tbuckley/cabot-search huggingface dataset:
Abstract 2672: Semaphorin 7a promotes cellular transformation via activation of pro-survival signaling
Authors: Taylor R. Rutherford, Traci R. Lyons
Journal: Cancer Research (2021)

Abstract We seek to further our understanding of normal mammary gland biology and determine how pregnancy associated changes in the mammary gland contribute to development of breast cancers. Though pregnancy is well-known to provide a protective effect against breast cancer risk, all women who give birth experience a transient increase in breast cancer risk following each pregnancy. The magnitude and length of this elevated risk is largely determined by a woman's age at first birth and for women over 30 at the time of first pregnancy the protective effect likely never occurs. Postpartum breast cancers (PPBC), defined as breast cancers diagnosed within 10 years of last childbirth, are more than twice as likely to become metastatic and result in death. This devastating diagnosis affects ~12,000 women annually. In 2006, for the first time, the number of women having children in their 30s was greater than the number under 25. Thus, PPBC cases are rising. We have shown that tumor cells and normal adjacent mammary epithelial cells (MECs) in PPBC patients exhibit high levels of semaphorin 7a (SEMA7A) protein expression, and SEMA7A expressing tumors are more metastatic. Thus, we believe that understanding the mechanisms underlying SEMA7A signaling in the mammary gland will lead to novel insights into aggressive PPBC. Our recent data reveal that SEMA7A+ MECs are evident during lactation, decreased during the reversible phase of postpartum mammary gland involution, and peak at involution day three, suggesting that SEMA7A promotes survival cell survival during postpartum glandular regression. Consistent with our hypothesis, we reveal that mammary luminal progenitor cells are decreased in SEMA7A knockout mice and SEMA7A promotes cell survival in cultured MECs. Interestingly, a portion of our SEMA7A KO dams exhibit evidence of lactation failure, suggestive of precocious involution. Thus, we propose that SEMA7A activates pro-survival signaling in MECs during lactation and involution. In support of this we show that exogenous SEMA7A activates pro-survival kinase AKT in a β1-integrin dependent manner. Additionally, we show that sustained signaling by SEMA7A leads to cellular transformation in vivo and in vitro and that SEMA7A KO mice crossed to MMTV-PyMT mice exhibit longer latency, ~250 days compared to 50-100 in controls. Since we also observe that SEMA7A levels in blood correlate with SEMA7A levels in breast cancer patient tumors, our results suggest that SEMA7A is a driver of tumorigenesis that could be safely monitored in postpartum women. Citation Format: Taylor R. Rutherford, Traci R. Lyons. Semaphorin 7a promotes cellular transformation via activation of pro-survival signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2672.
Abstract 1462: KF1601, a novel orally bioavailable inhibitor of Bcr-Abl T315I, without inducing thrombotic microangiopathy
Authors: HyunJin Kwon, Sung-Min Ahn, Kiho Chang, WooSik Kim, Amir Khan, Doohyun LEE, Seungyeon Lee, Ye Ri Han, Chun Young Im
Journal: Cancer Research (2021)

Abstract Targeting Bcr-Abl with tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myeloid leukemia (CML) by significantly improving patients' survival. However, the gatekeeper mutation T315I confers resistance to TKIs targeting Bcr-Abl, presenting a formidable task in CML's clinical management. Ponatinib is the only approved drug for Bcr-AblT315I, but often accompanies severe, life-threatening side effects. Herein, we report KF1601, a novel orally bioavailable TKI: 1) KF1601 inhibited kinase functions of both Bcr-AblWT and Bcr-AblT315I with nanomolar IC50 values; 2) In xenograft models using Ba/F3 Bcr-AblT315I cell line, it showed promising in vivo antitumor efficacy, comparable to that of ponatinib; 3) In animal models, it did not cause thrombotic microangiopathy, a major mechanism of ponatinib's toxicity. In summary, KF1601 is a promising drug candidate for safely treating CML patients with drug-resistant Bcr-AblT315I mutation. Citation Format: HyunJin Kwon, Sung-Min Ahn, Kiho Chang, WooSik Kim, Amir Khan, Doohyun LEE, Seungyeon Lee, Ye Ri Han, Chun Young Im. KF1601, a novel orally bioavailable inhibitor of Bcr-Abl T315I, without inducing thrombotic microangiopathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1462.
