bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2150: Alternative treatment strategies to overcome MAPK inhibitor resistance in melanoma
Authors: Goetz Eva , Rabasha Bokang , Garraway Levi 
Published: July 2016

Abstract
Inhibitors of the BRAF/MEK/ERK pathway have promise in the treatment of BRAF mutant melanoma and other MAPK activated cancers. Treatment of metastatic melanoma patients with the combination of RAF + MEK inhibitor has extended progression free survival over single agent therapy. However, in a large subset of patients, resistance invariably develops. Most clinical models show reactivation of the MAPK pathway in resistant samples, suggesting further downregulation of MAPK signaling might be beneficial. Therefore, we took BRAF mutant melanoma grown to resistance by continuous culture in dabrafenib plus trametinib (RAF + MEK inhibitor) or SCH772984 (ERK inhibitor), and treated them with a triple combination of RAF+MEK+ERK inhibitors. We found cells resistant to RAF+MEK inhibitors were cross-resistant to ERK inhibitor, but sensitive to RAF+MEK+ERK inhibitors. Conversely, cells resistant to the ERK inhibitor were cross-resistant to RAF+MEK inhibitor, but sensitive to the triple combination. However, given the possible deleterious side effects of a triple combination in patients, we explored whether alternative dosing and timing strategies could delay development of resistance. We compared chronic dosing of RAF+MEK or ERK inhibitors to weekly exposures alternating between RAF+MEK and ERK inhibitors. This alternative dosing strategy delayed development of resistance in vitro over chronic dosing, while also resulting in a slower proliferation rate in resistant cells. In addition, cells exposed to a higher dose of inhibitor for a shorter period of time was equivalent to chronic exposure. These studies suggest that alternative dosing strategies (other than chronic exposure) may prevent development of resistance, and allow for treatment of patients with higher order combinations and less side effects.
Citation Format: Eva Goetz, Bokang Rabasha, Levi Garraway. Alternative treatment strategies to overcome MAPK inhibitor resistance in melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2150.
Abstract 2164: Tenascin-C binding peptides for cancer targeting
Authors: Lingasamy Prakash , Tobi Allan , Hunt Hedi , Säälik Pille , Salumäe Markko , Teesalu Tambet , Teesalu Tambet 
Published: July 2016

Abstract
Extracellular matrix protein tenascin C (TNC) is strongly overexpressed in the stroma of many solid tumors. TNC expression is upregulated at the invasive front of tumors while being nearly undetectable in normal adult tissues. TNC-targeted humanized antibodies are undergoing clinical development for targeting compounds to solid tumors. Compared to antibodies, homing peptides may have more favorable extravasation and tumor penetration properties.
We used in vitro T7 peptide display to identify peptides that bind to the alternatively spliced domain C of the large isoform of Tenascin-C (TNC FnIIIC). The selected phage pool showed 500-fold increase in binding to immobilized TNC FnIIIC. Candidate TNC FnIIIC-binding peptides (designated PL1- 3) were found to bind to TNC FnIII C protein, to the extracellular matrix extracted from PC3 prostate tumors and to cultured tumor cells known to overexpress TNC. To evaluate candidate peptides in vivo, we used mice bearing patient-derived xenografts of P3 glioma (R. Bjerkvig, Bergen, Norway), 4T1 breast tumors, and PC-3prostate carcinoma. A pool of the phages displaying TNC FnIIIC binding peptides, and a panel of phages displaying published tumor homing and control peptides was injected intravenously in tumor-bearing mice, and relative tumor homing and background in control tissues was determined for each phage using high-throughput sequencing (HTS) of phage genomic DNA. These studies demonstrated that among TNC FnIIIC targeting peptides, the PL3 peptide showed the best tumor homing and specificity profile. To evaluate the potential of the synthetic PL3 peptide for tumor targeting of nanoparticles, we coupled PL3 peptide to iron oxide nanoworms (IONW) - paramagnetic nanoparticles that are PEGylated to extend blood half-life, and have because of their elongated shape more effective targeting properties than spherical nanoparticles. 5 hours after intravenous administration of 7.5mg/kg of IONW in mice bearing PC3 prostate cancer xenografts, PL3-IONW but not control IONW showed a robust accumulation in tumor vasculature, and some extravasation into extravascular tumor tissue. Our data suggests that the newly identified TNC FnIIIC targeting peptide, PL3, may be used for payload delivery into tumor stroma. Currently, we are evaluating PL3-targeted IONWs as a MRI contrast agent and as carriers for cytotoxic compounds to TNC expressing tumors.
