bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A37: Anti-telomerase therapy provokes ALT and mitochondrial adaptive mechanism in cancer
Authors: Hu Jian , Hwang Sarah , Boutin Adam , Wang Alan , Chin Lynda , Liesa Marc , Shiriha Orian , DePinho Ronald 
Published: March 2013

Abstract
Because telomerase is activated in 85–90% of all human cancers, inhibition of telomerase activity has been proposed as an anti-cancer strategy. However, telomere erosion resulting from telomerase inhibition can generate rampant genomic instability which may fuel adaptive mechanisms. Here, we determined the impact of telomerase activation and its subsequent extinction in T-cell lymphomas arising in Atm−/− mice engineered with an inducible telomerase reverse transcriptase-estrogen receptor (TERT-ER) knock-in allele. Endogenous telomerase reactivation in late generation TERTER/ER Atm−/− mice with telomere dysfunction enabled full malignant progression with accompanying alleviation of telomere checkpoint signaling and acquisition of copy number alterations targeting genes known to be important in human T-cell lymphomas/leukemia. Upon telomerase extinction, tumors eventually showed impaired growth due to reinstatement of telomere dysfunction-induced checkpoint signaling, yet subsequently resumed growth with accompanying alternative lengthening of telomeres (ALT) features. Transcriptomic analysis of ALT+ tumors showed altered transcriptional networks centering on mitochondrial biology and oxidative defense, and genomic analysis showed amplification of PGC-1β, a master regulator of mitochondrial biogenesis and oxidative defense. Relative to telomerase+ tumors, ALT+ tumors showed marked sensitivity to PGC-1β or SOD2 knockdown which compromised mitochondrial function and/or caused increased reactive oxygen species (ROS). Together, these studies provide in vivo genetic evidence that naturally arising tumors adapt to telomerase extinction by acquisition of both ALT and mitochondrial maintenance mechanisms, and show that targeting mitochondrial function and oxidative defense may enhance the effectiveness of anti-telomerase therapy in cancer.
Abstract A4: A novel class of selective ERα degraders acts as full antagonists/ inverse agonists and displays efficacy in pre-clinical models of endocrine-resistant breast cancer and endometrial cancer
Authors: Darimont Beatrice , Lu Ninh , Sensintaffar John , Lee Kyoung-Jin , Aparicio Anna , Kaufman Joshua , Bischoff Eric , Rix Peter , Heyman Rich , Smith Nicholas , Hager Jeffrey , Joseph James , Grillot Katherine , Qian Jing , Gang Shao , Govek Steven , Nagasawa Johnny , Lai Andiliy , Kahraman Mehmet 
Published: March 2013

Abstract
While endocrine therapies are initially effective to treat estrogen receptor (ERα) positive breast cancer tumors, acquired resistance invariably emerges. Although resistant tumors typically display changes in PI3K or other kinase pathways, the majority of these tumors continue to express and depend on ERα for growth and survival. Exploring the hypothesis that endocrine resistance might involve hormone-independent activities of ERα, we have developed two distinct classes of potent, non-steroidal ERα modulators that antagonize hormone-mediated transcriptional activities of ER and lower ERα steady state levels. These compounds showed robust efficacy in pre-clinical models of endocrine-resistant breast cancer, including some with up-regulated PI3K pathways. In contrast to their activity as full antagonists/ inverse agonists in the breast, the two classes of ERα modulators displayed distinct abilities to oppose the activity of estradiol in the uterine endometrium, another well-characterized ERα target tissue. Similar to endocrine-resistant breast cancer, a large percentage of endometrial cancers have altered PI3K pathways and typically respond poorly to endocrine therapy. In mouse xenograft models one of our compounds inhibited the growth of ECC-1 endometrial cancer tumors with substantially higher efficacy than the selective ER modulator arzoxifene, which in a phase II clinical trial exhibited a 30% response rate in patients with recurring ERα-positive endometrial cancers. Hence, beyond their promise as a next generation therapy for the treatment of endocrine resistant ER+ breast cancer, these novel classes of selective estrogen receptor degraders might also open new opportunities for endocrine therapies targeting endometrial cancer.
Abstract A47: Inhibition of Rho kinase signaling in angiosarcomas leads to decreased tumor growth and invasiveness, but enhanced resistance to standard chemotherapeutics
Authors: Mitchell Dianne Courtenay , Bryan Brad Allen 
Published: March 2013

