bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2537: CDK4/6 inhibition synergizes with KRAS-MAPK pathway targeting in pancreatic cancer
Authors: Castellanos Jason A. , Nagathihalli Nagaraj , Van Saun Michael N. , Kasmai Cameron , Xiong Yanhua , Merchant Nipun 
Published: August 2015

Abstract
Introduction:
Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult human malignancies to treat due to its innate and acquired therapeutic resistance. Our hypothesis is that cyclin-dependent kinase 4 (CDK4) mediates therapeutic resistance to targeting of the KRAS-MAPK pathway in PDAC.
Experimental Procedure:
We characterized the expression of total and phosphorylated Retinoblastoma (Rb) and MEK protein levels in KRAS wild-type (BxPC3) and KRAS mutant (PANC1, MiaPaca2) human PDAC cell lines at baseline and with MEK and CDK4 inhibition alone or in combination. We then assessed the effects of combined therapy on cell-cycle progression and tumorigenicity (in vitro and in vivo). Finally, using the Ptf1a cre/+;LSL-Kras G12D/+;Tgfbr2 flox/flox (PKT) mouse model of PDAC, we assessed the in vivo overall tumor growth and survival after combined treatment with CDK4/6 and MEK inhibitors.
Results:
Rb functions as a tumor suppressor, and it is inactivated when phosphorylated by CDK4-Cyclin-D1. The CDK4/6 inhibitor (LEE011) effectively inhibits phosphorylation of Rb in cell lines regardless of KRAS mutational status. Combined inhibition of CDK4/6 and MEK (MEK162) decreased phosphorylation of RB and MAPK expression synergistically in the KRAS mutant cell lines, but not the KRAS wild-type BxPC3 cell line. Cell cycle progression was delayed effectively with MEK inhibition alone in the KRAS wild-type cell line, yet only combined CDK4/6 and MEK inhibition effectively delayed cell cycle progression in the KRAS mutant cell lines. Colony formation and invasion were also significantly decreased when Kras mutant cells were treated with combined CDK4/6 and MEK inhibition compared to all monotherapy and control groups. Finally, treatment of PKT mice resulted in a modest increase in OS with MEK inhibition alone, but mice receiving combined CDK4/6 and MEK inhibition exhibited a four-fold increase in OS.
Conclusions:
Combined inhibition of CDK4/6 and MEK results in significantly enhanced therapeutic efficacy and prolonged survival in the aggressive PKT mouse model of PDAC. This study suggests that concurrent inhibition of CDK4/6 and MEK may be an effective treatment for PDAC.
Citation Format: Jason A. Castellanos, Nagaraj Nagathihalli, Michael N. Van Saun, Cameron Kasmai, Yanhua Xiong, Nipun Merchant. CDK4/6 inhibition synergizes with KRAS-MAPK pathway targeting in pancreatic cancer. [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 2537. doi:10.1158/1538-7445.AM2015-2537
Abstract 2538: The dietary isoflavone biochanin-A in combination with atorvastatin induces cell cycle arrest and apoptosis in human pancreatic cancer cells
Authors: Bhushan Alok , Selvakumar Ponniah , Tadinada Satya Murthy , Lai James C.K. 
Published: August 2015

Abstract
Pancreatic cancer is a devastating disease with a poor prognosis. The American Cancer Society's estimates for pancreatic cancer in the United States for 2014 are about 46,420 new cases of pancreatic cancer and about 39,590 deaths from pancreatic cancer. There remains a clear need for effective mechanism-based approaches that can achieve long-term improvements in the management pancreatic cancer. While natural products are well recognized as sources of drugs for various diseases including cancer, very few studies systematically explored the role of natural products for their potential preventive/therapeutic benefit in pancreatic cancer. Although several studies have examined the effect of flavonoids, there are no studies examining how biochanin-A or atorvastatin regulates pancreatic cancer cells. We investigated the cell proliferation studies in pancreatic cancer cell lines, AsPC-1 and MiaPaCa-2. Interestingly, we observed that by combination of treatment of Biochanin-A and atorvastatin significantly decreased the viability of AsPC-1 and MiaPaCa-2 cells. Several studies have been demonstrated the STAT3 play an important roll in the progression cancer pathogenesis in various cancers. We examined the STAT3 expression in pancreatic cell line, PANC-1 in biochanin-A or atorvastatin or in combination treatments and observed 95% decrease in the phosphorylation of STAT3 observed. Similarly the combination drug treatment employing biochanin A and atorvastatin decreased activation of Akt in AsPC-1 cell line. The decreased cell viability in AsPC-1 cell line involved increased induction of apoptosis with combination treatment and this evidence was further strengthened by increased PARP cleavage in combination treated cells. Further studies will delineate the mechanism of signaling arrested by the combination of drugs, Biochanin-A and atorvastatin in pancreatic cells with the possibility for uncovering improved therapeutic strategies to overcome the effectiveness to treat pancreatic cancer patients.
