bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1846: HPV oncoproteins cause specific types of chromosomal instability in head and neck cancer
Authors: Funk Laura C. , Lee Denis L. , Kimple Randall J. , Lambert Paul F. , Weaver Beth A. 
Published: August 2018

Abstract
Aneuploidy, a karyotype that differs from a multiple of the haploid, is a hallmark of cancer. Aneuploidy can be caused by an ongoing rate of chromosome missegregation during mitosis, known as whole chromosomal instability (CIN). Work from our lab and others has shown that while low rates of CIN can promote tumorigenesis, high levels of CIN are tumor suppressive. Combining two insults that each cause low CIN results in high CIN, cell death, and tumor suppression. We recently showed that the chemotherapy drug paclitaxel causes CIN due to multipolar divisions in breast cancer. Preliminary evidence suggests that tumors which exhibit CIN prior to therapy are sensitized to paclitaxel because it increases their level of CIN over a maximally tolerated threshold. Radiation also induces CIN, and rectal adenocarcinomas which exhibit CIN prior to treatment are sensitized to chemoradiation therapy. Human papillomavirus (HPV), specifically HPV subtype 16, is a growing cause of head and neck cancer worldwide. In cervical cancer, HPV is associated with CIN, which has been attributed largely to the expression of its E6 and E7 oncoproteins. HPV+ head and neck cancer patients show improved responses to radiation therapy than HPV- head and neck patients, potentially due to an increased basal rate of CIN. Here, we tested the ability of HPV E6, E7, or E6+E7 expression to induce CIN in normal oral keratinocytes (NOKs). Expression of E6 alone robustly induced misaligned chromosomes and multipolar spindles with supernumerary centrosomes, while E7 expression alone produced more moderate effects. Combined expression of E6 and E7 exacerbated the phenotypes observed in NOKs expressing E6 alone. Expression of E6, either alone or in combination with E7 caused reduced protein levels of the mitotic kinesin CENP-E, which is sufficient to induce misaligned chromosomes. Interestingly, HPV+ patient-derived xenograft (PDX) models of head and neck squamous cell carcinoma showed less evidence of mitotic defects than NOKs expressing E6 alone. A subset of HPV+ PDX tumors showed an increase in misaligned chromosomes when compared to HPV- tumors, but no increase in lagging chromosomes or multipolar spindles was observed. Together, these data suggest HPV infection causes an incompletely penetrant increase in specific types of CIN in head and neck cancer and that a basal rate of CIN may be predictive of treatment response independent of HPV status.
Citation Format: Laura C. Funk, Denis L. Lee, Randall J. Kimple, Paul F. Lambert, Beth A. Weaver. HPV oncoproteins cause specific types of chromosomal instability in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1846.
Abstract 1848: A comprehensive image cytometry method to identify and functionally characterize a rare subpopulation of platinum-induced aneuploid tumor cells in high-grade serous carcinoma
Authors: Yeung Yu Wing , Fung Oliver , Bashkurov Mikhail , Rottapel Robert , Kapus Andras 
Published: August 2018