Citation Format: Prakash Lingasamy, Allan Tobi, Hedi Hunt, Pille Säälik, Markko Salumäe, Tambet Teesalu, Tambet Teesalu. Tenascin-C binding peptides for cancer targeting. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2164.
Abstract 2170: Molecular modeling of novel peptide-receptor interaction for targeted drug delivery of prostate cancer
Authors: Salam Ahmad , Hembrick Vincent , Jaynes Jesse , Turner Timothy , Abdalla Mohamed 
Published: July 2016

Abstract
Prostate Cancer (PCa) is the second leading cause of cancer-related deaths among men in the United States. Due to the harsh side effects of conventional chemo- and radiotherapies, targeted drug delivery is now gaining the focus of cancer researchers. The key for success of any newly developed targeted drug delivery systems is the novel design of targeting peptides which have high binding affinities to differentially over-expressed receptors on the surface of PCa cells. Two over-expressed such receptors, which can be targeted to the cell surface of PCa cells are: Gonadotropin Releasing Hormone Receptor (GnRH-R), and Prostate Specific Membrane Antigen (PSMA). The analysis done from molecular dynamics simulation data gave an important information about each interaction; such as RMSD, The number of contacts between receptor and peptide within a cutoff distance of 5 Å and the binding free energies, ΔGGBSA of the interactions. In all systems, the back bone RMSD deviation of the receptor was calculated using the last 10 ns of the sampling process and averaged over all trajectories. The RMSD data deviated between 1.22 - 2.51 Å. The free binding energies or ΔGGBSA was calculated from the last 10 ns of the sampling process. The QH1 system has the more negative ΔGGBSA -36.15 kcal mol-1 and the QH4 system has the least negative ΔGGBSA of -18.4 kcal mol-1 among the eight systems of GnRH-R. QH2 system exhibits a highly interactive hydrogen bond (bond distance is 2.65 Å) between 134th position of the receptor amino acid sequence GLU and 5th position of the qh2 peptide's TYR. The ΔGGBSA is for the qh2 system is – 34.92 kcal mol-1. In the PSMA and its targeting peptide interactions, T2IA has the least negative ΔGGBSA of -47.37 kcal mol-1. A salt bridge was observed between the 10th position of the T2IA peptide sequence ARG and the 328 position of the 3RBU receptor's GLU. Based on our molecular modeling studies, we have determined the best targeting peptides among all the newly designed peptides. The binding efficiency of the targeting peptides with the lowest binding energies will be further investigated surface plasmon resonance (SPR) in near future.
Citation Format: Ahmad Salam, Vincent Hembrick, Jesse Jaynes, Timothy Turner, Mohamed Abdalla. Molecular modeling of novel peptide-receptor interaction for targeted drug delivery of prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2170.
Abstract 222: Inhibitors of mitochondrial transcription (IMT) specifically affect cancer cell proliferation
Authors: Bergbrede Tim , Choidas Axel , Di Lucrezia Raffaela , Menninger Sascha , Unger Anke , Uwe Koch , Nussbaumer Peter , Bonekamp Nina , Hoberg Emily , Posse Victor , Felser Andrea , Falkenberg Maria , Larsson Nils Göran , Gustafsson Claes M. , Klebl Bert M. 
