tbuckley/cabot-search huggingface dataset:
Abstract 291: RAS Fingerprinting: Patient-Specific Evaluation of the Renin-Angiotensin-System in Plasma by LC-MS/MS-Based Multiplex Quantification of Angiotensin Peptides
Authors: Marko Poglitsch, Cornelia Schwager, Manfred Schuster, Hans Loibner
Journal: Circulation Research (2012)

The Renin-Angiotensin-System (RAS) is critically involved in the regulation of important physiological functions including blood pressure and fluid balance. It is constituted by multiple enzymes giving rise to a meshwork of effector peptides, which mediate their functions through binding to specific receptor molecules. Therefore, the modification of angiotensin peptide levels represents a common strategy for the treatment of RAS-associated diseases and is frequently achieved by the pharmacologic regulation of enzymes taking part in angiotensin metabolism. We developed a highly sensitive method, which allows the simultaneous absolute quantification of up to 10 different angiotensin peptides in human plasma and whole blood (RAS-Fingerprinting). Either the measurement of in vivo RAS-Fingerprints (immediate sample stabilization) or heparin derived ex vivo RAS-Fingerprints in plasma or whole blood, provide unique insights into the biochemical constitution of the human RAS and therefore represent powerful tools for the patient specific evaluation of this physiologically important peptide hormone system. During the development and validation of a new LC-MS/MS based method for angiotensin quantification, comprehensive datasets for various applications of RAS-Fingerprinting have been generated. RAS-Fingerprints were measured in blood of healthy volunteers during the treatment with different RAS-blockers, which provided deep insights in the physiology and regulation of the human RAS and revealed surprising differences between individual patients. With the help of RAS-Fingerprinting, we were able to re-draw the picture of the human RAS at a previously unachieved level of detail and accuracy. Due to the availability of new selection criteria for pharmacologic screens, RAS-Fingerprinting could contribute to the development of innovative therapeutic approaches affecting the RAS. The extensive utilization of RAS-Fingerprinting in clinical studies will substantially enhance our understanding of the human RAS and could lead to the development of personalized treatment schemes in the management of RAS-associated diseases in the near future.
Abstract CT140: PINC trial: Preventing invasive breast neoplasia with chloroquine
Authors: Virginia A. Espina, Lance Liotta, Svetlana Rassulova, Holly Gallimore, Thalia Grant-Wisdom, Geetha Menezes, Hassan Nayer, Kirsten Edmiston
Journal: Cancer Research (2017)

Abstract The PINC trial (NCT01023477) examined the dosage efficacy of oral chloroquine (CQ), an autophagy inhibitor, as a neoadjuvant therapy to reduce the volume, cause regression and decrease the recurrence of breast ductal carcinoma in situ (DCIS), for any grade or ER/PR/Her2 status. Study Objectives: Establish the safety of preventive doses of chloroquine in patients receiving external beam radiation. Elucidate functional molecular and cellular impacts of in vivo autophagy pathway treatment for DCIS. Study the impact of autophagy inhibitors on the MRI characteristics of DCIS lesions. Study the molecular cytogenetic profile of DCIS lesions before and after therapy. This trial implemented a general strategy to accelerate the pace of community-based translational research. Technology for providing immediate feedback on the therapeutic efficacy at the molecular level can be broadly extended to other trials. Methodology: 12 patients diagnosed with DCIS (any grade or ER/PR/Her2 status) were enrolled and randomly assigned to receive CQ at 250mg/week (n=5) or 500mg/week (n=7) for 4 weeks, followed by standard of care surgical therapy. MRI was performed before/after CQ treatment. DCIS spheroid forming cells were isolated and propagated from fresh human DCIS lesions. DCIS cells were characterized by organ culture, xenograft transplantation, molecular cytogenetics, and 59 cell signaling kinases were quantified by Reverse Phase Protein Microarrays. Results: 12 patients completed 4 weeks of CQ treatment prior to surgical excision of their DCIS lesion, with 1 yr follow-up information. CQ treatment reduced PCNA proliferation index in DCIS lesions compared to untreated controls (p=0.001) and inhibited autophagic flux (LC3B positive puncta by IHC). CQ reduced the number of mammospheres in organoid culture without altering copy number variation. Xenograft transplants in NOD/SCID mouse mammary fat pads failed to generate tumors (n=4). 7/12 patients exhibited a reduction in lesion diameter by MRI, 3/12 patients exhibited no measurable change, and 2/12 had a slight increase. Calcium export channel protein (PMCA2) co-localized with 3+ HER2 positive DCIS lesions. Tumor infiltrating macrophages migrated into DCIS ducts following CQ therapy compared to controls (p=0.006). Conclusion: Oral chloroquine, as anti-autophagy therapy, generates a measurable reduction in proliferation of DCIS lesions and enhances immune cell migration into the duct. Citation Format: Virginia A. Espina, Lance Liotta, Svetlana Rassulova, Holly Gallimore, Thalia Grant-Wisdom, Geetha Menezes, Hassan Nayer, Kirsten Edmiston. PINC trial: Preventing invasive breast neoplasia with chloroquine [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 CT140. doi:10.1158/1538-7445.AM2017-CT140
Abstract 2742: Cross-platform comparison of four leading technologies for detectingEGFRmutations in circulating tumor DNA from plasma of patients with non-small cell lung carcinoma
Authors: Ting Xu, Xiaozheng Kang, Xiaofang You, Dai Liang, Dequan Tian, Wanpu Yan, Yongbo Yang, Hongchao Xiong, Zhen Liang, Grace Q. Zhao, Shengrong Lin, Ke-Neng Chen, Guobing Xu
Journal: Cancer Research (2017)