Citation Format: Alok Bhushan, Ponniah Selvakumar, Satya Murthy Tadinada, James C.K. Lai. The dietary isoflavone biochanin-A in combination with atorvastatin induces cell cycle arrest and apoptosis in human pancreatic cancer cells. [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 2538. doi:10.1158/1538-7445.AM2015-2538
Abstract 2540: A new mathematical model and software, to enable improved quantification and interpretation of combinatorial drug effects
Authors: Di Veroli Giovanni Y. , Jodrell Duncan I. , Richards Frances M. , Goldlust Ian 
Published: August 2015

Abstract
Drug combinations are used commonly to treat patients with cancer. Combination studies are conducted in vitro, to support advancement to in vivo and/or clinical research. In order to interpret in vitro data, mathematical models and numerical methods are used to quantify degrees of drug synergism. Several traditional approaches exist but they have been questioned with regard to how resulting synergy or antagonism levels should be interpreted. Our aim was to develop a robust method to analyse in vitro drug combination data, avoiding the issues related to traditional models and methods. To facilitate its implementation, software to enable rigorous and systematic assessment of combinations in vitro was also developed. We have derived a new mathematical model to identify synergy distributions based on drug combination dose response surfaces. Our new model and the classical Bliss, Loewe and HSA models were incorporated into the newly developed Combenefit software. Combenefit enables systematic quantification of high-throughput screening data, incorporating statistical assessment, metrics to describe synergy distributions and advanced graphical visualisation. Using multiple simulations of combination data with expected outcomes, our approach showed that it always provided appropriate evaluation while classical models failed to do so. We showed how our new model is in principle better aligned with in vivo requirements of identifying combinations which provide improvements compared to single agents. We then proceeded to analyse a large high-throughput combination screen. We first demonstrated that dataset assessment is strongly model-sensitive. We then demonstrated that our new model identified the best combinations in terms of dose response, thus confirming our simulated cases. Therefore, we have developed a new mathematical model that solves fundamental issues of model relevance that are encountered with classical models in the context of drug combinations. The newly developed Combenefit software enables easily performing rigorous and systematic quantification of in vitro combinations based on this novel approach. (Combenefit is freely available on our institutional website http://www.cruk.cam.ac.uk/combenefit). The resulting procedure is robust and better aligned with our perception of in vivo requirements.
Citation Format: Giovanni Y. Di Veroli, Duncan I. Jodrell, Frances M. Richards, Ian Goldlust. A new mathematical model and software, to enable improved quantification and interpretation of combinatorial drug effects. [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 2540. doi:10.1158/1538-7445.AM2015-2540
Abstract 2543: Akt and Myc cooperate to promote cell proliferation in Lck-Dlx5 T-cell lymphomas
Authors: Tan Yinfei , Sementino Eleonora , Testa Joseph 
Published: August 2015

Abstract
Constitutive activation of AKT is a frequent occurrence in the development of human T-cell acute lymphocytic leukemia/lymphoma (T-ALL), due largely to inactivation of PTEN. Up regulation of MYC is also commonly observed in T-ALL. We previously demonstrated that transgenic expression of a constitutively active form of Akt2 alone is sufficient to initiate T-cell lymphoma in mice, and that tumor formation typically requires up regulation of c-Myc or Dlx5 caused by specific chromosomal rearrangements. Here we report that transgenic overexpression of Dlx5 specifically in the mouse thymus can also drive T-cell lymphomagenesis. Tumors from these mice were characterized by loss of Pten expression and trisomy 15. Proliferation of these lymphoma cells was highly sensitive to the Akt pathway inhibitors BEZ235 and RAD001 as well as to the Myc inhibitor JQ1. Additionally, BEZ235 was found to cooperate with JQ1 to induce a more profound effect on cell cycle arrest and apoptosis. Moreover, BEZ235 potentiated vincristine-induced apoptosis when cells were treated with both drugs simultaneously, whereas pretreatment with BEZ235 antagonized the cell-killing effect of vincristine. These findings suggest that combination therapies with AKT and MYC inhibitors hold promise for the treatment of T-ALL in the clinic.