Abstract
Background: Although platinum treatment effectively reduces tumor bulk for high grade serous carcinomas of tubal-ovarian origin, there are often scattered tumor cells exhibiting reparative and aneuploid features that remained within the peritoneal cavity. The biological importance of these aneuploid cells has not been well elucidated. In this study, we used HGSC cell line models and developed an improved image cytometry approach to identify these aneuploid cells for functional interrogation.
Methods: We have developed a comprehensive image cytometry approach to assess DNA ploidy and cell cycle phase distribution within a standard flow cytometry software platform and validated this methodology using phase-specific markers (EdU, pRb, Geminin, pH3). We further introduced a novel ‘brightness vs. nuclear size' scatter plot to enhance the cell cycle assessment at the single-nucleus level. The method was applied to correlate the kinetics of the DNA damage and checkpoint response with the cell cycle status and cell viability on HGSC cell lines (OVCAR3, TOV3133G) after in-vitro carboplatin treatment.
Results: Using this improved image cytometry method, we identified the emergence of a rare subpopulation of large aneuploid tumor cells at 1 week after platinum treatment. These large aneuploid cells remained viable (PI- and cleaved-PARP negative) but were uniquely dependent on anti-apoptotic signaling for their continual survival. While the bulk population of treated tumor cells underwent mitotic catastrophe following premature G2-M checkpoint exit, a rare subpopulation escaped cell death likely via mitotic slippage as they exhibit characteristic features of aneuploidy. These large aneuploid cells remained KI-67 positive and clonal dilutional experiments are being performed to assess their regrowth potential.
Conclusions: This study has identified a rare subpopulation of tumor cells that avoided mitotic cell death after platinum treatment and then survived in an aneuploid state. The derivation of aneuploid cells via mitotic slippage subsequent to platinum treatment is an under-recognized phenomenon but may pose as an important drug-resistant mechanism due to enhanced survival strategies co-opted by these aneuploid cells.
Research funding: Ontario Institute for Cancer Research
Citation Format: Yu Wing Yeung, Oliver Fung, Mikhail Bashkurov, Robert Rottapel, Andras Kapus. A comprehensive image cytometry method to identify and functionally characterize a rare subpopulation of platinum-induced aneuploid tumor cells in high-grade serous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1848.
Abstract 1850: CDK inhibitor PHA-848125 preferentially inhibits proliferation of triple negative breast cancer and synergizes with cisplatin
Authors: Cheung Douglas G. , Buzzetti Marta , Croce Carlo M. , Leva Gianpiero di 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC), defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is highly aggressive with a poor prognosis as it lacks targeted therapies. Several inhibitors of the cyclin-dependent kinase 4 and 6 (CDK4/6) have been approved by the FDA for the treatment of ER-positive breast cancer. However, the effectiveness of these inhibitors against TNBC tumors is less than expected. Here, we tested the efficacy of PHA-848125, a potent ATP-competitive CDK2 inhibitor, on a panel of breast cancer cell lines showing a selective impaired proliferation in TNBC cells (IC50 of ER-positive MCF7 cells: 25.9 μM vs. IC50 of TNBC MDA-MB-231 cells: 430.8 nM). TNBC cells treated with PHA-848125 exhibited effects consistent with CDK2 inhibition, including G1 cell cycle arrest and reduced phosphorylation levels of the retinoblastoma protein (pRB) and CDK2. Interestingly, PHA-848125 was also effective against pRB-null TNBC cell lines, unlike other approved CDK inhibitors. Oral administration of PHA-848125 to TNBC xenograft mice and MMTV-PyMT transgenic mice impaired both tumor growth and metastasis at a tolerable dose (40 mg/kg), but not in ER-positive xenograft mice. A combination treatment of PHA-848125 and cisplatin inhibited tumor growth and induced apoptosis synergistically in vitro and in vivo. Thus, our preclinical experiments set the rationale for the clinical evaluation of PHA-848125, either alone or in combination with cisplatin, for the treatment of TNBC.
Citation Format: Douglas G. Cheung, Marta Buzzetti, Carlo M. Croce, Gianpiero di Leva. CDK inhibitor PHA-848125 preferentially inhibits proliferation of triple negative breast cancer and synergizes with cisplatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1850.
Abstract 1854: Treatment of head and neck squamous cell carcinoma cells with BMS754807 and Dasatinib induce synergistic cytotoxicity through altered focal adhesion signaling
Authors: Lehman Christine E. , MEndez Rolando , Axelrod Mark , Wulfkuhle Julia , Petricoin Emanuel , Gioeli Daniel , Jameson Mark 
Published: August 2018

Abstract
Head and neck cancer (HNC) is the 6th most common cancer worldwide and the 9th most common cancer in the United States. Singular, targeted cancer therapies rarely produce a robust, complete and durable response and often do not substantially prolong patient survival. Adaptive survival responses often blunt the cytotoxic effects of drugs resulting in resistance. Therefore, targeting compensatory signaling pathways may provide improved therapeutic responses. Even with the current best treatment, 5-year survival for all patients with head and neck squamous cell carcinomas (HNSCC) is only approximately 65%, further highlighting the need for improved combinatorial treatments. Previous work in our laboratory has shown that inhibitors of Insulin Like Growth Factor 1 Receptor (IGF1R) and Src family kinases, when used in combination, synergistically inhibit HNSCC growth in vitro. Therefore, to explore the mechanisms which may contribute to this synergistic cytotoxicity, we utilized reverse phase protein arrays to assess the proteome of HNSCC lines treated with BMS754807 and Dasatinib to inhibit IGF1R and Src, respectively. We identified focal adhesion signaling as a potentially vital node in the cell signaling network of synergistic cytotoxicity upon treatment of HNSCC with BMS754807 and Dasatinib. Focal Adhesion Kinase (FAK) and Paxillin phosphorylation was decreased synergistically with the combination of BMS754807 and Dasatinib. Using western blot analysis, we confirmed a decrease in phosphorylation of FAK Y576/577 and Paxillin Y118 upon combined treatment with BMS754807 and Dasatinib. Interestingly, FAK is upregulated in radioresistant HNSCC patients and, metastases have increased phosphorylation of FAK compared to normal tissues. FAK is amplified in up to 26% of HNSCC and overexpression of Paxillin is associated with unfavorable prognosis, highlighting the importance of focal adhesion signaling in head and neck cancers. Our data suggests that interactions between integrins, receptor tyrosine kinase, and non-receptor kinase signaling regulate cell survival in HNSCC. Disruption of IGFR and Src activity leads to convergent inhibition of focal adhesion signaling and synergistic cytotoxicity in a variety of HNSCC cell lines.
Citation Format: Christine E. Lehman, Rolando MEndez, Mark Axelrod, Julia Wulfkuhle, Emanuel Petricoin, Daniel Gioeli, Mark Jameson. Treatment of head and neck squamous cell carcinoma cells with BMS754807 and Dasatinib induce synergistic cytotoxicity through altered focal adhesion signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1854.
Abstract 1859: Inhibition of proteasome deubiquitinase activity prevents cytoprotective aggresome formation in cancer cells
Authors: Hillert Ellin-Kristina , Brjnic Slavica , Mazurkiewicz Magdalena , Larsson Rolf , Fryknäs Mårten , Swanton Lisa , High Stephen , Linder Stig , D'Arcy Padraig B. 
Published: August 2018

