bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 9: Effect of C8-side chain on the cytotoxicity and NF-kB inhibitory capacity of pyrrolobenzodiazepines
Authors: Corcoran David B. , Lewis Thomas , Nahar Kazi S. , Fegan Christopher , Pepper Chris , Thurston David E. , Rahman Khondaker Miraz 
Published: August 2019

Abstract
Pyrrolobenzodiazepines (PBDs) have long been of interest in chemotherapeutic research as potential clinical agents. Recently, the conjugation of non-covalently interactive moieties to the C8-position of the PBD structure via a linker of variable length has emerged as a strategy to enhance the DNA sequence specificity of PBDs. This has led to the development of highly cytotoxic agents, which also act as inhibitors of transcription factors such as NF-κB. For example, GWL-78, a C8-linked PBD-Py-Py (Py = pyrrole) conjugate, has been shown to block interaction of the transcription factor NF-Y, and KMR-28-39, a C8-linked PBD-MPB conjugate with an affinity for GC-rich sequences of DNA inhibits activity of the transcription factor NF-κB. As up-regulation of NF-κB has been implicated in the development and progression of several cancer types, this may contribute to the high potency observed for PBD monomers such as KMR-28-39 (i.e., femtomolar IC50 values in some cell lines). In this study, the relationship between the cytotoxicity and transcription factor inhibition of a series of C8-linked PBD hybrid structures was explored. The systematic shortening of the non-covalent element of a C8-linked PBD conjugate, DC-1-92 led to the synthesis of a 19-member library of novel C8-PBD monomers. The critical elements of DC-1-92, which were required to render the molecule cytotoxic, were elucidated by an annexin V assay. The effects of shortening the non-covalent element of the molecule on transcription factor inhibitory capacity were also explored through an ELISA-based measurement of nuclear NF-κB subunit DNA binding following exposure of JJN3 cells to the synthesised molecules. While shortening the non-covalently interactive component of DC-1-92 had less of an effect than expected upon cytotoxicity, the shortening notably reduced the NF-κB inhibitory activity of the shortened analogues. DC-1-92, containing the longest non-covalently interactive C8-element, displayed the most effective inhibition of NF-κB, and effects upon nuclear p65, and RelB levels appeared to diminish in tandem with the shortening of the length of the C8 side chain. These data suggest that the length of the C8 side chain of PBD hybrid structures impacts upon the DNA binding of both canonical and non-canonical NF-κB subunits but this is independent of their cytotoxic effects.
Citation Format: David B. Corcoran, Thomas Lewis, Kazi S. Nahar, Christopher Fegan, Chris Pepper, David E. Thurston, Khondaker Miraz Rahman. Effect of C8-side chain on the cytotoxicity and NF-kB inhibitory capacity of pyrrolobenzodiazepines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 9.
Abstract 921: Novel clinical targets revealed by kinome reprogramming in mutant ESR1 metastatic breast cancer
Authors: Dustin Derek , Gu Guowei , Chan Doug , Beyer Amanda , Edwards David , Corona-Rodriguez Arnoldo , Ellis Matthew , Fuqua Suzanne 
Published: August 2019

Abstract
Background: Approximately half of women with estrogen receptor (ER)-positive breast cancer who undergo adjuvant endocrine therapy (ET) develop disease progression and metastasis. Studies have revealed that up to 40% of metastatic patients develop tumors bearing a mutation in ESR1. ESR1 mutant (ESR1m) tumors are associated with a more aggressive metastatic disease course. Studies have shown that cancers can undergo “kinome reprogramming” in response to therapy and acquired genetic alterations within the tumor. Thus, we hypothesize that expression of ESR1 mutations induces kinome reprogramming, which presents novel potential therapeutic targets to selectively treat ESR1m metastatic breast cancer.
Methods: We performed Kinobeads Precipitation (KiP) using broad specificity kinase inhibitors to capture and quantify by MS the level of active kinases in MCF-7 ESR1 wild-type and ESR1 Y537S mutant cells. We performed targeted siRNA screens and immunoblots to validate the hyperactivity of several of these kinases. Specific kinase inhibitors are being used to test their effects on proliferation and invasion in vitro, and in ex vivo organoid growth assays. Xenograft models are being used to evaluate the effects of the inhibitors on primary tumor growth and distant metastasis.
