind Javle, Renato Lenzi, Linus Ho, Donghui Li, Manal Hassan. Common chronic medical conditions in pancreatic cancer: impact on overall survival [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 3282. doi:10.1158/1538-7445.AM2017-3282
Real-Time Genomic Profiling of Pancreatic Ductal Adenocarcinoma: Potential Actionability and Correlation with Clinical Phenotype
Authors: Maeve A. Lowery, Emmet J. Jordan, Olca Basturk, Ryan N. Ptashkin, Ahmet Zehir, Michael F. Berger, Tanisha Leach, Brian Herbst, Gokce Askan, Hannah Maynard, Danielle Glassman, Christina Covington, Nikolaus Schultz, Ghassan K. Abou-Alfa, James J. Harding, David S. Klimstra, Jaclyn F. Hechtman, David M. Hyman, Peter J. Allen, William R. Jarnagin, Vinod P. Balachandran, Anna M. Varghese, Mark A. Schattner, Kenneth H. Yu, Leonard B. Saltz, David B. Solit, Christine A. Iacobuzio-Donahue, Steven D. Leach, Eileen M. O'Reilly
Journal: Clinical Cancer Research (2017)

Purpose: Molecular profiling in cancer has identified potential actionable drug targets that have prompted attempts to discover clinically validated biomarkers to guide therapeutic decision-making and enrollment to clinical trials. We evaluated whether comprehensive genetic analysis of patients with pancreatic adenocarcinoma is feasible within a clinically relevant timeframe and whether such analyses provide predictive and/or prognostic information along with identification of potential targets for therapy.Experimental Design: Archival or prospectively acquired FFPE samples and matched normal DNA from N = 336 patients with pancreatic cancer were analyzed using a hybridization capture-based, next-generation sequencing assay designed to perform targeted deep sequencing of all exons and selected introns of 410 key cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles.Results: The median time from protocol consent to reporting of the genomic results was 45 days with a median time from tissue delivery of 20 days. All genetic alterations identified were stratified based upon prior evidence that the mutation is a predictive biomarker of drug response using the MSKCC OncoKB classification. Three of 225 patients (1%) received a matched therapy based upon the sequencing results.Conclusions: The practical application of molecular results to guide individual patient treatment is currently limited in patients with pancreatic adenocarcinoma. Future prospective molecular profiling efforts should seek to incorporate routine germline genetic analysis and the identification of DNA profiles that predict for clinical benefit from agents that target DNA damage repair and or immunotherapy. Clin Cancer Res; 23(20); 6094-100. ©2017 AACR.
Unique Clinical Epidemiologic Risk Factors Are Associated with Distinct Methylation Subgroups in Newly-Diagnosed Acute Myeloid Leukemia (AML)
Authors: Amanda Shreders, Michael Heckman, Dan Zhou, Man Yang, Laura E. Finn, Lisa Sproat, Liuyan Jiang, Nancy Diehl, Ryan Hlady, Rhett P. Ketterling, Raoul Tibes, Keith D Robertson, James M. Foran
Journal: Blood (2016)
Abstract SY23-02: Host immune responses to HPV and HPV vaccines
Authors: Ligia Pinto
Journal: Cancer Research (2017)

Abstract Human papillomavirus (HPV) infection is the cause of multiple cancers in both women and men. There are three different licensed HPV prophylactic vaccines. Currently licensed L1 virus-like particles (VLP)–based HPV vaccines target two to nine different HPV types and have demonstrated excellent efficacy against the targeted HPV types and associated disease. Host immune responses to HPV vaccines and infection will be presented and discussed. Briefly, HPV vaccines induce nearly 100% seroconversion to all HPV types included in the vaccine. High titers of high-affinity anti-L1 IgG antibodies, to the HPV types included in the vaccine, are generated after vaccination, and these persist for several years after vaccination at levels considerably higher than those observed in natural infection. Although correlates of vaccine protection have not been identified, neutralizing antibodies are believed to be the main effectors of protection against HPV infection. Vaccine-induced antibodies are detectable not only in serum but also at mucosal sites of infection, such as the cervix and oral cavity. Local HPV-specific antibody levels, although lower, correlate well with circulating levels. Immunogenicity data have shown noninferiority of antibody responses after two doses of HPV vaccine, and the recommended number of vaccine doses was recently reduced from three to two. There is some evidence suggesting that even one dose of the bivalent HPV vaccine may provide similar protection to the recommended dose regimens. Antibody levels following one dose of the bivalent vaccine, although lower, have been shown to be stable over 4 years of follow-up and vaccine recipients remained HPV16/18 seropositive, suggesting that a single dose of the bivalent vaccine may provide durable protection against infection. The robust immunogenicity of the HPV vaccines contrasts with the immune responses observed after natural infection, in which seroconversion has been shown in only a percentage of individuals with incident HPV infection. Furthermore, levels of antibodies induced by vaccination are much higher than the levels observed after infection and appear to be preserved over time. A better understanding of long-term protection of the vaccine as well as a more comprehensive evaluation of correlates of immune protection against HPV infection are still needed. Citation Format: Ligia Pinto. Host immune responses to HPV and HPV vaccines [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 SY23-02. doi:10.1158/1538-7445.AM2017-SY23-02
Abstract 4040: Short-term romidepsin treatment combined with clotrimazole or bifonazole leads to decreased mitochondrial hexokinase 2 and apoptosis in cancer cells
Authors: Robert W. Robey, Andrew J. McDonald, Hanna Kozlowski, Michael M. Gottesman, Susan E. Bates
Journal: Cancer Research (2017)

