bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2954: The role of hedgehog signaling in breast cancer progression through macrophage polarization
Authors: Hanna Ann , Shevde Lalita A. 
Published: July 2017

Abstract
The tumor microenvironment is comprised of stromal cells that constantly crosstalk with the cancer cells. Stromal cells, specifically tumor infiltrating immune cells, secrete cytokines and chemokines that regulate host responses to cancer through tumor-suppressing or tumor-promoting mechanisms. Macrophages within the tumor microenvironment are very plastic and can modulate different functions that promote tumor growth or tumor suppression, depending on their phenotype. Classically activated macrophages (M1) suppress tumor growth by mounting a pro-inflammatory immune response; while alternatively activated macrophages (M2) promote tumor progression by inducing an anti-inflammatory response which suppresses immune system function.
Hedgehog (Hh) signaling is essential for normal mammalian embryonic development by modulating vital functions such as cell proliferation, differentiation, and angiogenesis. Although the Hh signaling pathway is tightly controlled, it often is deregulated, thus promoting tumorigenesis and tumor progression. Aberrant Hh signaling has particularly been implicated in breast cancer progression and metastasis.
In this project, we investigate the role of Hh signaling in polarizing cancer associated macrophages toward the tumor-promoting M2 phenotype in a breast cancer model. We have discovered that using small molecule inhibitors to inhibit Hh signaling attenuates the cytokine profile associated with M2 macrophages, while adding recombinant Hh ligand potentiates it. Our data thus far supports a role for Hh signaling in alternatively polarizing macrophages. We hypothesize that Hh inhibitors will reduce the abundance of M2 macrophages and prevent metastasis.
Citation Format: Ann Hanna, Lalita A. Shevde. The role of hedgehog signaling in breast cancer progression through macrophage polarization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2954. doi:10.1158/1538-7445.AM2017-2954
Abstract 2955: Gr1-MDSCs and Tregs modulate the prostate cancer progression
Authors: Kumar Sanjay , Stokes James , Singh Udai , Gunn Karyn Scissum , Manne Upender , Ponnazhagan Selvarangan , Mishra Manoj K. 
Published: July 2017

Abstract
Myeloid-derived suppressor cells (MDSCs) and Regulatory T cells (Tregs) are the major components of immunosuppressive network that play a critical role in tumor immune evasion. The mechanisms by which tumors induce expansion of suppressive cells and the crosstalk between Gr1-MDSCs (Gr1+, CD11b+, F4/80+) and Tregs relative to TGF-β secretion remain incompletely defined. Prior studies have suggested that MDSCs may contribute to Treg recruitment in cancer. Herein, the goal of this investigation is to examine the role of TGF-β mediated generation of Tregs and Gr1-MDSCs during prostate cancer progression and clearance. To achieve this goal, matrigel system was used along with transgenic adenocarcinoma of mouse prostate (TRAMP-C1, C2 and C3 cell) in C57BL/6 mice. Interestingly, TRAMP-C3 cells are characterized as non-tumorigenic; however, TRAMP-C1 and TRAMP-C2 cells do form tumor. Mice were administered with serial log concentration of TRAMP (C1, C2 and C3) cells along with the matrigel. After three weeks, matrigels along with or without tumor were excised from tumor bearing mice, single cell suspensions was prepared and cells were flow analyzed for GR1-MDSCs and Tregs. Additionally, the TGF-β level was also estimated (colorimetric) in culture supernatant in context to MDSCs and Treg expansion. Our initial findings suggest that the expression of Gr1-MDSCs (Gr1+, CD11b+, F4/80+) and Foxp3+ Tregs increased in TRAMP-C1 and C2 as compared to TRAMP-C3 bearing C57BL/6 mice. These findings indicate that the modulation of Gr1-MDSCs and Tregs could help in tumor suppression.
Citation Format: Sanjay Kumar, James Stokes, Udai Singh, Karyn Scissum Gunn, Upender Manne, Selvarangan Ponnazhagan, Manoj K. Mishra. Gr1-MDSCs and Tregs modulate the prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2955. doi:10.1158/1538-7445.AM2017-2955
Abstract 2963: Inhibition of stromal p38MAPK abrogates breast cancer metastasis
Authors: Stewart Sheila A. , Murali Bhavna , Ren Qiaho , Su Xinming , Flannagan Kevin , Luo Xianmin , Sponagel Jasmine , Fu Yujie , Alspach Elise , Leahy Kathlees , Faccio Roberta , Weilbaecher Kathleen , Monahan Joseph 
Published: July 2017

