bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5164: A pyrrole-Imidazole polyamide conjugate targeting KRAS oncogenic mutations is a promising approach against KRAS mutated colorectal and pancreatic cancers
Authors: Nagase Hiroki , Takatori Atsushi , Watanabe Takayoshi , Koshikawa Nobuko , Lin Jason 
Published: July 2017

Abstract
Although a tremendous amount of studies has been made to directly target oncogenic drivers, such as RAS and MYC, no drug is clinically available because of difficulties to develop RAS- or Myc-targeted anti-cancer therapeutics due to the smooth 3D surface topology. One of major limitations of targeting the RAS pathway may be intrinsic or acquired resistance as seen in the other molecular target therapy. A new approach that directly target driver genes may provide a more direct route to help address unmet medical needs for refractory cancer conquest. We therefore synthesized the Pyrrole-Imidazole polyamide conjugate, KR12, specifically alkylated KRAS codon 12 mutant DNA (G12D or G12V). KR12 reduced expression of the mutated oncogenic-protein by RNA transcription inhibition and induced cancer cell death at low dose (1 to 50 nM). We also applied a novel enrichment-based sequencing and computational pipeline, which first identifies a PIP’s genomic binding sites through next-generation sequencing followed by gene expression microarray studies. The computational analysis suggested non-KRAS binding overall had little contribution to changes at the phenotypic level in colorectal cancer cell lines. We also the anti-cancer event is not only for colorectal but also pancreatic ductal adenocarcinoma (PDAC). Significant tumor reduction was observed in a mouse model of spontaneous PDAC (LSL-KrasG12D/+,Ptf1aCre/+,Tgfbr2flox/flox). In animal studies we also observed KR12 intakes and retentions in tumor but not any other organs 24 hours after I.V. administration. We will summarize the sequence-dependent alkylating approach using antibiotic mimics of alkylating PI-polyamide conjugates, may open a new strategy targeting the driver oncogene mutated DNA sequence. This approach should be used for medicine against variety of unfavorable KRAS mutated cancers.
Note: This abstract was not presented at the meeting.
Citation Format: Hiroki Nagase, Atsushi Takatori, Takayoshi Watanabe, Nobuko Koshikawa, Jason Lin. A pyrrole-Imidazole polyamide conjugate targeting KRAS oncogenic mutations is a promising approach against KRAS mutated colorectal and pancreatic cancers [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 5164. doi:10.1158/1538-7445.AM2017-5164
Abstract 5166: Sensitivity of melanoma cells to a novel class of Ras inhibitors
Authors: Saville Kate M. , Lee Kevin , Mattox Tyler E. , Chen Xi , Valiyaveettil Jacob , Berry Kristy , Ramírez-Alcántara Veronica , Zhu Bing , Keeton Adam , Boyd Michael , Piazza Gary , Lindsey Ashley S. 
Published: July 2017

Abstract
A high percentage of human cancers arise from mutations in the ras gene that encodes an abnormal Ras protein locked in a constitutively active GTP-bound state that promotes tumor cell proliferation, survival, and metastasis. These gain-in-function mutations in the ras gene or constitutive activation of tyrosine kinase receptors upstream of the Ras protein drive tumor cell growth by activating Raf/MAPK and PI3K/AKT signaling pathways. Ras has been an elusive drug target for which no inhibitors are available to treat Ras-driven cancers. Screening a library of indene derivatives in a differential phenotypic assay identified a novel compound class displaying high potency and selectivity to inhibit the growth of tumor cells harboring mutant Ras relative to tumor cells with wild type (WT) Ras. Lead optimization resulted in a drug development candidate (DC070-547) and several back-up analogs (e.g. ADT-006) with IC50 values in the low nanomolar range and selectivity indices of 100 fold or greater to inhibit the growth of tumor cells with constitutively activated Ras relative to tumor cells with low levels of activated Ras. Sensitivity among a large panel of tumor cell lines to this compound class strongly correlated with levels of activated Ras, but did not appear to be limited to a specific ras gene mutation or Ras protein isoform. Here, we report that DC070-547 and ADT-006 potently and selectively inhibit the growth of the human melanoma cell line, SK-MEL-2, harboring a mutation in the ras gene that encodes the constitutively active N-Ras protein with IC50 values of 7 and 25 nM, respectively. In addition, both compounds potently inhibited the growth of the murine melanoma cell line, B16-F10 with WT ras, but harboring a mutation in a tyrosine kinase receptor upstream of Ras, specifically PDGFRα, which results in high levels of active, GTP-bound Ras as confirmed by Ras-RBD pull-down assays. To determine if treatment can disrupt Ras signaling, B16-F10 cells were incubated with the compounds before being subjected to Western blotting for phosphorylated signaling molecules downstream of Ras. Treatment reduced levels of phosphorylated c-Raf and MEK at concentrations that inhibit tumor cell growth. These findings support further investigation of this novel class of Ras inhibitors for the treatment of Ras-driven melanoma.
