bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2069: Overcoming drug resistance by targeting melanoma dedifferentiation through information-theoretic analysis and single cell proteomics
Authors: SU Yapeng , Wei Wei , Robert Lidia , Tsoi Jennifer , Xue Min , Kim Jungwoo , Graeber Thomas , Levine Raphael , Ribas Antoni , Heath James 
Published: July 2017

Abstract
Despite impressive initial response of BRAF targeted therapy in mestastic melanoma patients, acquired drug resistance, often times derived from tumor heterogeneity, always limit its clinical outcome. A dedifferentiation process named melanocyte to neural crest transition (MNT) has shown to be critical in the early stage resistance development. The dedifferentiation could induce a whole cell state change resulting a drug tolerant state of melanoma cells, which will lead to initial drug resistance. Mathematic modeling indicates the nature of the transition as results of both stochastic phenotypic transition and non-genetic drug selection, which indicates and further proved that the whole cell state transition should be reversible during drug removal. Information theoretic analysis reduced the dimensional of thousands of gene expression level changes as results of only two unbalanced processes onto a cellular steady state. Reversible transition trajectory defined through two processes indicates it to resemble a critical transition in physical systems. Refined single cell proteomic analysis of those proteins that associate with major unbalanced processes identify the critical points of the transition as early as day6, which cannot be resolved from bulk proteomic measurement. By co-targeting the drivers at the critical points in combination with original brafi targeted drug successfully arrested the transition and induced a sustained tumor growth inhibition in multiple patient-derived melanoma cell lines. This study provides us a noval methodology of mining whole transcriptomic transition with information theoretic analysis to reduce the dimensionality and then using single cell proteomic analysis for refining critical points and driver proteins which eventually rationalized a effective combination therapy to stop the drug resistance development early on.
Citation Format: Yapeng SU, Wei Wei, Lidia Robert, Jennifer Tsoi, Min Xue, Jungwoo Kim, Thomas Graeber, Raphael Levine, Antoni Ribas, James Heath. Overcoming drug resistance by targeting melanoma dedifferentiation through information-theoretic analysis and single cell proteomics [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 2069. doi:10.1158/1538-7445.AM2017-2069
Abstract 2096: Bozitinib, a highly selective inhibitor of cMet, demonstrates robust activity in gastric, lung, hepatic and pancreatic in vivo models
Authors: Shih Joe , Zhong Boyu , Shi Hepeng , Xue David , Choy Gavin S. , Redkar Sanjeev 
Published: July 2017

Abstract
Background: cMET is a receptor tyrosine kinase that is located on the cell surface and is activated by the binding of its ligand, hepatocyte growth factor (HGF). In cancer cells, MET can be aberrantly active and cause abnormal signaling, which leads to tumor growth, angiogenesis, and metastasis. In vitro studies have demonstrated that bozitinib (CBT-101, PLB-1001) is a highly selective and specific inhibitor (8 nM) of tumor cell proliferation.
Methods: In-vivo PD studies of gastric (MKN45), lung (LUM858, LU1901, LU2503), hepatic (LIM0612, LIM0801), and pancreatic (KP4) were evaluated. These models covered both the HGF-dependent and HGF-independent mechanisms. Among these models, LUM858, LU1901, LU2503, LIM0612 and LIM0801 are PDX models. In particular, in the LU1901 model, bozitinib (BT) was compared to capmatinib (INC280). Groups included: BT at 1, 3 and 10 mg/kg QD×21 and INC280 at 1, 3, and 10 mg/kg QD×21 and 10 mg/kg BID×21 via IG, CDDP 5 mg/kg, Q7D×3 as a positive control via IP and the vehicle control (QD×21 via IG). Each group (n=8 mice) and the tumor volume was evaluated on D21.
