bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-197: NBE-002, an anthracycline-based immune-stimulatory antibody drug conjugate (iADC) targeting ROR1 for the treatment of triple-negative breast cancer
Authors: Beerli Roger R. , Waldmeier Lorenz , Gébleux Rémy , Pretto Francesca , Grawunder Ulf 
Published: August 2019

Abstract
Introduction: We report on the development and preclinical validation of NBE-002, a next-generation antibody drug conjugate (ADC) for the treatment of triple-negative breast cancer (TNBC). NBE-002 consists of a humanized monoclonal antibody directed against the receptor tyrosine kinase ROR1, expressed on the surface of numerous solid cancers including TNBC, and is site-specifically conjugated to a derivative of the highly potent anthracycline PNU-159682.
Results: Therapeutic efficacy of NBE-002 was evaluated in ROR1-low/-intermediate/-high patient-derived xenograft (PDX) models of TNBC, lung adenocarcinoma, ovarian carcinoma, and a variety of sarcomas. NBE-002 was found to display significant anti-tumor activity in each indication. The most pronounced effect was achieved in TNBC, where complete tumor regression was observed already at the lowest ADC dose tested (0.33 mg/kg), even in models expressing low levels of ROR1 (H-score ≤70). Since these PDX studies were performed in immune-compromised hosts, and anthracyclines are known inducers of immunogenic cell death, anti-tumor activity was also investigated in syngeneic tumor models in immune-competent hosts. Anti-tumor activity of PNU-ADCs involved activation of the immune system, as shown by evaluation of NBE-002 or a Trastuzumab-PNU conjugate (T-PNU) in ROR1- or HER2-positive syngeneic breast cancer models, respectively. Depletion of CD8 T cells severely reduced anti-tumor activity, demonstrating an important role for T cells in driving tumor regression. Furthermore, when tumor free animals were re-challenged with the same tumor, tumor growth was inhibited in the absence of any further ADC administration, indicating the development of an immunological memory. Notably, combination of ADC and checkpoint inhibition, such as α-PD1 or α-CTLA4, significantly enhanced tumor eradication following the treatment.
Conclusion: Our results demonstrate that NBE-002 is a highly effective and promising targeted therapeutic for the treatment of ROR1 positive TNBC and potentially other solid tumor indications that warrants clinical development. Considering the pronounced immune-modulatory functions of the PNU payload, NBE-002 may be particularly well suited for combination therapy with immune checkpoint inhibitors. NBE-002 is currently undergoing GMP manufacturing and initiation of clinical studies is expected in mid-2020.
Citation Format: Roger R. Beerli, Lorenz Waldmeier, Rémy Gébleux, Francesca Pretto, Ulf Grawunder. NBE-002, an anthracycline-based immune-stimulatory antibody drug conjugate (iADC) targeting ROR1 for the treatment of triple-negative 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 LB-197.
Abstract LB-198: Discovery of a novel anti-CD47 antibody with anti-cancer therapeutic potential and minimal RBC binding
Authors: Feng Xiao , Sun Dawei , Qin Suofu , Jin Lei , Wang Tao , Yan Hongbo 
Published: August 2019

Abstract
CD47 is a widely expressed cell surface protein that functions as a checkpoint in the immune system. When overexpressed on tumor cells, CD47 can bind SIRPα on myeloid cells, leading to suppression of tumor cell phagocytosis and other innate immune functions. Thus, targeting CD47 is becoming a hot spot of cancer immunotherapy. However, its ubiquitous expression on circulating cells, especially RBCs and hepatocyte, poses a safety concern in CD47 targeted therapy.In this study, we discovered a novel anti-CD47 antibody, GenSci-059. GenSci-059 exhibited equivalent anticancer effects with Hu5F9-G4, a humanized anti-CD47 antibody in clinical trial, evidenced by inducing significant phagocytosis of tumor cells in vitro and prolonging the survival of xenografted mice. Especially for non-Hodgkin’s lymphoma (NHL), GenSci-059 showed almost 100% tumor growth inhibition with 100% response rate in the patient-derived xenograft (PDX) NHL models tested. Remarkably, GenSci-059 did not bind to human RBCs and induced minimal RBC phagocytosis by in vitro assay. In cynomolgus monkeys, GenSci-059 was well tolerated at doses up to 300 mg/kg, and did not produce adverse effects including anemia and hepatic dysfunction, which are common side effects of other anti-CD47 therapies. Overall, GenSci-059 is a promising candidate with great potential and safety profile for cancer immunotherapy.
