tbuckley/cabot-search huggingface dataset:
Phase II study of nab-paclitaxel/gemcitabine (NabP-Gem) alternating with FOLFIRI as 1st line therapy ( Rx) in patients (pts) with metastatic pancreatic cancer (mPC).
Authors: Vincent J. Picozzi, Joseph Leach, Tim Larson, Carol Y. Nishikubo, Stephen Patrick Anthony, Bruce S. Lin, Vanessa Bolejack, Amy C. Stoll, Daniel D. Von Hoff, Ramesh K. Ramanathan
Journal: Journal of Clinical Oncology (2015)

e15277 Background: NabP-Gem and FOLFIRINOX are standard mPC regimens.The optimal sequence is unknown.This phase II study evaluated the feasibility of NabP-Gem alternating with FOLFIRI as 1stline Rx for untreated mPC. Methods: Eligibility criteria included: 1) diagnosis untreated mPC, 2) ECOG PS 0-1 and 3) adequate organ function. Pts received Nab-P (125 mg/m2) and Gem (1000 mg/ m2) weekly x 3 every 4 weeks (wks) for 8 wks, alternating with FOLFIRI (irinotecan 180 mg/m2, folinic acid 400mg/m2, 5FU 2400 mg/m2over 46 hrs) x 4 for 8 wks. Rx continued in alternating fashion unless disease progression/toxicity for 48 wks, followed by Rx per investigator discretion, including “molecular guidance” as able. Primary study endpoint was overall survival (OS) with the goal to increase 1 year (yr) OS to > 70%, (n = 30, 95% CI +/- 20%). Results: The study accrued 27 pts. Median pt age 65 yrs. 1 pt withdrew consent prior to Rx. 14/26 (54%) pts experienced grade > 3 all cause adverse events during Rx including 15% grade ≥ 4 infections (1 grade 5) and 15% grade ≥ 4 neutropenia. 13/26 (50%) pts initiated FOLFIRI with stable/responding disease and acceptable Nab P-Gem toxicity after 8 weeks . The remaining 13 pts experienced disease progression (6 pts), NabP-Gem drug toxicity (3 pts), early death (2 pts) or other (2 pts). ORR by RECIST was 36% (8/22 evaluable pts). Of pts with elevated CA 19.9, median decline was 62%; 40% had > 90% decline. For all pts, current median follow up is 12.3 months (mo), median OS is 10.2 mo, 1-yr OS is 47%. For the 13 pts receiving FOLFIRI on protocol as defined above, med OS is currently 15.3 mo. Conclusions: 1) Alternating NabP-Gem and FOLFIRI can be feasible with toxicity comparable to either regimen alone. 2) Alternating Nab- P Gem and FOLFIRI yields ORR and OS that seem similar, but not superior, to Nab - P Gem, FOLFIRINOX, or, as reported by our group, Nab –P Gem followed by FOLFIRINOX (Ramanathan et.al. ASCO 2014). 3) The trial did not achieve 70% 1-yr OS, but pts able to receive both regimens may display superior OS. 4) Further study of Rx regimens that alternate/integrate both Gem and fluoropyrimidine-based treatments is warranted. (Supported by the Seena Magowitz foundation). Clinical trial information: NCT01488552.
Abstract LB-033: The transcriptional landscape of p53 signaling pathway
Authors: Koichi Matsuda, Chizu Tanikawa
Journal: Cancer Research (2017)

Abstract Although recent cancer genomics studies have identified a large number of genes that were mutated in human cancers, p53 remains as the most frequently mutated gene. To further elucidate the p53-signalling network, we performed transcriptome analysis on 24 tissues in p53+/+ or p53-/- mice after whole-body X-ray irradiation. Here we found transactivation of a total of 3,551 genes in one or more of the 24 tissues only in p53+/+ mice, while 2,576 genes were downregulated. p53 mRNA expression level in each tissue was significantly associated with the number of genes upregulated by irradiation. Annotation using TCGA (The Cancer Genome Atlas) database revealed that p53 negatively regulated mRNA expression of several cancer therapeutic targets or pathways such as BTK, SYK, and CTLA4 in breast cancer tissues. In addition, stomach exhibited the induction of Krt6, Krt16, and Krt17 as well as loricrin, an epidermal differentiation marker, after the X-ray irradiation only in p53+/+ mice, implying a novel mechanism to protect damaged tissues by rapid induction of differentiation. Our comprehensive transcriptome analysis elucidated tissue specific roles of p53 and its signalling networks in DNA-damage response that will enhance our understanding of cancer biology. Citation Format: Koichi Matsuda, Chizu Tanikawa. The transcriptional landscape of p53 signaling pathway [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 LB-033. doi:10.1158/1538-7445.AM2017-LB-033
Abstract 2436: Non canonical activation of Sonic Hedgehog pathway in uterine leiomyosarcoma
Authors: Natalia Garcia, Bianca C. Oliveira, Kelly P. Ferreira, Edmund C. Baracat, Katia C. Carvalho
Journal: Cancer Research (2017)

