bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2917: Caspase-8 expression is predictive of tumor response to death receptor 5 agonist antibody conatumumab in Ewing's sarcoma
Authors: Kang Zhigang , Goldstein D Seth , Yu Yunkai , Meltzer Paul S. , Loeb David M. , Cao Liang 
Published: August 2015

Abstract
Despite good initial response to cytotoxic chemotherapy, approximately 30% of Ewing's sarcoma (EWS) patients who present with localized tumors develop recurrent disease, which is associated with poor prognosis. Addressing this clinical challenge requires the development of targeted therapies. This study shows that many EWS cell lines are selectively sensitive to a death receptor DR5 antibody and are more resistant to a DR4 antibody. Preclinical evaluation of these cell lines indicates their sensitivity to human DR5 agonist antibody conatumumab in vitro, which induces rapid activation of caspase-8 and apoptosis. Further analysis reveals the correlation of sensitivity to conatumumab with the expression of caspase-8, with its catalytic activity both necessary and sufficient to confer such sensitivity. In vivo, conatumumab has active against both EWS cell lines and a patient-derived xenograft with higher caspase-8 expression, but is not effective against another patient-derived xenograft with lower caspase-8 expression. These studies suggest the potential of conatumumab as a therapeutic agent against EWS and caspase-8 as a biomarker for correlative studies.
Citation Format: Zhigang Kang, D Seth Goldstein, Yunkai Yu, Paul S. Meltzer, David M. Loeb, Liang Cao. Caspase-8 expression is predictive of tumor response to death receptor 5 agonist antibody conatumumab in Ewing's sarcoma. [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 2917. doi:10.1158/1538-7445.AM2015-2917
Abstract 2922: Development of Bcl2 BH4 antagonist for cancer therapy
Authors: Han Bingshe , Park Dongkyoo , Li Rui , Xie Maohua , Owonikoko Taofeek , Sica Gabriel , Ding Chunyong , Zhou Jia , Magis Andrew , Ramalingam Suresh , Khuri Fadlo , Curran Walter , Deng Xingming 
Published: August 2015

Abstract
The BH4 domain of Bcl2 is required for its antiapoptotic function, thus constituting a promising anticancer target. We identified a novel small molecule Bcl2-BH4 domain-antagonist (BDA-366) that binds BH4 with high affinity and selectivity. BDA-366-Bcl2 binding induces conformational change in Bcl2 that abrogates its antiapoptotic function, converting it from a survival to a cell death inducer. BDA-366 induces regression of lung cancer xenografts derived from cell line and patient without significant normal tissue toxicity at effective doses. mTOR inhibition up-regulates Bcl2 in lung cancer cells and tumor tissues from clinical trial patients. Combined BDA-366 and RAD001 treatment exhibits strong synergy against lung cancer in vivo. Development of this Bcl2-BH4 antagonist may provide a novel strategy to improve lung cancer outcome.
Citation Format: Bingshe Han, Dongkyoo Park, Rui Li, Maohua Xie, Taofeek Owonikoko, Gabriel Sica, Chunyong Ding, Jia Zhou, Andrew Magis, Suresh Ramalingam, Fadlo Khuri, Walter Curran, Xingming Deng. Development of Bcl2 BH4 antagonist for cancer therapy. [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 2922. doi:10.1158/1538-7445.AM2015-2922
Abstract 2923: A novel cell-penetrating peptide targeting ATF5 (CP-d/n-ATF5) exerts anti-cancer activity in vitro and in vivo against a broad spectrum of human cancers
Authors: Karpel-Massler Georg , Shu Chang , Chau Lily , Angelastro James M. , Greene Lloyd A. , Siegelin Markus D. 
Published: August 2015