Citation Format: Xiao Feng, Dawei Sun, Suofu Qin, Lei Jin, Tao Wang, Hongbo Yan. Discovery of a novel anti-CD47 antibody with anti-cancer therapeutic potential and minimal RBC binding [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 LB-198.
Abstract LB-210: An enhanced tumor evolution model for colorectal cancer evolution
Authors: Yang Lixing 
Published: August 2019

Abstract
The classical genetic model of colorectal cancer presents somatic APC mutations as the earliest genomic alterations, followed by KRAS and TP53 mutations. However, the timing and relative order of clonal expansion and other types of somatic genome alterations such as genomic rearrangements are still unclear. Here, we performed detailed analysis of somatic genetic alterations, including point mutations, copy number alterations and genomic rearrangements, in 63 whole-genome sequenced colorectal cancers from the Cancer Genome Atlas Research Network. The relative order of these alterations occurring during tumorigenesis was inferred from variant allele fractions. We found that driver point mutations, gene fusions, and arm level copy losses typically arise early. Copy-neutral loss of heterozygosity is often a two-step event: a deletion followed by a duplication. Different mechanisms act in different genomic regions to optimize the DNA dosage. Chromothripsis, clustered genomic rearrangements previously thought to occur as a single catastrophic event, is frequent and may occur multiple times independently in the same tumor through different mechanisms. In contrast to recent studies reporting neutral growth of tumors, selection is often present on subclones. Our results suggest that different evolutionary models can operate in a single tumor at different stages. Combining these results, we present a refined tumor progression model for human colorectal cancer. Our enhanced genetic model significantly expands our understanding of tumorigenesis process.
Citation Format: Lixing Yang. An enhanced tumor evolution model for colorectal cancer evolution [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 LB-210.
Abstract LB-238: Characterization of circulating tumor cells and its PD-L1 expression with high-sensitivity liquid biopsy panel in non-small cell lung cancer patients
Authors: Liu Xiaohe , Ao Zheng , Preiss Jordan S. , Neal Joel , Zhou Lisa Ya , Sambucetti Lidia , Wakelee Heather A. 
Published: August 2019

Abstract
Early detection and intervention are crucial for long-term survival of either primary or recurrent lung cancer patients. Circulating tumor cells (CTCs) could be powerful biomarkers for the diagnosis, prognosis, and treatment planning of cancer. In this work we applied our FAST cytometer, a fiber-optic array scanning technology (FAST) to develop a sensitive diagnostic blood tests (“liquid biopsies”) for NSCLC. This technology is based on the ultra-rapid, sensitive and accurate detection of rare circulating cells expressing the biomarker(s) of interest. By applying the FAST cytometer with a unique NSCLC specific cocktail, we were able to detect CTC in NSCLC setting with higher sensitivity as compared with traditional cytokeratin-based detection. In a pilot cohort of 51 NSCLS patients, we have detected CTC in 74.2% using our unique panel for NSCLC CTC, this has raised our sensitivity from 48.8% using traditional cytokeratin-based detection. In addition, we have also interrogated circulating cancer associated fibroblasts (cCAF) as an additional liquid biopsy marker for NSCLC. We detected cCAF in 67% NSCLC patients. When combined with our enhanced CTC detection method, addition of cCAF further increased our sensitivity to 88.5%. Moreover, using clinically validated PD-L1 antibody (Ventana SP263) as reference, we have demonstrated our capacity to analyze PD-L1 expression on CTC at protein level, we have shown detection of PD-L1+ CTC in 80% of the patients. To summarize, we have developed an unique panel to detect CTC with higher sensitivity using combinational detection and we have demonstrated that by combining CTC detection with cCAF detection, liquid biopsy sensitivity for cancer detection can be further increased without significant increase in false positive rates. Lastly, we developed a method to analyze the PD-L1 expression on CTC using clinically validated Ventana PD-L1 (SP263) rabbit monoclonal antibody as reference which can potentially serve as a companion diagnostics tool for NSCLC immunotherapy
Citation Format: Xiaohe Liu, Zheng Ao, Jordan S. Preiss, Joel Neal, Lisa Ya Zhou, Lidia Sambucetti, Heather A. Wakelee. Characterization of circulating tumor cells and its PD-L1 expression with high-sensitivity liquid biopsy panel in non-small cell lung cancer patients [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 LB-238.
