bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A138: Loss of the lysosomal transporter SLC46A3 is a mechanism for innate and acquired resistance to non-cleavable maytansine and pyrrolobenzodiazepine-based antibody-drug conjugates
Authors: Kinneer Krista , Meekin John , Phipps Sandrina , Bezabeh Binyam , Fleming Ryan , Kiefer Christine , Rebelatto Marlon , Dimasi Nazzareno , Wick Michael J. , Moriarty Alyssa , Groves Megan , Herbst Ronald , Tiberghien Arnaud , Masterson Luke , Howard Philip , Tice David 
Published: August 2018

Abstract
Antibody-drug conjugates (ADCs) combine a monoclonal antibody with a potent cytotoxic drug to preferentially eliminate antigen-positive cells for the treatment of cancer. ADCs bearing non-cleavable warheads such as the pyrrolobenzodiazepine (PBD) SG3376 rely upon lysosomal degradation of the antibody for release of the cytotoxic warhead. Here we sought to identify the mechanism of lysosomal membrane transport following release of these membrane-insoluble warheads. We used a multiplexed RT-PCR screen to compare the expression of 43 lysosomal membrane-specific genes in cell lines with inherent sensitivity or resistance to various SG3376-based ADCs. We discovered that only the expression of SLC46A3 correlated with sensitivity to the ADCs. Functional validation through gene knockout or forced gene expression in vitro revealed that loss or gain of SLC46A3 altered the potency of SG3376- and DM1-ADCs but had no effect on ADCs carrying the non-cleavable warhead MMAF or the cleavable PBD payload SG3249. To explore a role in acquired resistance, we interrogated trastuzumab-DM1 (T-DM1) sensitive and resistant cell line pairs and found that resistant lines had lost expression of SLC46A3. Sensitivity to both SG3376- and DM1-ADCs was restored upon reintroduction of SLC46A3. Furthermore, we examined a patient-derived xenograft (PDX) breast cancer model of acquired T-DM1 resistance and found that expression of SLC46A3 was decreased by 92% compared to the parental, T-DM1 sensitive model. Taken together, our results establish SLC46A3 as a transporter of both SG3376 and DM1 catabolites from the lysosome, and suggest that SLC46A3 may be a predictive response marker for ADCs bearing these non-cleavable warheads.
Citation Format: Krista Kinneer, John Meekin, Sandrina Phipps, Binyam Bezabeh, Ryan Fleming, Christine Kiefer, Marlon Rebelatto, Nazzareno Dimasi, Michael J. Wick, Alyssa Moriarty, Megan Groves, Ronald Herbst, Arnaud Tiberghien, Luke Masterson, Philip Howard, David Tice. Loss of the lysosomal transporter SLC46A3 is a mechanism for innate and acquired resistance to non-cleavable maytansine and pyrrolobenzodiazepine-based antibody-drug conjugates [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A138.
Abstract A141: Preclinical evaluation of a new ROS1 inhibitor to overcome resistance to EGFR therapy in glioblastoma
Authors: Aljohani Hashim M. , Aittaleb Mohamed , Park Byung Sun , Lee So Ha , Bahassi El Mustapha 
Published: August 2018

Abstract
Glioblastoma (GBM) is the most aggressive brain tumor in adults and remains incurable despite multimodal intensive treatment regimens. The majority of GBM tumors show a mutated or overexpressed epidermal growth factor receptor (EGFR); however, tumors treated with EGFR inhibitors such as gefitinib or erlotinib inevitably recur. This recurrence highlights the need to identify signaling pathways involved in GBM resistance to EGFR therapy that may serve as targets for intervention. In our recently published work, we found that activation of the ROS1 pathway is a primary mechanism by which glioma cells become resistant to EGFR-targeted therapy. ROS1 is a proto-oncogene receptor tyrosine kinase activated by chromosomal rearrangement in several human cancers, including non-small cell lung cancer (NSCLC), cholangiocarcinoma, gastric cancer, ovarian cancer, and glioblastoma. We therefore designed, synthesized, and screened a series of new ROS1 inhibitors. The lead compound, ROS-Ic, is very potent (IC50 = 24nM) and highly specific to ROS1 protein. Treatment of gefitinib-resistant GBM cells with ROS1-lc sensitized the resistant cells to low concentrations of gefitinib, resulting in apoptosis following a prolonged S-phase cell cycle arrest. When compared to crizotinib, an FDA-approved small-molecule tyrosine kinase inhibitor currently used to treat ALK- and ROS1+ NSCLC patients, ROS-Ic showed superior cytotoxic activity in vitro towards ROS1-positive GBM cells. Crizotinib resistance is thought to be due to abolished crizotinib binding by ROS1 mutations in crizotinib binding pocket. Interestingly, the binding of our leading compound ROS1-Ic was not affected by these mutations and crizotinib-resistant cells harboring these mutations were still sensitive to ROS1-Ic, highlighting the potential therapeutic value of this compound.
