bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 68: Targeting macrophage that forms a chemotherapy-induced niche significantly reduces cancer stem cells and tumors
Authors: He Xi , Giles Paloma I. , Lin Edward H. , Li Linheng 
Published: August 2018

Abstract
Failure in cancer therapy is often caused by relapse resulting largely from chemo-resistant cancer stem cells (CSCs). Most colorectal cancer patients, after receiving chemoradiotherapy, still harbor treatment-resistant residual tumor cells that are akin to colorectal adenoma. We therefore exploited the APCMin adenoma model that allowed us to study the natural and dynamic interaction between CSCs and their microenvironment in vivo following therapeutic stress. We observed that macrophages were directly recruited from blood vessel to the CSC niche in response to chemotherapy, playing a role in protecting and further promoting activation of CSCs. Reduction in the Ly6c-CD11bintCX3CR1+ MHCII+ population of tumor associated macrophages (TAMs) by celecoxib or clodrosome was correlated with a decline in slow-cycling drug-resistant CSCs and tumorigenesis. Molecularly, we found that COX-2 inhibitor celecoxib suppressed Akt and Wnt signaling, downstream of macrophage-dependent PGE2-EP pathway, thus reducing CSC survival and activation. Taken together, in the naturally formed adenoma reflecting human familial adenomatous polyposis, Chemotherapy-induced recruitment of TAMs to the CSC niche protected and promoted activation of surviving CSCs via PGE2-EP mediated Akt-Wnt signaling, leading to tumor regrowth. Targeting the TAMs will benefit clinical treatment of colorectal cancer.
Citation Format: Xi He, Paloma I. Giles, Edward H. Lin, Linheng Li. Targeting macrophage that forms a chemotherapy-induced niche significantly reduces cancer stem cells and tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 68.
Abstract 682: The mechanism of PI3Kα activation by SH2 release
Authors: Zhang Mingzhen , Jang Hyunbum , Nussinov Ruth 
Published: August 2018

Abstract
Phosphoinositide 3-kinase α (PI3Kα) is a ubiquitous kinase mediating signaling cascades important for cell survival, proliferation and protein synthesis. It phosphorylates PIP2 to PIP3, to which downstream Akt kinase binds to execute singling. PI3Kα dysfunction has been extensively implicated in cancers. The kinase activity of PI3Kα is controlled by the interactions between its catalytic p110 and regulatory p85 subunits. The interactions of the SH2 domains in the p85 subunit, particularly nSH2, with p110 are key factors in PI3Kα inhibition. Release of the SH2 domains from the p110 subunit, is promoted by factors including phosphotyrosine peptides (RTK), calmodulin (CaM), and oncogenic mutations, thereby activating PI3Kα. Our recent data show that both phosphorylated and unphosphorylated CaMs are capable of binding to the SH2 domains, nSH2 and cSH2, thus promoting the PI3K activation. Despite numerous seminal publications over the past two decades, the mechanism of PI3Kα activation is still a mystery. The large distance between the PIP2 binding sites and the ATP pocket in the crystal structure suggests that the solved PI3Kα structure represents the inactive conformation. What is the activated conformation of PI3Kα, and how PI3Kα switches from the inactive to the active conformation in response to stimulus are the significant mechanistic questions. We employ the large-scale molecular dynamics (MD) simulations to visualize the PI3Kα activation stimulated by the release of SH2 domains in the p85 subunit at the atomic resolution. Our trajectories show that release of the nSH2 domain initiates a “switch-like” conformational change of the iSH2 domain, extracting the ATP from its pocket to the PIP2 binding sites, eventually leading to an activated conformation. This dynamic process is initiated by the break of salt-bridges between iSH2 and helical domains induced by the nSH2 release, and further facilitated by the various residues in activation loop of p110 subunit including His-917, Lys-802 and Lys-776 and in iSH2 of p85 subunit including Arg-461 and Arg-465. The release of the cSH2 domain in PI3Kα has a minor effect. This work, which for the first time uncovers the mechanism of PI3Kα activation at atomic resolution, is expected to promote cancer drug design from a mechanistic dynamic standpoint view. Funded by Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E.
Citation Format: Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov. The mechanism of PI3Kα activation by SH2 release [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 682.
Abstract 692: Systemic inflammation and survival in colon and rectal cancer patients: Results from the ColoCare Study
Authors: Ose Jennifer 
Published: August 2018