Abstract Analysis of circulating tumor DNA (ctDNA) is emerging as a powerful tool for guiding targeted therapy and monitoring tumor evolution in patients with non-small cell lung cancer (NSCLC), particularly when fresh tissue biopsy is not available. This study compared the ability of four leading technology platforms to detect epidermal growth factor receptor (EGFR) mutations (L858R, exon 19 deletion, T790M and G719X) in ctDNA from NSCLC patients. The platforms included two amplification refractory mutation systems (cobas-ARMS and ADx-ARMS), a droplet digital polymerase chain reaction platform (ddPCR) and a next-generation sequencing platform (Firefly NGS). Fifteen EGFR mutations across twenty NSCLC patients were identified. We observed superior sensitivity and specificity of cobas-ARMS, ddPCR and Firefly NGS platforms, while ADx-ARMS was only suitable for the qualitative detection of EGFR mutations with allele frequency higher than 1% in plasma samples. We observed high concordance between the plasma and tissue EGFR mutational profiles for three driver mutations that are known targets of the first generation EGFR-TKI therapy (L858R, E19-dels, and G719X). Discrepancies between plasma and tissue EGFR mutational profiling could be attributed to spatial and temporal tumor heterogeneity. This pilot study illustrates the promise of ctDNA analysis in the context of treatment evaluation and drug resistance detection, and results will be validated in follow-up studies. Citation Format: Ting Xu, Xiaozheng Kang, Xiaofang You, Dai Liang, Dequan Tian, Wanpu Yan, Yongbo Yang, Hongchao Xiong, Zhen Liang, Grace Q. Zhao, Shengrong Lin, Ke-Neng Chen, Guobing Xu. Cross-platform comparison of four leading technologies for detecting EGFR mutations in circulating tumor DNA from plasma of patients with non-small cell lung carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2742. doi:10.1158/1538-7445.AM2017-2742
Abstract 3615: Combined targeting of estrogen receptor alpha and nuclear transport pathways remodel metabolic pathways to induce apoptosis and overcome tamoxifen resistance
Authors: Eylem Kulkoyluoglu-Cotul, Zeynep Madak-Erdogan, Yosef Landesman, Kinga Wrobel
Journal: Cancer Research (2017)