Citation Format: Yinfei Tan, Eleonora Sementino, Joseph Testa. Akt and Myc cooperate to promote cell proliferation in Lck-Dlx5 T-cell lymphomas. [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 2543. doi:10.1158/1538-7445.AM2015-2543
Abstract 2545: Effect of aldehydes in anthracycline cytotoxicity in S. cerevisiae
Authors: Miles Jana S. , Mazu Tryphon K. , Flores-Rozas Hernan 
Published: August 2015

Abstract
Anthracyclines constitute drugs of choice as single agents or in combination therapy in cancers that are refractory to other therapies, such as triple negative breast cancer, commonly observed in African-American women (AA) and is characterized for lacking biomarkers for targeted therapy, and for being aggressive and carrying bad prognoses. Anthracyclines effectiveness is dose-dependent, which increases the risk of side-effects and eventually the development of drug resistance. In S. cerevisiae, mutants of HOM6 display hypersensitivity to doxorubicin by inactivation of the homoserine dehydrogenase. We hypothesized that the L-aspartate-semialdehyde accumulating at this step, sensitizes the cells to anthracyclines. We confirmed this by inactivating HOM3, a prior step in the threonine biosynthesis pathway which prevents the accumulation of the L-aspartate-semialdehyde, rescuing the hom6 strain. To expand our knowledge of the relationship between aldehydes and anthracyclines, we sought to identify other aldehydes that can enhance the toxic effects of doxorubicin. We exposed S. cerevisiae to aldehydes (acetaldehyde, formaldehyde and glutaraldehyde) alone and combined with doxorubicin, cisplatin and menadione. Combination of formaldehyde (2 mM) and doxorubicin was most effective at reducing cell survival by between 31 to 39-fold (in wild type cells) relative to doxorubicin and formaldehyde alone. This effect was dose-dependent on doxorubicin. Co-treatment with formaldehyde and doxorubicin also showed increased toxicity in anthracycline-resistant strains siz1 and msh2. Combination of formaldehyde (2 mM) and menadione (60 mM) reduced cell survival by between 1- to 1.5-fold in wild type cells. Combination of acetaldehyde (2 mM) and menadione (60 mM) reduced cell survival by between 1.6- to 2.2-fold in wild type cells. Wild type cells treated with the combination of cisplatin (80 μM) and acetaldehyde (2 mM) or glutaraldehyde (2 mM) showed a reduced cell survival by between 0.4- to 3.12-fold with the combination of cisplatin and glutaraldehyde being the more cytotoxic of the two. Acetaldehyde, formaldehyde and glutaraldehyde show enhanced toxicity of wild type cells when combined with cytotoxic drugs. The potential use of a combination of aldehydes and cytotoxic drugs could potentially lead to applications intended to enhance anthracycline-based therapy.
Citation Format: Jana S. Miles, Tryphon K. Mazu, Hernan Flores-Rozas. Effect of aldehydes in anthracycline cytotoxicity in S. cerevisiae. [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 2545. doi:10.1158/1538-7445.AM2015-2545
Abstract 2547: PEGPH20 enhances chemotherapy in patient-derived and traditional cell-derived xenograft NSCLC models
Authors: Cowell Jessica A. , Li Xiaoming , Jiang Ping , Zimmerman Susan , Symons Rebecca , Shepard H. Michael , Maneval Daniel C. , Thompson Curtis B. 