Abstract
Background
The purpose of this study was to validate the anti-neoplastic activity of a novel ATF5-targeted therapeutic approach against various recalcitrant human malignancies. Activating transcription factor 5 (ATF5) is a member of the cAMP response element binding (CREB)/ATF subfamily of basic leucine zipper transcription factors and has been shown to be overexpressed in many human cancers. CP-d/n-ATF5 is a novel peptide specifically designed to contain a cell-penetrating domain and a domain inhibiting the function of ATF5 in a unique and novel targeted therapeutic approach. This therapeutic strategy was tested among a large panel of different therapy refractory human cancers including glioblastoma, melanoma, breast, prostate-, lung- and pancreatic cancer.
Methods
Cellular viability was assessed by MTT-assays. The induction of apoptosis was examined by staining for annexin V/propidium iodide or JC-1 (loss of mitochondrial membrane potential) prior to flow cytometric analysis. Western blotting was performed for further molecular analysis detecting caspase cleavage and expression of Bcl-2 family members. Subcutaneous xenograft models were used to examine the anti-neoplastic effects of CP-d/n-ATF5 in vivo.
Results
Our data show that CP-d/n-ATF5 yields a significant increase in apoptosis across a panel of 10 different cancer cell lines when compared to treatment with a mock-mutated control peptide or penetratin. On the molecular level, treatment with CP-d/n-ATF5 resulted in a marked down-regulation of the anti-apoptotic Bcl-2 family members Mcl-1 and Bcl-2. This effect was amplified in a synergistic manner by adding either ABT-263 or TRAIL to a combined targeted therapeutic approach. In vivo, treatment with CP-d/n-ATF5 resulted in a significant reduction of tumor growth in a heterotopic glioblastoma- and an orthotopic melanoma model.
Conclusions
The novel ATF5-targeting compound CP-d/n-ATF5 provides a broad and pronounced anti-neoplastic activity against human cancers in vitro and in vivo. On the molecular level, this effect is at least in part due to a shift of the cellular homeostasis towards a pro-apoptotic cellular phenotype by inhibiting anti-apoptotic Bcl-2 family proteins. Overall, CP-d/n-ATF5 may represent a promising novel anti-cancer agent.
Citation Format: Georg Karpel-Massler, Chang Shu, Lily Chau, James M. Angelastro, Lloyd A. Greene, Markus D. Siegelin. A novel cell-penetrating peptide targeting ATF5 (CP-d/n-ATF5) exerts anti-cancer activity in vitro and in vivo against a broad spectrum of human cancers. [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 2923. doi:10.1158/1538-7445.AM2015-2923
Abstract 2926: DR5-targeting sensitizes Lgr5+ stem cells to p53 and Chk2-dependent chemotherapy-induced cell death and produces dose-limiting gastrointestinal toxicity (GIT)
Authors: Finnberg Niklas K. , Gokare Prashanth , Navaraj Arunasalam , Lang Kuhs Krystle A. , Cerniglia George , Yagita Hideo , Takeda Kazuyoshi , Motoyama Noboru , El-Deiry Wafik S. 
Published: August 2015

Abstract
Current ongoing clinical trials are exploring combined targeting of the TRAIL-death receptor DR5 with radiochemotherapy. It is not clear mechanistically why targeting of the DR5 increasingly sensitizes cancer cells to cell death without affecting cells in normal tissues. Preclinical data suggests that integration of DR5 agonist antibodies into chemotherapy protocols has the promise to significantly improve cancer specific responses without negatively impacting dose-limiting toxicities. Here we show that targeting of DR5 in mice with the mouse-specific mAb MD5-1 in combination with chemotherapy triggers synergistic gastrointestinal toxicities (GIT) that is associated with the death of Lgr5+ crypt basal columnar (CBC) cells. This type of GIT is mediated by p53 and in the case of irinotecan, the cell cycle checkpoint kinase 2 (Chk2). Pharmacologic targeting of Chk2 sensitized syngeneic mouse colorectal cancer tumors lacking P53 to the irinotecan/MD5-1 combination while at the same time protecting the gastrointestinal tract from injury. Our data indicates that blockade of cell cycle checkpoint kinases can help prevent GIT triggered by a combination of DNA damaging chemotherapy and DR5 agonists. Pharmacologic targeting of Chk2 can improve the anti-tumor response of such drug combinations and subsequently provides a rationale on how to improve therapeutic indices of DR5-targeting in the context of chemotherapy usage.
Citation Format: Niklas K. Finnberg, Prashanth Gokare, Arunasalam Navaraj, Krystle A. Lang Kuhs, George Cerniglia, Hideo Yagita, Kazuyoshi Takeda, Noboru Motoyama, Wafik S. El-Deiry. DR5-targeting sensitizes Lgr5+ stem cells to p53 and Chk2-dependent chemotherapy-induced cell death and produces dose-limiting gastrointestinal toxicity (GIT). [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 2926. doi:10.1158/1538-7445.AM2015-2926
Abstract 2932: Role of death receptor 5 (DR5) in apoptosis induced by anticancer agents in colon cancer cells
Authors: Tong Jingshan , Yu Jian , Zhang Lin 
Published: August 2015