Abstract 964: β-catenin antagonist peptide attenuates Wnt-dependent oncogenic activity
Authors: Jim A. Rotolo, Erin Gallagher, Lila Ghamsari, Siok Leong, Ricardo Ramirez, Mark Koester, Gene Merutka, Barry J. Kappel
Journal: Cancer Research (2021)

Abstract β-catenin is an oncogenic transcription factor that has an essential role in cell development and biology. Increased β-catenin expression or activity has been implicated in many cancers, including breast and colorectal, and is associated with poor prognosis. Despite extensive ongoing research, β-catenin is conventionally considered ‘undruggable', and there are no current drugs available to target Wnt/β-catenin signaling. B-cell CLL/lymphoma 9 protein (BCL9) is a positive regulator of β-catenin transcriptional activity that is overexpressed in tumors. Disruption of β-catenin interaction with BCL9 has been shown genetically to suppress oncogenic Wnt/β-catenin transcription and represents a powerful approach to inhibit this previously undruggable target. Here, we describe the anti-tumor activity of a β-catenin antagonist peptide (BCAP), designed to disrupt the association of β-catenin with co-activator BCL9. Target engagement of BCAP with recombinant β-catenin was demonstrated in biophysical studies by circular dichroism spectroscopy, and inhibition of the β-catenin/BCL9 interaction was demonstrated in transiently transfected A549 cells by NanoBRET assay. Administration of BCAP to HEK293 cells stably transfected with TOPFlash reporter plasmid resulted in dose-dependent inhibition with an EC50 of 1.7 µM. Further, BCAP attenuated oncogenic gene transactivation in colorectal cancer cells (HCT116 and COLO320DM) and HRPOS breast cancer cells (MCF7), significantly decreasing the expression of Axin2 and CDK4 (p&amp;lt;0.05), while not impacting Axin2 or CDK4 gene expression in Wnt-independent RKO and NCI-H460 cells. Administration of BCAP to 4T1-luc triple-negative breast cancer, HCT116 and COLO320DM cells resulted in dose-dependent in vitro cytotoxicity 48 hours post exposure, with EC50 values of 1.4, 4.4 and 1.2 µM, respectively. In in vivo orthotopic 4T1-luc tumor models, administration of BCAP via subcutaneous injection resulted in dose-dependent inhibition of tumor growth and significantly reduced tumor volume compared to control tumors (p&amp;lt;0.05). These data demonstrate the significant in vitro and in vivo anti-cancer activity of BCAP and emphasize it's potential as a potent therapeutic for Wnt/β-catenin-dependent cancers. Citation Format: Jim A. Rotolo, Erin Gallagher, Lila Ghamsari, Siok Leong, Ricardo Ramirez, Mark Koester, Gene Merutka, Barry J. Kappel. β-catenin antagonist peptide attenuates Wnt-dependent oncogenic activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 964.