Abstract There is a critical need for novel therapeutic approaches to re-sensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and XPO1, a nuclear transport protein in overcoming endocrine resistance. Using Cignal Finder pathway analysis, Seahorse metabolic profiling and GC/MS whole metabolite profiling, we found that combination of 4-OH-Tam and Selinexor (SXR), being evaluated in multiple later stage clinical trials in patients with relapsed and /or refractory hematological and solid tumor malignancies, inhibited Akt phosphorylation by changing the localization of the kinase. Since we observed dramatic changes in Akt activity we hypothesized that glucose utilization pathways and metabolic profile of breast cancer cells would change in the presence of 4-OH-Tam and SXR. These cells were more dependent on mitochondria for energy production. Their glucose and fatty acid dependency decreased in the presence of SXR and cells were more dependent on glutamine as the mitochondrial fuel source. We showed that combined targeting of XPO1 and ERα rewires metabolic pathways, increase demand on mitochondria and causes increased production of ROS that would eventually lead to apoptosis. Re-modelling metabolic pathways to regenerate new vulnerabilities in endocrine-resistant tumors is novel, and given the need for better strategies for improving therapy response of relapsed ERα (+) tumors, our findings show great promise for uncovering the role ERα-XPO1 crosstalk plays in reducing cancer recurrences. Citation Format: Eylem Kulkoyluoglu-Cotul, Zeynep Madak-Erdogan, Yosef Landesman, Kinga Wrobel. Combined targeting of estrogen receptor alpha and nuclear transport pathways remodel metabolic pathways to induce apoptosis and overcome tamoxifen resistance [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 3615. doi:10.1158/1538-7445.AM2017-3615
Abstract 2078: CK-101 (RX518), a mutant-selective inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC
Authors: Xiangping Qian, Yong-Liang Zhu, Edward Cullen, Robert M. Niecestro, James F. Oliviero
Journal: Cancer Research (2017)

Abstract Patients with non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations initially respond to small molecule inhibitors of the EGFR tyrosine kinase such as gefitinib and erlotinib. However, secondary mutations in the kinase domain lead to acquired resistance to these inhibitors and limited clinical efficacy, with the EGFR T790M mutation being the most common mechanism of acquired resistance in more than half the patients that experience disease progression. CK-101 (also known as RX518) is a novel, irreversible, orally administered EGFR kinase inhibitor that specifically targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type (WT) EGFR. WT EGFR inhibition is believed to drive the commonly observed side effects of skin rash and diarrhea. The 50% inhibitory concentrations (IC50s) of CK-101 and 2 reference compounds, afatinib and AZD-9291, were determined in cell proliferation assays in human cancer cell lines in vitro after incubation for 72 hours. Xenograft studies were conducted in BALB/c nude mice or SCID/Beige mice using once daily oral administration of CK-101 or afatinib for 14 or 21 days. CK-101 selectively inhibited cell proliferation of cell lines expressing both the activating (e.g. HCC827, IC50 &amp;lt;0.015 µM) and resistance mutations (NCI-H1975, IC50 &amp;lt;0.005 µM), but was much less potent at inhibiting proliferation of cell lines expressing the WT form of the receptor (e.g. A431, IC50 &amp;gt;0.5 µM; i.e., CK-101 was over 100 fold less potent against A431 than against NCI-H1975). Single agent CK-101 significantly inhibited tumor growth in EGFR-mutated NSCLC tumor xenograft models, with no activity in a WT EGFR tumor xenograft model. In a xenograft study of PC-9 cells (exon 19 deletion) in SCID/Beige mice, CK-101 inhibited tumor growth by up to 90% (p &amp;lt;0.001). In a xenograft study of NCI-H1975 cells (L858R/T790M double mutant) in BALB/c nude mice, CK-101 inhibited tumor growth by up to 95% (p &amp;lt;0.001). The pre-clinical findings from this work strongly supported the clinical development of CK-101, and a first-in-human study of CK-101 was initiated in September 2016. Citation Format: Xiangping Qian, Yong-Liang Zhu, Edward Cullen, Robert M. Niecestro, James F. Oliviero. CK-101 (RX518), a mutant-selective inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC [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 2078. doi:10.1158/1538-7445.AM2017-2078
Abstract 349: Eribulin induces cortical localization of E-cadherin, p120-catenin and beta-catenin in breast cancer cells
Authors: Alison D. Clark, Nicholas F. Dybdal-Hargreaves, Susan L. Mooberry
Journal: Cancer Research (2017)

