bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1344: Autophagy contributes to therapeutic resistance in head and neck cancer
Authors: Eckers Jaimee , Skiba Justin , Senthilkumar Gopika , Nickel Kwang P. , Swick Adam D. , Kimple Randall J. 
Published: August 2018

Abstract
Background: In the curative setting for head and neck cancer (HNC) a common treatment is radiation combined with cetuximab, an antibody therapeutic targeting EGFR. Despite decades of research into improved treatments, therapeutic resistance remains a major challenge for this malignancy, with roughly 40% of patients developing recurrent disease. Recent evidence has suggested that autophagy, a cellular stress response, may be an additional contributor to therapy resistance, by protecting HNC cells from the cytotoxic effects of radiotherapy and the growth inhibitory effects of anti-EGFR treatment. The mechanism of radiation-induced autophagy is under current investigation.
Methods: Cell lines were source from commercial sources, cultured under recommended conditions, and identity confirmed by short tandem repeat testing. Induction of autophagy was detected by immunoblot flux assays for LC3 and p62, immunofluorescent staining of autophagic vesicles, LC3 reporter flux assay, and flow cytometry using acridine orange. The effect of autophagy inhibition was tested using clonogenic survival assays. Induction of apoptosis was analyzed by immunoblot against cleaved caspase and PARP and via AnnexinV staining.
Results: We evaluated a panel of both human papillomavirus (HPV) positive and negative HNC cell lines for autophagic response to both cetuximab (CTX) treatment and ionizing radiation (XRT). Flux assays revealed that both CTX and XRT treatment induced autophagy in a time- and dose-dependent manner. Immunofluorescent staining of LC3 to identify autophagic vesicles showed that a relatively small fraction of the total cell population is able to induce this response. Flow cytometry analysis demonstrated that autophagic cells were largely non-apoptoic. For example, in the UM-SCC47 cell line treated with CTX for 48 h, flow cytometry for autophagy (20.8%), apoptosis (13.7%) or dual staining (5.4%) suggests a cytoprotective role for autophagy. The addition of the ULK1 inhibitor, SBI-0206965) to CTX and XRT induced apoptosis as shown by caspase activity and AnnexinV staining and reduced clonogenic cell survival.
Conclusions: These preclinical studies have established the proof of concept for the cytoprotective effect of autophagy in response to anticancer treatments including EGFR inhibition and radiotherapy in HNC. Further, we have identified the addition of specific autophagy inhibitors to standard treatments as a potential strategy to overcome this mechanism of resistance.
Citation Format: Jaimee Eckers, Justin Skiba, Gopika Senthilkumar, Kwang P. Nickel, Adam D. Swick, Randall J. Kimple. Autophagy contributes to therapeutic resistance in head and neck cancer [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 1344.
Abstract 1699: Treatment with agonist anti-GITR antibody after chemotherapy enhances tumor immunity
Authors: Warner Allison Betof , Hirschhorn Daniel , Cohen Adam , Liu Cailian , Newman Walter , Sirard Cyndi , Wolchok Jedd , Merghoub Taha 
Published: August 2018

Abstract
Stimulation of glucocorticoid-induced tumor necrosis factor receptor (GITR) has been shown to enhance antitumor immunity by stimulating effector CD4+ and CD8+ T cells and attenuating suppression and depleting by CD4+Foxp3+ regulatory T cells (Treg). However, GITR monotherapy does not effectively control tumor growth. We hypothesize that cyclophosphamide (CTX), a cytotoxic chemotherapeutic agent with key immunomodulatory properties, can enhance the potency of GITR engagement anti-tumor effects. Further, we hypothesize that CTX can induce neoantigen formation by increasing tumor mutation burden. In this study, we administered high-dose CTX (250 mg/kg) followed the next day by an agonist anti-GITR antibody (DTA-1) to C56BL/6 mice bearing poorly immunogenic B16 melanoma tumors. We found that the combination therapy can cause regression of established tumors whereas the single agents did not. Mechanistically, we found that CTX administration results in tumor antigen release, which enhances the antitumor T cell response after treatment with DTA-1. This effect is lost when lower doses of CTX are given or CTX is administered prior to tumor inoculation, suggesting that tumor cell death and cross-presentation of tumor antigens to T cells is necessary. Furthermore, Treg cells are an important target of combination therapy. Intratumoral Treg levels were substantially reduced in treated mice, which greatly increased the ratio of T effector/Treg in the tumor. In conclusion, CTX and agonist anti-GITR antibody slows tumor progression and can induce regression of palpable, poorly immunogenic B16 melanoma tumors, likely by enhancing cross-priming and increasing the T effector/Treg ratio in the tumor. Thus, this combination warrants further investigation as a novel immunotherapy approach and provides rational for exploring combination of GITR agonist antibodies with chemotherapeutic treatments in clinical settings.
