bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B22: Necuparanib inhibits pancreatic cancer progression and invasion in a 3D tumor and stromal cell co-culture system
Authors: MacDonald Amanda , Priess Michelle , Curran Jennifer , Krause Silva 
Published: October 2016

Abstract
Pancreatic cancer is one of the most aggressive types of cancer, with only about 5% of patients surviving 5 years past the initial diagnosis. Despite advances with new chemotherapy combinations, overall survival outcomes are still dismal due to the cancer's complex pathology. Novel multi-targeted agents or therapeutic combinations able to disrupt the aggressive fibrotic microenvironment and restrict tumor proliferation are a current focus in the field. Necuparanib (formerly M402) is a heparan sulfate-like molecule that binds and inhibits multiple heparin-binding growth factors, chemokines, and adhesion molecules in cancer progression and metastasis and as such has been shown to modulate multiple pathways in tumors. In order to further explore how necuparanib affects the tumor and its microenvironment, a 3-dimensional (3D) culture system mimicking pancreatic cancer was developed containing a co-culture of human pancreatic tumor cells and pancreatic stellate cells, the most abundant stromal cell in the pancreas. Morphological and histological assessment of the 3D tumor spheroids demonstrated that necuparanib inhibits a) pancreatic tumor cell growth, b) pancreatic tumor cell invasion, and c) pancreatic stellate cell growth. Necuparanib's activity in these assays was shown to be dose-dependent. Moreover, using a negative control for necuparanib engineered to lack the ability to bind growth factors, we established that necuparanib's activity is growth factor binding dependent. The ability to inhibit both tumor and stromal cells demonstrates that necuparanib is a very promising multi-targeting agent for difficult-to-treat cancers such as desmoplastic pancreatic tumors. These studies aid in our understanding of the key biological targets and pathways responsible for necuparanib's anti-tumor effects and support the current Phase 2 safety and efficacy study being performed in patients with metastatic pancreatic cancer.
Citation Format: Amanda MacDonald, Michelle Priess, Jennifer Curran, Silva Krause. Necuparanib inhibits pancreatic cancer progression and invasion in a 3D tumor and stromal cell co-culture system. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B22.
Abstract B24: Targeting hyaluronan sensitizes breast cancer-associated fibroblasts to lapatinib and overcomes stromal resistance
Authors: Marusyk Andriy , Tabassum Doris , Guerriero Jennifer , Place Andrew , Rozhok Andrii , Letai Antony , Polyak Kornelia 
Published: October 2016

Abstract
Tumors represent abnormal organs comprised not only of neoplastic cells, but also of normal cells and extracellular matrix (ECM). Therefore, clinical progression as well as response to therapies depends not only on properties of neoplastic cells, but also on the interactions between different types of cells within tumors. Cancer-associated fibroblasts (CAFs) are the major non-nenoplastic cell component of tumors and major the producers of ECM. Despite extensive research, mechanisms and consequences of interactions between breast carcinoma cells and CAFs remain insufficiently understood.
Using organotypic 3d co-cultures between breast carcinoma cell lines representing different sub-types of the disease and CAFs, we interrogated changes in gene expression and metabolism that result from the interaction. We found that while contact with fibroblats induces robust changes in expression and metabolism, the majority of changes are subtype and cell line specific. Furthermore, we found that fibroblasts can provide a dramatic protection against dual EGFR/HER2 inhibitor lapatinib. Protective effect requires close contact between the two cell types in context of 3d culture, and is mediated by both reduced accumulation of the drug within carcinoma cells and elevated apoptotic threshold. Using synthetic lethality screens, we have identified several signaling pathways whose inhibition enhances cytotoxic effects of lapatinib. Interrogation of functional relevance of ECM has revealed that the stromal protection can be reversed by targeting hyaluronan, a major ECM component produced by fibroblasts. Rather than simply enhancing cytotoxic activity of lapatinib against carcinoma cells, hyaluronidase treatment sensitized CAFs to lapatinib, thereby removing the protective niche. Our studies shed light on molecular changes induced by the interaction with CAFs and offer novel approaches for overcoming microenvironmental protection by therapeutically targeting CAFs.
Citation Format: Andriy Marusyk, Doris Tabassum, Jennifer Guerriero, Andrew Place, Andrii Rozhok, Antony Letai, Kornelia Polyak. Targeting hyaluronan sensitizes breast cancer-associated fibroblasts to lapatinib and overcomes stromal resistance. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B24.
Abstract B25: Characterization, targeting, and modulation of carbonic anhydrase IX activity for the development of small-molecule inhibitors to treat triple-negative breast cancer
Authors: Mboge Mam Y. , Chen Zhijuan , Mahon Brian P. , Lamas Nicole , Tu Shingkuang , Carta Fabrizio , Superan Claudiu T. , McKenna Robert , Frost Susan C. 
Published: October 2016