Citation Format: Kate M. Saville, Kevin Lee, Tyler E. Mattox, Xi Chen, Jacob Valiyaveettil, Kristy Berry, Veronica Ramírez-Alcántara, Bing Zhu, Adam Keeton, Michael Boyd, Gary Piazza, Ashley S. Lindsey. Sensitivity of melanoma cells to a novel class of Ras inhibitors [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 5166. doi:10.1158/1538-7445.AM2017-5166
Abstract 5172: E7386, an orally active CBP/beta-catenin modulator, induces T cells infiltration into tumor and enhances antitumor activity of anti-PD-1 mAb in Wnt1 tumor syngeneic mice model
Authors: Hori Yusaku , Yamada Kazuhiko , Kato Yu , Ozawa Yoichi , Odagami Takenao , Matsui Junji , Matsushima Tomohiro , Nomoto Kenichi , Kouji Hiroyuki , Owa Takashi 
Published: July 2017

Abstract
Recently, immunotherapeutic approaches have come to forefront in melanoma, non-small cell lung cancer, bladder cancer, and so on. However, sufficient benefits from these treatments have been limited. T cell infiltrating into tumor tissues is reported as one of the response biomarker candidates for the immune checkpoint inhibitors. Recent studies have shown that the activation of the Wnt/beta-catenin signaling pathway results in T cell exclusion and resistance to immune checkpoint inhibitor in melanoma patients. We established the Wnt1 tumor syngeneic mice model (Wnt1 model) by implantation of mammary adenocarcinomas isolated from MMTV-Wnt1 transgenic mice. Here we demonstrate whether E7386, a first-in-class orally active CBP/beta-catenin modulator, affects the recruitment of T cells into tumor tissues, leading to the enhancement of anti-PD-1 mAb in Wnt/beta-catenin signaling pathway activating tumor model. The mice were treated with E7386 (50 mg/kg, orally, BID) and/or anti-mouse PD-1 mAb (10 mg/kg, intraperitoneal, twice a week) for three weeks. Tumor diameters are measured with digital calipers, and the tumor volume in mm3 is calculated. Immunohistochemical (IHC) analysis was evaluated for tumor-infiltrating T cells. E7386 showed significant antitumor activity in Wnt1 model, but anti-PD-1 mAb did not. In contrast, E7386 with anti-PD-1 mAb indicated prominent antitumor activity compared to each single treatment. Enhancement of body weight loss in combination group was not observed. In IHC analysis, infiltration of T cells was limited in vehicle control group, in contrast T cell infiltration into tumors was clearly observed in both E7386 treatment group and combination group. As a result, antitumor activity of immune checkpoint inhibitor was limited in Wnt-driven tumor model and E7386 as a novel CBP/beta-catenin modulator enhanced the antitumor activity of anti-PD-1 mAb via induction of tumor-infiltrating T cells.
Citation Format: Yusaku Hori, Kazuhiko Yamada, Yu Kato, Yoichi Ozawa, Takenao Odagami, Junji Matsui, Tomohiro Matsushima, Kenichi Nomoto, Hiroyuki Kouji, Takashi Owa. E7386, an orally active CBP/beta-catenin modulator, induces T cells infiltration into tumor and enhances antitumor activity of anti-PD-1 mAb in Wnt1 tumor syngeneic mice model [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 5172. doi:10.1158/1538-7445.AM2017-5172
Abstract 5178: CB002, a novel p53 pathway-restoring compound that induces apoptosis through the pro-apototic protein NOXA
Authors: Borrero Liz J. Hernandez , Zhang Shengliang , Dicker David T. , El-Deiry Wafik S. 