Abstract
The Rho-associated coiled-coil protein kinases (ROCK 1 & 2) are serine/threonine kinases serving as key modulators of processes involving cytoskeletal rearrangement, focal adhesion formation, cell motility, and tumor cell invasion. Deregulation of ROCK signaling has been reported across diverse tumors types and overexpression of ROCK proteins in metastatic tumors directly contributes to their aggressive behavior through stimulating cell migration and epithelial-to-mesenchymal transition. Indeed, a number of published reports from our lab and others indicate that inhibiting ROCK signaling effectively disrupts solid tumor formation, progression, and metastasis. Interestingly, over the past decade more than 20 publications from different groups have reported diverse and often conflicting roles for the ROCK proteins in cell survival in differing tumor types, bringing into question what the overall response would be of a cancer patient who is taking standard chemotherapy combined with ROCK inhibitors. Despite the widespread interest in targeting ROCK signaling for cancer therapy, the molecular mechanisms explaining these conflicting pleiotropic roles for ROCK signaling in cell fate decisions is almost exclusively unknown. In this study, we examined the effects of ROCK inhibition combined with standard chemotherapy regimens on angiosarcoma tumor progression. Pharmacological inhibition of ROCK's kinase activity or shRNA knockdown of ROCK1 or 2 gene expression resulted in decreased angiosarcoma tumor formation and invasion, however led to significantly increased tumor cell survival following cisplatin or busulfan treatment. To determine the molecular mechanisms controlling the pro-survival response of inhibiting ROCK signaling following cytotoxic injury, we performed whole genome microarray analysis revealing that pharmacological inhibition or gene expression knockdown of ROCK proteins led to a statistically significant ablation in the expression of a number of cisplatin and busulfan responsive genes known to be downstream targets of p53 induction, DNA damage response and repair, and cell cycle control. This study provides one of the most detailed explanations at the molecular level as to how ROCK signaling modulates cell survival by regulating gene expression at a global level—a paradox that must be solved before inhibition of ROCK activity can be clinically used as an effective anticancer therapeutic, lest we develop an excellent antimetastatic drug that unfortunately (for some tumor types) enhances tumor resistance to chemotherapies.
Abstract A54: Potential mechanisms of resistance to targeted agents in human clear cell renal cell carcinoma
Authors: Grozav Adrian G. , Vaziri Susan A.J. , Eric Koegle R. , Grabowski Dale R. , Bukowski Ronald M. , Ganapathi Mahrukh K. , Ganapathi Ram N. 
Published: March 2013

Abstract
Targeted therapy with multiple receptor tyrosine kinase inhibitors (RTKI) has led to a substantial improvement in the standard of care for patients with advanced or metastatic clear cell renal cell carcinoma (CCRCC). We have previously reported that using a phosphoproteomics approach, Ras and Rab interactor 1 (RIN1) was identified as a potential target modulating the antiproliferative effects of sorafenib and sunitinib in a panel of human CCRCC (Proc. AACR 51: Abst. #1626, 2010). While both 10 μM sorafenib and 7.5 μM sunitinib were effective in down-regulating RIN1 protein levels in CCRCC following treatment for 48h, during subsequent recovery for 48h in drug free medium, recovery of RIN1 protein levels was observed in sorafenib but not sunitinib treated cells. mRNA expression profiling revealed that: (a) VEGF-A and HIF-1α levels were unaffected during 48h treatment with sorafenib or sunitinib or subsequent recovery; and (b) while HIF-2α levels were increased &gt;2-fold following 48h exposure to sorafenib or sunitinib, during subsequent recovery in drug-free medium, the increased levels of HIF-2α persisted in cells treated with sorafenib but not sunitinib. Compared to CCRCC cells that were growth inhibited in vitro at concentrations of 5–10 μM sorafenib or sunitinib, in 27 patient CCRCC samples evaluated, the median mRNA levels of RIN1 was 7.2-fold lower in 22 samples (Range 1.6–22.3) and 2.2-fold higher in 5 samples (Range 1.2–27.1). Stable over-expression and down-regulation of RIN1 in CCRCC led to resistance or sensitivity respectively, to the anti-proliferative effects of sorafenib and sunitinib but not the mTOR inhibitor temsirolimus. In contrast, CCRCC cells adapted to proliferate in 4 μM everolimus exhibited a &gt;3-fold increase in IC50, and cross-resistance to temsirolimus but not sorafenib or sunitinib. Evaluation in vitro of other targeted agents, demonstrated dose-dependent anti-proliferative effects with the PI3K/mTOR dual inhibitor BEZ235 (&gt;80% growth inhibition at 10nM) but not the pan-PI3K inhibitor BKM120 (&lt;30% growth inhibition at 10–500 nM) with CCRCC cells. The observed anti-proliferative effects of BEZ235 or BKM120 were comparable in CCRCC cells harboring the wild type or mutant von Hippel-Lindau gene. While BEZ235 (1–5 nM) or everolimus (100 nM) alone led to &lt;40% growth inhibition, the combination significantly enhanced anti-proliferative effects (&gt;85% growth inhibition) in CCRCC cells expressing resistance to everolimus. These results suggest the PI3K/mTOR dual inhibitor BEZ235 may possibly improve the treatment efficacy of mTOR inhibitors for CCRCC. The findings suggest RTKI and mTOR inhibitors have distinct mechanisms of resistance, and combinations may be useful to improve disease control of metastatic CCRCC.
Abstract A64: NFκB-IκBα Interaction: A Mechanism of Resistance to Cisplatin in Non Small Cell Lung Cancer (NSCLC)
Authors: Heavey Susan , Barr Martin , Godwin Peter , Edwards Connla , O'Byrne Ken , Gately Kathy 
Published: March 2013