Abstract 2166: The prevalence and molecular characteristics of <i>EGFR</i>large fragment deletion in Asian cancer population by comprehensive genome profiling
Authors: Ruoying Yu, Qiuxiang Ou, Hua Bao, Xue Wu, Yang Shao
Journal: Cancer Research (2021)

Abstract Background: Large fragment deletion(LFD) of EGFR was associated with carcinogenesis in many types of cancers, especially in glioblastoma. Overall, there are five major types of EGFR large fragment deletion across EGFR extracellular region and carboxyl terminal domain which were originally discovered in gliomas. The prevalence and molecular feature of EGFR-LFD have not been studied in Asian Cancer population. Method: We retrospectively reviewed records of 66,500 Asian cancer patients who underwent genetic testing using capture-based targeted NGS between January 2014 to May 2020 at hospitals across China. Five to ten mL peripheral blood was collected from each patient in EDTA-coated tubes. Plasma was extracted within 2 hours of blood collection and shipped to the central testing laboratory. Formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks/sections or fresh tumor tissues were obtained from the hospitals, with confirmation by the pathologists for diagnosis and tumor purity. Mean sequencing depths of tumor tissue and plasma were 500X and 3000X respectively. Result: Our finding showed that EGFR-LFD was detected at a frequency of 0.03%, of which the most frequent was EGFRvIII in glioblastoma. In this EGFR-LFD cohort, there were 9 males(53%), 7 females(41%) and one unknown sex type with a median age of 54 years old, ranging from 42 to 85 years old. Interestingly, novel EGFR-LFDs spanning exon2-7 were identified in unreported cancer type including deletions of EGFR exon2-11(1case, lung cancer), exon2-15(1case, lung cancer), exon2-17(2 cases, lung cancer and colorectal cancer), exon2-28(1 case, cholangiocarcinoma). TERT promoter(TERTp) variants(60%) showed highest frequency in EGFR-LFD carriers, consisting of 6 cases of −124C&amp;gt;T and 2cases of −146C&amp;gt;T in glioblastoma(7) and melanoma(1). Concurrent EGFR amplification was identified in 67% of EGF-LFD cohort including glioblastoma(6), colorectal cancer(3), unknown(1). Over half of EGFR-LFD carriers harbored deletion on both arms of chromosome 10. Conclusion: Our study provided valuable insights into the distribution and molecular characteristics of EGFR-LFD by employing a large Asian Cancer cohort, hoping to shed lights on the treatment management for Asian EGFR-LFD carriers. Citation Format: Ruoying Yu, Qiuxiang Ou, Hua Bao, Xue Wu, Yang Shao. The prevalence and molecular characteristics of EGFRlarge fragment deletion in Asian cancer population by comprehensive genome profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2166.
Abstract 1965: Discovery of ZN-c3, a potent Wee-1 inhibitor with a differentiated pharmacologic and kinase selectivity profile
Authors: Jiali Li, Brant Boren, Peter Q. Huang, Kevin D. Bunker, Fernando Doñate, Ahmed A. Samatar
Journal: Cancer Research (2021)

Abstract Genome instability initiated by DNA damage or DNA replication stress is a driver of tumor development. To ensure the accuracy of DNA replication, DNA damage response (DDR) mediated by various cell cycle checkpoints activate the DNA repair system. One such checkpoint system is the G2-M checkpoint which is involved in the repair and prevention of excessive DNA damage. A key regulator of the G2-M checkpoint is the Wee1 kinase which causes cell cycle arrest to prevent damaged cells from entering mitosis. Thus, inhibition of Wee1 should prevent G2-M checkpoint activation which would lead to unscheduled mitotic entry and induction of apoptosis. Small-molecule inhibitors of Wee1 are currently being tested in several tumor types. Preliminary results show promising clinical activity of AZD-1775, a potent inhibitor of Wee1, however, achieving an optimal dose and a schedule that is well-tolerated has been a challenge. Here, we describe the characterization of ZN-c3, a potent, selective and orally bioavailable small-molecule inhibitor of Wee1. ZN-c3 exhibits potent anti-proliferative activity across multiple tumor cell lines. Compared to AZD-1775, ZN-c3 has superior selectivity profile against a panel of kinases. In vivo, ZN-c3 induced tumor regression as a single agent in several tumor models including non-small cell lung cancer, ovarian cancer, and uterine sarcoma. In combination studies, ZN-c3 potentiates the antitumor efficacies of carboplatin and gemcitabine. The pharmacokinetic and efficacy profiles of ZN-c3 and AZD-1775 were compared in tumor xenograft models. ZN-c3 showed higher plasma and tumor exposure than AZD-1775, which correlated with more potent tumor growth inhibition than AZD-1775. In summary, ZN-c3, with its key differentiated pharmacologic and kinase selectivity profile, is a promising new generation of DDR inhibitor. ZN-c3 is currently in clinical development for the treatment of advanced solid cancers. Citation Format: Jiali Li, Brant Boren, Peter Q. Huang, Kevin D. Bunker, Fernando Doñate, Ahmed A. Samatar. Discovery of ZN-c3, a potent Wee-1 inhibitor with a differentiated pharmacologic and kinase selectivity profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1965.