Citation Format: Hashim M. Aljohani, Mohamed Aittaleb, Byung Sun Park, So Ha Lee, El Mustapha Bahassi. Preclinical evaluation of a new ROS1 inhibitor to overcome resistance to EGFR therapy in glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A141.
Abstract A150: Complex 3D cultures for combination compound screens reveal new insights
Authors: Evans David M. , Michael Selby H. , Bowles Lori , Delosh Rene M. , Julie Laudeman , Ogle Chad C. , Russell Reinhart , Thomas Silvers , Parchment Ralph , Doroshow James , Teicher Beverly 
Published: August 2018

Abstract
3D tumor cell cultures more closely mimic the tumor environment in drug screening assays. The tumor environment includes endothelial cells, infiltrating cells, and stromal cells and the extracellular matrix excreted by these cells. It is likely that the tumor microenvironment affects the response of tumor cells to therapeutic agents. We have used a complex spheroid model consisting of tumor cells, endothelial cells (HUVEC), and mesenchymal stem cells (MSCs) to explore response to selected therapeutic agents. Using 9-10 tumor lines of each of NSCLC, melanoma, and pancreatic cancer, we tested combinations of FDA-approved agents and investigational agents on viability. All agents were studied at multiple concentrations at their reported clinical Cmax values and below in a 6 by 5 concentration matrix. Bliss independence calculations identified drug combinations that were additive, synergistic, or antagonistic. Gemcitabine plus the Chk1/2 inhibitor AZD 7762 showed strong synergy in PANC-1 cells and weaker synergy in MiaPAca-2 complex spheroids. Under the same conditions, gemcitabine and AZD7762 were additive to antagonistic in cell killing and strong antagonism was observed in CFPAC-1 cells. A combination of gemcitabine with the BET inhibitor (GSK525762) was extremely cytotoxic even at low concentrations (Gem, 0.2uM; GSK525762, 10uM)–demonstrating synergy between the Bromodomain (BET) inhibitor GSK525762 and gemcitabine in PANC-1 cells. In one NSCLC cell line (NCI-H23) the combination of GSK525762 (concentrations &gt;1uM) was synergistic with carboplatin; however, in 5 NSCLC PDX lines, the combination had no synergy. In the LOX-IMVI melanoma line, GSK525762 was synergistic with cobimetinib. Cobimetinib and rabusertib were synergistic in the MDA-MB-435 line with &gt;99% cell killing at concentrations &lt; clinical Cmax. The results demonstrate that complex multicellular spheroids can be utilized in prolonged compound exposure screens (7 days) with robust and statistically relevant results using cell viability as an initial measure of cytotoxicity and can inform selection of combinations for progression. The observed additivity, synergy, or antagonism was cell line and tumor type dependent.
Citation Format: David M. Evans, Selby H. Michael, Lori Bowles, Rene M. Delosh, Laudeman Julie, Chad C. Ogle, Reinhart Russell, Silvers Thomas, Ralph Parchment, James Doroshow, Beverly Teicher. Complex 3D cultures for combination compound screens reveal new insights [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A150.