Results: Hyperactivation of 169 kinases in ESR1m cells was revealed by KiP analysis. Hyperactivation of several growth factor receptors, the PI3K/Akt/mTOR pathway, and the JAK/STAT pathway was demonstrated in Y537S mutant cells. We tested specific inhibitors of these pathways, and have shown that the mutant cells have reduced proliferation when these pathways are targeted. We developed organoid growth assays using primary and metastatic tumors from MCF-7 and T47D Y537S ESR1 xenograft tumors, and the Y537S ESR1 WHIM20 PDX model, and found that ET in combination with these selected targeted kinase inhibitors decreased the growth of organoids. We are currently testing inhibitors in combination with ET in vivo, and preliminary results demonstrate a significant inhibition of distant metastatic frequency. These results suggest that selective inhibition of hyperactivated “reprogrammed” kinase pathways can restore ET sensitivity in ESR1m tumors, and may show promise for use in ER-positive metastatic breast cancer patients.
Citation Format: Derek Dustin, Guowei Gu, Doug Chan, Amanda Beyer, David Edwards, Arnoldo Corona-Rodriguez, Matthew Ellis, Suzanne Fuqua. Novel clinical targets revealed by kinome reprogramming in mutant ESR1 metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 921.
Abstract 922: Preclinical anticancer activity of LSZ102, a novel oral selective estrogen receptor degrader targeting wild-type and mutant ER
Authors: Gaither L. Alex , Yip Choi Lai Tiong , Wang Chunrong , Toy Weiyi , Sheng Qing , Chen Jinyun , Mishina Yuji , Das Rita , Peukert Stefan , Loo Alice , Chandarlapaty Sarat , Crystal Adam , Abrams Tinya J. 
Published: August 2019

Abstract
Estrogen receptor (ER) blockade is a well-established therapeutic approach in ER+ breast cancer. A novel oral selective estrogen receptor degrader (SERD), LSZ102, is in development. LSZ102 induces proteasome-mediated degradation of both wild type and mutant ERα in MCF-7 cells. LSZ102 also inhibits transcription of ERα target genes and results in a decrease in cell proliferation in a dose dependent manner. Expression of ERα Y537S results in a shift in inhibition of cell proliferation upon incubation with either LSZ102 or fulvestrant; however, the shift with LSZ102 was less severe. Similarly, LSZ102 induced a more pronounced level of ERα degradation than fulvestrant in the Y537S mutant MCF7 cells. Overall, LSZ102 is effective in the wild type and Y537S ERα mutant setting in vitro. In vivo, LSZ102 treatment of ER+ breast cancer xenografts resulted in inhibition of ERα regulated transcripts and a decrease in ERα protein levels. In the MCF7 xenograft model, expression of ERα Y537S resulted in reduced activity by fulvestrant, but not by LSZ102. In vivo, LSZ102 exhibited single agent and combination efficacy upon co-administration with the CDK4/6 inhibitor ribociclib and the alpha-specific PI3K inhibitor alpelisib. LSZ102 is currently in a Phase I clinical trial in patients with ER+ breast cancer in which it is tested as a single agent, and in combination with either ribociclib or alpelisib.
Citation Format: L. Alex Gaither, Choi Lai Tiong Yip, Chunrong Wang, Weiyi Toy, Qing Sheng, Jinyun Chen, Yuji Mishina, Rita Das, Stefan Peukert, Alice Loo, Sarat Chandarlapaty, Adam Crystal, Tinya J. Abrams. Preclinical anticancer activity of LSZ102, a novel oral selective estrogen receptor degrader targeting wild-type and mutant ER [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 922.
Abstract 930: On-target resistance to mutant selective EGFR inhibitors develops in an allele-specific manner dependent on the original EGFR activating mutation
Authors: Zhang Yunkai , Brown Benjamin P. , Westover David , Yan Yingjun , Qiao Huan , Huang Vincent , Du Zhenfang , Smith Jarrod A. , Ross Jeffrey S. , Miller Vincent A. , Ali Siraj , Bazhenova Lyudmila , Schrock Alexa B. , Meiler Jens , Lovly Christine M. 