Abstract
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor, also called death receptor 5 (DR5; TRAIL receptor2), is a member of the death receptor family that shares a cysteine-rich extracellular domain and a cytoplasmic death domain. DR5 is located on cell surface, becomes activated upon binding to its ligand TRAIL or overexpression, and then signals apoptosis initiation through an FADD/caspase 8-dependant caspase activation cascade. A number of previous studies showed that DR5 expression is induced upon chemotherapy treatment. However, whether DR5 induction is necessary for apoptosis induction has remained unclear. To determine its functional role in chemotherapy-induced apoptosis, we used homologous recombination to knock out (KO) DR5 in HCT116 colon cancer cells, and then analyzed response of DR5 KO cells to a panel of anticancer agents. Compared to parental HCT116 cells, DR5 KO cells are less sensitive to TRAIL, the DNA damaging drug 5-FU, the non-steroidal anti-inflammatory drug (NSAID) sulindac, as well as several other classes of anticancer agents. We also investigated how these agents induce apoptosis through DR5. Together, our results indicate a critical role of DR5 in mediating therapeutic response of colorectal cancer cells.
Citation Format: Jingshan Tong, Jian Yu, Lin Zhang. Role of death receptor 5 (DR5) in apoptosis induced by anticancer agents in colon 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 2932. doi:10.1158/1538-7445.AM2015-2932
Abstract 2936: Mitochondria dysfunction-mediated apoptosis resistance associates with defective heat shock protein response in African American prostate cancer
Authors: Chaudhary Ajay K. , Bhatt Tariq A. , Kumar Sandeep , Underwood Willie , Koochekpour Shahriar , Shourideh Mojgan , Yadav Neelu , Chandra Dhyan 
Published: August 2015

Abstract
African American (AA) patients with prostate cancer (PCa) respond poorly to current therapy compared to Caucasian American (CA) patients. Although underlying mechanisms are not clearly defined, mitochondria dysfunction is a key reason for PCa disparity. We observed that glycolytic pathway inhibitor dichloroacetate (DCA) inhibited cell proliferation in both AA PCa cells (AA cells) and CA PCa cells (CA cells). CA cells were arrested at G1 and G2/M phases whereas S-phase arrest was observed in AA cells. AA cells showed resistance to cell death upon DCA exposure in spite of higher caspase activation than in CA cells. AA cells possess reduced level of reactive oxygen species (ROS) and mitochondrial membrane potential (mtMP) compared to CA cells. DCA induced cellular and mitochondrial ROS in AA cells but were unchanged in CA cells. DCA upregulated the levels of mtMP in both cell types. DCA enhanced taxol-induced cell death only in CA cells, but DCA sensitized doxorubicin-induced AA cell death. Expression of heat shock proteins (HSPs) were inhibited only in AA cells upon doxorubicin alone or combined treatment of DCA with doxorubicin, whereas Taxol alone or in combination with DCA did not show any changes in the levels of HSPs. DCA suppressed the metastatic features and reduced the population of cancer stem cell-like cells in CA cells but had a little effect on AA cells. Therefore, anticancer agents that can effectively restore mitochondria function may provide new therapeutic potential in reducing PCa health disparity and poor prognosis in AA men with PCa.
Citation Format: Ajay K. Chaudhary, Tariq A. Bhatt, Sandeep Kumar, Willie Underwood, Shahriar Koochekpour, Mojgan Shourideh, Neelu Yadav, Dhyan Chandra. Mitochondria dysfunction-mediated apoptosis resistance associates with defective heat shock protein response in African American prostate 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 2936. doi:10.1158/1538-7445.AM2015-2936
Abstract 2937: MEK/ERK inhibitor GDC-0623 dephosphorylates and accumulates BIM that enables a synergistic apoptosis with the Bcl-xL antagonist, ABT-263, in mutant KRAS colorectal cancer cells
Authors: Zaanan Aziz , Okamoto Koichi , Kawakami Hisato , Huang Shengbing , Sinicrope Frank 
Published: August 2015