Abstract Eribulin provides a survival advantage for breast cancer patients, particularly those with triple-negative and HER2-negative subtypes.1,2 Mechanistically, eribulin was shown to reverse epithelial-to-mesenchymal transition (EMT) in breast cancer models.3 E-cadherin is a central regulator responsible for maintenance of the epithelial phenotype and loss of cortical E-cadherin and its downstream signaling is an early and significant event in EMT. Short term treatment of HCC1937 breast cancer cells with eribulin initiated cortical E-cadherin localization in manner different from other microtubule targeting agents. Cortical E-cadherin plays essential roles in cell adhesion and in regulating the Wnt pathway, whose aberrant activity is implicated in EMT. At the adherens junctions p120-catenin and β-catenin bind to E-cadherin, an interaction facilitated by microtubules. Cortical sequestration of p120- and β-catenin at the adherens junctions stabilizes these complexes and inhibits their ability to stimulate signaling pathways that contribute to EMT. We tested whether eribulin, which binds to the plus ends of microtubules, promotes EMT reversal by influencing p120- and β-catenin localization and activity. Our results show that eribulin induces cortical localization of p120-catenin and β-catenin with E-cadherin in HCC1937 cells, consistent with the formation of normal adherens junctions. Eribulin also stimulated the phosphorylation of Ser33/37 and Thr41 on β-catenin which promotes proteasomal degradation, which would be expected to further inhibit oncogenic signaling. Collectively, our results suggest that eribulin contributes to reversal of EMT through modulation of downstream signaling initiated by cortical localization of p120- and β-catenin at the adherens junctions. Funding for this work was provided by Eisai Inc. 1. Cortes J., et al., Lancet 377:914-923, 2011 2. Twelves, C., et al., Breast Cancer Res Treat 148:553-561, 2014 3. Yoshida, T., et al., Br J of Cancer 110: 1497-1505, 2014 Citation Format: Alison D. Clark, Nicholas F. Dybdal-Hargreaves, Susan L. Mooberry. Eribulin induces cortical localization of E-cadherin, p120-catenin and beta-catenin in breast 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 349. doi:10.1158/1538-7445.AM2017-349
Abstract 1432: Precision lung cancer medicine based on information on cancer and the host genomes
Authors: Takashi Kohno, Kouya Shiraishi, Kazushi Yoshida, Motonobu Saito, Yukinori Okada
Journal: Cancer Research (2017)

Abstract Aberrations of oncogene, such as EGFR mutation; and ALK, RET, and ROS1 fusions, function as a driver in the development of lung adenocarcinoma (LADC). They are a solid target of therapy using tyrosine kinase inhibitors, as represented by a high response rate of RET-fusion positive LADC to vandetanib (LURET study, Yoh et al., Lancet Resp Med, 2016). Our genome-wide sequencing study revealed that oncogene aberration positive LADCs carry less numbers of mutations in cancer-related genes than negative ones (Saito, Cancer Res, 2015), indicating a small mutation burden in the development of the formers. Consistently, a clinical trial of anti-PD-1 therapy indicated that EGFR-mutation positive cases do not benefit well from the therapy (Borghaei et al., N Engl J Med. 2015). LADC driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). We recently revealed that variations in HLA-class II loci underlie the risk of the disease, by conducting a genome-wide association study of 3,173 patients and 15,158 controls, combined with imputation of HLA alleles using a Japanese-specific panel (Shiraishi et al., Nature Comm, 2016). The result indicates that LADC develops in vivo through interaction between somatic mutations and germline variations that modulate immune reaction. Therefore, efficacy of immune checkpoint blockade targeting therapy might also be influenced by such germline variations. On the other hand, oncogene-negative LADCs show a high mutation burden associated with nonsynonymous mutations in chromatin remodeling and other cancer-related genes. Thus, these cases would respond well to immune checkpoint blockade targeting therapies. We would like to discuss here precision lung cancer medicine based on information on cancer and the host genomes. Citation Format: Takashi Kohno, Kouya Shiraishi, Kazushi Yoshida, Motonobu Saito, Yukinori Okada. Precision lung cancer medicine based on information on cancer and the host genomes [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 1432. doi:10.1158/1538-7445.AM2017-1432
Abstract 190: Identification of compound isolated from <i>Beilschmiedia tsangii</i> as a liver cancer specific NRF2 inhibitor
Authors: Yi Siao Chen, Chih Chung Lai, Yi Ping Kuo, Hsun Shuo Chang, Ih Sheng Chen, Chia-Hung Yen
Journal: Cancer Research (2017)

