tbuckley/cabot-search huggingface dataset:
Abstract 1277: Honokiol, a natural product, overcomes acquired resistance of EGFR mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib
Authors: Hongjing ZANG, Songqing Fan, Jack Arbiser, Taofeek K. Owonikoko, Suresh S. Ramalingam, Shi-Yong Sun
Journal: Cancer Research (2019)

Abstract Osimertinib (AZD9291) is a FDA-approved EGFR inhibitor for treating non-small cell lung cancer (NSCLC) patients with activating EGFR mutations (first-line) or those who have become resistant to 1st generation EGFR inhibitors through the T790M mutation (second-line). The development of acquired resistance to osimertinib limits the long-term benefits of patients, and effective treatment options are urgently needed. We have identified that honokiol, a natural product with potential antitumor activity, may be used to overcome osimertinib resistance. In several osimertinib-resistant cell lines including HCC827/AR, PC-9/AR, PC-9/GR/AR and PC-9/3M (with EGFR 19del, T790M and C797S mutations), the combination of honokiol and osimertinib had synergistic effects on decreasing the survival of these cell lines. The combination inhibited cell colony formation and growth, and augmented induction of apoptosis of resistant cells. This combination enhanced reduction of Mcl-1, a critical mechanism by which osimertinib induces apoptosis in sensitive EGFR mutant NSCLC cells; this effect is likely due to enhanced Mcl-1 degradation since Mcl-1 was degraded much faster in cells exposed to the combination of honokiol and osimertinib than in DMSO-treated control cells. Moreover enforced overexpression of ectopic Mcl-1 abolished the enhanced effect of honokiol and osimertinib combination on induction of apoptosis, supporting a critical role of Mcl-1 reduction in inducing apoptosis of the osimertinib-resistant cells by this combination. Our findings warrant further study of this combination for overcoming osimertinib-resistance in vivo and potentially in the clinic. (This work was supported by the NIH/NCI R01 CA223220 to SYS and Winship lung cancer pilot award to SYS). Citation Format: Hongjing ZANG, Songqing Fan, Jack Arbiser, Taofeek K. Owonikoko, Suresh S. Ramalingam, Shi-Yong Sun. Honokiol, a natural product, overcomes acquired resistance of EGFR mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1277.
Abstract 1865: Buserelin trisphenylmethanol derivatives as anti-cancer prodrugs
Authors: Ryan Beni, William Boadi, Renner Antwi
Journal: Cancer Research (2019)

Abstract Buserelin (BUS) is a synthetic nonapeptide agonist analog of LH-RH, first reported by Hoechst in 1976. It is used for the treatment of advanced prostate cancer. Side effects of buserelin include musculoskeletal pain, hearing disorders, increased thirst, worsening hypertension, anxiety, memory and concentration disturbances, fatigue, nervousness, palpitations, leukopenia, thrombocytopenia, altered blood lipids, and glucose intolerance. Therefore, improving of the biological activity of BUS by increasing the cellular uptake and retention is a remedy to this end. In this research, tris(4-methoxyphenyl)methanol (TPM) derivatives were synthesized and linked to BUS through hydrophobic linkers to enhance and optimize the hydrophobicity of this drug with the expectation to improve the cellular uptake. In this regard, several BUS conjugates of TPM derivatives with optimized hydrophobicity were synthesized by the reaction of methoxy benzenes (e.g. anisole, 2-fluoroanisole, 2-trifluoromethylanisole, 2-methylanisole, or 1,2-dimethoxybenzene, and 1,3,5-trioxane, followed by the conjugation with BUS and lauric acid in the presence of HBTU/DIPEA/DIC in moderate yields. Comparative antiproliferative assays between TPM-BUS conjugates and the corresponding non-covalent physical mixtures of the TPM derivatives and BUS were performed against human acute lymphoblastic leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), and mouse pre adipocytes (3T3-L1) cells. TPM-BUS conjugates inhibited the cell proliferation of CCRF-CEM, SK-OV-3 and 3T3-L1 cells by 48-86%, 32-77%, 42-67%, respectively, at a concentration of 1-25 µM after 24-72 h of incubation. These data suggest that TPM-BUS derivatives with optimized hydrophobicity can be used to improve the biological activity of BUS. Note: This abstract was not presented at the meeting. Citation Format: Ryan Beni, William Boadi, Renner Antwi. Buserelin trisphenylmethanol derivatives as anti-cancer prodrugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1865.
Abstract 4778: Identification of promoters for targeted gene expression in tumors
Authors: Abdul Mohin Sajib, Maninder Sandey, Samantha Morici, Bradley Schuler, Payal Agarwal, Bruce Smith
Journal: Cancer Research (2019)