Abstract A178: Targeting the ATM-mediated DNA damage response pathway for cancer treatment
Authors: Grindrod Scott , Velena Alfredo , Jung Mira 
Published: August 2018

Abstract
Epigenetic modulators have emerged as potent therapeutic agents for treatment of patients with cancers. We have developed dual-function small molecules targeting activation of ATM, the DNA damage response transducer, ataxia telangiectasia mutated gene product, and inhibition of histone deacetylases (HDACi). The goal is to develop a single-molecule therapeutic that optimizes the protective effects of ATM activation in normal tissue while targeting HDAC inhibition to sensitize cancerous tissue to radiation. The candidate compound SP-1-161 is a hydroxamic acid that was rationally designed by optimizing ATM activation in the cap domain. In vitro assays against a panel of Class I and Class II HDAC enzymes identified SP-1-161 as a pan-HDAC inhibitor with nanomolar potency (IC50 = 8 nM). Western analysis confirms that SP-1-161 increases acetylated histone H3/H4 and α-tubulin and activates ATM (p-ATM/S1987) in MCF7 cells. The cytotoxicity values (IC50) were in low micro-molar ranges in normal breast epithelial (184A1) and breast cancer (MCF7) cell lines. Radiation clonogenic survival assays demonstrated that the compound protected nonmalignant 184A1 cells (from D0 = 1 Gy to D0 =1.4 Gy) while increasing sensitivity of malignant MCF7 cells to IR (from D0=1.6 Gy to D0=1.12 Gy). Furthermore, in vivo plasma pharmacokinetics following oral administration revealed the area under the curve of 415.79 ng/ml × h with the half-life 1.94 h. Together, our results demonstrate that SP-1-161 is an unprecedented radiation chemotherapeutic agent for treating cancers and protecting normal cells, potentially by targeting the DDR signaling pathways.
Citation Format: Scott Grindrod, Alfredo Velena, Mira Jung. Targeting the ATM-mediated DNA damage response pathway for cancer treatment [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A178.
Abstract B018: Breaking down cancer: IDH and its impact on metabolism and DNA damage and repair
Authors: Neville Kathryn , Arcand Elizabeth , Chiaramida Gabriela , O'Connell Kaylie , Tipping Marla 
Published: August 2018

Abstract
Metabolic reprogramming has been detected in many diseases, including cancer. Recently, a small number of metabolic enzymes have been identified as driver mutations for various types of cancer. To better understand how these genes lead to cancer, and to identify molecular targets for treatment, we are investigating the isocitrate dehydrogenase (IDH) mutation implicated in human glioma and acute myeloid leukemia. We are currently using Drosophila melanogaster as a model to study both the metabolic changes that occur when IDH is mutated, and the potential impact on DNA damage repair pathways. To analyze metabolic changes in the brain of IDH mutant flies, we have optimized a protocol for measuring the metabolism of whole brains using the XFe96 metabolic analyzer. We have also detected the expression of D2-HG, a metabolite produced by mutant IDH in human cells, in our fly IDH model. Generation of D2-HG in human cells has been reported to correlate with insufficient DNA repair. To study this further we are testing for increased DNA damage and lack of DNA repair initiation. In particular, we are investigating a hypothesized connection between the Fanconi anemia DNA repair pathway and IDH mutations.
Citation Format: Kathryn Neville, Elizabeth Arcand, Gabriela Chiaramida, Kaylie O'Connell, Marla Tipping. Breaking down cancer: IDH and its impact on metabolism and DNA damage and repair [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B018.
Abstract B031: Semaphorin 3E promotes pancreatic cancer metastasis through activating stromal cell
Authors: Liang Zhengdong , Yong Lin-Kin , Van Buren George , Fisher William , Hwang Rosa , Chen Changyi , Yao Qizhi Cathy 
Published: August 2018

Abstract
Background: Better understanding of the molecular mechanisms of pancreatic adenocarcinoma (PDAC) metastasis is important for the development of effective treatments for this devastating disease. We have previously shown that overexpression of Semaphorin 3E (Sema3E) enhances PDAC cell growth and is associated with poor patient survival. Here, we further determined the effect of Sema3E on stromal cells and the molecular mechanisms contributing to PDAC metastasis. Materials and Methods: Panels of stable PDAC cell lines were generated using either lenti-Sema3E for overexpression or the Crispr/Cas9 system to knock out (KO) Sema3E in both panc28 and panc48 cell lines. The effects of Sema3E overexpression or KO were measured in orthotopically implanted xenograft tumor mouse models in respect to tumor size, metastasis, and survival. After coculture with pancreatic stellate cells (PSCs), the effects of Sema3E on PSC activation were evaluated by GFAP and αSMA staining. Mixtures of PDAC cell lines with PSCs in vivo tumor growth were also evaluated. Result: After orthotopically implanting a panel of Sema3E-overexpressing or knockout panc28 cell lines, we found that the survival span of the sema3E-overexpression cell implant group was significantly shorter than the vector control group (31±9 days vs. 51±15 days) (p&lt;0.05). In addition, more lung metastases were found in the Panc28-Sema3E overexpressing group. Compared to the primary tumor, the lung metastases had increased sema3E expression. Furthermore, Sema3E overexpression promoted PSC activation with a greater ratio of αSMA to GFAP staining when cocultured with PSC cells. Cotransplant of Sema3E-overexpression cells and PSC cells promoted tumor growth and metastasis when compare to Sema3E-overexpressed cells alone. Conclusion: Sema3E overexpression in pancreatic cancer cells promotes tumor growth, lung metastasis, and poor survival. The interaction between Sema3E and PSC cells may play an important role in contributing to tumor growth and metastasis.