Citation Format: Allison Betof Warner, Daniel Hirschhorn, Adam Cohen, Cailian Liu, Walter Newman, Cyndi Sirard, Jedd Wolchok, Taha Merghoub. Treatment with agonist anti-GITR antibody after chemotherapy enhances tumor immunity [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 1699.
Abstract 1781: HPN536, a T cell-engaging, mesothelin/CD3-specific TriTAC for the treatment of solid tumors
Authors: Austin Richard , Aaron Wade , Baeuerle Patrick , Barath Manasi , Jones Adrie , Jones Susan D. , Law Che-Leung , Kwant Kathryn , Lemon Bryan , Muchnik Anna , Sexton Kenneth , Tatalick Laurie , Wesche Holger , Yu Timothy 
Published: August 2018

Abstract
Mesothelin (MSLN) is a GPI-linked tumor antigen overexpressed in a variety of solid tumors, including ovarian, pancreatic, lung and triple-negative breast cancer. Normal tissue expression is restricted to single-cell, mesothelial layers lining the pleural, pericardial, and peritoneal cavities. Overexpression of MSLN is associated with poor prognosis in lung adenocarcinoma and triple-negative breast cancer. MSLN has been used as cancer target antigen for numerous modalities, including immunotoxins, vaccines, antibody drug conjugates and CAR-T cells. Early signs of clinical efficacy have validated MSLN as target, but therapies with improved efficacy are still needed to address the significant, unmet medical need posed by MSLN-expressing cancers. HPN536 is a ~50-kDa antibody derivative called TriTAC (Tri-specific T cell Activating Construct) designed to simultaneously bind to MSLN on tumor cells and to CD3ε on T cells with an affinity of 1 nM and 14 nM, respectively. Transient bispecific binding leads to the formation of an immunological cytolytic synapse, T cell activation and redirected tumor cell killing. A third domain of HPN536 binds non-covalently to serum albumin with an affinity of 8 nM to extend serum half-life life. Because TriTACs are built using single domain antibodies, TriTACs are much smaller than full size antibodies and are anticipated to demonstrate improved penetration of human tumors compared to full sized antibodies. HPN536 is produced by eukaryotic cell culture and secreted as a highly stable, single polypeptide. It binds with similar affinity to human and cynomolgus MSLN, albumin and CD3. When incubated in co-cultures with resting, human or cynomolgus T cells and human tumor cells, T cells are induced to release cytokines, to proliferate, and to specifically lyse MSLN-positive target cells with EC50 values at single-digit picomolar concentrations. In an exploratory toxicological study in non-human primates, HPN536 was well tolerated and showed pharmacokinetics in support of weekly dosing in humans. Preclinical characterization suggests that HPN536 is an efficacious and safe novel therapeutic candidate for the convenient treatment of patients with MSLN-expressing malignancies.
Citation Format: Richard Austin, Wade Aaron, Patrick Baeuerle, Manasi Barath, Adrie Jones, Susan D. Jones, Che-Leung Law, Kathryn Kwant, Bryan Lemon, Anna Muchnik, Kenneth Sexton, Laurie Tatalick, Holger Wesche, Timothy Yu. HPN536, a T cell-engaging, mesothelin/CD3-specific TriTAC for the treatment of solid 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 1781.