Published: August 2015

Abstract
Hyaluronan (HA) accumulates in the tumor microenvironment (TME) of many solid tumors, including prostate, colon, breast, stomach, ovary, pancreas and lung, and HA accumulation is associated with tumor progression and a negative clinical outcome. Accordingly, the HA degrading enzyme pegylated recombinant human hyaluronidase PH20 (PEGPH20) was developed to allow systemic therapy and enable treatment of HA-high tumors. Preclinical studies have demonstrated that PEGPH20-mediated HA removal from HA-rich xenograft tumors in mice decreases tumor interstitial fluid pressure and water content; resulting in decompression of tumor vasculature, increased tumor perfusion and enhanced chemotherapeutic (CTX) activity. As non-small cell lung cancer (NSCLC) is the most common cancer worldwide and is characterized by high levels of HA (∼30%), we aimed to evaluate PEGPH20 enhancement of anti-tumor activity of NSCLC CTXs. Specifically, using both cell derived xenograft (CDX) models, peritibial H2170/HAS3 human NSCLC xenografts, and patient derived xenograft (PDX) models, we investigated CTX tumor growth inhibition (TGI)+/- PEGPH20. Nude mice were inoculated with either H2170/HAS3 cells adjacent to the tibial periosteum or patient derived tumor fragments of human NSCLCs implanted subcutaneously, and tumor growth was monitored via ultrasonography or caliper, respectively. When tumors reached ∼400 mm3, mice were staged into four groups: (1) vehicle; (2) PEGPH20, (3) CTX(s), or (4) PEGPH20 + CTX(s). PEGPH20 alone depleted tumor HA in both CDX and PDX models. In CDX studies, PEGPH20 increased tumor perfusion, reduced hypoxia and decreased HIF-1α expression (p&lt;0.05). A summary table of the TGI data is shown below. The average TGI for PEGPH20 plus CTX(s) was superior to all CTX(s) alone, suggesting that enzymatic depletion of TME HA increases tumor sensitivity to NSCLC CTXs, likely due to increased CTX access into the TME. PEGPH20 clinical trials in NSCLC are currently in development.
Summary of TGIsGroup (n≥5/group)CDX%TGI w/ docetaxelCDX%TGI w/ nab-paclitaxel + carboplatinPDX%TGI w/ docetaxelPDX%TGI w/ gemcitabine + cisplatin(p-value vs. V)Vehicle (V)----PEGPH20 (P)28.5 (p&lt;0.05)11.5 (p&gt;0.05)44.4 (p&lt;0.01)29.3 (p&gt;0.05)CTX(s)19.8 (p&gt;0.05)68.6 (p&lt;0.0001)52.5 (p&lt;0.001)38.4 (p&gt;0.05)P + CTX56.1 (p&lt;0.001)93.5 (p&lt;0.0001)&gt;100 (p&lt;0.0001)76.6 (p&lt;0.01)
Citation Format: Jessica A. Cowell, Xiaoming Li, Ping Jiang, Susan Zimmerman, Rebecca Symons, H. Michael Shepard, Daniel C. Maneval, Curtis B. Thompson. PEGPH20 enhances chemotherapy in patient-derived and traditional cell-derived xenograft NSCLC models. [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 2547. doi:10.1158/1538-7445.AM2015-2547
Abstract 2558: The mechanistic study on the effect of platinum-based chemotherapy efficacy imposed by EGFR-TKI regulated ERCC1 in non-small cell lung cancer (NSCLC)
Authors: Cheong Hio Teng , Hui Connie Wun Chun , Xu Fei , Mok Tony Shu Kam , Wong Chi Hang 
Published: August 2015

Abstract
Platinum-based chemotherapy is conventionally the first line treatment for EGFR wild type patients while EGFR-TKI is the standard for patients with mutation. Subgroup biomarker studies conducted in FASTACT-2 (Wu et al Lancet Oncology 2013) indicated that patients with positive ERCC1 attained longer overall survival and progression free survival under intercalated chemotherapy and EGFR-TKI, in comparison with solely chemotherapy. EGFR-TKI is postulated to down-regulate ERCC1 expression in EGFR wild type NSCLC cells, hence enhancing the Chemo efficacy. The study aims to investigate the missing link between EGFR and ERCC1 in the perspective of mechanistic means.