Citation Format: Zhengdong Liang, Lin-Kin Yong, George Van Buren, William Fisher, Rosa Hwang, Changyi Chen, Qizhi Cathy Yao. Semaphorin 3E promotes pancreatic cancer metastasis through activating stromal cell [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B031.
Abstract B032: The study of the role of Romo1 for angiogenesis/lymphangiogenesis in colorectal cancer
Authors: Kim Hong Jun , Lee Dae-Hee , Jo Min Jee , Oh Sang Cheul 
Published: August 2018

Abstract
Reactive oxygen species modulator-1 (Romo1) is a novel protein that has been reported to be crucial for cancer cell proliferation and invasion. In a previous work, for the first time we reported that Romo1 correlated with poor survival of patients with colorectal cancer (CRC). In the current study, we investigated the role of Romo1 for angiogenesis/lymphangiogenesis in CRC. Romo1 overexpression in clinical tumor samples was associated with a high lymph node ratio between the metastatic and examined lymph nodes (p=0.025). IHC staining was used to demonstrate the Romo1 expression in clinical tissues. In the Matrigel invasion assay, cell invasiveness decreased in the Romo1 knockdown CRC cells compared with the controlled cells; this tendency was shown to be associated with epithelial-mesenchymal transition (EMT) induced by Romo1. We identified EMT markers at the protein levels in the Romo1-overexpressing cells. Epithelial marker E-cadherin was decreased while mesenchymal markers N-cadherin and Snail were increased in the Romo1-overexpressing cells compared with controlled cells. We also evaluated the mechanism by which Romo1 affects vascular endothelial growth factors (VEGF) transcription and promotes angiogenesis/lymphangiogenesis. The expression levels of VEGF were detected by real-time PCR and Western blot. We found that VEGF expression levels were upregulated in Romo1 overexpressed cells. Also in clinical tumor samples, Romo1 expression level determined by IHC staining was positively related with VEGF. Based on these results, we used Romo1 overexpressed cell’s conditional medium (CM) to culture the human umbilical vein endothelial cells (HUVEC), and detected the tube formation. We found that Romo1 overexpressing cell CM enhanced the tube formation compared with the control CM. In conclusion, lymphatic metastasis induced by Romo1 was a key reason for the poor survival associated with highly expressed Romo1 in CRC. We have shown that Romo1 not only promotes cancer invasion via EMT, but also has a direct role in lymphangiogenesis and/or angiogenesis.
Citation Format: Hong Jun Kim, Dae-Hee Lee, Min Jee Jo, Sang Cheul Oh. The study of the role of Romo1 for angiogenesis/lymphangiogenesis in colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B032.