Abstract LB-259: FGFR- and EGFR-driven SHP2 activation displays differential sensitivity to allosteric SHP2 inhibition
Authors: Hao Huaixiang , Lu Hengyu , Liu Chen , LaMarche Matthew , Engelman Jeffrey A. , Hammerman Peter S. , Caponigro Giordano 
Published: August 2019

Abstract
Introduction: The non-receptor protein tyrosine phosphatase SHP2 mediates RAS activation downstream of various receptor tyrosine kinases (RTKs). Cancer cell lines dependent on RTK signaling are generally sensitive to SHP2 genetic knockdown but differ widely in their sensitivity to allosteric SHP2 inhibitors such as SHP099. A recent report suggested that FGFR can drive resistance to MAPK inhibitors independently of SHP2. We sought to understand the molecular basis of differential sensitivity to allosteric SHP2 inhibitors when SHP2 is activated by different RTKs, particularly FGFR versus EGFR.
Experimental procedures: We profiled a panel of cancer cell lines driven by various wild-type FGFR activation (receptor amplification or autocrine ligand mediated) for their sensitivity to SHP099 and characterized MAPK pathway inhibition at various time points and SHP099 doses, in comparison with EGFR-driven cell lines. We also compared the inhibitory effects of SHP099 on FGFR- and EGFR-mediated pathway feedback activation in response to MEK inhibitor treatment.
Results: We find FGFR-driven cell lines are often more resistant to SHP099 compared to EGFR-driven cell lines. Those SHP099-resistant FGFR-driven cell lines were sensitive to SHP2 knockdown and SHP099 inhibited p-ERK in those cells at earlier time points. However, p-ERK quickly rebounded after SHP099 treatment, which was not observed with FGFR inhibitors and can be attenuated with high concentrations of SHP099. Consistently, FGFR-driven MAPK pathway feedback activation following treatment with MEK inhibitor was also more resistant to SHP099 compared to EGFR-driven feedback activation. Additional studies are being performed in isogenic cell lines for direct comparison.
Conclusions: Our findings suggest that many FGFR-driven cell lines are dependent on SHP2 but are intrinsically resistant to allosteric SHP2 inhibition, compared to EGFR-driven cell lines. FGFR-driven cells tend to have a quick p-ERK rebound following initial pathway inhibition by SHP099, which is mediated by the feedback activation of FGFR. The feedback activated FGFR likely efficiently promotes the open conformation of SHP2 and causes resistance to allosteric SHP2 inhibitors. For certain FGFR-driven cancers, SHP2 inhibitor combinations such as with MAPK inhibitors might be needed for sustained efficacy.
Citation Format: Huaixiang Hao, Hengyu Lu, Chen Liu, Matthew LaMarche, Jeffrey A. Engelman, Peter S. Hammerman, Giordano Caponigro. FGFR- and EGFR-driven SHP2 activation displays differential sensitivity to allosteric SHP2 inhibition [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 LB-259.
Abstract LB-311: Exosomal gain-of-function p53 protein promotes cancer-associated phenotype
Authors: Ma Shaolin , McGuire Michael H. , Stur Elaine , Bayraktar Emine , Villar-Prados Alejandro , Wu Sherry Y. , Yokoi Akira , Dasari Santosh K. , Rodriguez-Aguayo Cristian , Liu Jinsong , Lopez-Berestein Gabriel , Sood Anil K. 