In vitro and in vivo studies were devised to examine the impact imposed on ERCC1 by EGFR-TKI. H1993 cells underwent a 72-hour EGFR-TKI treatment and transient siRNA transfection for ERCC1 suppression. Cell viability assay was employed for detecting the cisplatin sensitivity of the transfected cells. Xenograft tumor models were established with a 2-week treatment of oral erlotinib on animals, using western blot and IHC to study the ERCC1 expression. Human EGFR Phosphorylation Membrane Array was used to study the EGFR phosphorylation pattern involved in ERCC1 level alterations and its downstream pathways were further analyzed with western blot.
ERCC1 expression level is not correlated with EGFR-TKI sensitivity. Nonetheless, ERCC1 level gradually decreased along the 72-hour exposure of EGFR-TKI. The cells’ sensitivity towards cisplatin was raised upon ERCC1 knock-down with its IC50 reduced from 14.67μM to 0.16μM. Furthermore, TKI showed a significant reduction in ERCC1 level with IHC staining after treatment yet no sequel on the tumor volume of the xenografts. On the mechanistic side, 6 out of 17 EGFR phosphorylation sites were found compelling in respond to variations on ERCC1 level. We discovered that the MAPK/ERK and JNK pathways were the potential candidates that regulated EGFR associated ERCC1 expression.
In summary, the data manifested that EGFR-TKI may reduce ERCC1 expression and latently enhance sensitivity towards cisplatin. MAPK/ERK and JNK pathways may contribute in ERCC1 regulation. With the preliminary screening results, it warrants further investigation to validate the underlying mechanism for the regulation of ERCC1 expression level.
Citation Format: Hio Teng Cheong, Connie Wun Chun Hui, Fei Xu, Tony Shu Kam Mok, Chi Hang Wong. The mechanistic study on the effect of platinum-based chemotherapy efficacy imposed by EGFR-TKI regulated ERCC1 in non-small cell lung cancer (NSCLC). [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 2558. doi:10.1158/1538-7445.AM2015-2558
Abstract 2563: Modulation of DNA damage responses and cytotoxicity of bleomycin by vitamin C
Authors: Rubis Blazej , Zhitkovich Anatoly 
Published: August 2015

Abstract
Bleomycin (BL) is an iron-chelating chemical that is used for treatment of several types of cancer. The administration of this drug to patients is also associated with significant side effects, including life-threatening lung fibrosis. Biological factors affecting chemotherapeutic effectiveness of BL and the severity of its major side effects remain poorly understood. Cytotoxic effects of BL are attributed to its ability to cause DNA breaks via oxidative reactions by chelated iron. Ascorbate is a main cellular antioxidant, which can also promote redox cycling of iron by reducing its ferric form. Standard cultures of human cells contain less than 1% of physiological amounts of vitamin C, raising concerns whether common in vitro models adequately recapitulate major mechanistic aspects of BL toxicity in vivo. In this work, we investigated the effects of intracellular ascorbate on cell killing and DNA damage-activated stress responses by BL. We found that replenishment of human lung carcinoma cells with ascorbate increased cytotoxicity and clonogenic lethality of BL. Examination of DNA damage responses in BL-treated cells found that cellular ascorbate enhanced some signaling branches while suppressing others. Ascorbate-restored cells also displayed an increased dependence on nonhomologous end-joining DNA repair for their long-term survival. Overall, our results show that restoration of ascorbate levels increases sensitivity of cancer cells to killing by BL and alters their DNA damage responses. Low ascorbate levels in hypoxic tumors can contribute to their resistance to BL-based therapy.
Citation Format: Blazej Rubis, Anatoly Zhitkovich. Modulation of DNA damage responses and cytotoxicity of bleomycin by vitamin C. [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 2563. doi:10.1158/1538-7445.AM2015-2563