Abstract 180: OPNa variant expression is associated with matrix mineralization in thyroid cancer cell lines
Authors: Ferreira Luciana B. , Lima Raquel T. , Bastos Ana Clara Santos da Fonseca , Silva Andreia Machado , Tavares Catarina , Pestana Ana , Rios Elisabete , Eloy Catarina , Sobrinho-Simões Manuel , Gimba Etel Rodrigues Pereira , Soares Paula 
Published: August 2018

Abstract
Osteopontin (OPN) and its three spliced variants (OPN-SV: OPNa, OPNb and OPNc) are overexpressed in several tumors and frequently associated with cancer progression. This holds true for papillary thyroid carcinoma (PTC), which is the most common variety of thyroid cancer (TC), being the histologic type which often presents desmoplasia (collagen deposition) and dystrophic calcification, including a fairly typical feature, the psammoma bodies (PB). This study aims to investigate the OPN-SV expression in classical variant of PTC (cPTC) and the role of OPN in calcification and collagen deposition into the extracellular matrix of thyroid cancer cell lines. Total OPN and OPN-SV expression was analyzed by immunohistochemistry and real time PCR in a series of 48 cPTC cases and three diffuse sclerosing PTCs. The association of OPN expression and the presence of PB as well as between PB in cPTC and the clinicopathological features of the tumors were evaluated. TPC-1 and c643 TC cell lines overexpressing OPN-SV were tested for the ability to promote calcification and to synthesize collagen in vitro. We also evaluated the expression of calcification markers, including osteocalcin and collagen I. Overexpression of OPNa transcripts was significantly associated with the presence of PB in cPTC samples. The presence of PB in cPTC was associated with younger patients and lymph node metastasis. Moreover, OPNa overexpression displayed a strong capacity to promote calcification and substantial collagen deposition in thyroid cancer cell lines. Upon OPN knockdown, the mRNA expression levels of calcification markers (osteocalcin and collagen I) were downregulated, further evidencing the involvement of OPN on activating these processes. Our data suggest that OPNa plays a role in the extracellular matrix calcification associated with cPTC. Basic research on the interactions between OPNa overexpression by tumor cells and the surrounding microenvironment can give clues for a better understanding of cPTC biology and phenotype.
Citation Format: Luciana B. Ferreira, Raquel T. Lima, Ana Clara Santos da Fonseca Bastos, Andreia Machado Silva, Catarina Tavares, Ana Pestana, Elisabete Rios, Catarina Eloy, Manuel Sobrinho-Simões, Etel Rodrigues Pereira Gimba, Paula Soares. OPNa variant expression is associated with matrix mineralization in thyroid cancer cell lines [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 180.
Abstract 1818: Activation of IGF-1R pathway and NPM-ALK G1269A mutation confer resistance to crizotinib in NPM-ALK positive lymphoma
Authors: Li Yanrong , Wang Kai , Zhang Jingdong 
Published: August 2018

Abstract
ALK-positive Anaplastic Large Cell Lymphoma (ALCL), harboring NPM-ALK fusion gene, is sensitive to dual ALK/MET inhibitor crizotinib. However, cancer cells eventually develop resistance to crizotinib after remarkable initial responses, the mechanisms of crizotinib resistance in NPM-ALK positive ALCL remained unclear.
To investigate the mechanisms of ALCL cells resistant to crizotinib, we established a model of acquired resistance to crizotinib by gradually exposing sensitive NPM-ALK-positive ALCL cell line to higher concentration of crizotinib. We found that NPM-ALK G1269A mutation were selected in 400nM resistant clones and activation of IGF-1R pathway. Then we generated a G1269A-mutated sub-lines by limiting dilution, which were sensitive to second-generation ALK inhibitor NVP-TAE684. IGF-1R inhibitor picropodophyllotoxin had no effect on these sub-clones and didn't change sensitivity to first and second generation ALK TKIs. But IGF-1R inhibitor increased sensitivity to crizotinib and NVP-TAE684 in 400nM crizotinib-resistant cells. Thus, we have shown that IGF-1R pathway and NPM-ALK G1269A mutation contribute to resistance to ALK TKIs and combined ALK/IGF1R inhibition improves therapeutic efficacy.