Abstract A variety of novel therapeutic approaches to cancer have been proposed in the past several decades. One of the most compelling is the use of gene therapy to treat tumors. Restricting the expression of these genes to tumor avoids toxicity in normal cells and the concurrent side effects that this activity engenders. Promoter sequences can be used as a tool for transcriptional targeting, by restricting the expression of the therapeutic genes, or, in the case of oncolytic virotherapy, the replication of the viral agent. Several tumor-upregulated promoters have been identified in a wide variety of human tumors. Given the recognition of the validity of canine tumors as comparative models of human disease, it is critical to determine the activities of these promoters in the canine system. To achieve this goal, endogenous cSurvivin, cTERT, and cCXCR4 promoter activity was evaluated in a panel of canine normal and tumor cell lines/tissues and primary tumors by RT-Q-PCR. These three promoters, along with an E2F modified Canine Adenovirus 2 E1a promoter (E2F-E1a), were also assessed for their activity when supplied exogenously to tumor cells in an in vitro GFP reporter transfection assay. Endogenous expression of cTERT showed negligible differences between normal canine cells/tissues and tumor cell/tissues. cSurvivin showed elevated endogenous activity in non-hematopoietic tumor cells and moderately elevated activity in some normal tissues and hematopoietic tumors. cCXCR4 activity was elevated exclusively in a T-lymphoma cell line and a primary T-cell lymphoma. Exogenous expression in most cancer cell lines showed enhanced activity with most of the promoters tested. The percentage of cells expressing GFP was elevated in tumor compared to normal with all four tested promoters, when normalized to CMV-GFP expression. However, the relative fluorescence intensity varied significantly between cell lines, while the fluorescence intensity varied less between promoters within a specific cell line. Exogenous expression results did not correlate well with endogenous expression in tumor cells, but they did correlate well in normal cells. This disparity implies that promoter selection for transcriptional targeting of tumors should account for both endogenous and exogenous expression patterns. Additionally, these findings indicate that identification of a pan-cancer promoter is complex and that expression targeting may need to rely on selecting patient-specific promoters to drive the activity of therapeutic genes. Citation Format: Abdul Mohin Sajib, Maninder Sandey, Samantha Morici, Bradley Schuler, Payal Agarwal, Bruce Smith. Identification of promoters for targeted gene expression in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4778.
Abstract 3713: Strong expression of EZH2 and H3K27me3 is associated with poor survival time in small cell lung cancer
Authors: Ana Paula Fernandes, Rita deCassia S Alves, Guilherme Watte, Philipp Kunze, Adriana Vial Roehe, Regine Schneider-Stock
Journal: Cancer Research (2019)