Published: July 2016

Abstract
Mitochondria contain a unique DNA genome (mtDNA) that encodes a number of key components of the respiratory chain. Levels of mtDNA gene expression correlate with the metabolic requirements of mammalian cells. Recently, the role of mitochondrial function for the development and progression of cancer has been highlighted. Oncogenes have been identified to redirect mitochondrial functions to increase cancer cell survival. Increased levels of oxidative phosphorylation have also been implicated in cancer cell resistance towards drugs. In agreement with this notion, compounds that inhibit respiration may specifically target such resistant cells. Finally, it was demonstrated that inhibition of mitochondrial gene expression leads to apoptosis in rapidly dividing cells. Based on these observations, we present a completely novel principle different from known electron transfer chain blockers to treat cancer by inhibiting mtDNA transcription. To this end a study to identify and characterize inhibitors of mitochondrial transcription (IMTs) with lead-like properties was initiated. A high throughput biochemical screening campaign was performed identifying small molecular weight inhibitors of PolRMT, the mitochondrial RNA polymerase, which controls mtDNA transcription. Upon hit optimization, potent compounds with biochemical and cellular IC50s in the low nanomolar range have been identified. IMTs displayed good physicochemical and pharmacological properties. They have been shown to be inactive on other RNA polymerases proving their excellent specificity. Testing IMTs in assays for cancer cell proliferation revealed potent inhibition of sensitive cell lines (double digit nanomolar range). Interestingly, none of the tested primary non-cancer cell lines was affected by the IMTs, indicating a good therapeutic window. Testing selected IMTs in pharmacokinetic studies in vivo revealed high exposures and no detectable adverse effects (single and repeated dosing). Medicinal chemistry optimization will help to identify candidate compounds for efficacy testing in xenograft models.
Citation Format: Tim Bergbrede, Axel Choidas, Raffaela Di Lucrezia, Sascha Menninger, Anke Unger, Koch Uwe, Peter Nussbaumer, Nina Bonekamp, Emily Hoberg, Victor Posse, Andrea Felser, Maria Falkenberg, Nils Göran Larsson, Claes M. Gustafsson, Bert M. Klebl. Inhibitors of mitochondrial transcription (IMT) specifically affect cancer cell proliferation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 222.
Abstract 2222: Dual inhibition of cancer stemness and immune checkpoint genes by targeting Stat3
Authors: Gao Yuan , Keates Sarah , Hsu Eric , Huang Janet , Brooks Emily , Hitron Matt , Li Youzhi , Rogoff Harry A. , Li Chiang 
Published: July 2016

Abstract
Highly malignant stemness-high cancer cells, also termed cancer stem cells, have been found to hijack stemness genes important for embryonic stem cells to acquire a state of high-stemness. Cancer stemness has been associated with enhanced tumorigenicity and resistance to chemotherapies. Moreover, stemness-high cancer cells have been isolated from a variety of human cancer types. Therefore, targeting cancer stemness holds significant promise for advancing cancer treatment.
Recent clinical success with antibodies targeting PD1 and PDL1 has validated that cancer cells can hijack immune checkpoint genes to subvert endogenous anticancer surveillance by the immune system. It is, therefore, highly desirable to develop therapeutics that simultaneously target both cancer cell stemness and immune checkpoints.
The transcription factor Signal Transducer and Activator of Transcription 3 (Stat3) is activated by a multitude of upstream oncogenic pathways and cytokine receptors. Aberrant and constitutive activation of Stat3 has been found in a wide variety of human cancers, and has also been implicated in cancer cell proliferation, survival, and immune evasion.
By using aiRNA (asymmetric RNA duplexes) we have achieved potent Stat3 silencing with precision in stemness-high cancer cells. We observed that Stat3 silencing leads to simultaneous down regulation of cancer cell stemness and immune checkpoint gene expression. Treatment of stemness-high cancer cells with BB608, a small molecule inhibitor of Stat3, led to simultaneous inhibition of stemness-high cancer cell survival and self-renewal, as well as downregulation of immune checkpoint genes, including IDO1 in vitro and in vivo. Furthermore, while expression of stemness genes and immune checkpoint genes in tumor tissues are known to predict poor patient survival, patients with higher expression levels of stemness genes and immune checkpoint genes showed prolonged overall survival after treatment with BB608 in clinical trials. Targeting Stat3 is, therefore, a promising strategy to achieve dual inhibition of cancer cell stemness and immune evasion.