Published: July 2017

Abstract
P53 is a transcription factor that becomes stimulated upon genotoxic and cellular stress signals ultimately leading to the transcriptional activation of genes involved in processes such as DNA repair, cell cycle arrest, and apoptosis etc. TP53 is the most commonly mutated tumor suppressor and this is associated with cancer initiation, cancer progression and therapy resistance. P53-targeted therapy has proven to be challenging because direct functional restoration of p53 as a transcription factor has been difficult to achieve. We haven taken a different approach by investigating small molecules that functionally restore the p53-signaling pathway instead of direct p53 targeting. To date there is no approved drug that restores the p53 pathway in cancer cells with mutant p53. Therefore, we performed a high-throughput screen to identify such molecules. We identified a family of small molecules, CB002 and its structural analogs, as candidates for restoration of the p53 pathway in p53-null and mutant p53-expressing cancer cells. CB002 was specific in causing apoptosis in colorectal cancer cells and not in normal human fibroblasts cells as indicated by a Sub-G1 assay. Utilizing the xCELLigence RTCA DP system and CIM-Plate we show that CB002 treatment decreases the ability of colorectal cancer cells to migrate. The ability of CB002 to restore the p53 pathway was validated by studying the activation of p53 target genes p21, DR5, and NOXA in various cancer cell lines and expression of well-established apoptotic markers. Stable knockdown of NOXA completely abrogated the expression of cleaved PARP and reduced Sub-G1 cells, implicating the relevance of NOXA as a key mediator of cell death induction by CB002. We are currently exploring the mechanism by which NOXA induces apoptosis, as preliminary results suggest that degradation of Mcl-1 is not required for CB002 mediated cell death. In addition, we are evaluating the ability of CB002 structural analogs in decreasing the stability of mutant p53 using a larger panel of p53 mutants, as CB002 appears to target R175H p53 mutants. Our data supports the continued investigation of CB002 as a p53 pathway-restoring compound that may be further developed as a cancer therapeutic for p53-null tumors as well as tumors with p53 mutations.
Citation Format: Liz J. Hernandez Borrero, Shengliang Zhang, David T. Dicker, Wafik S. El-Deiry. CB002, a novel p53 pathway-restoring compound that induces apoptosis through the pro-apototic protein NOXA [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 5178. doi:10.1158/1538-7445.AM2017-5178
Abstract 518: Synergistic effects of dual inhibition of YAP1 and TAZ in non-small cell lung cancer cells
Authors: Shum Elaine , Liu Huijie , Zhu Liang , Perez-Soler Roman , Halmos Balazs , Cheng Haiying 
Published: July 2017

Abstract
Background: The Hippo signaling pathway is associated with regulation of cell growth and apoptosis. Downstream effectors of this pathway, YAP and its paralog, TAZ, interact with TEA domain (TEAD) transcription factors leading to cell proliferation and anti-apoptosis. As a result, YAP and TAZ have emerged as attractive anti-cancer therapeutic targets. Several studies, including our previous report, have noted the individual effects of YAP or TAZ ablation; however, consequences of dual inhibition have not yet been investigated in lung cancer. We hypothesize that dual inhibition of YAP and TAZ will lead to more pronounced cytotoxicity than each knockdown alone as a result of diminished compensatory mechanism by the remaining family member.
Methods: NSCLC cell lines, such as PC9 and A549, were transfected with individual YAP1, TAZ siRNA or a combination of both siRNAs. Western blotting was performed to determine the levels of YAP1 and TAZ proteins following knockdown. Quantitative RT-PCR was also performed to confirm effective YAP1 and TAZ knockdown. In addition, gene and protein expression of downstream targets, such as CTGF and Cyr61, were assessed. Clonogenic assays were performed to determine cell survival.
Results: Successful siRNA-mediated YAP and TAZ ablation were confirmed with Western blot and qRT-PCR. The expression of the Hippo-YAP/TAZ downstream targets, CTGF, Cyr61 and AXL, were also reduced accordingly. Moreover, dual knockdown of YAP and TAZ led to a more pronounced inhibition of cell survival/proliferation than ablation of individual genes alone. In addition, dual inhibition of YAP/TAZ exhibited significantly diminished levels of the mesenchymal markers, vimentin and N-cadherin, and increased levels of the epithelial marker, E-cadherin. EMT has been recognized as an essential process during lung cancer tumor migration and metastasis.