Abstract In light of disappointing clinical trials in solid tumors, we have sought novel combinations to increase the efficacy of the histone deacetylase inhibitor (HDI) romidepsin. Hexokinase 2 (HK2) expression is increased in cancer cells and is postulated to prevent Bax-mediated cytochrome c release from mitochondria. Since romidepsin treatment induces apoptosis via the mitochondrial pathway, combining romidepsin with agents that detach mitochondrial HK2 might result in synergistic apoptotic effects. HCT-116 colon carcinoma cells were treated with 25 ng/ml romidepsin alone for 6h, or with romidepsin in the presence of 25 µM clotrimazole or bifonazole, compounds known to detach mitochondrial HK2. The medium was removed and cells were treated for an additional 42 h with or without clotrimazole or bifonazole. Cells were also treated with clotrimazole or bifonazole alone for 48 h. Apoptosis was then quantitated by annexin staining. While short-term romidepsin treatment alone induced modest annexin staining and 25 µM clotrimazole or bifonazole had little effect, the combination resulted in significant apoptosis. Similar effects were observed for A549 lung cancer cells, MDA-MB-231 breast cancer cells and 786-0 renal carcinoma cells. We also treated HCT-116 and A549 cells lacking Bak, Bax or both with the clotrimazole/romidepsin combination. Apoptosis was slightly increased in Bak-/- cells, reduced in Bax-/- cells and nearly completely abrogated in cells lacking both proteins compared to wild-type cells suggesting apoptosis occurred through the intrinsic pathway. The clotrimazole analog TRAM-34 was similarly active to clotrimazole. Protein expression was determined in cytoplasmic and mitochondrial fractions of cells treated with romidepsin, clotrimazole or both and we found a &amp;gt;60% decrease in mitochondrial HK2 in cells treated with the combination versus untreated cells. Our results suggest that combining romidepsin with a compound that leads to decreased mitochondrial hexokinase, such as clotrimazole or bifonazole, results in increased apoptosis. We postulate that cell death following combined romidepsin and clotrimazole treatment requires an intact intrinsic apoptotic pathway and that HK2 serves an anti-apoptotic function at the mitochondria. Citation Format: Robert W. Robey, Andrew J. McDonald, Hanna Kozlowski, Michael M. Gottesman, Susan E. Bates. Short-term romidepsin treatment combined with clotrimazole or bifonazole leads to decreased mitochondrial hexokinase 2 and apoptosis in cancer 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 4040. doi:10.1158/1538-7445.AM2017-4040
Abstract 1347: <i>In vivo</i> efficacy of eflapegrastim in rats with chemotherapy-induced neutropenia
Authors: Young Hoon Kim, InYoung Choi, Prasad Kolli, Guru Reddy
Journal: Cancer Research (2017)

Abstract Introduction: Eflapegrastim (SPI-2012, HM10460A) is a novel, long-acting recombinant human granulocyte colony-stimulating factor (rhG-CSF). Eflapegrastim consists of an rhG-CSF conjugated to a recombinant E. coli derived Fc fragment of IgG4 via a polyethylene glycol linker. Eflapegrastim is in clinical development for the treatment of chemotherapy-induced neutropenia in cancer patients. The purpose of this study was to evaluate and compare the efficacy of eflapegrastim, pegfilgrastim and filgrastim in rats with chemotherapy-induced neutropenia. Methods: Rats were treated with 50 mg/kg of cyclophosphamide (CPA) intraperitoneally to induce neutropenia. Pegfilgrastim was administered subcutaneously as a single dose of 100 µg/kg on Day 1 and filgrastim was administered subcutaneously at a dose of 20 µg/kg daily for five days on days 1 to 5. Eflapegrastim was administered subcutaneously as a single dose on day 1, at doses ranging from 32 µg /kg to 322 µg/kg (or 8.8 µg/kg to 88 µg/kg as G-CSF equivalent). Blood samples were collected for 8 days after drug administration for the measurement of neutrophil counts and the Duration of Severe Neutropenia (DSN). Results: The DSN in neutropenic rats treated with eflapegrastim was compared with the DSN in neutropenic rats treated with pegfilgrastim or filgrastim. The DSN was 0.2 days when eflapegrastim was administered as a single dose at 88 µg/kg (as G-CSF equivalent) 24 hours after administering CPA. In contrast, the DSN was 3.04 days with filgrastim administered at a dose of 20 µg/kg for 5 days from Day 1 to Day 5 and 2.8 days with pegfilgrastim administered as a single dose of 100 µg/kg 24 hours after administering CPA. At the lowest eflapegrastim dose of 8.8 µg/kg that was about 1/10 of G-CSF equivalent dose for pegfilgrastim, the DSN in eflapegrastim treated rats was 2.94 days. Thus, eflapegrastim was found to be more potent in shortening the DSN with a lower G-CSF equivalent dose when compared to either pegfilgrastim or filgrastim. Conclusion: Eflapegrastim was about 10 times more potent than pegfilgrastim at G-CSF equivalent doses in this neutropenic rat model Citation Format: Young Hoon Kim, InYoung Choi, Prasad Kolli, Guru Reddy. In vivo efficacy of eflapegrastim in rats with chemotherapy-induced neutropenia [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 1347. doi:10.1158/1538-7445.AM2017-1347