Abstract
The microenvironment within a solid tumor is usually heterogeneous with certain regions being acidic and hypoxic. These acidic and hypoxic regions arise from rapidly proliferating cells combined with poor tumor perfusion. Cancer cells cope with these hostile changes in their microenvironment by expressing genes that are essential for survival. One of the coping mechanisms is an upregulation of pH regulatory factors, including carbonic anhydrase IX (CAIX). The action of CAIX helps to maintain physiological pH inside the cell (pHi) while regulating extracellular acidification (pHe). Extracellular acidification of the tumor microenvironment promotes local invasion, metastasis and decreases the effectiveness of adjuvant therapies, thus contributing to poor clinical outcome. Our goal was to compare the structure of a CAIX-mimic bound to ureidosulfonamide inhibitors with the biological activity of these inhibitors in a triple negative breast cancer cell line. CAIX is a reversible enzyme and at low pH (high proton concentration), the enzyme will consume protons, raising pH. Our hypothesis is that CAIX inhibition, in the context of an acidic microenvironment, will dysregulate its ability to maintain the acidic pH preferred by cancer cells which favors their growth and migration. In this study, we have shown the interaction of sulfonamide-based inhibitors using X-ray crystallography methods. These structures show the inhibitors make multiple contacts within the active site cavity. This is consistent with the inhibitor-induced decrease in CAIX activity measured as 18O exchange between H2O16 and H13C18O3 . We have also investigated the effect CAIX inhibition on cancer cell metabolism and extracellular acidification using Seahorse technology. This reveals that CAIX may contribute to the “non-glycolytic” acidification process. In total, these observations indicate that CAIX is a viable small molecular drug target and contribute to our understanding of the function of CAIX in modulating pH in cancer cells.
Citation Format: Mam Y. Mboge, Zhijuan Chen, Brian P. Mahon, Nicole Lamas, Shingkuang Tu, Fabrizio Carta, Claudiu T. Superan, Robert McKenna, Susan C. Frost. Characterization, targeting, and modulation of carbonic anhydrase IX activity for the development of small-molecule inhibitors to treat triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B25.
Abstract B27: Blockade of protein kinase A (PKA) localization augments the trafficking and anti-tumor efficacy of adoptively transferred chimeric antigen receptor-expressing T cells
Authors: Newick Kheng , O'Brien Shaun , Sun Jing , Kapoor Veena , Maceyko Steve , Lo Albert , Pure Ellen , Moon Ed K. , Albelda Steven M. 
Published: October 2016

Abstract
Infusion of T cells expressing chimeric antigen receptors (CAR T cells) is still relatively ineffective in solid tumors due to the presence of immunosuppressive mediators (such as prostaglandin E2 (PGE2) and adenosine), and poor T cell trafficking. Since PGE2 and adenosine activate protein kinase A (PKA), which then inhibits T cell receptor (TCR) activation, we generated CAR T cells that expressed a small peptide called the “regulatory subunit I anchoring disruptor” (RIAD) that inhibits the association of protein kinase A (PKA) with ezrin; this interaction is required for the negative effects of PKA on TCR activation. After exposure to PGE2 or adenosine in vitro, CAR-RIAD T cells showed increased TCR signaling, more cytokine release, and enhanced killing of tumor cells compared to CAR T cells. When injected into tumor-bearing mice, murine and human CAR-RIAD T cells demonstrated enhanced anti-tumor efficacy compared to CAR T cells due to increased T cell infiltration of established tumors, and attenuated tumor-induced hypofunction. Subsequent in vitro assays showed that both mouse and human CAR-RIAD cells migrated more efficiently than CAR cells in response to the chemokine CXCL10 and also adhered better to various matrices. Our data therefore show that the addition of the RIAD peptide to adoptively transferred CAR T cells augments their efficacy by increasing their effector function and by improving trafficking into tumor sites. This treatment strategy should therefore be considered for clinical application in treating solid tumors.
Citation Format: Kheng Newick, Shaun O'Brien, Jing Sun, Veena Kapoor, Steve Maceyko, Albert Lo, Ellen Pure, Ed K. Moon, Steven M. Albelda. Blockade of protein kinase A (PKA) localization augments the trafficking and anti-tumor efficacy of adoptively transferred chimeric antigen receptor-expressing T cells. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B27.
Abstract B34: Targeting M2-tumor associated macrophages (M2-TAMs) in prostate cancer
Authors: Zarif Jelani C. , Hernandez James R. , Pienta Kenneth J. 
Published: October 2016