Abstract BACKGROUND: Small-cell lung cancer (SCLC) is a highly aggressive neoplasm, characterized by early development of metastasis and very poor clinical outcome. The therapeutic possibilities are limited and poorly changed over the past three decades. Enhancer of zeste homolog 2 (EZH2) is a member of the polycomb repressive complex 2. It is involved in epigenetic gene silencing through the trimethylation of H3K27 and it has been identified as a biomarker of aggressive and highly proliferating tumors, emerging as a potential target for cancer therapy. OBJECTIVE: We aimed to correlate the expression profile of the EZH2 and H3K27me3 proteins in tumor tissues of non-treated SCLC patients with patient's outcome. METHODS: EZH2 and H3K27me3 expression were analyzed by immunohistochemistry in 48 SCLC tumor biopsies. The expression of the markers was quantified in a semi quantitative way and correlated with clinic pathological factors and patients overall survival. To mimic an EZH2 loss, H209 SCLC cells were treated with an EZH2 inhibitor for 48h and the in vivo growth pattern was investigated in the chorioallantoic membrane (CAM) assay. RESULTS: All patients died within one year after diagnosis. There was a heterogeneous expression pattern for EZH2 and H3K27me3. Strong expression of EZH2 and H3K27me3 was observed in appr. 50% of the patients. The Kaplan Meier curve showed a significant association of high expression pattern of EZH2 and shorter overall patient survival time after 12 and 25 weeks of follow up, respectively (p=0.030; p=0.014) Different markers of tumor aggressiveness after EZH2 inhibition were investigated in the CAM model. CONCLUSION: Strong EZH2 and H3K27me3 expression in non-treated SCLC patients was related to worse prognosis. EZH2 inhibitors should be considered in future trials for SCLC. Citation Format: Ana Paula Fernandes, Rita deCassia S Alves, Guilherme Watte, Philipp Kunze, Adriana Vial Roehe, Regine Schneider-Stock. Strong expression of EZH2 and H3K27me3 is associated with poor survival time in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3713.
Abstract 2207: The dual role of BI 2536, a small-molecule inhibitor that targets PLK1, in induction of apoptosis and attenuation of autophagy in neuroblastoma cells
Authors: Zhiheng Li
Journal: Cancer Research (2019)

Abstract Neuroblastoma(NB) is the most common extra-cranial solid tumor in childhood with the overall survival less than 40%. Polo-like kinase 1 (PLK1) is a serine/threonine-protein kinase expressed during mitosis and overexpressed in multiple cancers, including neuroblastoma. We found the PLK1 expression related to the outcome of NB patients. BI2536, a small molecule inhibitor against PLK1, significantly reduced cell viability in a panal of NB cell lines, with IC50 less than 100 nM. PLK1 inhibition by BI 2536 treatment induced cell cycle arrest at G2/M phase and cell apoptosis in NB cells. Realtime PCR array revealed the PLK1-regulated genes, such as BIRC7, TNFSF10, LGALS1 and DAD1 et al. Moreover, autophagy activity was investigated in the NB cells treated with BI 2536. BI 2536 treatment in NB cells increased LC3-II puncta formation and LC3-II expression. Formation of autophagosome induced by BI 2536 was observed by TEM. However, BI2536 abrogated the autophagic flux in NB cells by reducing SQSTM1/p62 expression and AMPKαT172 phosphorylation. These results provide new clues for the molecular mechanism of cell death induced by BI 2536 and suggest that BI 2536 may act as new candidate drug for neuroblastoma. Citation Format: Zhiheng Li. The dual role of BI 2536, a small-molecule inhibitor that targets PLK1, in induction of apoptosis and attenuation of autophagy in neuroblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2207.
Abstract MP047: Abdominal Skeletal Muscle Density is Significantly Associated With Selected Measures of Adiposity Associated Inflammation: the Multi-Ethnic Study of Atherosclerosis
Authors: Rachel Van Hollebeke, Mary Cushman, Matthew A Allison
Journal: Circulation (2017)