Abstract Background: Uterine leiomyoma (ULM) and leiomyosarcoma (ULMS) are smooth muscle tumors with distinct clinical and biological behavior. They can be a cause of infertility and even death. Little is known about the factors that can to influence these tumors behavior and biology. Sonic Hedgehog (SHH) pathway components were previously implicated in the ULMS malignancy risk; however its activation mechanism is unknown. In this study, we investigated the gene expression profile of Sonic Hedgehog Signaling and pathway upstream genes in myometrium (MM), ULM and LMS cell lines. Methods: Total RNA obtained from cell lines were submitted to cDNA synthesis and quantitative real time PCR (qRT-PCR), using 7500 System (Life Technologies, USA). Gene expression of SHH, PTCH1, SMO, SUFU, GLI 1-3, CCND1, BCL-2 and BMP4 were assessed. Results: Gene expression data showed an upregulation of SMO, SUFU, GLI1, BCL-2 and BMP4 in LMS cells when compared to MM. GLI1 (RQ=11) and BCL-2 (RQ=20) genes had higher expression. In the other side, SHH, PTCH1, GLI2 and GLI3 showed upregulation in MM cells. Conclusion: Our results showed that the Sonic hedgehog pathway is activated in LMS cells but by SHH independent form (non-canonical pathway). This could be explained by the downexpression of SHH ligand and the PTCH1 receptor, and by the upexpression of SMO, GLI1 and pathway target genes as BCL-2 and BMP4 in uterine LMS cells compared to LM and MM. These results suggest a new therapeutic perspective for LMS by target drugs to inhibit SMO and GLI1 molecules. Citation Format: Natalia Garcia, Bianca C. Oliveira, Kelly P. Ferreira, Edmund C. Baracat, Katia C. Carvalho. Non canonical activation of Sonic Hedgehog pathway in uterine leiomyosarcoma [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 2436. doi:10.1158/1538-7445.AM2017-2436
Abstract 3555: Lipid droplets, a novel metabolic target in glioblastoma
Authors: Feng Geng, Jeffrey Guo, Xiang Cheng, Xiaoning Wu, Chunming Cheng, Arnab Chakravarti, Deliang Guo
Journal: Cancer Research (2017)

Abstract Lipid metabolism reprogramming is a novel feature of malignancies. Identifying the vulnerability of lipid alteration in tumor cells provides a new window to treat cancer. Here, we unraveled that glioblastoma (GBM) patients containing high levels of lipid droplets (LDs), special organelles storing cholesterol esters and triglycerides in cells, presented poor survival. We found that LDs largely formed in tumor tissues from GBM patients, but rarely in low grade of gliomas and normal brain tissues, demonstrating that LDs might serve as a novel diagnostic biomarker and prognostic marker for GBM. We further revealed that sterol O-acyltransferase 1 (SOAT1), the key enzyme controlling cholesterol esterification and LD formation, is highly expressed and correlated with LD prevalence in tumor tissues from GBM patients. Genetic or pharmacologic inhibition SOAT1 using avasimibe, a phase III clinical trial drug in human atherosclerosis patients, significantly suppressed GBM growth and prolongs survival in xenograft models. Moreover, we found that inhibiting SOAT1 suppressed sterol regulatory element-binding protein-1 (SREBP-1), a key transcription factor playing a central role in lipid synthesis, underlying the molecular mechanism of targeting SOAT1-mediated GBM growth suppression. In summary, our data demonstrate that LDs/cholesterol esters uniquely formed in tumor tissues provides an ideal target to specifically inhibit GBM cells whereas sparing normal brain tissues, and reveal that blocking cholesterol storage via targeting SOAT1 represents a promising strategy for GBM treatment. Citation Format: Feng Geng, Jeffrey Guo, Xiang Cheng, Xiaoning Wu, Chunming Cheng, Arnab Chakravarti, Deliang Guo. Lipid droplets, a novel metabolic target in glioblastoma [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 3555. doi:10.1158/1538-7445.AM2017-3555
miRomics and Proteomics Reveal a miR-296-3p/PRKCA/FAK/Ras/c-Myc Feedback Loop Modulated by HDGF/DDX5/β-catenin Complex in Lung Adenocarcinoma
Authors: Qiaofen Fu, Xin Song, Zhen Liu, Xiaojie Deng, Rongcheng Luo, Chunlei Ge, Ruilei Li, Zhen Li, Mengyang Zhao, Yiyu Chen, Xian Lin, Qianbing Zhang, Weiyi Fang
Journal: Clinical Cancer Research (2017)