Abstract
Bone metastasis is a devastating and fatal complication of breast cancer for which we lack effective therapies. Thus, identifying therapies that effectively limit metastases will significantly reduce comorbidities and improve long-term survival. Recently we demonstrated that the p38MAPK pathway sustains the pro-tumorigenic senescence-associated secretory phenotype (SASP) and targeting this pathway limits the tumor-promoting capabilities of senescent cells and cancer-associated fibroblasts (CAFs). Because we found that a significant percentage of p38MAPK-dependent SASP factors are expressed in the stroma associated with breast cancer lesions, we asked whether targeting p38MAPK could limit primary and metastatic breast cancer growth. While p38MAPK inhibition modestly limited primary tumor growth, we found that its inhibition significantly reduced breast cancer bone metastases by specifically targeting the stromal compartment. Further, p38MAPK inhibition was as effective as paclitaxel at limiting tumor growth in the bone but in contrast to paclitaxel, which failed to protect from cancer-induced bone loss, p38MAPK inhibition also protected against devastating bone loss. This contrasts our p38MAPK approach from zoledronic acid, which limits bone loss but fails to slow tumor growth in already engrafted tumors. Analysis of the mechanism(s) responsible for this reduced metastasis suggests that p38MAPK inhibition targets reactive and/or senescent osteoblasts within the bones of animals harboring metastatic lesions. Because we find that senescent osteoblasts are present in human bone, we postulate that they promote metastatic outgrowth and thus p38MAPK inhibition limits the pro-metastatic activities of these cells. Finally, we will present recent data from our preclinical model that demonstrates that inhibition of the p38MAPK pathway can drastically reduce metastasis from the primary site. We propose that p38MAPK is an important stromal-specific therapy for breast cancer metastasis to the bone.
Citation Format: Sheila A. Stewart, Bhavna Murali, Qiaho Ren, Xinming Su, Kevin Flannagan, Xianmin Luo, Jasmine Sponagel, Yujie Fu, Elise Alspach, Kathlees Leahy, Roberta Faccio, Kathleen Weilbaecher, Joseph Monahan. Inhibition of stromal p38MAPK abrogates breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2963. doi:10.1158/1538-7445.AM2017-2963
Abstract 2981: Identification of circulating stroma-related biomarkers for pancreatic ductal adenocarcinoma
Authors: Resovi Andrea , Porcu Luca , Anastasia Alessia , Allavena Paola , Cappello Paola , Falanga Anna , Taraboletti Giulia , Bani Mariarosa , Belotti Dorina , Giavazzi Raffaella 
Published: July 2017

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive epithelial malignancies characterized by a relevant amount of tumor stroma. It is usually diagnosed late and has limited treatment options. Plasmatic markers capable of detecting the disease in its early stages and monitoring treatment effectiveness might change the fate of PDAC patients. This study investigates the potential value of circulating stroma-related molecules as PDAC biomarkers capable to detect the disease and to monitor treatment response. Thirty-eight stroma-related candidate biomarkers were selected from published proteomic studies on PDAC. Levels of these molecules were tested by ELISA and Multiplex Luminex assays in a first cohort of plasma samples from PDAC patients and healthy subjects. Thirteen molecules -extracellular matrix proteins and proteolytic fragments, matrix-degrading enzymes and their inhibitors, growth factors and adhesion molecules-, were found to be differentially expressed in PDAC plasma compared to healthy subjects. A second analysis in an independent cohort of PDAC patients, chronic pancreatitis patients and healthy controls confirmed the previous findings and allowed restricting the number of biomarkers up-regulated in the plasma of PDAC patients. The plasma analysis of two genetically engineered mouse models of pancreatic cancer [Pdx-1-Cre;LSL-KrasG12D and Pdx-1-Cre;LSL-KrasG12D/+;LSL-Trp53R172H/+] revealed an up-regulation of four markers in association with PanIN development, indicating their potential role in the early diagnosis of pancreatic cancer. These markers were also elevated in the plasma of mice bearing patient derived orthotopic PDAC xenografts (PDAC-PDX), but not in a mouse model of caerulein-induced chronic pancreatitis. Their level was associated with PDAC-PDX tumor growth and response to gemcitabine combined with nab-paclitaxel. In conclusion this analysis has identified a panel of stroma-related potential biomarkers associated with tumor progression and drug response of PDAC.
Supported by Associazione Italiana per la Ricerca sul Cancro (AIRC 5 per mille grant n. 12182) and Fondazione “Eugenio Morandi” ONLUS per lo studio e la cura dei tumori del pancreas.
Citation Format: Andrea Resovi, Luca Porcu, Alessia Anastasia, Paola Allavena, Paola Cappello, Anna Falanga, Giulia Taraboletti, Mariarosa Bani, Dorina Belotti, Raffaella Giavazzi. Identification of circulating stroma-related biomarkers for pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2981. doi:10.1158/1538-7445.AM2017-2981
Abstract 2997: The tetravalent bispecific antibody AFM13 engages and primes innate immune cells for anti-cancer immunity
Authors: Pahl Jens , Koch Joachim , Reusch Uwe , Gantke Thorsten , Cerwenka Adelheid , Treder Martin 
Published: July 2017