Abstract B033: Transcriptional dissection and therapeutic modulation of metastasis development in pancreatic cancer
Authors: Lopez-Casas Pedro P. , Dimitrov Spas , Perales-Patón Javier , Baños Natalia , Muñoz Manuel , Dopazo Ana , Al-Shahrour Fátima , Hidalgo Manuel 
Published: August 2018

Abstract
Pancreatic cancer (PDAC) is a highly metastatic disease, and up to 70% of patients who are diagnosed with early-stage disease recur with metastatic disease despite treatment with chemotherapy. The development of metastasis remains the leading cause of cancer-related mortality in this disease, and little is known about the molecular mechanisms that drive the spreading of the primary tumor cells to the metastatic niche. Therefore, there is an urgent need to discover druggable antimetastatic targets. To generate a robust model of PDAC metastasis we implanted PDAC patient-derived samples orthotopically in NOD scid gamma (NSG) mice. We observed recurrent dissemination to distant organs, liver, and lung that resulted in animal death with a median of 50 days. We obtained human cancer single-cell suspensions at the primary location (graft), the mouse blood, and the metastatic lesions by using magnetic methods and an anti-HLA-ABC antibody, which recognized the human cells. Next, we captured single-cells by utilizing the Fluidigm technology and performed RNA-seq on each isolated cell. Using bioinformatic tools, we analyzed the transcriptional landscape of the cells isolated from the three compartments to search for potential druggable metastatic drivers. The data show that PDAC circulating tumor cells (CTCs) keep high tumorigenic and metastatic capability and that CTC-derived tumors preserve the morphologic characteristics of parental tumor. The metastatic disease of pancreatic cancer is a well-organized evolutionary process, in which the primary tumor cells, metastatic cells, and CTCs are transcriptionally divergent. The transcriptional heterogeneity between these three biological emerges from three biologic hallmarks including extracellular matrix interaction and focal adhesion, cell cycle, and ribosome biogenesis. The analysis of transcriptionally overexpressed genes identified BIRC5 (Survivin), a key regulator of mitosis and apoptosis, as one of the highest expressed genes in CTCs as well as the most promising target. Intriguingly, in vivo targeting of BIRC5 with YM155, a small molecule described as transcriptional repressor of BIRC5, aborted the metastatic process and significantly increased the survival of treated mice compared to control.
Citation Format: Pedro P. Lopez-Casas, Spas Dimitrov, Javier Perales-Patón, Natalia Baños, Manuel Muñoz, Ana Dopazo, Fátima Al-Shahrour, Manuel Hidalgo. Transcriptional dissection and therapeutic modulation of metastasis development in pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B033.
Abstract B039: KDM4B inhibition confers suseptibility to PI3K inhibitor in PTEN-deficient TNBC through overactivating UPR pathway
Authors: Wang Wenyu , Oguz Gokce , Lee Puay Leng , Yatim Siti Maryam , Yu Qiang 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC) is among the most lethal cancers in females. Up to 35% of TNBC show PTEN mutation or PTEN loss (PTEN deficiency). Although PTEN deficiency leads to aberrant activation of PI3K/AKT signaling, therapeutic targeting of PI3K/AKT pathway has yielded very limited clinical benefit. The effective therapeutic targets for PTEN-deficient cancers are in urgent need of identifying common vulnerabilities of this important pathway. To identify additional chemical drugs that target PTEN-deficient TNBC, we performed a drug screening together with a series of in vitro and in vivo validation. Here, we show that PTEN deficiency confers vulnerability to inhibition of histone demethylase KDM4B, resulting from perturbation of endoplasmic reticulum (ER) homeostasis through activating eIF2α/ATF4 unfolded protein response (UPR) pathway. Mechanistically, KDM4B suppresses UPR pathway by interacting with and inhibiting eIF2α activation, and this function requires its demethylase activity but is independent of histone modification. Consistent with the sensitivity, PTEN-deficient cells and samples from PTEN-deficient patients show constitutively activation of UPR, which usually confers survival advantage but induces cell death once it is further activated and prolonged by KDM4B inhibition. More importantly, targeting KDM4B can robustly synergize with PI3K inhibitor to induce cell death in PTEN-deficient TNBC. This synergistic killing is caused by "overactivating" the UPR pathway resulting from transcriptional activation of UPR genes by ATF4 and FoxO1. Collectively, our study thus identifies a novel cytoplasmic function of KDM4B in regulating cellular stress and provides a new therapeutic approach to treat PTEN-deficient TNBC.
Citation Format: Wenyu Wang, Gokce Oguz, Puay Leng Lee, Siti Maryam Yatim, Qiang Yu. KDM4B inhibition confers suseptibility to PI3K inhibitor in PTEN-deficient TNBC through overactivating UPR pathway [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B039.