Purpose: This study was performed to identify the detailed mechanisms by which miR-296-3p functions as a tumor suppressor to prevent lung adenocarcinoma (LADC) cell growth, metastasis, and chemoresistance.Experimental Design: The miR-296-3p expression was examined by real-time PCR and in situ hybridization. MTT, EdU incorporation, Transwell assays, and MTT cytotoxicity were respectively performed for cell proliferation, metastasis, and chemoresistance; Western blotting was performed to analyze the pathways by miR-296-3p and HDGF/DDX5 complex. The miRNA microarray and luciferase reporter assays were respectively used for the HDGF-mediated miRNAs and target genes of miR-296-3p. The ChIP, EMSA assays, and coimmunoprecipitation combined with mass spectrometry and GST pull-down were respectively designed to analyze the DNA-protein complex and HDGF/DDX5/β-catenin complex.Results: We observed that miR-296-3p not only controls cell proliferation and metastasis, but also sensitizes LADC cells to cisplatin (DDP) in vitro and in vivo Mechanistic studies demonstrated that miR-296-3p directly targets PRKCA to suppress FAK-Ras-c-Myc signaling, thus stimulating its own expression in a feedback loop that blocks cell cycle and epithelial-mesenchymal transition (EMT) signal. Furthermore, we observed that suppression of HDGF-β-catenin-c-Myc signaling activates miR-296-3p, ultimately inhibiting the PRKCA-FAK-Ras pathway. Finally, we found that DDX5 directly interacts with HDGF and induces β-catenin-c-Myc, which suppresses miR-296-3p and further activates PRKCA-FAK-Ras, cell cycle, and EMT signaling. In clinical samples, reduced miR-296-3p is an unfavorable factor that inversely correlates with HDGF/DDX5, but not PRKCA.Conclusions: Our study provides a novel mechanism that the miR-296-3p-PRKCA-FAK-Ras-c-Myc feedback loop modulated by HDGF/DDX5/β-catenin complex attenuates cell growth, metastasis, and chemoresistance in LADC. Clin Cancer Res; 23(20); 6336-50. ©2017 AACR.
Abstract 4121: Androgen receptor as a potential target in non-small cell lung cancer
Authors: Sean Brennan, Albert R. Wang, Hope Beyer, Dylan Wiese, Darya Buehler, Anwaar Saeed, Andrew M. Baschnagel, Gopal Iyer
Journal: Cancer Research (2017)

Abstract The cancer genome atlas (TCGA) has identified androgen receptor (AR) to be mutated, deleted and amplified across human lung squamous cell carcinoma and adenocarcinoma. Expression of AR is critical for early lung development. However, the intriguing expression of AR in non-small cell lung cancer (NSCLC) opens up an alternative treatment paradigm in the event of onset of clinical resistance to lung cancer drugs. To investigate this potential, a) 10 NSCLC cell lines and 3 control prostate cancer cell lines were stimulated with synthetic AR agonist, R1881 at 24, 48 and 72 hours. 0.5-4-fold RNA and protein expression was found across these lung cancer cell lines when compared to unstimulated cells. b) droplet digital PCR revealed varying copies of AR DNA when benchmarked to prostate AR. c) cell proliferation assays of these cell lines with enzalutamide (MVD3100) treatment resulted in 50-65% cell survival at concentrations ranging from 10 - 25 µM. d) Immunohistochemical staining of AR in a NSCLC human tissue microarray (TMA) revealed 10 out of 88 patients (11%) to have AR positive staining in their tumor. This included 6 adenocarcinomas and 2 squamous cell carcinomas. 8 patients had focal while 2 had diffuse staining. Validation of the TMA performed with whole mount slides confirmed diffuse staining in these 11 samples. Taken together, these findings suggest AR is a potential therapeutic target in NSCLC and further work is underway to test these observations in drug resistant lung cancer cell lines and pre-clinical mouse models. Citation Format: Sean Brennan, Albert R. Wang, Hope Beyer, Dylan Wiese, Darya Buehler, Anwaar Saeed, Andrew M. Baschnagel, Gopal Iyer. Androgen receptor as a potential target in non-small cell lung 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 4121. doi:10.1158/1538-7445.AM2017-4121
Analysis of the background of neuropathic pain due to cancer and the factors that affect its control.
Authors: Kazuki Tahara, Masaharu Yamazaki, Masatoshi Kanno, Daisuke Igawa, Toshiaki Shinomiya
Journal: Journal of Clinical Oncology (2016)