Citation Format: Yanrong Li, Kai Wang, Jingdong Zhang. Activation of IGF-1R pathway and NPM-ALK G1269A mutation confer resistance to crizotinib in NPM-ALK positive lymphoma [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 1818.
Abstract 2039: Cordycepin inhibits breast cancer migration and invasion by targeting epithelial to mesenchymal transition-inducing transcription factors (EMT-TFs)
Authors: Fu Junjiang , Wei Chunli , Cheng Jingliang , Khan Md. Asaduzzaman , Yang Lisha , Zou Hui 
Published: August 2018

Abstract
Cancer metastasis is one of the major causes of human death. The developmental stage epithelial to mesenchymal transition (EMT) is associated with cancer metastasis. Cordycepin (CD) is a natural compound, found in traditionally used medicinal mushroom Cordyceps. In this study, we have investigated the anticancer and antimetastatic activity of CD, and whether this compound regulates epithelial to mesenchymal transition-inducing transcription factors (EMT-TFs). By employing cell viability assay and real-time cell analysis in BT549, 4T1 and MDA-MB-435 cell lines, we found that CD can potentially inhibit cancer cell growth, migration and invasion. By using quantitative PCR (qPCR) and Western blot analysis, we also studied the expression of EMT associated proteins N-Cadherin and E-Cadherin, and their transcription factors TWIST1, SNAIL1, SLUG and ZEB1 in BT549 and 4T1 cell lines. By dual-luciferase reporter assay, we confirmed that CD is able to inactivate EMT signaling pathway with mediatory of TWIST1 and SLUG. CD treatment also inhibited the growth and metastasis of cancer cell-derived xenograft tumors in mouse model. Taken together, CD inhibits breast cancer cell migration and invasion by targets EMT-TFs, which might be a possible CD mechanism of antimetastatic action. In addition, CD derivatives by conjugating thymoquinone, a promising anti-cancer compound from nature, were designed to investigate whether there are dramatically improvements on their antimetastatic activities. In conclusion, this study suggests CD as a potential anticancer and antimetastatic molecule, which might be a promising therapeutic agent against breast cancer. Funding: This work was supported by the NSFC (81172049, 81672887).
Citation Format: Junjiang Fu, Chunli Wei, Jingliang Cheng, Md. Asaduzzaman Khan, Lisha Yang, Hui Zou. Cordycepin inhibits breast cancer migration and invasion by targeting epithelial to mesenchymal transition-inducing transcription factors (EMT-TFs) [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 2039.
Abstract 2098: Quantitative modeling as a systematic approach for drug combination evaluation in immuno-oncology (IO)
Authors: Helmlinger Gabriel , Kosinsky Yuri , Chu Lulu , Peskov Kirill , Voronova Veronika , Borodovsky Alexandra , Woessner Richard , Sachsenmeier Kris , Al-huniti Nidal 
Published: August 2018

Abstract
Objectives: Multiple strategies for eliciting and enhancing antitumor immunity are currently being evaluated. However, a more systematic approach is needed, to analyze and translate such results into clinic practice, while rationally designing combination therapies based on mechanistic understanding of potential synergistic effects (1). The objective of this study was to provide predictive simulations, via a quantitative systems pharmacology (QSP) model, capable of categorizing the types of synergistic effects that may arise from IO agent combinations, across realistic baseline conditions prevailing in the tumor microenvironment (TME).