Background: Excess adiposity is associated with higher levels of certain inflammatory markers that have been linked to cardiometabolic disease. Lean skeletal muscle is the largest regulator of glucose metabolism but few population-based studies have examined the associations between muscle and inflammation. Therefore, we studied the relationships between abdominal muscle mass [area] and density with selected measures of adiposity-associated inflammation. Methods: Nearly 2,000 subjects enrolled in the Multi-Ethnic Study of Atherosclerosis underwent computed tomography (CT) of the abdomen and had venous fasting blood drawn concomitantly. The CT scans were interrogated for visceral and subcutaneous fat, as well as lean muscle areas and densities in the rectus abdominus, obliques, paraspinus and psoas muscle groups. We then categorized the muscle in locomotion (psoas) and stabilization groups (rectus, obliques and paraspinus). The blood samples were assayed for interleukin-6, resistin, C-reactive protein, and tumor necrosis factor - alpha. Multivariable linear regression was used to determine the independent associations between muscle area and density with each of the aforementioned adipokines. Results: The mean age was 64.7 years and 49% were female. Forty percent were non-Hispanic White, 26% were Hispanic/ Latino American, 21% were African American, 13% were Chinese American. The mean BMI was 28.0 kg/m 2 and 30% were obese (BMI &gt; 30 kg/m 2 ). With adjustment for age, gender, race, dyslipidemia, diabetes, hypertension, eGFR, coronary artery calcium, physical activity, sedentary behavior, selected adipokines and both subcutaneous and visceral fat, a 1-SD increment in the mean densities for total abdominal muscle, total stabilization muscle and total locomotive muscle were each significantly associated with lower levels of interleukin-6 (-15%, -15% and -9%, p &lt; 0.01 for all) and resistin (-0.11, -0.11 and -0.07 ng/mL, p &lt; 0.02 for all), but not CRP or TNF-alpha. These associations remained significant after additional adjustment for muscle area in the corresponding muscle group. Conversely, the areas of the muscle variables were not independently associated with any of the adipokines, especially after adjustment for muscle density. There were no significant interactions between ethnicity and both muscle area and density for any of the adipokines. Conclusions: Higher densities of several muscle groups in the abdomen are significantly associated with lower interleukin-6 and resistin levels, independent of the muscle area in these groups. Techniques that either enhance or maintain muscle density levels may reduce the risk of cardiometabolic diseases linked to adverse levels of inflammation.
Abstract 16207: Comparison of Long Term Outcomes After ST Segment Elevation Myocardial Infarction and Non ST Segment Elevation Myocardial Infarction With or Without Creatine Kinase Elevation Stratified by Global Registry of Acute Coronary Events Risk Score: A J-MINUET Substudy
Authors: Takashi Morita, Masatake Fukunami, Takahisa Yamada, Koichi Nakao, Yukio Ozaki, Kazuo Kimura, Junya Ako, Teruo Noguchi, Satoshi Yasuda, Satoru Suwa, Kazuteru Fujimoto, Yasuharu Nakama, Wataru Shimizu, Yoshihiko Saito, Atsushi Hirohata, Yasuhiro Morita, Teruo Inoue, Atsunori Okamura, Toshiaki Mano, Kunihiro Nishimura, Kazuhito Hirata, Kengo Tanabe, Yoshisato Shibata, Mafumi Owa, Kenichi Tsujita, Hiroshi Funayama, Nobuaki Kokubu, Ken Kozuma, Shirou Uemura, Tetsuya Toubaru, Keijirou Saku, Shigeru Ohshima, Yoshihiro Miyamoto, Hisao Ogawa, Masaharu Ishihara
Journal: Circulation (2017)

Aim: In this study, we compared long term outcomes of AMI patients with and without ST elevation, and with and without CK elevation. Furthermore, we investigated differences of long term outcomes i...
Sorafenib in patients with hepatocellular carcinoma: 10 years of real life
Authors: G. Rovesti, G. Orsi, L. Faloppi, L. Gramantieri, N. Silvestris, G. Marisi, F. Foschi, E. Tamburini, K. Andrikou, E. Molinaro, M. Riggi, M. Scartozzi, S. Cascinu, A. Casadei Gardini
Journal: Annals of Oncology (2019)
Abstract 1966: Obesity and prostate cancer progression: Role of the chemokine CXCL12
Authors: Songyeon Ahn, Achinto Saha, Mikhail G. Kolonin, John DiGiovanni
Journal: Cancer Research (2019)