Abstract
AFM13 is a tetravalent bispecific antibody with bivalent binding to both CD30 and CD16A. It has been shown to engage NK-cells through CD16A with high affinity and specificity, resulting in strong NK-cell cytotoxicity, and is currently being tested in Phase 2 monotherapy and in combination with pembrolizumab in Phase 1b clinical trials. We have previously shown that AFM13-dependent activation of NK-cell cytotoxicity towards CD30+ tumor cells is more pronounced than that of anti-CD30 mAbs. In addition, AFM13 enhances NK-cell sensitivity to low doses of IL-2 and IL-15, leading to an increased NK-cell proliferative potential. Here, we have extended the panel of phenotypic markers on NK-cells that are modulated after exposure to CD30+ tumor cells in the presence of AFM13. Targeting some of these markers may enable the development of novel combination therapies. Moreover, we have analyzed the kinetics of NK-cell responses to AFM13 exposure. Even though short-term exposure to AFM13 significantly enhanced NK-cell cytotoxicity, long-term exposure led to a partial, transient functionally exhausted phenotype in vitro, which could be fully restored by cytokine stimulation for several days in the absence of AFM13. Importantly, these recovered cells displayed high cytotoxicity towards CD30+ target cells in the presence of AFM13. Interestingly, the transient NK-cell exhaustion was not related to the expression of typical exhaustion markers or insufficient levels of perforin and granzyme. These data may warrant the development of novel metronomic application regimens of AFM13. Further studies imply that immune cells other than NK-cells are able to inhibit growth of CD30+ tumor cells in an AFM13-dependent manner. This appears to be strictly dependent on CD16A and a specific cytokine milieu. Taken together, AFM13 specifically enhances the cytotoxic, proliferative and cytokine-producing potential of NK-cells, parameters that can be utilized to monitor NK-cell responses during AFM13 therapy. Moreover, based on our data, engagement of CD16A+ cells to the tumor site might enable several innate immune effector functions within the tumor microenvironment for synergistic anti-tumor activity.
Citation Format: Jens Pahl, Joachim Koch, Uwe Reusch, Thorsten Gantke, Adelheid Cerwenka, Martin Treder. The tetravalent bispecific antibody AFM13 engages and primes innate immune cells for anti-cancer immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2997. doi:10.1158/1538-7445.AM2017-2997
Abstract 3000: Defining the subclonal landscape of high-risk neuroblastoma
Authors: Harenza Jo Lynne , Diamond Maura A. , Oldridge Derek A. , Padovan-Merher Olivia , Raman Pichai , Mosse Yael P. , Maris John M. 
Published: July 2017