Conclusion: Our findings show that dual inhibition of YAP1 and TAZ are synergistic in blocking NSCLC cell survival signaling. Thus, dual inhibition may serve as a better therapeutic strategy in targeting the Hippo pathway than sole YAP1 blockade in the management of NSCLC.
Citation Format: Elaine Shum, Huijie Liu, Liang Zhu, Roman Perez-Soler, Balazs Halmos, Haiying Cheng. Synergistic effects of dual inhibition of YAP1 and TAZ in non-small cell lung cancer 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 518. doi:10.1158/1538-7445.AM2017-518
Abstract 5180: Effects of soy isoflavones and SRC inhibitors on metastatic activity in prostate cancer
Authors: Rice Lori P. , Siemann Dietmar W. 
Published: July 2017

Abstract
Background: In advanced prostate cancer (PCa), cells escape from the primary tumor and enter the bloodstream, preferentially targeting the bone. This results in weakened bones, spinal compressions, fractures and intense pain. Efforts to interfere with early steps in the metastatic cascade by affecting the tumor microenvironment have led to the development of promising small molecule targeting agents. The tyrosine kinase inhibitors, saracatinib and dasatinib, have been shown to inhibit activation of Src and downstream effectors thought to be involved in cancer cell dissemination. Soy-derived isoflavones (ISFs) have been shown to have cytostatic effects on PCa cells without toxicity.
Aim: The aim of these studies was to determine if ISFs enhance the effects of Src inhibitors on PCa cells, resulting in lower doses of these agents needed to produce optimum results.
Methods: PC-3 ML and LNCaP cells were treated with either a Src inhibitor (dasatinib or saracatinib), a soy isoflavone extract (ISFs), or a combination. Modified Boyden transwell chambers were used to evaluate migration and invasion. Cell cycle and proliferation were measured using FACS analyses and trypan blue staining, respectively.
Results: ISFs and Src inhibitors did not cause cytotoxicity or reduce proliferation. However, Src inhibitors produced an increase in cells in G1 phase, while ISFs increased cells in G2/M phase. When ISFs were combined with Src inhibitors, both phases were increased with a concomitant decrease in S phase cells. In transwell migration studies, all agents significantly decreased the number of cells found on the bottom of the membrane: dasatinib&gt;saracatinib&gt;ISFs. Lower doses of Src inhibitors were needed to produce inhibition of migration when ISFs were added to the treatment. Invasion studies with PC-3 ML and LNCaP cells suggest that ISFs can reduce metastatic activity by 39% and 35%, respectively. Therefore, by adding ISFs, lower doses of inhibitors might be used to achieve optimal response and decrease toxicity.
Conclusions: In vitro studies suggested that a combination of a Src inhibitors and ISFs, at non-cytotoxic doses, results in greater inhibition of metastatic or invasion activity than either alone. Further studies are needed to determine if this strategy could be used clinically to treat patients with lower doses of small molecule inhibitors by including soy isoflavone concentrates in the treatment regimen.