Abstract
Introduction: The purpose of this study was to investigate the role of the PI3K-NFκB pathway in resistance to cisplatin in Non-small cell lung cancer (NSCLC). This form of malignancy is the leading cause of cancer morbidity and mortality in the western world with a poor overall 5 year survival of &lt;15%. The most effective systemic chemotherapy for NSCLC is cisplatin-based combination treatment. However, chemoresistance is a major therapeutic problem and understanding the mechanisms involved is critical to the development of new therapeutic intervention strategies. The PI3K/AKT/mTOR pathway signals through NFκB and plays an important role in NSCLC, representing a novel therapeutic target for overcoming cisplatin resistance.
Methods: A panel of cisplatin resistant NSCLC cell lines (H460, SKMES1, A549) were developed in our laboratory. H460 parent & resistant cell lines were screened for changes in mRNA expression using the PI3K Profiler array (SABiosciences). Changes in gene expression were validated by QPCR and protein expression by Western blot and HCA. IκBα exons 3–5 were screened for mutations by sequencing. DHMEQ is an inhibitor of NFκB translocation. The effects of DHMEQ on NFκB translocation as well as on cell apoptosis and proliferation were assessed by HCA and BrdU assays.
Results: An 11.99 fold increase in IκBα mRNA expression was identified in the cisplatin resistant H460 cells compared to parent cells. QPCR, Western blot and HCA confirmed this overexpression of IκBα. No mutations were identified in exons 3-5 of the IκBα gene. Inhibition of NFκB by DHMEQ led to significantly increased apoptosis and significantly decreased proliferation in cisplatin resistant cells versus parent cells.
Conclusions: The transcription factor NFκB is involved in cell survival and regulates the transcription of its own inhibitor, IκBα. Both IκBα and NFκB were found to be upregulated in cisplatin resistant cells compared to cisplatin sensitive cells. Inhibiton of NFκB by the inhibitor DHMEQ succeeded in reducing resistant cell survival and proliferation. NFκB inhibition could represent a novel therapeutic strategy to overcome NSCLC resistance to cisplatin.
Abstract B21: Resistance to B-RAF inhibitor is mediated by reactivation of MAPK pathway by FGFR3/Ras signaling in B-RAF V600E mutant melanoma
Authors: Yadav Vipin , Zhang Xiaoyi , Liu Jiangang , Estrem Shawn , Li Shuyu Dan , Gong Xue-Qian , Buchanan Sean , Henry James R. , Starling James J. , Peng Sheng-Bin 
Published: March 2013