Abstract
BACKGROUND
Systemic inflammation is an established risk marker for colorectal cancer that may also predict survival. We investigated associations between systemic inflammation and overall survival in a prospectively followed cohort of colorectal cancer patients.
METHODS
Pre-operatively collected serum samples from n=228 newly diagnosed colorectal cancer patients (stage I-IV) from the ColoCare Study were utilized to measure CRP, SAA, IL-6, IL-8, sICAM-1 and sVCAM-1 (Meso Scale Discovery platform). We used Cox proportional hazard models to investigate associations of biomarkers with overall survival after 24 months follow-up overall, and in analyses stratified by colon (n=92) and rectal tumors (n=136). Analyses were adjusted for age, sex, tumor stage and neo-adjuvant therapy (y/n).
RESULTS
After 24 months follow-up n=45 patients (20%) were deceased. CRP was significantly associated with increased risk of death in colon (HR:1.27; 95% CI: 1.03-1.57; pValue=0.02) but not rectal cancer (HR:1.06; 95% CI: 0.87-1.29; pValue=0.55). A doubling of circulating sICAM and sVCAM concentrations was significantly associated with increased risk of death in colorectal cancer (sICAM: HR:2.82; 95% CI: 1.57-5.05; pValue=0.0005; sVCAM: HR:3.70; 95% CI: 1.93-7.10; pValue&lt;0.0001). For both biomarkers we observed stronger associations in rectal compared to colon cancer (e.g., sVCAM: rectal cancer (HR:8.13; 95% CI: 3.13-21.11; pValue&lt;0.0001); colon cancer (HR:1.42; 95% CI: 0.68-2.98; pValue=0.35). Circulating IL-6 and IL-8 were not associated with increased risk of death in colon and/or rectal cancer.
CONCLUSIONS
Inflammatory biomarkers are significantly associated with increased risk of death in colorectal cancer patients. Our data suggest that the role of inflammation in disease progression may be particularly strong relevant in rectal cancer.
Keywords: colorectal cancer; inflammation, biomarkers, overall survival,
Citation Format: Jennifer Ose. Systemic inflammation and survival in colon and rectal cancer patients: Results from the ColoCare Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 692.
Abstract 699: Pd-l1 gene alterations identify a subset of diffuse large B cell lymphoma harboring a T cell inflamed phenotype
Authors: Kline Justin Paul , Godfrey James , Tumuluru Sravya , Venkataraman Girish , Bao Riyue , Smith Sonali M. 
Published: August 2018

Abstract
Programmed death – ligand 1 (PD-L1) expression on malignant cells is a dominant immune escape mechanism across a variety of human cancers, and classically occurs as an adaptive response to the presence of activated T cells and interferon gamma (IFN-γ) in the tumor environment. Interestingly, a unique genetic mechanism underlying PD-L1 up-regulation has been described in classical Hodgkin lymphoma (cHL) and in uncommon variants of diffuse large B cell lymphoma (DLBCL), in which the chromosomal region (9p24.1) encoding the PD-1 ligands is highly amplified. While chromosome 9p24.1 copy number alterations (CNA) are ubiquitous in cHL, which is exquisitely sensitive to PD-1 blockade therapy, they also occur in DLBCL, albeit with a lower incidence. Here, FISH was utilized to identify DLBCLs harboring pd-l1 CNA, thereby enabling a characterization the immunogenomic landscape of these lymphomas compared to those lacking pd-l1 CNA. Among 76 DLBCLs analyzed, 25% harbored pd-l1 CNA (12 copy gain, 6 amplified, 1 translocation). Pd-l1 CNA were highly enriched among DLBCLs with an activated B cell (ABC) phenotype (75%). PD-L1 cell surface expression was strikingly enhanced in DLBCLs with pd-l1 CNA versus those without, as assessed by PD-L1 H score. Furthermore, pd-l1 CNA were associated with a pronounced infiltration of DLBCLs by T cells with a restricted T cell receptor (TCR) – beta (β) repertoire, suggesting that lymphoma antigen-specific T cells had expanded in these samples. RNA-sequencing of pd-l1 gene-altered versus non-altered DLBCLs revealed differential expression of pd-l1, as well as genes involved in T cell and cytokine signaling in the former, indicating that pd-l1 gene-amplified DLBCLs have been subjected to host immune surveillance. Lastly, whole exome sequencing (WES) of pd-l1 gene altered versus non-altered DLBCLs to identify potential differences in mutational loads and profiles is ongoing. Collectively, our results indicate that pd-l1 CNA identify a unique biological subset of DLBCL that has activated an endogenous anti-lymphoma immune response, and that may be more likely to respond to checkpoint blockade therapy with anti-PD-1 antibodies. We propose that a straightforward FISH analysis for pd-l1 gene amplification may be useful as a predictive biomarker for immunotherapy responsiveness in DLBCL.
Citation Format: Justin Paul Kline, James Godfrey, Sravya Tumuluru, Girish Venkataraman, Riyue Bao, Sonali M. Smith. Pd-l1 gene alterations identify a subset of diffuse large B cell lymphoma harboring a T cell inflamed phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 699.
Abstract 702: IMLEC: A population of innate myelolymphoblastoid effector cell expanded by inactivation of mTOR complex 1
Authors: Tang Fei , Zhang Peng , Ye Peiying , Lazarski Christopher A. , Wu Qi , Bergin Ingrid L. , Bender Timothy P. , Hall Michael N. , Cui Ya , Zhang Liguo , Jiang Taijiao , Liu Yang , Zheng Pan 
Published: August 2018