Abstract
Proteasome inhibitors kill cancer cells by inducing an acute proteotoxic stress response characterized by the cytosolic accumulation of poly-ubiquitinated proteins, ER stress and the production of reactive oxygen species (ROS). The aggresome pathway has been described as an escape mechanism from proteasome inhibitor-induced cytotoxicity that functions by sequestering the accumulated protein. We show that b-AP15, an established small molecule inhibitor of proteasome deubiquitinase activity, induces the accumulation of cytosolic poly-ubiquitin in the absence of aggresome formation. In contrast to the clinically used proteasome inhibitor bortezomib, the accumulated poly-ubiquitin complexes induced by b-AP15 remain localized in the cytoplasm and fail to form typical aggresome structures. Inhibition of aggresome formation is dependent on ubiquitin but independent of tubulin dynamics, and may result in the accumulation of a range of substrates of the intracellular transport system on microtubules. Finally, b-AP15 induces hyper-ubiquitination of the aggresome chaperone HDAC6, as well as altering HDAC6 association with the proteasome. This suggests a potential mechanism for the present findings, which will require further investigation. Our data suggests that b-AP15 inhibition of aggresome formation may circumvent a potential resistance pathway following cytotoxicity due to proteasome inhibition via the blocking of microtubule transport.
Citation Format: Ellin-Kristina Hillert, Slavica Brjnic, Magdalena Mazurkiewicz, Rolf Larsson, Mårten Fryknäs, Lisa Swanton, Stephen High, Stig Linder, Padraig B. D'Arcy. Inhibition of proteasome deubiquitinase activity prevents cytoprotective aggresome formation in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1859.
Abstract 186: Small-molecule inhibition of cathepsins L and K as potential therapeutics for macrophage-driven breast cancer
Authors: Dykes Samantha S. , Siemann Dietmar W. 
Published: August 2018

Abstract
Tumor-associated macrophages secrete many factors including proteases and growth factors, which ultimately promote the metastatic phenotype of mammary tumors. Due to their numerous pro-tumor functions, tumor-associated macrophages represent an attractive cell population for stromal-targeted anti-cancer therapies. Interleukin-4 stimulation promotes macrophage differentiation from a baseline M0 state to a more pro-tumorigenic M2 phenotype, which is often associated with increased expression of proteases including the lysosomal cathepsin L. Cathepsin L is important in both macrophage and tumor cell invasion, whereby secreted cathepsin L degrades the extracellular matrix allowing for cell infiltration. M0 to M2 differentiation was not accompanied by an overall increase in the protein expression of cathepsin L, however, secreted cathepsin L was increased in the M2 macrophage population. The present study examined the role of cathepsin L in M0 to M2 differentiation and macrophage-mediated tumor cell invasion using the novel cathepsin L/K inhibitors KGP94 and KGP207 [Dr. Kevin Pinney, Baylor University]. Boyden chamber assays revealed that KGP94 and KGP207 prevented in vitro M2 macrophage invasion and reduced macrophage-stimulated invasion of 4T1 murine breast cancer cells. KGP94 and KGP207 treatment also partially prevented IL-4-stimulated M0 to M2 differentiation of macrophages as determined by a decrease in the IL-4-induced expression of the M2 marker Arginase-1 upon drug treatment. Furthermore, exogenous recombinant cathepsin L partially stimulated the expression of Arginase-1 in M0 macrophages. Together, these data suggest that cathepsin L may play a role in macrophage M0 to M2 differentiation. In summary, the novel cathepsin L/K inhibitors KGP94 and KGP207 altered M0 to M2 differentiation, reduced macrophage invasion, and reduced macrophage-stimulated invasion of breast cancer cells. These data highlight the importance of cathepsin L in macrophage functions and suggest that cathepsin inhibition strategies may be therapeutically beneficial by impairing the progression of tumors, particularly those with high recruitment of M2 macrophages.
Citation Format: Samantha S. Dykes, Dietmar W. Siemann. Small-molecule inhibition of cathepsins L and K as potential therapeutics for macrophage-driven breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 186.
Abstract 1864: Pharmacologic inhibition of NAMPT sensitizes pancreatic cancer cells to the antineoplastic effects of metformin
Authors: Ferbeyre Gerardo , Parisotto Maxime , Rowell Marie-Camille , Bourdeau Véronique , Schmitzer Andreea R. 
Published: August 2018