Citation Format: Yuan Gao, Sarah Keates, Eric Hsu, Janet Huang, Emily Brooks, Matt Hitron, Youzhi Li, Harry A. Rogoff, Chiang Li. Dual inhibition of cancer stemness and immune checkpoint genes by targeting Stat3. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2222.
Abstract 2268: Detection of T790M mutation in EGFR gene, an EGFR-TKI resistant mutation, in tumor samples unexposed to EGFR TKIs
Authors: Koba Hayato , Kimura Hideharu , Nishikawa Shingo , Yoneda Taro , Sone Takashi , Kasahara Kazuo 
Published: July 2016

Abstract
Background: T790M mutation in EGFR gene is the commonest mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with EGFR mutation. The third-generation EGFR-TKIs are expected to overcome the resistance caused by T790M existence. On the other hand, several reports using highly sensitive detection assays showed a minute amount of T790M mutation alleles was detected in tumor tissues obtained before EGFR-TKI treatment.
Aim: To clear whether T790M dominancy in tumor cells before EGFR-TKI treatment reflects between about the EGFR-mutated lung cancer which was not until exposed EGFR TKI therapy and actual resistance mechanism. Methods: We assessed T790M dominancy in tumor cells from 29 NSCLC patients with EGFR mutations, who had not received EGFR-TKIs. T790M mutation and common mutations, such as deletional mutations in exon 19 and L858R, were detected by droplet digital PCR (ddPCR) separately. T790M dominancy was calculated from each level of mutation-alleles about common mutation and T790M mutation.
Results: We can detect the T790M mutation in initial biopsy tissues from 21 cases (72%). The mean value of T790M mutation dominancy ratio before EGFR-TKI treatment was 0.48% (0.00-69.09%) and it is not difference between in patients with T790M-positive at resistance and in that with negative (p = 0.87). Conclusions: T790M mutation was detected in most of the tumor tissues unexposed to EGFR TKIs. T790M mutation dominancy calculated by our assays in tumor tissues before EGFR-TKI treatment may not be related to induce T790M resistance to EGFR-TKIs.
Citation Format: Hayato Koba, Hideharu Kimura, Shingo Nishikawa, Taro Yoneda, Takashi Sone, Kazuo Kasahara. Detection of T790M mutation in EGFR gene, an EGFR-TKI resistant mutation, in tumor samples unexposed to EGFR TKIs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2268.
Abstract 2277: Multiplexed gene expression profiling of resected intrahepatic cholangiocarcinoma: Implication of FGFR4-FGF19 as a novel treatment target
Authors: Yoo Changhoon , Kim Kyu-pyo , Ryoo Baek-Yeol , Hong Seung-Mo , Hwang Jung Jin , Jeong Seong-Yun , Hoeflich Klaus , Schmidt-Kittler Oleg , Miller Stephen , Choi Eun Kyung 
Published: July 2016

Abstract
Background: The fibroblast growth factor receptor 4 (FGFR4) pathway is an essential regulatory component of bile acid synthesis and its relationship with hepatocellular carcinoma (HCC) has been reported. We investigated the gene expression and clinical significance of FGFR4 and related pathways in intrahepatic cholangiocarcinoma (IH-CCa).
Methods: We assessed the expression of 98 genes in formalin-fixed paraffin embedded tumor tissue specimens from 46 patients with IH-CCa surgically resected using the NanoString platform. This included 10 FGF pathway genes (e.g. FGFR1-4, KLB, FGF3, 4, 19, 21, 23), 19 distal marker genes (e.g. CYP7A1, CYP17A1) and 31 genes relevant to HCC and CCa (e.g. AFP, TS) and 18 CNV matched genes and 20 control genes. Log-transformation of the gene expression was done for normalization and statistical analysis. Overall survival of 44/46 patients was correlated with gene expression (&lt; median vs ≥ median) using a log-rank test. Two patients were excluded from analysis, due to death from postoperative complications and metastasectomy respectively.