Results: In MKN45, LU2503, LIM0612 and LIM0801, the effect of BT seemed superior than that of crizotinib; in LUM858, its effect was higher than that of erlotinib; in LU1901, its effect was higher than that of crizotinib and INC280. In the LU1901 model, the strongest activity was observed at BT 10 mg/kg with a T/C ratio of 2%, compared to an equi-dose of INC280 (T/C of 22%). All doses of BT and INC280 were well tolerated; no mouse experienced weight loss. In MKN45 model, BT showed a PK/PD correlation and dose-dependence. BT inhibited the phosphorylation of c-Met protein; the rate of target inhibition exceeded 90% at &gt;7 mg/kg. The plasma concentration for BT decreased over time with a significant decrease 16h after its administration, conferring at least 16h of phosphorylation inhibition of the c-Met protein.
Conclusions: In conclusion, BT was well-tolerated, with no animal death nor major weight loss. The in vivo experiments demonstrated that BT is a viable candidate with effective anti-tumor activities. BT is currently under evaluation in cMet dysregulated NSCLC (NCT02896231) with additional trials planned.
Citation Format: Joe Shih, Boyu Zhong, Hepeng Shi, David Xue, Gavin S. Choy, Sanjeev Redkar. Bozitinib, a highly selective inhibitor of cMet, demonstrates robust activity in gastric, lung, hepatic and pancreatic in vivo models [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 2096. doi:10.1158/1538-7445.AM2017-2096
Abstract 2109: Transcriptional analysis of human leukemia cells treated with the experimental anticancer drug laromustine
Authors: Loya Amanda J. , Cincotta Dylan J. , Elkahloun Abdel , Bodine David , Rice Kevin P. 
Published: July 2017

Abstract
Laromustine is an experimental anticancer prodrug that demonstrated significant activity against acute myeloid leukemia in human clinical trials. Upon base-catalyzed activation, laromustine yields two reactive, electrophilic species in situ: 90CE, which can chloroethylate the O6 position of guanine in DNA causing lethal interstrand crosslinks, and methyl isocyanate, which can carbamoylate biochemically relevant nucleophiles, such as cysteine sulfhydryl groups. Previous in vitro and ex vivo investigations into laromustine’s molecular mechanism of action reveal several biochemical consequences of methyl isocyanate, many of which may explain either the acute cytotoxicity of the drug’s carbamoylating activity or the observed synergism with the cytotoxicity of guanine O6 chloroethylation. The combined activities of the electrophilic subspecies of laromustine are believed to induce apoptosis in leukemia cells. Presented herein are extensive flow cytometry experiments using FITC-AnnexinV and propidium iodide suggesting a dose-dependent cytotoxicity that includes apoptotosis. So as to gain a more complete understanding of the drug’s toxicity, an investigation into how laromustine modulates gene transcription in HL60 cells is also carried out and reported here. Total mRNA was harvested from cultured HL60 cells treated with sub-lethal doses of laromustine or analogs lacking either carbamoylating or chloroethylating activity. These samples were subjected to GeneChip analyses against control mRNA. More than 4,000 genes were significantly dysregulated upon the cells’ exposure to laromustine. The analog of laromustine possessing only carbamoylating activity caused the dysregulation of nearly 3,000 genes, the vast majority of which were also dysregulated in response to laromustine. 90CE, which lacks carbamoylating activity but retains chloroethylating activity, understood to be principally responsible for therapeutic cytotoxicity, demonstrated very little effect on gene transcription in HL60 cells. Preliminary analysis of gene pathways affected by laromustine suggests that among the altered pathways, those associated with cancer progression, the G1/S checkpoint, and hematological disorders are particularly stressed. The carbamoylating activity of laromustine is responsible for most of these effects. Identifying genetic pathways disrupted by this potentially useful drug may inform clinical strategies or identify potential targets for co-therapeutic agents.