Abstract Obesity is a significant risk factor for several cancers in both men and women. A number of studies have shown that obesity is associated with increased prostate cancer (PCa) progression and higher mortality. However, the mechanism(s) for obesity-driven PCa remain unclear. In earlier studies, we showed that obesity enhances PCa progression in the HiMyc mouse model by changing the surrounding tumor microenvironment, especially the white adipose tissue (WAT). WAT consists of many cells including inflammatory cells, mature adipocytes and adipose stromal cells (ASCs). Here, we further investigated the role of ASCs and ASC derived CXCL12 in obesity-driven PCa progression. In HMVP2 cells, a PCa cell line derived from HiMyc mice expressing high levels of CXCR4, we observed activation of MAPKs (JNK and ERK), AKT, STAT3 and NFkB following treatment with CXCL12. These CXCL12-induced signaling pathways were inhibited by treating with AMD3100, a CXCR4 antagonist, and also by CXCR4 knock-down. To confirm this in vivo, we compared PCa tumor growth in lean and obese mice using the HMVP2 allograft model. Our data demonstrates that obesity promotes EMT in tumor cells and increases invasion of surrounding WAT into the tumor stoma. Treatment of mice with AMD3100 significantly inhibited the growth of HMVP2 tumors and suppressed EMT in both the obese and control diet groups. Furthermore, D-CAN, a hunter-killer peptide developed for targeting ASCs, also suppressed obesity-induced EMT and tumor growth in HMVP2 tumor allografts. Lastly, AMD3100 in combination with D-CAN, showed a significant reduction in PCa growth in obese mice compared to either agent used alone. These results provide evidence that ASCs activate the CXCL12/CXCR4 signaling as well as other pathways playing an important role in obesity-driven PCa progression. Our data suggests this pathway as a novel therapeutic target for inhibiting obesity-driven PCa growth and progression. Research supported by NCI Grant CA196259. Citation Format: Songyeon Ahn, Achinto Saha, Mikhail G. Kolonin, John DiGiovanni. Obesity and prostate cancer progression: Role of the chemokine CXCL12 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1966.
Abstract 647: Immunoprevention of triple negative breast cancer by a TOP2A multi-peptide vaccine
Authors: Sang Beom Lee, Jing Pan, Yueqiang Jiang, Katie Palen, Bryon Johnson, Romaine Ingrid Fernando, Shizuko Sei, Ronald Lubet, Ming You, Yian Wang
Journal: Cancer Research (2019)

Abstract Triple negative breast cancer (TNBC) comprises approximately 20% of all breast cancers, and it has a poor prognosis due to aggressive growth characteristics and lack of effective targeted therapies. Emerging data suggest vaccination as a promising approach to prevent TNBC as well as other cancer types, but appropriate vaccine targets need to be identified. In the present study, we employed in silico analyses to select genes that are uniquely expressed in TNBC. Topoisomerase 2 alpha (Top2A) was found to be highly expressed in human TNBC. Top2A is a key enzyme in DNA replication and has been identified as a target of anti-cancer therapy. Overexpression of Top2A was confirmed in human breast cancer tissue microarrays and in mouse TNBCs derived from C3(1)/TAg mice. Top2A-specific MHC class II epitopes with optimal binding affinity were identified using the “combined scoring system”, based on their potential to elicit a Th1 immune response. Furthermore, all peptides were selected to have 100% amino acid sequence homology between humans and mice for potential clinical translation. Four Top2A peptides with strong immunogenic responses were selected by immunization of tumor naïve mice followed by IFN-γ-based ELISPOT assays. These peptides were combined to form a multi-peptide Top2A vaccine. The anti-tumor efficacy of the Top2A vaccine was tested in a preventive setting using a syngeneic TNBC model in C3(1)/TAg-REAR mice. Vaccinated animals demonstrated a significant reduction in tumor growth when compared to the adjuvant control with tumor size decreasing from 278.1 mm3 in adjuvant control to 150.4 mm3 in vaccinated group (p &amp;lt; 0.05). Taken together, our data clearly demonstrate that the Top2A multi-peptide vaccine is highly immunogenic and provides immunopreventive efficacy against TNBC in mice. Citation Format: Sang Beom Lee, Jing Pan, Yueqiang Jiang, Katie Palen, Bryon Johnson, Romaine Ingrid Fernando, Shizuko Sei, Ronald Lubet, Ming You, Yian Wang. Immunoprevention of triple negative breast cancer by a TOP2A multi-peptide vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 647.