Results: The median age of our patient cohort was 56 years (range 30-78) and 34 patients (74%) were male. All but one tumor specimen (98%) were from the primary tumor resection and microscopic complete resection (R0) was achieved in 37 patients (80%). Six patients (13%) had hepatitis B virus infection with or without liver cirrhosis. FGFR4 was expressed 100 times over background in IH-CCa, the expression of FGF19, FGF21, CYP7A1, CYP17A1, AFP and KLB was lower. Overall survival was significantly stratified according to the expression of FGFR4 (p = 0.004), FGF19 (p = 0.046), FGF21 (p = 0.04), KLB (p = 0.03), CYP8B1 (p = 0.02), ADH1B (p = 0.045), CDKN1B (p = 0.005), NCOR1 (p = 0.03), NF1 (p = 0.006), NROB2 (p = 0.001), MAP2K3 (p = 0.009), MYC (p = 0.04), CYP2E1 (p&lt;0.001), and LGR5 (p = 0.03).
Conclusions: Our results indicate that FGFR4 might have a crucial role in IH-CCa, and its overexpression was associated with better prognosis, supporting that FGFR4 may define a subset of IH-CCa and be used as a promising target for therapeutic interventions.
Citation Format: Changhoon Yoo, Kyu-pyo Kim, Baek-Yeol Ryoo, Seung-Mo Hong, Jung Jin Hwang, Seong-Yun Jeong, Klaus Hoeflich, Oleg Schmidt-Kittler, Stephen Miller, Eun Kyung Choi. Multiplexed gene expression profiling of resected intrahepatic cholangiocarcinoma: Implication of FGFR4-FGF19 as a novel treatment target. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2277.
Abstract 2295: GDNF family receptor alpha 4 (GFRa4)-targeted adoptive T-cell immunotherapy for medullary thyroid carcinoma
Authors: Bhoj Vijay G. , Nunez-Cruz Selene , Zhou Kenneth , Arhontoulis Dimitrios , Feldman Michael , Mansfield Keith , Peng Haiyong , Rader Christoph , Siegel Don L. , Milone Michael C. 
Published: July 2016

Abstract
Metastatic medullary thyroid cancer (MTC) is a rare, but often aggressive, thyroid malignancy with a 5-year survival rate of 28% and few effective therapeutic options. Adoptive T-cell immunotherapy using chimeric antigen receptor (CAR)-modified T cells (CARTs) is showing encouraging results in the treatment of cancer, but development is challenged by the availability of suitable target antigens. We identified glial-derived neurotrophic factor (GDNF) family receptor alpha 4 (GFRα4), which associates with the RET receptor tyrosine kinase, as a putative antigenic target for CAR-based therapy of MTC. Using RNA in situ hybridization (RNAscope) and quantitative RT-PCR, we show that GFRα4 is highly expressed in MTC. Normal tissue expression of GFRα4 mRNA is restricted to parafollicular cells (C-cells) within the thyroid, the normal cell type from which MTC originates, and normal thymus.Based upon the highly restricted expression, we generated two high affinity single chain variable fragments (scFvs) targeting GFRα4 isoforms a and b by selecting a naïve rabbit antibody library by phage display. Second generation CARs bearing the CD137 costimulatory domain were constructed using these GFRα4-specific scFvs. GFRα4-specific CARTs trigger antigen-dependent cytotoxicity and cytokine production in vitro, and they are able to control pre-established TT cell tumors in an immunodeficient mouse xenograft model of MTC. These data demonstrate the feasibility of targeting GFRα4 by CARTs, and support this molecule as a promising target for adoptive T cell immunotherapy and other antibody-based therapy of MTC.
Citation Format: Vijay G. Bhoj, Selene Nunez-Cruz, Kenneth Zhou, Dimitrios Arhontoulis, Michael Feldman, Keith Mansfield, Haiyong Peng, Christoph Rader, Don L. Siegel, Michael C. Milone. GDNF family receptor alpha 4 (GFRa4)-targeted adoptive T-cell immunotherapy for medullary thyroid carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2295.