Abstract
Melanoma is the most aggressive form of skin cancer. The RAF/MEK/ERK MAP kinase signaling plays a key role in melanoma progression and etiology, and is considered an important target for anti-melanoma therapies. Approximately 50% of melanomas carry an activating B-RAF V600E mutation that results in constitutive activation of B-RAF and downstream MAPK signaling. Recently, vemurafenib (PLX4032), a selective B-RAF inhibitor, was recently approved by U.S. FDA for treatment of metastatic and unresectable melanomas that carry an activating B-RAF V600E mutation. However, patients eventually developed resistance to vemurafenib and relapsed within an average of 7 months. To improve the clinical benefit of B-RAF inhibitors, it is critical to identify the molecular mechanisms that confer resistance to B-RAF inhibition. Recent reports indicate that multiple mechanisms may render mutant B-RAF expressing melanoma cells resistant to B-RAF inhibition. In this study, we generated vemurafenib-resistant cell lines by chronic treatment of the human B-RAF V600E melanoma cell lines, and investigated the underlying mechanism(s) of resistance. Our analysis revealed that MAPK pathway reactivation through Ras is the key resistance mechanism in these cells. Furthermore, microarray-based gene expression profiling confirmed a significant elevation of RTK and Ras gene signatures in the vemurafenib-resistant cells. Mechanistically, we found that the enhanced activation of FGFR3 is linked to elevated Ras and MAPK activation in the resistant cells, therefore conferring resistance to vemurafenib. Constitutive or inducible activation of FGFR3 sufficiently reactivated Ras/MAPK signaling and conferred resistance to vemurafenib in the parental B-RAF V600E melanoma cells. Additionally, genetic or pharmacological inhibition of the FGFR3/Ras axis restored the sensitivity of the resistant cells to vemurafenib. Finally, we demonstrated that vemurafenib-resistant cells are sensitive to MEK or pan-RAF inhibition and maintain their addiction to the MAPK pathway. Therefore, inhibition of MEK or pan-RAF activities is an effective therapeutic strategy to overcome acquired-resistance to vemurafenib. Together, we describe a novel FGFR3/Ras mediated mechanism for acquired-resistance to B-RAF inhibition. Our results shed new light on the complexity of the resistance mechanisms and have implications for the development of new therapeutic strategies to improve the outcome of patients with B-RAF V600E melanoma.
Abstract B39: Mechanisms of multidrug resistance in AMLs and selective targeting via small molecules
Authors: Xing Chengguo , Hermanson David , Das Sonia 
Published: March 2013

Abstract
Multidrug resistance (MDR) is a major hurdle in the treatment of cancer and there is a pressing need for new therapies. We have recently developed a small molecule, CXL017, with selective cytotoxicity towards MDR cancer cells. In this study, we offer new mechanistic insights about multidrug resistance in acute myeloid leukemias and present evidence for the selective therapeutic potential of CXL017 in the treatment of MDR AMLs.
CXL017 significantly and selectively suppresses the growth of tumors derived from the MDR AML cells. In addition, drug resistant AML cells failed to develop stable resistance to CXL017 upon prolonged exposure. Remarkably, instead of acquiring cross-resistance, drug resistant AML cells exposed to CXL017 were re-sensitized to standard therapies (10 to 100-fold). Through gene profiling, protein characterization, and genetic up/down-regulation, we have identified several key signaling processes both at the transcription, such as Topo IIβ, and post-transcription levels, such as Mcl-1, that contribute to the multidrug resistance. Some of these changes also contribute to the selective sensitivity of multidrug resistant AMLs to CXL017. These results overall demonstrate the possibility of developing small-molecule therapies selective against multidrug resistance in cancer therapy upon gaining the mechanistic insights of drug resistance.
Abstract B52: Design and synthesis of GADD45β agonists for sorefenib-resistance hepatocellular carcinoma cells
Authors: Ou Da-Liang , Fan Hsiang-Hsuan , Hsu Chiun , Cheng Ann-Lii , Hsu Cheng-Yi , Shiau Chung-Wai 
Published: March 2013

Abstract
Background: Growth arrest DNA damage-inducible gene 45β (GADD45β) have been reported in regulating cellular stress response, survival, senescence, and apoptosis in cancer cells. Our previous data showed that GADD45β was induced in sorafenib-treated hepatocellular carcinoma (HCC) cell line and xenograft models. Sorafenib induction was not induced after the treatment ERK kinase inhibitor (U1206) and Raf inhibitor (ZM336372), suggesting that Raf/MEK/ERK kinase signaling pathway did not involve in induction of GADD45β by sorafenib.
Methods: We have designed and synthesized a series of SC-compounds. These compounds were treated with and analyzed in terms of GADD45β expression in HCC cell lines (Huh-7, Huh7R). Also, Effects of SC-compounds and sorafenib induced cell apoptosis were evaluated.
Results: In seeking new GADD45β agonists, we have screened a series of compounds with GADD45β expression assay. SC-20, a small molecule with N-(4-(quinolin-4-yloxy)phenyl)benzamide skeleton, has shown significantly in induction of GADD45β expression. Interestingly, SC-20 has no inhibition in phosphorylation of ERK, indicating that GADD45β induction by SC-20 is independent of ERK signaling pathway. In addition, SC-20 is able to inhibit HCC cell growth with MTT assay and further induce cell apoptosis. Moreover, SC-20 is able to overcome sorafenib resistance cell line by activating GADD45β expression.
Conclusions: SC-20 provides a new concept that increasing GADD45β along will be applicable in sorafenib-sensitive and resistant HCC therapy.
Grant support: NSC-100-2325-B-002-042, DOH100-TD-B-111-001, NSC-100-2325-B-010-007
Abstract B9: Activated MAPK Pathway Mediates Resistance to Romidepsin via Bim Degradation in Romidepsin-Selected HuT 78 Cells
Authors: Chakraborty Arup , Robey Robert , Gillet Jean-Pierre , Luchenko Victoria , Piekarz Richard , Gottesman Michael , Collie Nathan , Bates Susan 
Published: March 2013