e21616 Background: Thirty percent to ninety percent of cancer patients suffer from pain, including neuropathic pain (NP), which results in great burden for cancer patients.We analyzed the background of NP due to cancer and the factors that affect its control. Methods: We analyzed the background of NP due to cancer and the factors that affect its control among the 241 patients of cancer pain referred to our department in 2007-2012, we divided into a neuropathic pain (NP: 94 cases) and other pain group (OP: 147cases). And we compared for background factors and treatment interventions of those patients. Results: At the time of intervention by our department, there was not significant difference between the numerical rating scale (NRS) of the NP and that of the OP [5.5 (± 2.1) vs 5.1 (± 2.1); p = 0.176]. There was no significant difference of NRS of intervention three weeks later[2.8(±2.1) vs 2.6(±2.1);p= 0.266].In the study of treatment intervention, both groups increased opioids and adjuvant analgesics usage. Both groups increased opioids and adjuvant analgesics usage to compared at the time of therapeutic intervention introduced to our department with at the time of the intervention three weeks later. In particular, adjuvant analgesics usage has increased markedly to 91.5% from 24.5% in NP group. Cause site of pain was included in the irradiation range, in all cases of intervention within three weeks started radiation therapy (RT). RT enforcement rate is a high rate in more significant compared NP with OP (36.1% vs 19.7%; p = 0.007). Conclusions: This has been suggested that neuropathic pain which is generally intractable can be also controlled by adjuvant analgesics use and RT combination with same as the other of pain.
Abstract 2460: Copy number alterations in NOTCH2 and PTP4A3 are associated with prognosis and support novel therapeutic strategies for malignant pleural mesothelioma
Authors: Leticia G. Leon, Maria Gemelli, Paolo A. Zucali, Christos Zoumadakis, Elisa Giovannetti
Journal: Cancer Research (2017)

Abstract Malignant pleural mesothelioma(MPM) is an aggressive cancer, which incidence has constantly increased over the past two decades and is expected to peak in 2020. The overall prognosis is poor, and predictive biomarkers of drug activity are missing. Given the heterogeneous and complex nature of MPM, it is likely that genomic aberrations changing the expression of several genes, might affect therapeutic response. Therefore, the aim of the present study was to identify genes whose copy number alterations might predict the MPM prognosis. Recurrent copy number alterations of genes were analyzed by high-resolution whole-genome sequencing in DNA obtained from a “discovery cohort” of 26 resected MPM patients treated with pemetrexed-based chemotherapy (8 with progressive disease, vs. 10 with stable disease and 8 with partial response). Prognostic markers identified by Copy Number Variation analysis with Nexus, Control-FREEC and ReadDepth software were validated by PCR gene copy number and gene expression analyses both in the “discovery” and in two “validation” cohorts of pemetrexed-treated and untreated patients (N=45 and 40). The role of emerging genes was evaluated through siRNA and pharmacological studies using proliferation, migration and apoptosis assays in MPM cells. As reported previously we observed copy number loss of CDKN2A (15.4%) and BAP1 (7.7%). Interestingly, copy number gain of NOTCH2 was observed in 50% of samples of the patients who underwent progression, whereas losses of PTP4A3 were associated with clinical benefit (SD+PR). The prognostic relevance of NOTCH2 was confirmed by PCR analysis. NOTCH-2 silencing reduced MPM cell migration and enhanced apoptosis induction by pemetrexed, while a PTP4A3 inhibitor overcame pemetrexed resistance in MPM cells characterized by high NOTCH2 and PTP4A3 expression. These results support the role of NOTCH2 as a novel prognostic/predictive biomarker for MPM, prompting prospective randomized trials for its validation. Moreover, preclinical data suggest that NOTCH2 and PTP4A3 are oncogenes suitable for effective therapeutic targeting in pemetrexed-resistant MPM cells. Citation Format: Leticia G. Leon, Maria Gemelli, Paolo A. Zucali, Christos Zoumadakis, Elisa Giovannetti. Copy number alterations in NOTCH2 and PTP4A3 are associated with prognosis and support novel therapeutic strategies for malignant pleural mesothelioma [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 2460. doi:10.1158/1538-7445.AM2017-2460
Abstract 3613: Development of chemically modified peptide inhibitor ERAP targeting BIG3-PHB2 complex on hormone-resistant breast tumor
Authors: Toyomasa Katagiri, Tetsuro Yoshimaru
Journal: Cancer Research (2017)