Citation Format: Amanda J. Loya, Dylan J. Cincotta, Abdel Elkahloun, David Bodine, Kevin P. Rice. Transcriptional analysis of human leukemia cells treated with the experimental anticancer drug laromustine [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 2109. doi:10.1158/1538-7445.AM2017-2109
Abstract 2114: Targeting invasive and drug-resistant PDAC with photodynamic therapy
Authors: Cramer Gwendolyn , Jafari Seyedehrojin , El-Hamidi Hamid , Jones Dustin , Celli Jonathan 
Published: July 2017

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with an extensive desmoplastic reaction and a characteristic extracellular matrix (ECM)-rich stromal microenvironment which is a major determinant of disease progression and therapeutic response. Using 3D cell culture models of PDAC, we recently showed that an invasion-promoting ECM composition leads to differential response to chemotherapy agents and photodynamic therapy (PDT), in which cytotoxic response is triggered by light activation of a photosensitizing agent. In particular, ECM-infiltrating populations with characteristic mesenchymal phenotype display a marked increase in sensitivity to PDT (using the photosensitizer verteporfin), while the same cells exhibit increased chemoresistance. Here, motivated by these findings we systematically disentangle influences associated with the physical and biochemical properties of ECM as regulators of PDAC growth behavior and treatment response. In 3D tumor spheroids transplanted into invasion-promoting type 1 collagen gels, we use riboflavin-mediated photocrosslinking as a tool to regulate ECM stiffness (independent of its concentration), combined with high-content imaging to co-register invasive progression and differential response to chemotherapy and PDT. Increased extent of photocrosslinking correlates with increased collagen stiffness as confirmed by bulk oscillatory rheology, and is associated with a decrease in the invasive velocity (migration speed directed away from the primary transplanted spheroid) of ECM-infiltrating PDAC cells. Preliminary comparisons of PDT and oxaliplatin chemotherapy in low and high collagen crosslinking conditions show that PDT is significantly more effective than oxaliplatin in ECM-invading populations regardless of collagen stiffness. We also compare oxaliplatin chemotherapy and PDT before and after PDAC invasion into Matrigel ECM, and find that PDT efficacy is only enhanced after extensive invasion into the surrounding matrix. These results support the efficacy of PDT in targeting locally invasive PDAC while stressing the importance of elucidating how both biochemical and biophysical ECM interactions regulate therapeutic susceptibilities.
Citation Format: Gwendolyn Cramer, Seyedehrojin Jafari, Hamid El-Hamidi, Dustin Jones, Jonathan Celli. Targeting invasive and drug-resistant PDAC with photodynamic therapy [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 2114. doi:10.1158/1538-7445.AM2017-2114
Abstract 2117: TRAIL-induced apoptosis in TRAIL-resistant breast carcinoma
Authors: Manouchehri Jasmine M. , Kalafatis Michael 
Published: July 2017

Abstract
Recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL), the optimized form of the endogenous death ligand TRAIL, shows therapeutic potential for cancer due to its ability to induce apoptosis in cancer cells independent of p53, while exhibiting minimal toxicity to normal cells. Despite this, a majority of breast cancers display resistance to rhTRAIL treatment due to up-regulation of pro-apoptotic proteins, down-regulation of anti-apoptotic proteins, and/or up-regulation of death receptors (DR) 4 and 5. To overcome rhTRAIL resistance, natural compounds have been investigated as sensitizing agents. This study considered the application of the naturally occurring flavonol Quercetin (Q). Q has been shown to have the ability to up-regulate DR5 and down-regulate anti-apoptotic proteins in cancer cells, and thereby, making Q a favorable choice to be employed as a sensitizing agent. The intention of this study was to ascertain the capacity of Q to sensitize rhTRAIL-resistant triple negative breast cancer BT-20 cells and hormone-dependent breast cancer MCF-7 cells to rhTRAIL-induced apoptosis and elucidate the underlying mechanism for Q’s sensitization. Q demonstrated the ability to intensify rhTRAIL’s pro-apoptotic effects in the breast cancer BT-20 and MCF-7 cell lines as detected through Annexin V/PI assays followed by FACS analysis. In comparison to single agent treatments, the cotreatment of Q and rhTRAIL enhanced the induction of the extrinsic pathway of apoptosis as marked by PARP cleavage (a hallmark of apoptosis), activation of caspase 8, and activation of the executioner caspases 3 and 7. The mechanism for Q’s augmentation in breast cancer was determined to be through the down-regulation of c-FLIPL (caspase 8 inhibitor) in a dose-dependent manner. Furthermore, Q promoted the ubiquitination of c-FLIPL facilitating the proteasome-mediated degradation of c-FLIPL in breast cancer. An additional mechanism for Q’s sensitization was displayed in breast cancer BT-20 cells. Q up-regulated DR5 membrane and protein expression in breast cancer BT-20 cells in a dose-dependent manner. RT-PCR analysis revealed that Q’s influence on DR5 expression occurred at the transcriptional level in those breast cancer cells. Thus, these data suggest that the cotreatment of Q and rhTRAIL possesses the therapeutic potential to be an effective anti-breast carcinoma regimen.