Mixed T cell lineage chimerism in acute leukemia/MDS using pre-emptive donor lymphocyte infusion strategy—Is it prognostic?—a single-center retrospective study
Authors: Vipul Sheth, Victoria Potter, Hugues de Lavallade, Shreyans Gandhi, Austin Kulasekararaj, Pramila Krishnamurthy, Varun Mehra, Francesco Dazzi, Ghulam Mufti, Antonio Pagliuca, Donal Mclornan, Kavita Raj
Journal: Blood Cancer Journal (2021)

Pre-emptive DLI (pDLI) is an effective strategy in lowering the risk of relapse without significantly increasing the risk of graft-versus-host disease (GVHD) in the case of T cell lineage mixed chimerism (MC) post allogeneic transplant in hematological malignancies. Many patients, however, fail to receive timely pDLI and have dismal outcomes, which are not taken into consideration. We compared long-term outcomes of 106 patients having T cell MC after day 60 and undergoing allogeneic stem cell allograft for acute leukemia from an unrelated donor (UD), with 111 patients having complete chimerism (CC). Fifty-three (56%) patients received prophylactic pDLI. Thirty-six patients (67%) had a response (RR), 17 (33%) had no response (NR), and fifty-two (54%) did not receive any pDLI (ND). OS was better in MC group as compared to CC (54% vs 43%, p = 0.04), mainly due to reduction in NRM (14% vs 25%, p = 0.05), and all grade acute and chronic GVHD. Within the MC group, response to pDLI was the only significant factor predicting OS, DFS, and relapses with NR and ND having unfavorable outcomes as compared to RR (p = 0.001). T cell MC in patients undergoing UD allografts with alemtuzumab is no longer an adverse prognostic factor, as compared to patients having CC, after timely implementation of pDLI.
薬剤性1型ECGを有する無症状性患者の不整脈イベントに対する低リスク-薬剤性Brugada型ECGを有する患者は予後不良か?(Con)-
Authors: Nishizaki Mitsuhiro, Sakurada Harumizu, Yamawake Noriyoshi, Ueda-Tatsumoto Akiko, Hiraoka Masayasu
Journal: Circulation (2010)
Is a New Era Coming for Bronchopulmonary Dysplasia Prevention With Corticosteroids?
Authors: Luca Bonadies, Daniel Nardo, Eugenio Baraldi
Journal: JAMA Pediatrics (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Abstract 2651: Combination of an anti-angiogenic antibody with PD1/PDL1 blockade agents produces synergistic anti-tumor efficacy in preclinical models
Authors: Liting Xue, Haoyu Zhang, Qian Wang, Feng Li, Xinxin Li, Xiaohong Yu, Zhihong Lu, Yue Huang, Wenqing Yang
Journal: Cancer Research (2021)

Abstract Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play a fundamental role in tumor growth and angiogenesis. Signalling through VEGF/VEGFR not only induces cancer angiogenesis but also affects immune cells, making VEGF/VEGFR a pair of well-documented cancer therapeutic targets. Recently more and more studies have focused on combination of anti-VEGF/VEGFR agents and immune checkpoint inhibitors in preclinical and clinical settings. BD0801 is a humanized rabbit anti-VEGF monoclonal antibody currently in clinical development stage. In this study, we have revealed that BD0801 presents more potent activity than Bevacizumab in blockade of VEGF/VEGFR2 binding (IC50=275 ng/ml for BD0801; IC50=1451 ng/ml for Bevacizumab) and VEGFR2 activation in HUVEC assays. BD0801 also showed enhanced inhibitory effects on the proliferation (IC50=87 ng/ml for BD0801; IC50=476 ng/ml for Bevacizumab) and migration of the HUVECs, compared to Bevacizumab. We found that BD0801 exhibits dose-dependent tumor growth inhibitory activities in both lung cancer PC9 xenograft and lung cancer 3LL murine syngeneic tumor models. In addition, we obtained PK parameters of BD0801 using lung cancer PC9 tumor bearing mice and successfully made correlations between the in vitro function, PK profile and in vivo efficacy of BD0801. Notably, combination of BD0801 with either anti-PD-1, or anti-PD-L1 antibodies showed