Abstract
Adaptive autoimmunity is restrained by controlling population sizes and pathogenicity of harmful clones, while innate destruction is controlled at effector phase. We report here that deletion of Rptor in hematopoietic stem/progenitor cells causes self-destructive innate immunity by massively increasing the population of previously uncharacterized innate myelolymphoblastoid effector cells (IMLECs). IMLECs are CD3-B220-NK1.1-Ter119- CD11clow/-CD115-F4/80low/-Gr-1- CD11b+, but surprisingly express high levels of PD-L1. Although they morphologically resemble lymphocytes and actively produce transcripts from Immunoglobulin loci, IMLECs have non-rearranged Ig loci, are phenotypically distinguishable from all known lymphocytes, and have a gene signature that bridges lymphoid and myeloid leukocytes. Rptor deletion unleashes differentiation of IMLECs from common myeloid progenitor cells by reducing expression of Myb. Importantly, IMLECs broadly overexpress pattern-recognition receptors and their expansion causes systemic inflammation in response to Toll-like receptor ligands. Our data unveil a novel leukocyte population and an unrecognized role of Raptor/mTORC1 in innate immune tolerance. Moreover, since IMLECs constitutively express high levels of PD-L1, it is interesting to investigate their functions in cancer immunotherapy.
Citation Format: Fei Tang, Peng Zhang, Peiying Ye, Christopher A. Lazarski, Qi Wu, Ingrid L. Bergin, Timothy P. Bender, Michael N. Hall, Ya Cui, Liguo Zhang, Taijiao Jiang, Yang Liu, Pan Zheng. IMLEC: A population of innate myelolymphoblastoid effector cell expanded by inactivation of mTOR complex 1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 702.
Abstract 727: A novel rMVA combination immunotherapy triggers potent innate and adaptive immune responses against established tumors
Authors: Medina-Echeverz Jose , Hinterberger Maria , Testori Marco , Geiger Marlene , Giessel Raphael , Chaplin Paul , Hochrein Hubertus , Lauterbach Henning 
Published: August 2018