Abstract Drug resistance is the main cause of cancer recurrence and a major obstacle to the success of anticancer therapy. NRF2, a pivotal transcription factor regulates antioxidant response and detoxification, has been shown to participate in the development of cancer drug resistance. Functional suppression of NRF2 rendered cancer cell more susceptible to anticancer treatments. Beilschmiedia tsangii Merr. (Lauraceae) is a medium-sized evergreen tree. It has been reported that Beilschmiedia extract showed a strong antioxidant activity. In continuation of our bioactivity studies on this species, we tested the effects of 23 compounds isolated from the B. tsangii on NRF2 activity. We identified rel-(7R,8R,7′R,8′R)-3,4,3′,4′-dimethylene-dioxy-5,5′-dimethoxy-7,7′-epoxylignan (BT04) significantly inhibited NRF2 activity in liver cancer cell (Huh7) with an IC50 value of 17 μM, but not in keratinocyte (HacaT cell). By contrast, luteolin, a known NRF2 inhibitor, suppressed NRF2 activity in both Huh7 cell and HacaT cell. Moreover, the mRNA level of NRF2 target genes, NQO1 and HO1, were significantly decreased in Huh7 upon BT04 treatment, while those NRF2 target genes remained unchanged in BT04-treated HacaT cell. A moderate cytotoxic effect of BT04 on Huh7 cell was also observed. Accordingly, our result suggested that BT04 can specifically inhibit NRF2 activity in liver cancer, which in turn indicated that BT04 could be a potential adjuvant to improve chemoresistance. Citation Format: Yi Siao Chen, Chih Chung Lai, Yi Ping Kuo, Hsun Shuo Chang, Ih Sheng Chen, Chia-Hung Yen. Identification of compound isolated from Beilschmiedia tsangii as a liver cancer specific NRF2 inhibitor [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 190. doi:10.1158/1538-7445.AM2017-190
Abstract 1692: <i>KRAS-</i>mediated therapeutic resistance abrogates immunogenic cell death in colorectal cancer cells
Authors: Yi-Jun Wang, Dongshi Chen, Jingshan Tong, Jian Yu, Alberto Bardelli, Lin Zhang
Journal: Cancer Research (2017)

Abstract A hallmark of cancer is compromised immune surveillance, which is characterized by failure of the immune system to recognize tumor-associated antigens and specifically eliminate malignant cells. A number of studies showed the tumor microenvironment in colorectal cancer (CRC) patients is highly immunosuppressive. Conventional chemotherapy and recent targeted therapy can restore anti-tumor immune response through induction of immunogenic cell death (ICD) in tumor cells. However, the mechanism and functional role of ICD in CRC treatment remains vague. In this study, we found FOLFIRI (Leucovorin/5-Fluorouracil/Irinotecan) combined with the anti-EGFR antibody cetuximab, a commonly used regimen for CRC treatment, induces death of CRC cells with characteristics of necroptosis, including ATP depletion, release of HMGB1, and phosphorylation of RIP3 and MLKL. Cells subjected to the combination treatment exhibited features of ICD including plasma membrane exposure of calreticulin and phagocytosis by dendritic cells. We identified the BH3-only Bcl-2 family protein PUMA as a key mediator of necroptosis induced by the combination treatment in vitro and in vivo. Furthermore, we found that CRC cells with acquired cetuximab resistance due to KRAS mutation or amplification are deficient in ICD. Collectively, our results suggest that oncogenic mutations cause resistance of CRC cells to anticancer therapies in part by suppressing ICD. Citation Format: Yi-Jun Wang, Dongshi Chen, Jingshan Tong, Jian Yu, Alberto Bardelli, Lin Zhang. KRAS-mediated therapeutic resistance abrogates immunogenic cell death in colorectal 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 1692. doi:10.1158/1538-7445.AM2017-1692