Published: August 2019

Abstract
TP53 is the most commonly mutated gene in cancer. Certain mutations can produce gain-of-function (GOF) phenotypes, resulting in pathogenic effects beyond the loss of p53 function. Recent study suggested that tumor cells could affect the p53 status of stromal cells while the mechanisms remains unclear. Exosomes have emerged as an important mode of extracellular communication and a major player in cancer pathogenesis, by promoting pro-tumor microenvironment. We hypothesized that packaging of mutated p53 protein into exosomes and dissemination via exosomes could impact a variety of stromal cell processes, producing a pro-tumorigenic microenvironment. In this study, we carried out a series of in vitro (immunoblot analysis, Q-PCR, Gene array, Co-Immunoprecipitation and lentiviral transfection) and in vivo (subcutaneous mouse models) experiments to determine the presence of mutant p53 in exosomes and its biological significance in tumor microenvironment. We demonstrated that gain-of-function (GOF) p53 protein is packaged into p53 mutant cancer cell-derived exosomes and transferred to fibroblasts. Further studies showed that this process is facilitated by the enhanced stability and consequent intracellular concentration of GOF p53. The packaging of GOF p53 into exosomes is selectively bound by HSP90 chaperone proteins. Inhibition of HSP90 blocks the packaging of GOF p53, but not wild-type into exosomes. Uptake of GOF p53-containing exosomes by fibroblasts results in conversion to a cancer-associated phenotype. In vivo study have shown that GOF p53 exosomes-induced cancer-associated fibroblasts promote tumor growth in a colon cancer cells (HT29 cells) xenograft mouse model. These findings reveal a crucial role of exosomes in modifying tumor microenvironment and hold great consequence in broadening our understanding of tumor biology.
Citation Format: Shaolin Ma, Michael H. McGuire, Elaine Stur, Emine Bayraktar, Alejandro Villar-Prados, Sherry Y. Wu, Akira Yokoi, Santosh K. Dasari, Cristian Rodriguez-Aguayo, Jinsong Liu, Gabriel Lopez-Berestein, Anil K. Sood. Exosomal gain-of-function p53 protein promotes cancer-associated phenotype [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 LB-311.
Abstract LB-312: Interleukin 6 transsignaling is a candidate mechanism to drive progression of human DCCs during periods of clinical latency
Authors: Werner-Klein Melanie , Grujovic Ana , Obradovic Milan , Hoffmann Martin , Lu Xin , Kirsch Stefan , Treitschke Steffi , Köstler Cäcilia , Weidele Kathrin , Irlbeck Christoph , Botteron Catherine , Werno Christian , Polzer Bernhard , Guzvic Miodrag , Buchholz Stefan , Rümmele Petra , Heine Norbert , Rose-John Stefan , Klein Christoph A. 
Published: August 2019

Abstract
While thousands of breast cancer cells disseminate and home to bone marrow (BM) until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. Signals and mechanisms determining failure or success of disseminated cancer cells (DCCs) are largely unknown and there is no in vivo model available to study the spontaneous progression and genomic evolution from early bone marrow infiltration to manifestation of bone metastasis, as spontaneous or transgenic mouse models do not generate bone metastases. We therefore profiled DCCs from BM of breast cancer patients long before manifestation of metastasis by RNAseq to identify signals supporting survival or outgrowth of DCCs and identified IL6/PTEN/PI3K signaling as candidate pathway for DCC activation. Since early DCCs often display close-to-normal genomes we used mammary epithelial cells ex vivo isolated from reduction mammoplasties and immortalized pre-malignant breast cancer cell lines as model for functional testing in vitro. Using specific activators and inhibitors of IL6 signaling revealed that IL6 trans, but not classical signaling, regulates stemness of mammary epithelial cells. Moreover, knock-down of PTEN revealed that PI3K/PTEN pathway activation renders cells independent of IL6 trans-signaling. Interestingly, gp130 expression, a pre-requisite for IL6 trans-signaling was found to be down-regulated by bone marrow stromal and endosteal, but not vascular niche cells, and as a consequence the number of cells with stem-like ability was significantly reduced. Consistent with a bottleneck function of microenvironmental DCC control, we found PIK3CA mutations highly associated with late-stage metastatic DCCs and CTCs while generally absent in early DCCs. Our data suggest that the initial steps of metastasis formation depend on microenvironmental signals and are not cancer cell-autonomous.