Abstract
Virus-based vaccines and appropriate costimulation enhance potent antigen-specific T cell immunity against cancer. However, the tumor microenvironment exerts intrinsic and extrinsic mechanisms to evade tumor destruction. In the present study we exploit both innate and adaptive immune responses triggered by a novel recombinant modified vaccinia virus Ankara (rMVA) encoding costimulatory CD40L against solid tumors in combination regimes to overcome tumor-induced resistance to immunotherapy. Therapeutic treatment with rMVA-CD40L resulted in strong antitumor effects in unrelated established tumor models. Tumor infiltration was composed of non-exhausted, antigen-specific CD8+ T cells with proliferative capacity after rMVA-CD40L immunization. Strikingly, this antitumor effect was not entirely dependent on cross-presenting CD8α+ DC -induced CD8+ T cell expansion, as experiments with MVA encoding for T. gondii profilin (TLR11 ligand) and using Batf3-/- tumor bearers depicted. Indeed, rMVA-CD40L-induced tumor control did not depend on cytosolic DNA sensor STING. Interestingly, rMVA-CD40L induced strong NK cell activation and thereby potent Antibody Dependent Cell Cytotoxicity (ADCC) against Tumor-Associated Antigen (TAA) targeting antibodies. Hence, the combination of TAA targeting antibodies and rMVA-CD40L resulted in increased therapeutic antitumor efficacy. We describe a novel and translationally relevant therapeutic synergy between viral vaccination and CD40L costimulation. We connect CD40 ligation to cross-presenting CD8α+ DC -mediated expansion of non-exhausted CD8+ T cells in the tumor microenvironment. Taking advantage from intrinsic MVA-induced NK cell activation and further improved NK cell function by CD40 ligation, we show strengthened antitumor immune responses when both rMVA-CD40L-induced innate and adaptive immune mechanisms are exploited by combining immunotherapeutic regimes. This finding has a direct potential impact in clinical trials where TAA targeting antibodies are currently under evaluation.
Citation Format: Jose Medina-Echeverz, Maria Hinterberger, Marco Testori, Marlene Geiger, Raphael Giessel, Paul Chaplin, Hubertus Hochrein, Henning Lauterbach. A novel rMVA combination immunotherapy triggers potent innate and adaptive immune responses against established tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 727.
Abstract 734: Thienoindoles: New highly promising agents for antibody-drug conjugates generation
Authors: Caruso Michele , Gasparri Fabio , Valsasina Barbara , Albanese Clara , Beria Italo , Candiani Ilaria , Ciomei Marina , Colombo Nicoletta , Cribioli Sabrina , Cucchi Ulisse , Felder Eduard , Fraietta Ivan , Galvani Arturo , Isacchi Antonella , Marsiglio Aurelio , Orsini Paolo , Perego Rita , Rizzi Simona , Tomasi Attilio , Troiani Sonia , Visco Carlo , Donati Daniele 
Published: August 2018

Abstract
Thienoindoles are a new proprietary class of highly potent DNA minor groove alkylating agents.
This class is characterized by a fused thiophene ring whose intrinsic electron-withdrawing character provides a nearly optimal increase in stability and potency of alkylating subunits. Furthermore, the presence of a solubilizing moiety on the minor groove portion provides compounds with physicochemical properties highly compatible with deployment as antibody payloads.
Extensive optimization of this class has led to the identification of the highly potent toxin NMS-P528 with sub-nanomolar IC50 in proliferation assay across a large panel of tumor cell lines.
NMS-P945, a drug-linker generated from NMS-P528, is highly suited for conjugation with targeted antibodies, consistently yielding ADCs with favorable drug-antibody ratios in the absence of significant antibody aggregation and with full maintenance of antigen binding capability.
Proof of concept efficacy and mechanism of action studies were performed using NMS-P945 conjugated with trastuzumab, observing for the resulting conjugate excellent in vitro target-directed cytotoxicity in HER2-positive vs. negative cancer cell lines. In animal efficacy studies against HER2-positive human breast cancer tumors, trastuzumab-NMS-P945 ADC administration yielded complete tumor regression with no effects on body weight gain, while unarmed trastuzumab and armed control antibody showed little and no effect, respectively. PK data indicated long plasma half-life of our novel ADCs in the monkey. Promising results were also obtained with a range of different antibody/antigen systems, e.g. with an antibody directed to the ALK receptor tyrosine kinase.
Extensive process research has been completed for the production of NMS-P528 and NMS-P945, resulting in an efficient stereoselective method for the preparation of GMP materials on the 100g scale and both products are proposed as a licensing opportunity for conjugation with tumor-targeting antibodies.
Citation Format: Michele Caruso, Fabio Gasparri, Barbara Valsasina, Clara Albanese, Italo Beria, Ilaria Candiani, Marina Ciomei, Nicoletta Colombo, Sabrina Cribioli, Ulisse Cucchi, Eduard Felder, Ivan Fraietta, Arturo Galvani, Antonella Isacchi, Aurelio Marsiglio, Paolo Orsini, Rita Perego, Simona Rizzi, Attilio Tomasi, Sonia Troiani, Carlo Visco, Daniele Donati. Thienoindoles: New highly promising agents for antibody-drug conjugates generation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 734.
Abstract 741: Targeting trastuzumab and T-DM-1 resistant breast cancer cells with EV20/MMAF, an antibody drug-conjugate against HER3
Authors: Sala Gianluca , Gandullo Lucia , Capone Emily , Diaz-Rodriguez Maria Elena , D'Agostino Daniela , Laurenzi Vincenzo De , Sauniere Jean-Frederic , Iacobelli Stefano , Pandiella Atanasio 
Published: August 2018