Abstract Approximately 70% of breast cancer cells express estrogen receptor alpha (ERα), and depend on estrogen (E2) for proliferative and metastatic activity. The current endocrine therapies for breast cancer are mainly based on targeting ERα signaling using selective ERα modulators, ERα downregulators, and aromatase inhibitor. However, up to 50% of patients with ERα-positive tumors either initially do not respond or become resistant to these drugs. The precise molecular mechanisms for the endocrine resistance contributes to be an active area of research. Therefore, identifying the factors and pathways responsible for resistance and defining ways to overcome it lead to develop novel molecular-target therapies to endocrine resistance. Recent findings support that the Brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex plays a crucial role in E2/ERα signaling modulation in these cells. Moreover, specific inhibition of the BIG3-PHB2 interaction using ERα activity-regulator synthetic peptide (ERAP: 165-177 amino acids) derive from a helical BIG3 sequence, a dominant-negative peptide inhibitor leads to the significant anti-tumor effect. However, duration of its effect is very short for clinical use. Here, we report the development of the chemically modified ERAP using stapling methods (stapled ERAP) to improve duration of its antitumor effects. The stapled ERAP specifically inhibited the BIG3-PHB2 interaction, thereby exhibiting the long-lasting suppressive activity and their intracellular localization without membrane-permeable polyarginine sequence supposedly through the formation of stable α-helix structure induced by the stapling. Importantly, a combination of stapled ERAP and tamoxifen caused a synergistic inhibitory effect in breast cancer cell growth. Tumor bearing mice treated with every 7 days with stapled ERAP treatment effectively prevented the BIG3-PHB2 interaction as well as daily treatment, leading to the complete regression of E2-dependent tumor in vivo. Our findings suggest that the stapled ERAP may be a promising anti-tumor drug to suppress the growth of luminal-type breast cancer in clinical use. Citation Format: Toyomasa Katagiri, Tetsuro Yoshimaru. Development of chemically modified peptide inhibitor ERAP targeting BIG3-PHB2 complex on hormone-resistant breast tumor [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 3613. doi:10.1158/1538-7445.AM2017-3613
Abstract 5472: Yeast Bax Inhibitor (<i>BXI1</i>) is involved in redox and calcium homeostasis of the ER in <i>S. cerevisiae</i>
Authors: David Eagan, Joseph Alisch, Liam McDonough, Savannah Benko, Walter Jacob, Lukas Ritzer, James Mullin, John O'Reilly, Nicanor Austriaco
Journal: Cancer Research (2017)

Abstract In mammals, the Bax inhibitor (TMBIM) family of proteins has cytoprotective properties that are most evident in paradigms of endoplasmic reticulum (ER) stress. The canonical gene of the family called BI-1 has been linked to several human cancers. The crystal structure of a prokaryotic member of the family, BsYetJ, has revealed that the Bax inhibitor proteins are pH sensitive calcium leaks. Our published studies have shown that the yeast Bax Inhibitor, Bxi1p, is localized to the endoplasmic reticulum and is involved in the unfolded protein response (UPR) that is triggered by endoplasmic reticulum (ER) stress. We now show that cells lacking BXI1 have an altered redox microenvironment in the ER: The ER of Δbxi1 cells exposed to dithiothreitol (DTT) and tunicamycin, two drugs known to induce the unfolded protein response (UPR), become more reduced than their wildtype counterparts. Moreover, we also report that cells lacking BXI1 accumulate more calcium in the ER than wildtype cells. Together, our data suggests that Bxi1p is involved in regulating the ER microenvironment. Other members of the TMBIM family may have the same role in normal and cancer cells. [Our laboratory is supported by grant NIGMS R15 GM110578, awarded to N. Austriaco.] Note: This abstract was not presented at the meeting. Citation Format: David Eagan, Joseph Alisch, Liam McDonough, Savannah Benko, Walter Jacob, Lukas Ritzer, James Mullin, John O'Reilly, Nicanor Austriaco. Yeast Bax Inhibitor (BXI1) is involved in redox and calcium homeostasis of the ER in S. cerevisiae [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 5472. doi:10.1158/1538-7445.AM2017-5472