Citation Format: Melanie Werner-Klein, Ana Grujovic, Milan Obradovic, Martin Hoffmann, Xin Lu, Stefan Kirsch, Steffi Treitschke, Cäcilia Köstler, Kathrin Weidele, Christoph Irlbeck, Catherine Botteron, Christian Werno, Bernhard Polzer, Miodrag Guzvic, Stefan Buchholz, Petra Rümmele, Norbert Heine, Stefan Rose-John, Christoph A. Klein. Interleukin 6 transsignaling is a candidate mechanism to drive progression of human DCCs during periods of clinical latency [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 LB-312.
Abstract LB-314: Fibroblast growth factor-2, derived from cancer-associated fibroblasts, stimulate proliferation and migration of human breast cancer cells though FGFR1
Authors: Suh Jinyoung , Kim Do-Hee , Na Hye-Kyung , Surh Young-Joon 
Published: August 2019

Abstract
Cancer-associated fibroblasts (CAFs) constitute a major compartment of the tumor microenvironment. CAFs are distinct from normal fibroblasts for their overexpression of α-smooth muscle actin (α-SMA) and fibroblast activating protein. Recent studies suggest that CAFs play an important role in proliferation and migration of cancer cells through crosstalk with them. In the present study, we investigated the role for CAFs in breast cancer progression and underlying molecular mechanisms. We found the increased expression of α-SMA in human breast tumor tissues compared with normal adjacent tissues. In particular, α-SMA was highly expressed in the most of estrogen receptor (ER)-negative tumor tissues. When ER-negative breast cancer MDA-MB-231 cells and MDA-MB-468 cells were treated with the CAF-conditioned medium (CM), the cell viability was significantly elevated. In addition, MDA-MB-231 cells exhibited elevated expression of proliferative and invasive genes when incubated with CAFs. Notably, fibroblast growth factor-2 (FGF2) expression was correlated with the presence of CAFs. We noticed that mRNA level of FGF2 in CAFs as well as the concentration of FGF2 in CAF-CM was higher than that in normal fibroblasts. FGF2 exerts its biological effects by binding to FGF receptor 1 (FGFR1). In the breast cancer tissue microarray, 42% ER-negative patients co-expressed FGF2 and FGFR1 proteins, whereas only 19% ER-positive patients co-expressed those proteins. While the expression of FGFR1 was up-regulated in breast cancer cells, another major FGF2-corresponding receptor FGFR2 was barely expressed.This prompted us to explore FGF2-FGFR1 signaling in the context of paracrine communication. CAF-stimulated MDA-MB-231 cell migration and invasion as well as FGFR1 signaling activation were abolished when FGF2-neutralizing antibody was added to the CAF-CM. In a xenograft mouse model, co-injection of shmock-MDA-MB-231 cells with activated fibroblasts expressing FGF2 dramatically enhanced tumor growth, which suggests that stromal-derived FGF2 enhances tumor formation through activation of FGFR1 in cancer cells. Furthermore, FGF2 promotes nuclear localization of FGFR1 which might be associated with cancer cell proliferation and migration. In conclusion, secretion of FGF2 by CAFs stimulates proliferation and migration of breast cancer cells through interaction with FGFR1 which may contribute to human breast cancer progression.
Citation Format: Jinyoung Suh, Do-Hee Kim, Hye-Kyung Na, Young-Joon Surh. Fibroblast growth factor-2, derived from cancer-associated fibroblasts, stimulate proliferation and migration of human breast cancer cells though FGFR1 [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 LB-314.