Published: August 2019

Abstract
In-frame deletions within exon 19 (Ex19Del) and the Leu858Arg mutation within exon 21 (L858R) are the two most common oncogenic EGFR mutations found in non-small cell lung cancer (NSCLC). Currently, there is little data differentiating Ex19Del from L858R, and patients whose tumors harbor Ex19Del and L858R are approached similar in clinic when choosing EGFR tyrosine kinase inhibitors (TKIs). Unfortunately, resistance mutations may emerge against all classes of EGFR TKIs, including osimertinib. Recently, G724S has been identified as a novel mutation which is selected in osimertinib resistant tumors. Interestingly, in a large genomic profile database of NSCLC patient samples we found that G724S co-occurs preferentially with Ex19Del (15/19 G724S cases) but not with L858R (0/19 G724S cases). We further combined in silico and in vitro investigations to demonstrate the mechanism of G724S mutation confers resistance to TKIs in an oncogenic variant-dependent manner. Our in silico investigations showed evidence of reduced stability of the osimertinib-bound G724S/Ex19Del complex but not the osimertinib-bound G724S/L858R complex. G724S/Ex19Del-transduced cells are resistant to osimertinib treatment in vitro, while G724S/L858R-transduced cells are sensitive to osimertinib treatment. These results suggest G724S/Ex19Del may emerge under selective pressure from EGFR TKIs, and the underlying oncogenic profile of EGFR can influence the development of drug resistance mutations. Our results have potential direct implications for the treatment of patients with EGFR-mutant NSCLC.
Citation Format: Yunkai Zhang, Benjamin P. Brown, David Westover, Yingjun Yan, Huan Qiao, Vincent Huang, Zhenfang Du, Jarrod A. Smith, Jeffrey S. Ross, Vincent A. Miller, Siraj Ali, Lyudmila Bazhenova, Alexa B. Schrock, Jens Meiler, Christine M. Lovly. On-target resistance to mutant selective EGFR inhibitors develops in an allele-specific manner dependent on the original EGFR activating mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 930.
Abstract 946: Early signs of activity of Tedopi OSE2101, a multiple neoepitope vaccine, in a phase 3 trial in advanced lung cancer patients after failure to previous immune checkpoint inhibitors ATALANTE-1
Authors: Viteri Santiago , Vanel François-Roger , Hilgers Werner , Remon Jordi , Viteri-Ramirez Guillermo , Quoix Elisabeth 
Published: August 2019

Abstract
Introduction: Tedopi is a neoepitope vaccine restricted to HLA-A2 positive patients targeting five tumor-associated antigens frequently expressed in lung cancer cells. Potential enhanced efficacy of cancer vaccines after ICI treatment remains unexploited and its biological basis is poorly understood. The integrity of the antigen presentation pathway is crucial in vaccine activity and genetic alterations such as beta-2-microglobulin inactivating mutation may explain lack of efficacy. Tedopi is currently being tested in the phase III ATALANTE-1 trial compared with chemotherapy in advanced NSCLC patients (pts.) who relapse after ICI. We report early signs of safety and efficacy with Tedopi in the first step of the open-label study.
Methods: 18 pts have been enrolled in the experimental arm and received at least one dose of Tedopi. These pts have been assessed every 6 weeks for radiological response according to RECIST 1.1 criteria as well as toxicity according to CTCAE criteria. Tedopi dose was 5 mg injected subcutaneously every 3 weeks for 6 doses, then every 2 months completing 1 year of treatment and thereafter every 3 months until progression or toxicity. Description of three patients with significant clinical benefit with third-line treatment with Tedopi is presented.
Results: Patients’ clinical characteristics are reported in table 1. Treatment duration with Tedopi ranges from 4.9 to more than 12 months, including one patient with brain metastases. One patient achieved a partial response and two patients achieved stable disease by RECIST 1.1 criteria. Safety profile was manageable and no patient withdrawn for toxicity.
Conclusions: Tedopi after failure to previous ICI therapy as third-line treatment has shown long-term clinical benefit and good safety profile. Baseline genomic molecular profile assessment, as well as, immunophenotype searching evidence of vaccination are ongoing.