Abstract
Trastuzumab and its derivative Trastuzumab-emtansine (T-DM1) are drugs approved to treat HER-2+ tumors. Despite the impressive clinical efficacy observed in many patients, intrinsic and acquired resistance to both drugs has emerged as a challenge. The HER-3 receptor is emerging as an attractive molecule in therapeutics because of its overexpression across many human cancers and because of its role in resistance to certain anticancer drugs. We recently showed that the EV20 humanized anti-HER-3 antibody has the ability of selectively and efficiently deliver the plant toxin Saporin to tumor cells. Here, we describe the antitumor activity of a novel ADC derivative of EV20 coupled to the cytotoxic drug monomethyl auristatin F (MMAF). This HER-3/ADC (EV20/MMAF) demonstrated a powerful and target-dependent killing activity in a panel of HER2+ breast cancer cells, including those resistant to trastuzumab and T-DM1 with an IC50 in the pico/nanomolar range.
EV20/MMAF mediated potent antitumor activity in mice bearing trastuzumab resistant xenograft models. Notably, we found that the novel conjugate was well tolerated and caused tumor shrinkage in 100% of tumor-bearing mice. In summary, these findings open the possibility to use EV20/MMAF as a novel ADC targeting HER-3 and support its clinical development for malignancies, such as HER-2+ breast cancer, in which HER-3 is frequently overexpressed.
Citation Format: Gianluca Sala, Lucia Gandullo, Emily Capone, Maria Elena Diaz-Rodriguez, Daniela D'Agostino, Vincenzo De Laurenzi, Jean-Frederic Sauniere, Stefano Iacobelli, Atanasio Pandiella. Targeting trastuzumab and T-DM-1 resistant breast cancer cells with EV20/MMAF, an antibody drug-conjugate against HER3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 741.
Abstract 747: A new class of DNA alkylating indolino-benzodiazepine agents (BIAs) linked with a DNA binding moiety for use with antibody-drug conjugates (ADCs)
Authors: Miller Michael L. , Reid Emily E. , Archer Katie E. , Shizuka Manami , McShea Molly A. , Maloney Erin K. , Ab Olga , Lanieri Leanne , Wilhelm Alan J. , Ponte Jose F. , Yoder Nicholas C. , Chari Ravi V. 
Published: August 2018

Abstract
We have previously disclosed antibody-drug conjugates (ADCs) that incorporate our highly potent novel DNA alkylating indolino-benzodiazepine (termed IGN) pseudo dimer. ADCs of these DNA alkylating IGNs were found preclinically to demonstrate better tolerability and an improved overall therapeutic index (TI) compared with those of DNA crosslinking IGNs (Miller, et al., AACR 2017 #53). In our ongoing effort to further explore DNA alkylating effector molecules for ADCs, we disclose here a new class of IGNs (termed BIAs) in which one IGN monomer subunit is connected to a bis-aryl moiety with affinity for the DNA binding pocket. Our initial structure activity relationship (SAR) studies around a series of BIAs identified a set of scaffolds that met our requirement for high in vitro potency. These scaffolds were subsequently modified to incorporate functionalities that allow linkage to an antibody using various linker chemistries. These linkable BIAs displayed high in vitro potency across a panel of cell lines, indicating that the incorporation of a linker was not detrimental to their overall potency. Furthermore, we found that the potency of these linkable BIAs could be modulated by careful selection of substituents on the bis-aryl moiety providing enhanced binding affinity with DNA. Upon identification of lead BIA molecules, conjugates with a folate receptor-α (FRα)-binding antibody were prepared. These ADCs displayed potent, antigen-specific in vitro activity across a panel of FRα-expressing cell lines. In vivo, these ADCs demonstrated potent efficacy in xenograft models at doses well below the maximum tolerated dose. In light of these findings, BIA ADCs represent a promising new class of DNA alkylating effector molecules for use in the development of ADCs.
Citation Format: Michael L. Miller, Emily E. Reid, Katie E. Archer, Manami Shizuka, Molly A. McShea, Erin K. Maloney, Olga Ab, Leanne Lanieri, Alan J. Wilhelm, Jose F. Ponte, Nicholas C. Yoder, Ravi V. Chari. A new class of DNA alkylating indolino-benzodiazepine agents (BIAs) linked with a DNA binding moiety for use with antibody-drug conjugates (ADCs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 747.