Methods: The QSP model was developed and qualified using in vivo mouse data published in the literature and from internal research. The following pharmacologic modalities were calibrated: PD-L1/PD-1, CTLA-4, CXCR2, A2AR inhibition, and OX40 agonism. Various combination scenarios were simulated for these modalities, at four baseline conditions prevailing in different syngeneic murine models.
Results: Simulated efficacy results were highly dependent on the baseline conditions. Several combinations and monotherapies were effective only within a specific baseline TME phenotype. These findings were in agreement with experimental data (2). At baselines with higher levels of MDSC, best results were obtained for a PD-L1 mAb combined with either an OX40 agonist or a CXCR2 inhibitor, with 90% of complete responders. Anti (PD-L1 + CTLA-4) combinations showed high efficacy in Treg prevalence, but only moderate efficacy (22% complete responders), under baseline conditions of a dual (Treg + MDSC) immunosuppressive TME.
Conclusion: This work provides a quantitative modeling framework to comparatively predict responses to IO combinations, based on realistic baseline conditions prevailing in the TME, while revealing mechanistic interactions underlying such responses in IO combinations.
References:
1. Melero I et al. Nat Rev Cancer 2015;15:457-72.
2. Mosely S et al. Cancer Immunol Res 2016;5:29-41.
Citation Format: Gabriel Helmlinger, Yuri Kosinsky, Lulu Chu, Kirill Peskov, Veronika Voronova, Alexandra Borodovsky, Richard Woessner, Kris Sachsenmeier, Nidal Al-huniti. Quantitative modeling as a systematic approach for drug combination evaluation in immuno-oncology (IO) [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 2098.
Abstract 2195: Temporal and spatial dynamics of metastatic colonization revealed by 26 rapid-autopsy tumor biopsies from a TNBC patient
Authors: Huang Xiaomeng , Qiao Yi , Brady Samuel W. , Cohen Adam , Bild Andrea H. , Marth Gabor T. 
Published: August 2018

Abstract
Metastatic breast cancer is an advanced-stage disease in which the cancer cells have spread to distant organs. To understand the patterns of metastatic colonization in a patient who presented with aggressive disease, we have collected tumor biopsies at initial diagnosis, at mastectomy necessitated by the patient's relapse, twenty-six metastatic tumors across seven organs and two normal tissue control skin biopsies via a rapid autopsy procedure within hours after the patient's death.
All biopsy samples were subjected to 60X Illumina whole genome sequencing. Our analysis revealed extensive chromosomal changes including amplifications, deletions, LOH and translocations, as well as known driver mutations in RB1, TP53, and PTEN in all tumor samples. We used the CNV and LOH data to reconstruct the phylogenetic relationships among the tumor samples. We used the somatic SNV allele frequencies in copy number-normal regions to refine these phylogenetic relationships, and to establish the evolution of the tumor at the subclonal level across different metastatic sites, with an extension of our SubcloneSeeker algorithm.
Our analysis reveals the lung as the first metastatic site. In fact, this invasion occurred before relapse at the primary site in the breast, indicating early metastatic escape. This initial invasion was followed by distinct waves of massive metastatic expansion, beginning with the abdominal organs, then the lymph nodes, brain and bones. As the initial invasion, each metastatic wave involved other distinct sites in the lungs, these sites serving as incubators where subclones further evolved prior to seeding new metastatic sites. Finally, we see clear evidence for metastatic “recolonization” where such further evolved subclones invaded already established, earlier metastatic sites.
The high number of biopsied sites in this study, 30 in all, allowed us to reconstruct the evolution of the aggressive disease in our patient with unprecedented resolution, and to identify characteristic patterns of metastatic colonization. If confirmed in additional, similarly high resolution datasets, these patterns will lead to better understanding of the metastatic process, and guide effective clinical intervention.
Citation Format: Xiaomeng Huang, Yi Qiao, Samuel W. Brady, Adam Cohen, Andrea H. Bild, Gabor T. Marth. Temporal and spatial dynamics of metastatic colonization revealed by 26 rapid-autopsy tumor biopsies from a TNBC patient [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 2195.