Citation Format: Lori P. Rice, Dietmar W. Siemann. Effects of soy isoflavones and SRC inhibitors on metastatic activity in prostate 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 5180. doi:10.1158/1538-7445.AM2017-5180
Abstract 5184: Radiosensitizing effect of lapatinib in HER2-overexpressing breast cancer cells: scientific rationale for RTOG1119 study
Authors: Yu Tosol , Cho Bong Jun , Choi Eun Jung , Park Ji Min , Kim Dan Hyo , Kim In Ah 
Published: July 2017

Abstract
Trastuzumab has been widely used for the treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer, however, it cannot easily cross the blood-brain barrier (BBB) and is known to increase the incidence of brain metastases. In contrast, lapatinib has a low molecular weight and can cross the BBB and it could be useful to treat brain metastases in patients with HER2-positive breast cancer. To explore the impact of lapatinib on radiation response, we conducted an in vitro experiment using SKBR3 and BT474 breast carcinoma cells exhibiting HER2/neu amplification. Lapatinib down-regulated phosphorylated p-HER2, p-EGFR, p-AKT, and p-ERK. Pretreatment of lapatinib increased the radiosensitivity of SKBR3 (sensitizer enhancement ratio [SER]: 1.21 at a surviving fraction of 0.5) and BT474 (SER: 1.26 at a surviving fraction of 0.5) cells and hindered the repair of DNA damage, as suggested by the prolongation of radiation-induced γH2AX foci and the down-regulation of phosphorylated DNAdependent protein kinase, catalytic subunit (p-DNAPKcs). Increases in radiation-induced apoptosis and senescence were suggested to be the major modes of cell death induced by the combination of lapatinib and radiation. Furthermore, lapatinib did not radiosensitize a HER2- negative breast cancer cell line or normal human astrocytes. These results suggest that lapatinib can potentiate radiation-induced cell death in HER2-overexpressing breast cancer cells and may increase the efficacy of radiotherapy. Based on these findings, RTOG1119 study which is a phase II randomized study for lapatinib combined with radiation therapy in patients with brain metastases from HER2-positive breast cancer is ongoing (NCT 01622868).
Citation Format: Tosol Yu, Bong Jun Cho, Eun Jung Choi, Ji Min Park, Dan Hyo Kim, In Ah Kim. Radiosensitizing effect of lapatinib in HER2-overexpressing breast cancer cells: scientific rationale for RTOG1119 study [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 5184. doi:10.1158/1538-7445.AM2017-5184
Abstract 5193: Hafnium oxide nanoparticles (NBTXR3), a novel radiation enhancer achieves marked antitumor efficacy across five tumor types
Authors: Zhang Ping , Vivet Sonia , Paris Sébastien , Pottier Agnès 
Published: July 2017

Abstract
NBTXR3 are hafnium oxide nanoparticles (NPs) used for a single intratumor administration as radioenhancer in combination with radiation therapy (RT) as part of multi-modality of cancer treatment. The size, shape and surface of the NPs have been designed to develop strong interactions with cancer cells - effective cell binding and uptake - and to persist within the tumor mass during the whole RT treatment. The high electron density of the NPs is responsible for an increased probability of interaction with incoming ionizing radiations (when compared to tumor tissues with low electron density) and an increased energy dose deposition within the cancer cells which results in an enhanced tumor destruction when compared to RT alone. NBTXR3 works similar to the physical mode of action of RT, it does not rely on any biological system or target and constantly amplifies the radiation dose deposition (“on/off” activation). Here we present the transferability of the approach from one type of cancer to the other evaluating (i) the feasibility of the intratumor injection (intratumor availability of NBTXR3 nanoparticles by Computed Tomography (CT) or µCT) and (ii), the antitumor efficacy of NBTXR3 exposed to radiation. NBTXR3 NPs demonstrated a good intratumor availability and persistence across all tested tumor models (epithelial or mesenchymal origin), including human PDX tumor models. Notably, in PAC-120 tumor model the persistence of NBTXR3 NPs within the tumor mass was observed for more than 50 days which is equivalent to the entire duration of RT treatment. The antitumor efficacy was systematically enhanced in terms of tumor growth delay for animals treated with NBTXR3 and exposed to RT when compared to RT alone. NBTXR3 is currently in clinical trials in seven cancer indications including: soft tissue sarcoma, head and neck (H&N), liver, rectal and prostate. These preclinical studies support the rationale for the development of NBTXR3 across all cancer indications where radiation treatment is used.
NBTXR3 intratumor availability and antitumor efficacyTumor modelX-ray sources (antitumor efficacy)CT or µCTSarcomaHT1080200kV, Ir192LPS80T3 (PDX)200kV, Co60xA673Co60ProstatePC3150kVxDU145200kVxPAC120 (PDX)xH&NCAL33200kVxFaDu200kVxColorectalHCT116Ir192xLungNCI-H460-luc2200kVx
Citation Format: Ping Zhang, Sonia Vivet, Sébastien Paris, Agnès Pottier. Hafnium oxide nanoparticles (NBTXR3), a novel radiation enhancer achieves marked antitumor efficacy across five tumor types [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 5193. doi:10.1158/1538-7445.AM2017-5193