synergistic anti-tumor efficacy in both lung and colorectal cancer mouse models. Mechanistic studies were conducted to reveal possible mechanism of actions (MOA) underlying the modification in tumor microenvironment. Our data demonstrated that the MOA of the anti-tumor synergy may involve enhanced T-cell mediated immunity, including increased tumor infiltration of CD8+ and CD4+ T cells and reduced double positive CD8+PD-1+ T cells, as well as improved vasculature normalization. Taken together, these data provide a foundation for combining BD0801 with immunotherapy for cancer treatment and support further clinical development plans for BD0801 toward this direction. Citation Format: Liting Xue, Haoyu Zhang, Qian Wang, Feng Li, Xinxin Li, Xiaohong Yu, Zhihong Lu, Yue Huang, Wenqing Yang. Combination of an anti-angiogenic antibody with PD1/PDL1 blockade agents produces synergistic anti-tumor efficacy in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2651.
Abstract 2582: Gnetin C inhibits reactivated AR signaling in advanced prostate cancer
Authors: Rabab M. Al Deabel, Joyce Zhang, Anand Puaar, Avinash Kumar, Anait S. Levenson
Journal: Cancer Research (2021)

Abstract The activation of androgen receptor (AR) is a key process in the development and progression of prostate cancer (PCa). After significant clinical response to androgen-deprivation therapy, patients with advanced PCa regularly relapse with more aggressive castrate-resistant PCa, in which AR and its oncogenic variants are reactivated. Therefore, there is an urgent necessity to develop therapeutic strategies that effectively suppress the tumor promoting signals associated with AR action in castrate-resistant PCa. Dietary stilbenes found in grapes and various berries are promising anticancer agents with multiple cellular targets, including AR. Particularly, we previously demonstrated that resveratrol (Res) and its naturally occurring analogs, pterostilbene and piceatannol, can decrease expression of AR in LNCaP and 22Rv1 cells, therefore presenting an attractive potential for stilbenes as promising pharmacologically safe agents in managing PCa. Gnetin C, a Res-dimer found abundantly in melinjo (Gnetum gnemon) plant, which possesses potent biological properties compared to Res and analogs due to its improved pharmacokinetics, is shown to be safe in healthy volunteers. Here, for the first time, we examine the efficacy of Gnetin C in targeting both full-length and ligand-independent AR splice variant (AR-V7) expressed in the castrate-resistant 22Rv1 cells. First, we found that Gnetin C shows significantly more potent cytotoxic effect in 22Rv1 cells compared to Res and Pter. Immunoblot analysis demonstrated that Gnetin C inhibited expression of both full-length (100 kDA) and truncated (80 kDA) AR-V7 in a dose-dependent manner and, importantly, with significantly higher efficacy than Res and Pter when treated with the same dose (50 μM). In addition, Gnetin C used in twice lesser dose (25 μM), showed substantially more inhibitory effect compared to flutamide and enzalutamide (50 μM), two known AR antagonists used in clinic. Moreover, since neuroendocrine trans-differentiation (NED) is associated with AR-dependent mechanisms and enzalutamide resistance in PCa, we evaluated the effects of Gnetin C on SYP and CHGA. Ongoing in vivo studies using transgenic mice with activated AR signaling treated with Gnetin C are in progress. Taken together, we propose that Gnetin C is a lead compound among stilbenes for effectively blocking AR reactivation in PCa and may potentially have noteworthy therapeutic implications against advanced PCa. Citation Format: Rabab M. Al Deabel, Joyce Zhang, Anand Puaar, Avinash Kumar, Anait S. Levenson. Gnetin C inhibits reactivated AR signaling in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2582.