Citation Format: Jasmine M. Manouchehri, Michael Kalafatis. TRAIL-induced apoptosis in TRAIL-resistant breast carcinoma [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 2117. doi:10.1158/1538-7445.AM2017-2117
Abstract 2119: Acetylated secretory APE1/Ref-1 induces apoptotic cell death in orthotopic xenografts of triple-negative breast cancer
Authors: Lee Yu Ran , Joo Hee Kyoung , Lee Eun Ok , Park Myoung Soo , Jeon Byeong Hwa , Choi Sunga 
Published: July 2017

Abstract
The anticancer properties of acetylated secretory apurinic/apyrimidinic endonuclease-1 (Ape1/Ref-1) was suggested in triple-negative breast cancer (TNBC) cells; Posttranslational modification, hyperacetylation in MDA-MB-231 cells caused extracellular secretion of acetylated-APE1/Ref-1 (Ac-APE1/Ref-1) and initiated apoptotic cell death by auto-, paracrine binding to the receptor for advanced glycation end products (RAGE). In the present study, we observed potential therapeutic efficacy of Ac-APE1/Ref-1 in preclinical orthotopic models of TNBC in response to hyperacetylation. The extracellular Ac-APE1/Ref-1 was confirmed by proximity ligation assay in hyperacetylated tumor tissue, showing direct binding of Ac-APE1/Ref-1 and RAGE. Treatment of orthotopic TNBC xenografts with acetylating agents induced a strong growth inhibition in the tumor development as observed in computed tomography: it caused an increase of RAGE expression and activation of caspase-3 and PARP. The tumors also exhibited markedly higher count of apoptotic bodies and reduced proliferation index and neovascularization compared with control tumors. However, the Ac-APE1/Ref-1-stimulated apoptotic cell death was remarkably retarded in RAGE-knockout tumor even in hyperacetylation compared with RAGE-overexpressed one. The functional role of secreted Ac-APE1/Ref-1 in hyperacetylated TNBC was confirmed in vivo, demonstrating its relevance to the anticancer agent. Our findings suggest that Ac-APE1/Ref-1 protein possesses potent chemotherapeutic efficacy against TNBC, resistant to standard chemotherapeutic agents, warranting further evaluation as an anticancer agent
Citation Format: Yu Ran Lee, Hee Kyoung Joo, Eun Ok Lee, Myoung Soo Park, Byeong Hwa Jeon, Sunga Choi. Acetylated secretory APE1/Ref-1 induces apoptotic cell death in orthotopic xenografts of triple-negative 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 2119. doi:10.1158/1538-7445.AM2017-2119
Abstract 2121: Deguelin-derivative, L80 suppresses tumor growth and metastasis via inhibition of STAT3 activation in triple-negative breast cancer
Authors: Cho Tae-Min , Oh Eunhye , Sung Daeil , Kim Yoon-Jae , Kim Ji Young , Lee Jeewoo , Seo Jae Hong 
Published: July 2017

Abstract
Triple-negative breast cancer TNBC is associated with aggressive metastasis and poor clinical outcomes due to a lack of effective treatment options. Therefore, new drugs that effectively target both cancer cell proliferation and metastasis are needed to improve clinical outcomes. The 90-kDa molecular chaperone heat-shock protein, HSP90 has been implicated in cancer progression and metastasis by modulating the stabilization and maturation of many oncogenic proteins. Our objective was to investigate the mechanism of action of C-terminal HSP90 inhibitor, deguelin-derivative L80 on TNBC proliferation and metastasis in vitro and in vivo. L80 induced apoptosis and suppression of cell viability in TNBC cell lines via inhibition of Akt activation with concomitant nuclear accumulation of p27. L80 treatment also caused a marked suppression of cell migration and invasion. These responses were associated with inhibition of STAT3 phosphorylation (Tyr705) as evidenced by downregulation of STAT3 downstream target genes including cyclin D1 and survivin. The syngeneic orthotopic mouse model with 4T1 cells, L80 administration resulted in significant reduction in tumor growth together with decreased number of Ki-67-positive cells and downregulation of phospho-STAT3. Double-label immunofluorescence analysis showed that individuals receiving L80 exhibited a marked reduction in co-localization and expression of HIF-1α and HSP90 compared to their control groups in vivo. Finally, we observed that L80 administration significantly suppressed lung metastasis, as determined by in vivo bioluminescent imaging system. Our findings suggest that L80 may be potentially effective for the treatment for metastatic TNBC patients.