Citation Format: Santiago Viteri, François-Roger Vanel, Werner Hilgers, Jordi Remon, Guillermo Viteri-Ramirez, Elisabeth Quoix. Early signs of activity of Tedopi OSE2101, a multiple neoepitope vaccine, in a phase 3 trial in advanced lung cancer patients after failure to previous immune checkpoint inhibitors ATALANTE-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 946.
Abstract 976: Regulation of breast tumor metastasis by the dynamic interaction between the TMEM macrophage, tumor, and endothelial cells
Authors: Surve Chinmay R. , Harney Allison , Wang Yarong , Chen Xiaoming , Sharma Ved , Stanley Richard , Oktay Maja , Condeelis John 
Published: August 2019

Abstract
Tumor cell intravasation is an essential step in the metastatic cascade, but its exact mechanism is not completely understood. We have previously shown that the direct physical association of a tumor cell over-expressing Mena, a perivascular Tie2hi/Vegfhi macrophage and an endothelial cell, forming a cell triad termed “tumor microenvironment of metastasis” (TMEM), increases vascular permeability, facilitating intravasation of tumor cells. It is only at the TMEM site that intravasation occurs leading to breast tumor metastasis. TMEM density is a clinically validated prognostic marker of distant metastasis in breast cancer patients. The precise molecular mechanisms relating TMEM function had not been elucidated. Here we describe the molecular mechanism. We show here that TMEM function involves the three cells in TMEM: firstly endothelial cell-secreted Ang2 stimulates VEGF build up in the TMEM macrophage, secondly a tumor cell secretes CSF1 which, third, stimulates the TMEM macrophage VEGF secretion, leading to vascular opening and metastasis. In addition, we show that acute blockage of CSF1R and Tie2-Ang2 signaling by inhibitors and blocking antibodies both in vitro and in mammary tumors leads to decreased macrophage VEGF production and secretion, decreased trans-endothelial migration of tumor cells, and decreased TMEM-dependent vascular permeability, circulating tumor cells and lung metastases. We conclude that dynamic interaction between the cells associated with TMEM leads to Ang2 and CSF1-mediated stimulation of macrophage VEGF expression and secretion leading to vascular opening, resulting in tumor cell intravasation. This is the first description of the molecular mechanism behind the predictive power of the clinically used prognostic marker TMEM and represents a major step in defining new biomarkers and targets for the treatment of metastatic tumors.
Citation Format: Chinmay R. Surve, Allison Harney, Yarong Wang, Xiaoming Chen, Ved Sharma, Richard Stanley, Maja Oktay, John Condeelis. Regulation of breast tumor metastasis by the dynamic interaction between the TMEM macrophage, tumor, and endothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 976.
Abstract 978: Tim-4+ tissue-resident macrophages impair antitumor T-cell immunity
Authors: Chow Andrew , Schad Sara , Sharma Sai K. , Budhu Sadna , Gupta Aditi , Pimentel Corrin , Zhong Hong , Lewis Jason S. , Poirier John T. , Wolchok Jedd D. , Rudin Charles M. , Merghoub Taha 
Published: August 2019

Abstract
Over 600,000 Americans and 8 million worldwide die of cancer each year. The success of immune checkpoint blockade with anti-PD-1 therapy has been a remarkable clinical advance. However, most patients do not respond to anti-PD-1 monotherapy and the majority of those who initially do respond eventually succumb to the disease. There is currently an unmet need to identify therapeutic strategies to overcome resistance and further enhance the efficacy of anti-PD-1 therapy. Tim-4 is a phosphatidylserine (PS) receptor that has been reported to be expressed on myeloid cells. Prior work has demonstrated that Tim-4 deficiency or blockade in mice is associated with features of autoimmunity and enhanced anti-tumor immunity. Using flow cytometry, immunohistochemistry, and in vivo biodistribution, we determined that Tim-4 is expressed predominantly on tissue-resident macrophages, such as Kupffer cells, peritoneal macrophages, pleural macrophages, and lymph node macrophages, but not tumor-associated macrophages, in mice and humans. We provide evidence that Tim-4+ macrophages produce high levels of the cytokines TNF-α and TGF-β, which have been linked to T cell dysfunction, and also the TGF-β activating integrin αv (CD51). Antibody blockade of Tim-4 enhances the anti-tumor activity of anti-PD-1 therapy after subcutaneous tumor inoculation of B16 melanoma, CT26 colon carcinoma, and MC38 colon carcinoma. Finally, combined blockade of Tim-4 and PD-1 resulted in substantially more curative responses in a MC38 model of peritoneal carcinomatosis, compared to anti-PD-1 monotherapy. This was associated with enhanced CD8+ T cell infiltration into the peritoneal cavity, increased CD8+ T cell/Foxp3+ regulatory T cell ratio, and reduced expression of the exhaustion marker PD-1. Thus, we show that Tim-4+ tissue-resident macrophages impair anti-tumor T cell immunity and antibody blockade of Tim-4 is a strategy that should be considered for clinical studies in cancers resistant to anti-PD-1 monotherapy.