Abstract
We recently showed that relapsed neuroblastoma (NB) tumors harbor an increased somatic mutational burden, enriched for ALK or RAS-MAPK activating lesions, nominating targeted therapeutic strategies for a condition that is largely incurable. We also showed that these mutations can be present in subclonal tumor cell populations at diagnosis, suggesting that they may contribute to acquired chemoradiotherapy resistance. We hypothesize that subclonal mutations in NB oncogenes are common at diagnosis, are biomarkers for treatment failure, and can be targeted in conjunction with standard chemotherapy to improve patient survival. Here, we focus on the first aspect of this broad hypothesis by presenting the subclonal landscape of diagnostic, high-risk neuroblastomas. A meta-analysis of our previously published primary/relapse (N=23), whole exome (N=232) and whole genome (N=159) diagnostic data, and recent sequencing study of 78 diagnostic and 67 relapse cases were used to inform design of a custom amplicon panel for ultra-deep sequencing. The 28-gene panel covers 57 mutations in frequently mutated genes. Here, 250 high-risk primary tumors were sequenced to an average depth of 50,000X. More subclonal mutations were called (mean=36) compared to clonal alterations (mean=3), demonstrating the complex subclonal architecture in these tumors. We validated five clonal ALK mutations we originally discovered and identified 15 additional pathogenic ALK mutations with mutant allele frequencies (MAFs) ranging from 0.03-23%. Known ALK activating mutations were found at codons 1170, 1174, 1196, 1245, 1275 in 15 of 38 diagnostic primary tumors. This 39.5% frequency is much higher than the 14% frequency defined by us using Sanger or other sequencing methods. Improvement of subclonal mutation detection of actionable, relapse-specific driver mutations demonstrates the clinical utility of utilizing this sequencing methodology at diagnosis to enable timely improvement of outcomes for children with high-risk refractory NB.
Citation Format: Jo Lynne Harenza, Maura A. Diamond, Derek A. Oldridge, Olivia Padovan-Merher, Pichai Raman, Yael P. Mosse, John M. Maris. Defining the subclonal landscape of high-risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3000. doi:10.1158/1538-7445.AM2017-3000
Abstract 3015: Selective inhibition of mutant KRAS cell and tumor growth by PHT-7.3, an inhibitor of the KRas signaling nanocluster protein Cnk1
Authors: Delaney Roisin , Maruggi Marco , Indarte Martin , Lemos Robert , Grandjean Geoff , Kirkpatrick Lynn , Powis Garth 
Published: July 2017

Abstract
Activating mutations of KRas is the most common proto-oncogenic event in human cancer but there remains no effective therapy for patients harboring mutated KRas (mut-KRas). Despite intense efforts, tight nucleotide binding, few defined pockets, and redundant localization signals have impeded the development of compounds that bind or inhibit KRas. We have identified connector enhancer of kinase suppressor of Ras 1 (Cnk1) as a critical mediator for growth driven by mut-KRas in human cancer cells. Cnk1 co-localizes with mutant KRas at the membrane and deletion of Cnk1 abrogates KRas activation and the activation of the Ras effectors Ral and Rho. Cnk1 deletion caused cells with mutant KRas to accumulate at the G1 checkpoint similar to selective deletion of mutant KRas itself. Following a screen and initial structural optimization a small molecule probe compound PHT-7.3 was identified and shown to bind selectively to the pleckstrin homology PH domain of Cnk1 preventing Cnk1 and mut-KRas co-localization. PHT-7.3 inhibited mut-KRas but not wt-KRas non small cell lung cancer (nsclc) cell growth, and selectively blocks mut-KRas downstream signaling in cells. PHT-7.3 exhibited cytostatic antitumor activity in the mut-KRas(G12S) A549 and mut-KRas(G12V) H441 nsclc xenografts, but not in the wt-KRas H1975 nsclc xenograft. Mut-KRas downstream signaling was inhibited by PHT-7.3 in the xenografts with downregulation of activated Rho and Ral signaling. PHT-7.3 showed further increased antitumor activity in A549 xenografts in combination with erlotinib or trametinib. Thus, the work identifies the PH domain of Cnk1 as a druggable target whose inhibition selectively blocks mutant-KRas activation, and PHT-7.3 as a lead agent in the development of therapies for KRas tumors.
Citation Format: Roisin Delaney, Marco Maruggi, Martin Indarte, Robert Lemos, Geoff Grandjean, Lynn Kirkpatrick, Garth Powis. Selective inhibition of mutant KRAS cell and tumor growth by PHT-7.3, an inhibitor of the KRas signaling nanocluster protein Cnk1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3015. doi:10.1158/1538-7445.AM2017-3015
Abstract 3020: Novel therapeutic targets in head and neck cancer
Authors: Kondratyev Maria , Pesic Aleksandra , Ketela Troy , Sayad Azin , Marastoni Stephano , Virtanen Carl , Ailles Laurie , Samadian Soroush , Bashkurov Mikhail , Koritzinsky Marianne , Wouters Brad 
Published: July 2017