Abstract
Acquired and intrinsic resistance to histone deacetylase inhibitors (HDIs), a new targeted group of anti-tumor agents, limits their clinical efficacy. A detailed understanding of the mechanisms of resistance to HDIs may lead to strategies designed to increase clinical efficacy. To investigate molecular mechanisms of resistance to the HDI romidepsin (Dp), we studied a cutaneous T-cell lymphoma (CTCL) cell line, HuT 78, independently selected in verapamil (Vp) or valspodar (PSC833) to prevent the emergence of P-glycoprotein (Pgp), a known resistance mechanism. The HuT 78 sublines DpVp 50 and DpP 75 display 100-200-fold resistance to romidepsin, not due to Pgp expression. A custom-made Taqman low density gene expression array detected increased expression of insulin receptor (IR) in the resistant cells. Real-time PCR analysis confirmed the results of gene array and detected more than 50-fold upregulation of IR in the romidepsin-selected cells compared to the parental cells. Increased phosphorylation (5- to 8- fold) of mitogen activated protein kinase kinase (MEK), a downstream effector of the IR pathway, was also observed in the resistant cells compared to the parental cells. While HuT 78 cells were insensitive to MEK inhibition, resistant cells were found to be exquisitely sensitive to MEK inhibition (IC50 &lt; 10 nM) but not to phosphatidylinositol 3-kinase (PI3K) inhibition. Combined treatment of romidepsin with low concentrations (1- 3 nM) of MEK inhibitor also resulted in increased cell death in romidepsin-resistant HuT 78 cells. The exquisite sensitivity to MEK inhibition in the resistant sublines was found to correlate with restoration of the expression of Bim (BCL2L11), a Bcl-2-homology domain-3 only (BH-3) proapoptotic protein. In the resistant cells, the MAPK pathway appeared to regulate Bim expression posttranslationally as we did not detect any gene induction of BCL2L11 or FOXO3, a transcription factor known to activate BCL2L11 expression, following MEK inhibition. These findings implicate increased activation of the MAPK pathway as a mechanism of resistance to romidepsin, and suggest that combining romidepsin with MEK inhibitors may be an effective strategy to overcome resistance.
Abstract IA11: Using Molecular Profiling Strategies in Clinical Trials to Understand Resistance Mechanisms in the Era of Personalized Cancer Medicine
Authors: Siu Lillian L. 
Published: March 2013

Abstract
Resistance to molecularly targeted agents remains a key challenge in cancer therapeutics. Even in the setting of oncogenically addicted tumor types matched with potent and specific kinase inhibitors, the duration of drug response is limited. For example, in the phase III trial of vemurafenib versus dacarbazine in patients with advanced malignant melanoma harboring BRAF V600E mutations, 48% of patients in the vermurafenib arm achieved an objective response with a progression-free survival of 5.3 months (Chapman et al. N Engl J Med 2011). A caveat to this clearly positive clinical trial is that there are patients whose tumors have the same mutations who did not respond to vemurafenib and amongst those who did, the duration of response remains limited. In tumors that harbor driver mutations or other genetic aberrations, mechanisms of resistance are of relevance, including both primary resistance that renders them insensitive to specific inhibitors, and evolved/acquired resistance that results in tumor growth despite initial sensitivity. Comprehensive molecular profiling of pre-treatment tumor samples and at progression would be informative to offer insight into such mechanisms of primary and evolved/acquired resistance and guide clinical trial designs to counteract them. Combinatorial strategies may be considered upfront for patients who have tumor characteristics suggestive of primary resistance. For patients with sensitive disease which evolve/acquire resistance during treatment, a repeat tumor biopsy may help detect newly emerged aberrations that are potentially druggable. Additional areas of interest in defining tumor resistance include the observations that same mutation may have different degrees of functionality in different tumor types (e.g. BRAF mutations in melanoma versus colorectal cancer) and different mutations of the same gene may confer different drug sensitivities (e.g. activating and inactivating BRAF mutations), These context-dependent phenomena further complicate the planning of histology-agnostic, mutation-specific clinical trials using targeted agents. Efforts to provide detailed tumor molecular profiling information in clinical trials are relevant to help distinguish signatures of sensitivity versus resistance.