Citation Format: Andrew Chow, Sara Schad, Sai K. Sharma, Sadna Budhu, Aditi Gupta, Corrin Pimentel, Hong Zhong, Jason S. Lewis, John T. Poirier, Jedd D. Wolchok, Charles M. Rudin, Taha Merghoub. Tim-4+ tissue-resident macrophages impair antitumor T-cell immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 978.
Abstract 983: Antibody-drug conjugates of NAMPT inhibitors: Discovery, optimization, and preclinical characterization
Authors: Neumann Chris , Olivas Kathleen C. , Wang Kung Pern , Waight Andrew B. , Meyer David W. , Loftus Luke V. , Zaval Margo C. , Anderson Martha E. , Jin Steven , Cochran Julia H. , Simmons Jessica K. , Pittman Paul G. , Li Fu , Ulrich Michelle L. , Wong Abbie , Zeng Weiping , Lyon Robert P. , Senter Peter D. 
Published: August 2019

Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) regulates the biosynthesis of NAD from nicotinamide via a salvage biosynthetic pathway. Inhibition of NAMPT depletes cellular NAD levels leading to disruption of energy metabolism and cell death. Non-targeted small molecule NAMPT inhibitors have demonstrated poor tolerability in clinical trials and in preclinical models, including cardiac and retinal toxicities in rats. In an effort to improve the therapeutic window of this drug class, we pursued a targeted-delivery approach using antibody-drug conjugates. Through a medicinal chemistry effort, we identified novel NAMPT inhibitors that incorporate chemical functionality in the solvent-exposed terminus to allow construction of enzyme-cleavable drug linkers. Additionally, we applied a pyridinium-based linker strategy that allows for traceless linker attachment through a conserved nicotinamide-mimetic moiety of NAMPT inhibitors. Candidate molecules were evaluated for NAMPT binding affinity and cellular cytotoxicity as free drugs, and for cellular cytotoxicity as ADCs with the alternate linker strategies. Comparisons across inhibitors and linker strategies provide insight into optimal design of cleavable drug linkers for this class of drugs. In vitro, the ADCs deplete NAD and lead to downstream ATP depletion in a time-dependent manner. In vivo evaluation using human tumor xenografts shows translation of the pharmacodynamic effect resulting in tumor regression in models of Hodgkin lymphoma, non-Hodgkin lymphoma, and acute myeloid leukemia. Toxicology studies in Sprague Dawley rats demonstrate excellent tolerability at active doses, with no observable cardiac or retinal toxicities at the highest tested doses in single- and multi-dose regimens. These findings detail the development of a novel payload class and optimized linker strategy for use with antibody-drug conjugates, and demonstrate a preclinical efficacy and safety profile to support continued efforts toward clinical therapeutics.
Citation Format: Chris Neumann, Kathleen C. Olivas, Kung Pern Wang, Andrew B. Waight, David W. Meyer, Luke V. Loftus, Margo C. Zaval, Martha E. Anderson, Steven Jin, Julia H. Cochran, Jessica K. Simmons, Paul G. Pittman, Fu Li, Michelle L. Ulrich, Abbie Wong, Weiping Zeng, Robert P. Lyon, Peter D. Senter. Antibody-drug conjugates of NAMPT inhibitors: Discovery, optimization, and preclinical characterization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 983.