Abstract
HNSCC is 6th most common malignancy in the world. Despite advances in diagnosis and treatment, the survival rates remain low due to frequent recurrences the biology of which remains unclear. Using functional genomic technologies, we identified new therapeutic targets for metastatic disease in HNSCC. Whole genome shRNA screens were conducted in matched sets of cell lines derived from primary tumors and respective metastatic sites, identifying genes essential for cell survival only following metastasis. To test if knockdown of selected targets inhibits metastasis in a therapeutic setting, we established orthotropic model of HNSCC that metastasize to lymph nodes in the mouse. Components of Notch pathway were identified as essential for survival of cells derived from metastatic sites. Whole exome sequencing identified a novel mutation in one of the EGF domains of Notch3 that was acquired only in the metastatic line. Utilizing CRISPR methodology, we established that “fixing” the mutation results in reversal of metastatic phenotype of the cells, making them Notch independent similar to their primary tumor counterparts. Mutations in EGF domains have been reported to influence interaction with specific ligands, dictating which ligand can activate Notch signaling. Our data indicate that a distinct set of target genes is induced upon interaction between Notch3 and Jag2 ligand. Furthermore, our results indicate that suppression of Notch3 improves survival in mice bearing orthotropic tumors derived from the metastatic HNSCC lines. Overall, our data demonstrate that metastatic cells from head and neck tumors acquire dependency on Notch3 signaling. Novel treatments targeting components of this pathway may prove effective in targeting metastatic cells alone or in combination with conventional therapies.
Citation Format: Maria Kondratyev, Aleksandra Pesic, Troy Ketela, Azin Sayad, Stephano Marastoni, Carl Virtanen, Laurie Ailles, Soroush Samadian, Mikhail Bashkurov, Marianne Koritzinsky, Brad Wouters. Novel therapeutic targets in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3020. doi:10.1158/1538-7445.AM2017-3020
Abstract 3021: CCR5 inhibition: macrophage repolarization therapy for colorectal cancer
Authors: Halama Niels , Zoernig Inka , Berthel Anna , Kahlert Christoph , Klupp Fee , Suarez-Carmona Meggy , Brand Karsten , Krauss Juergen , Lasitschka Felix , Ulrich Alexis , Weitz Juergen , Schneider Martin , Buechler Markus , Zitvogel Laurence , Herrmann Thomas , Benner Axel , Kunz Christina , Luecke Stephan , Springfeld Christoph , Falk Christine S. , Jaeger Dirk 
Published: July 2017

Abstract
In patients with metastatic colorectal cancer (CRC), the local immune response influences the clinical course. An in-depth analysis of the invasive margin of human CRC liver metastases revealed a distinct immunological microenvironment. Within this microenvironment, two distinct subsets of myeloid cells induce an influx of T cells into the invasive margin via CXCL9/CXCL10. CCL5 is produced by these T cells and stimulates pro-tumoral effects via CCR5, creating an exploitive loop. CCR5 was found on macrophages, lymphocytes and on the vast majority of tumor cells. Inhibition of CCR5 in patient-derived functional in vitro organotypic culture models showed a promising macrophage repolarization with anti-tumoral effects. These effects are mediated by activation of an antiviral program in macrophages, leading to interferon and reactive oxygen species production and subsequent selective tumor cell death. These anti-tumoral effects were confirmed in a phase I trial with a CCR5 antagonist in 14 patients with liver metastases of advanced refractory CRC. Treatment with the oral CCR5 Inhibitor was very well tolerated and objective responses were seen, especially in combination with previously ineffective chemotherapy. Biopsies revealed mitigation of tumor-promoting inflammation within the tumor tissue, confirming the validity of the explant model and highlighting the feasbility of this approach. It furthermore shows the proof-of-concept for macrophage repolarization in cancer patients.
Citation Format: Niels Halama, Inka Zoernig, Anna Berthel, Christoph Kahlert, Fee Klupp, Meggy Suarez-Carmona, Karsten Brand, Juergen Krauss, Felix Lasitschka, Alexis Ulrich, Juergen Weitz, Martin Schneider, Markus Buechler, Laurence Zitvogel, Thomas Herrmann, Axel Benner, Christina Kunz, Stephan Luecke, Christoph Springfeld, Christine S. Falk, Dirk Jaeger. CCR5 inhibition: macrophage repolarization therapy for colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3021. doi:10.1158/1538-7445.AM2017-3021