Note: This abstract was not presented at the meeting.
Citation Format: Tae-Min Cho, Eunhye Oh, Daeil Sung, Yoon-Jae Kim, Ji Young Kim, Jeewoo Lee, Jae Hong Seo. Deguelin-derivative, L80 suppresses tumor growth and metastasis via inhibition of STAT3 activation in triple-negative 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 2121. doi:10.1158/1538-7445.AM2017-2121
Abstract 2131: Tanshinone IIA can decrease growth factor receptors expression and dural-block both Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR pathways to inhibit human breast cancer BT-20 cells
Authors: Su Chin Cheng 
Published: July 2017

Abstract
Background : Tanshinone IIA (Tan-IIA, C19H18O3) with anti-inflammatory activities and antioxidant properties, is one of the diterpine quinones extracted from Salviae miltiorrhizae radix (Danshen). Tan-IIA can inhibit many human cancer cell lines through different molecular mechanisms. The phosphoinositide-3-kinase (PI3K)/AKT/ mammalian target of rapamycin (mTOR) and RAS/RAF/MEK/ERK pathways are two of the most frequently dysregulated kinase cascades in human cancer. Transmembrane tyrosine kinase has been strongly implicated in the proliferation, survival, and metastasis of human tumors. Both pathways represent important signal transduction mechanisms that facilitate the proliferation and survival of cancers driven by growth factor receptors, such as vascular endothelial growth factor receptor (VEGFR), insulin-like growth factor-I receptor (IGF-IR), or epidermal growth factor receptor (EGFR). Targeting both the Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR Pathways for suppressing inhibitor resistant cells is necessary because the individual downstream components of these signaling cascades either through epigenetic modification or somatic mutation are also known to be frequently altered in cancer, thus contributing to resistance to anticancer therapies and tumorigenesis.
Material and methods: In the present study, the human breast cancer BT-20 cells were treated with Tan-IIA in vitro. The cytotoxicity of Tan-IIA was evaluated by MTT assay. The effects of Tan-IIA on the protein expressions of EGFR, IGF-IR, VEGFR, PI3K, AKT, mTOR, Ras, Raf, MEK and ERK and β-actin in the BT-20 cells were examined by western blot analysis.
Results: The results showed that Tan-IIA can induce the proliferation inhibition with time and dose dependent and inhibit the activity of the Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR pathways. In addition, it was showed that Tan-IIA treatment inhibited the protein expression levels of EGFR, VEGFR and IGF-IR significantly.
Conclusions: These findings indicated that one of the molecular mechanisms for Tan-IIA to inhibit BT-20 cells maybe through inhibiting the protein expression levels of EGFR, VEGFR, IGF-IR and both Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR pathways. The use of Tan-IIA for breast cancer may become a feasible novel therapy option. Further studies are warranted to elucidate its mechanisms fully.
Citation Format: Chin Cheng Su. Tanshinone IIA can decrease growth factor receptors expression and dural-block both Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR pathways to inhibit human breast cancer BT-20 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 2131. doi:10.1158/1538-7445.AM2017-2131