Abstract
Background. Oncogenic KRAS mutations occur in nearly one-half of colorectal cancers (CRC) where they contribute to de novo apoptosis resistance and treatment failure. Inhibition of MEK/ERK is a promising strategy to sensitize KRAS mutant tumors to apoptosis that may involve upregulation of pro-apoptotic BH3-only proteins, including BIM. However, BH3-only proteins can be neutralized by anti-apoptotic Bcl-xL that we found was upregulated in isogenic KRAS mutant compared to wild-type HCT116 and DLD1 CRC cells.
Aims. We determined the ability and mechanism by which a novel MEK/ERK inhibitor, GDC-0623, can induce BIM to promote apoptotic signaling. A strategy of concurrent induction of BH3-only proteins and antagonism of Bcl-xL was studied to overcome mutant KRAS-mediated apoptosis resistance.
Results. Using isogenic KRAS HCT116 cells and KRAS mutant SW620 cells, we found that GDC-0623 can potently induce the BH3-only protein BIM, and to a lesser extent BIK, in both KRAS wild-type and mutant cells. Only KRAS mutant cells remained resistant to GDC-0623-induced apoptosis. Knockdown of Bcl-xL or use of a BH3 mimetic drug, ABT-263, sensitized KRAS mutant cells to GDC-0623-mediated apoptosis. GDC-0623 and ABT-263 were shown to interact synergistically to promote apoptosis in KRAS mutant cells. Dependence on BIM or BIK for synergy between GDC-0623 and ABT-263 was shown by shRNA knockdown that each attenuated drug-induced apoptosis. Mechanistically, ABT-263 treatment was shown to release BIM from its binding to Bcl-xL using immunoprecipitation. The ability of GDC-0623 to induce apoptosis occurred via BIM that was phosphorylated by MEK/ERK activation leading to BIM degradation. GDC-0623 was shown to dephosphorylate BIM at serine 69 in cells with wild-type BIM or a phospho-mimic mutation (S69E). However, GDC-0623's ability to dephosphorylate BIM was lost in cells containing a phosphorylation-defective BIM mutation (S69G) that showed delayed BIM degradation.
Conclusion. GDC-0623 was shown to dephosphorylate BIM to enhance its accumulation and to promote apoptosis. Concurrent induction of BIM/BIK and antagonism of Bcl-xL can overcome mutant KRAS-mediated apoptosis resistance, suggesting a promising therapeutic strategy against KRAS mutant CRCs.
Note: This abstract was not presented at the meeting.
Citation Format: Aziz Zaanan, Koichi Okamoto, Hisato Kawakami, Shengbing Huang, Frank Sinicrope. MEK/ERK inhibitor GDC-0623 dephosphorylates and accumulates BIM that enables a synergistic apoptosis with the Bcl-xL antagonist, ABT-263, in mutant KRAS colorectal 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 2937. doi:10.1158/1538-7445.AM2015-2937
Abstract 2938: BMI-1 inhibition by PTC-209 induces mitochondrial apoptosis in acute myeloid leukemia cells
Authors: Kojima Kensuke , Nishida Yuki , Maeda Aya , Chachad Dhruv , Kitamura Hiroaki , Ishizawa Jo , Andreeff Michael , Kimura Shinya 
Published: August 2015