Abstract
The use of the anti-diabetic drug metformin has been correlated with a reduced cancer incidence, suggesting an unexpected anti-neoplastic activity for this compound. Since metformin treatment is safe and economical, there is considerable interest in exploring its anticancer activity in patients. Pancreatic cancer (pancreatic ductal adenocarcinoma: PDAC) is one of the most aggressive neoplastic diseases, for which there is no treatment significantly increasing patient's survival. Metformin use was associated with reduced pancreatic cancer incidence or better survival in diabetics. In vitro, metformin decreases cell survival and growth of pancreatic cancer cells and appears to target tumor-initiating cells. In vivo, metformin decreases growth of human pancreatic cancer cell lines xenografts in mice. However, clinical trials using metformin failed to decrease pancreatic cancer progression in patients, raising important questions about molecular mechanisms that protect tumor cells from the antineoplastic activities of metformin. We discovered a new mechanism of resistance to the anti-oncogenic properties of metformin in PDAC cells through up-regulation of NAMPT and increase of NAD+ synthesis. Using an inhibitor specific to NAMPT, FK866, we sensitized PDAC cells to the effects of metformin in vitro. In vivo, FK866 increased the efficiency of metformin treatment on KP4 cells xenografts. As both metformin and FK866 clinical trials have failed to efficiently treat cancer, the combination of these two compounds may be a promising strategy to treat pancreatic cancer and maybe other malignancies.
Citation Format: Gerardo Ferbeyre, Maxime Parisotto, Marie-Camille Rowell, Véronique Bourdeau, Andreea R. Schmitzer. Pharmacologic inhibition of NAMPT sensitizes pancreatic cancer cells to the antineoplastic effects of metformin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1864.
Abstract 1865: The combined treatment of 150 kHz Tumor Treating Fields (TTFields) and sorafenib inhibits hepatocellular carcinoma in vitro
Authors: Gotlib Karnit , Zeevi Einav , Schneiderman Rosa S. , Voloshin Tali , Giladi Moshe , Kinzel Adrian , Kison Eilon D. , Weinberg Uri , Palti Yoram 
Published: August 2018

Abstract
Hepatocellular carcinoma (HCC) remains a major health problem worldwide as the third cause of cancer related mortality and the primary cause of death. Currently, sorafenib, an oral multikinase inhibitor that blocks various signaling pathways, is the only drug that has been approved for patients with advanced hepatocellular carcinoma, yet its survival benefit is still limited. Tumor Treating Fields (TTFields) therapy is an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. TTFields are employed as a local treatment with the intent to target dividing cells by disrupting microtubules leading to mitotic catastrophe, abnormal chromosome segregation and the induction of different forms of cancer cell death. The aim of this work is to explore the potential of the use of TTFields alone and in combination with Sorafenib as a treatment for HCC.
HepG2 and Huh-7D12 cells were treated with various TTFields frequencies for 72 hours using the inovitro system. Efficacy of the combined treatment of TTFields and Sorafenib was tested by applying TTFields at the optimal frequency together with various drug concentrations. Cell counts, induction of apoptosis, cell cycle and clonogenic potential were determined at the end of treatment.
The optimal TTFields frequency leading to the highest reduction in cell counts was found to be 150 kHz for both HepG2 and Huh-7D12 cells. TTFields application (1.0 - 1.7 V/cm, 72 hours) at 150 kHz led to 53-64% reduction in cell counts and to additional reduction of over 70% in the clonogenic potential. The combined treatment of TTFields and Sorafenib led to a significant reduction in the number of HepG2 and Huh-7D12 cells (2-way ANOVA, p&lt;0.001 in both cell lines) as compared to each treatment alone.
The results presented in this work demonstrate that TTFields can be an effective treatment against HCC cells and that the combination with Sorafenib may further enhance treatment efficacy. Based on the above, there is a strong rational to continue exploring the potential of the use of TTFields together with standard of care for the treatment of HCC in the clinical settings.
Citation Format: Karnit Gotlib, Einav Zeevi, Rosa S. Schneiderman, Tali Voloshin, Moshe Giladi, Adrian Kinzel, Eilon D. Kison, Uri Weinberg, Yoram Palti. The combined treatment of 150 kHz Tumor Treating Fields (TTFields) and sorafenib inhibits hepatocellular carcinoma in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1865.