Abstract
Leukemia stem cells play important roles in leukemia initiation, progression, and relapse, and represent a critical target for therapeutic intervention. BMI-1 is essential for the self-renewal of normal hematopoietic and leukemia stem cells. High expression of BMI-1 has been associated with poor prognosis in AML. PTC-209 is a novel transcriptional inhibitor of BMI-1, which has been reported to exhibit antitumor activity against cancer-initiating cells in colorectal cancer. We investigated anti-leukemia effects of the BMI-1 inhibitor PTC-209 on AML cells. A total of 8 AML cell lines (MOLM-13, OCI-AML3, MV4-11, NB4, HL-60, U-937, MOLM-14, OCI-AML2) were treated with different concentrations of PTC-209 for 48 hours and the IC50 values (concentration at which cell growth is inhibited by 50% at 48 hours of exposure) and the ED50 values (effective concentration inducing 50% killing as measured by Annexin V positivity) were determined. The IC50 values were 0.38 ± 0.07 μM (mean ± SEM), indicating high anti-proliferation effect. The ED50 values ranged from 1.2 to 2.6 μM in 7 cell lines (1.97 ± 0.22 μM) and the remaining cell line (NB4) showed relative resistance to PTC-induced apoptosis (&gt; 10 μM). PTC-209 exhibited dose- and time-dependent anti-proliferative and cytotoxic activities, by inducing G1-S transition delay and apoptosis. PTC-209 induced conformational change of BAX (i.e., BAX activation), loss of mitochondrial membrane potential (MMP), caspase-3 activation and DNA fragmentation in addition to phosphatidylserine (PS) externalization, indicating mitochondrial apoptosis. PTC-209 induced Annexin V in primary AML cells (23.4 ± 4.6% after 48-hour treatment with 1 μM PTC-209, n = 23) in a dose-dependent manner, which is more prominent in immature CD34+CD38- population (33.7 ± 6.0%; P = 0.0036). In accordance with its high anti-leukemia activity, PTC-209 strongly reduced cellular BMI-1 levels in CD34+CD38- AML cells. Higher reduction of BMI-1 expression was positively correlated with higher susceptibility to PTC-209 in CD34+CD38- AML cells (r = 0.88; P = 0.047). The apoptotic activity was observed independent of p53 or FLT3 mutational status of the leukemia cells. Our data suggest that BMI-1 inhibition by small molecule inhibitors may be developed into a novel therapeutic strategy for AML. (Drs M. Andreeff and S. Kimura are co-senior authors with equal contribution to the work)
Citation Format: Kensuke Kojima, Yuki Nishida, Aya Maeda, Dhruv Chachad, Hiroaki Kitamura, Jo Ishizawa, Michael Andreeff, Shinya Kimura. BMI-1 inhibition by PTC-209 induces mitochondrial apoptosis in acute myeloid leukemia 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 2938. doi:10.1158/1538-7445.AM2015-2938
Abstract 2939: Induction of apoptosis in prostate cancer cells by altering cell metabolism
Authors: Torga Gonzalo , Mooney Steven , Zarif Jelani C. , Pienta Kenneth J. 
Published: August 2015

Abstract
The levels of ceramides, sphingosine and their related metabolites have been reported to play an important role in cell fate by determining the balance between apoptosis and cell survival signaling through what has been called the sphingolipid rheostat. One of sphingosine metabolic product, sphingosine-1-phosphate, has been widely proven to be related with tumor growth, resistance to apoptosis, angiogenesis, metastasis and invasiveness in several tumors. In prostate cancer, sphingosine-1-phosphate levels correlate with risk of progression to castration-resistant prostate cancer (CRPC), PSA levels, Gleason score, positive surgical margins, lymph node extension, metastatic extension and mortality.
Hypoxia-inducible factors (HIFs) act as pleiotropic transcription factors which serve as major components for cancer progression, upregulation of HIFs are essential for metastasis and tumor growth once hypoxia has ensued. Several relations between HIFs and ceramides/sphingosine metabolism have been reported recently, suggesting that both mechanisms might be somehow interconnected.
Despite decades of research inhibitors to HIF have been few and far between. The DNA-intercalating agent doxorubicin was identified one such inhibitor by a mechanism not yet understood. The major mechanism of doxorubicin-mediated apoptosis has been established to be induced by the transcription factor, p53. The p53 cell cycle arrest is usually through p21 which has been shown to have enhanced expression in response to sphingosine kinase 2, one of the enzymes that mediate the conversion of sphingosine to sphingosine-1-phosphate.
Several studies associating chemotherapy with different drugs that attempt to modify sphingosine and ceramides metabolism have been published with some remarkable results, although never complete responses. We hypothesize that the incomplete responses may be due to an incomplete blockade of the conversion of ceramides and sphingosine towards their phosphorylated metabolites, sphingosine-1-phosphate and ceramide-1-phospate respectively.
Previous work has focused on single agents to enhance chemotherapy. In this work we are interested in studying the combination of different modifiers in the metabolism of ceramides/sphingosine with doxorubicin in order to achieve a total metabolic blockade in an effort to elicit a complete clinical response for prostate cancer.
Citation Format: Gonzalo Torga, Steven Mooney, Jelani C. Zarif, Kenneth J. Pienta. Induction of apoptosis in prostate cancer cells by altering cell metabolism. [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 2939. doi:10.1158/1538-7445.AM2015-2939