Abstract
Prostate cancer is a leading cause of cancer-related deaths of men in the U.S., and in the past year, over 30,000 men died from this disease. While localized prostate cancer is highly treatable by surgical resection and radiation, cancer that has metastasized remains incurable. Alternatively activated macrophages, also known as M2-macrophages, primarily scavenge debris and in the process, promote angiogenesis and wound repair. M2-macrophages are phenotypically similar to M2 tumor-associated macrophages (M2-TAMs) have been reported to associate with solid tumors such as prostate cancer to facilitate epithelial to mesenchymal transition (EMT), tumor invasiveness, metastasis, and resistance to therapy. As an invasive species within the tumor microenvironment, this makes M2-TAMs an ideal therapeutic target in prostate cancer. The purpose of this project is to develop novel therapeutics that will directly target M2-TAMs for destruction and subsequently attenuate prostate tumor growth, progression and metastasis. The central hypothesis of this study is to determine if targeting of M2-TAMs using specific surface antigens will be an effective therapy for lethal prostate cancer and potentially, other cancers. Our study elucidated M2-Macrophage biology including creating homogenous populations of both M1 and M2 macrophages using a new strategy as to allow for identification of novel surface antigen markers. We then assessed novel markers of macrophage populations and assessed whether these surface antigens that are expressed on M2-macrophages are also expressed in human prostate cancers indicative of myeloid infiltration. Validation studies using metastatic prostate cancer tissues from rapid autopsies and surgical specimens supplied by the Department of Urology at Johns Hopkins University School of Medicine were also be performed. Complementary studies will be executed to target these markers for anti-tumor cell efficacy using these relevant model systems. By identifying and targeting specific markers on M2-TAMs, we predict that this targeting will provide a better prognosis for patients who have been diagnosed with lethal prostate cancer.
Citation Format: Jelani C. Zarif, James R. Hernandez, Kenneth J. Pienta. Targeting M2-tumor associated macrophages (M2-TAMs) in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B34.
Abstract B39: Identifying molecular signatures of tumor dormancy as a basis for the rational design of precision nanomedicines
Authors: Tiram Galia , Ferber Shiran , Satchi-Fainaro Ronit 
Published: October 2016

Abstract
Tumor progression is dependent on a number of sequential steps, including initial tumor-vascular interactions and recruitment of blood vessels (i.e., the “angiogenic switch”), as well as an established interaction of tumor cells with their surrounding microenvironment and its different immune, endothelial and connective cellular and extra-cellular components. Failure of a microscopic tumor, either primary, recurrent or metastatic, to complete one or more of these early stages may lead to delayed clinical manifestation of the cancer (i.e., tumor dormancy). Micrometastasis, dormant tumors, and residual tumor cells - referred to as minimal residual disease, contribute to the occurrence of relapse, and constitute fundamental clinical manifestations of tumor dormancy that together are responsible for the vast majority of cancer deaths. However, although the tumor dormancy phenomenon has critical implications for early detection and treatment of cancer, it is one of the most neglected areas in cancer research and the associated biological mechanisms are still mostly unknown.
We have created several models of patient-derived xenografts mimicking pairs of dormant vs fast-growing, primary vs metastatic and drug-sensitive vs resistant cancers. We investigated the molecular and cellular changes in tumor-host interactions that govern tumor progression. Those led to the discovery of novel targets and provided important tools for cancer theranostics (therapy and diagnostics). Based on the acquired knowledge, we designed a new strategy to improve treatment outcomes of patients with bone neoplasms, glioblastoma, brain metastases, melanoma, breast and prostate cancers. We have identified molecular signatures which following their selective delivery into target cells, can potentially induce a dormant-like phenotype. This goal was achieved by utilizing polymeric nanomedicines and guidance by high resolution, intravital non-invasive imaging techniques.
A better understanding of tumor dormancy and the availability of relevant markers will most likely change the way we diagnose and treat the disease using novel combined theranostic nanomedicines.
Citation Format: Galia Tiram, Shiran Ferber, Ronit Satchi-Fainaro. Identifying molecular signatures of tumor dormancy as a basis for the rational design of precision nanomedicines. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B39.
Abstract C11: The role of immune cells and androgen receptor splice variant 567 exon-skipping in prostate cancer
Authors: Hara Jared HL , Plymate Stephen R. , Sprenger Cynthia T. 
Published: October 2016

Abstract
Importance: Nearly all metastatic prostate cancer treated with first-line androgen deprivation therapies (ADT) will progress to castrate resistant prostate cancer (CRPC). Current ADT treatments and use are associated with upregulation of constitutively active androgen receptor splice variants. Androgen receptor splice variant 567 exon-skipping (ARv567es) is correlated with a marked decrease in 5-year survival in spite of ADT treatment. In our ARv567es mouse models, we have observed a high immune cell infiltrate in places common for mouse prostate cancer metastases such as the lung. Thus, there is an increased need to understand the role of the immune system and ARv567es in prostate cancer metastasis and resistance.
Objective: To understand the role of immune cells in metastasis of prostate cancer expressing splice variants.
Design: M12 human prostate cancer cells transfected with a plasmid containing ARv567es cDNA were grown in vitro and exposed to Bone Marrow Macrophages (BMM) isolated from C57BL/6 mice femurs. BMM were differentiated into M0, M1, and M2 macrophages. M1 macrophages are thought to attack tumor cells while M2 macrophages promote their growth. The following experiments were performed: proliferation studies (MTS assays), migration studies (scratch assays), and invasion studies (Boyden chambers).
Results: Proliferation was significantly higher when M12 ARv567es cells were exposed to M2 conditioned medium as compared to M1 conditioned medium. Scratch assays revealed a significantly increased migration of M12 cells co-cultured with M0 and M2 conditioned medium. Boyden chamber studies demonstrated an increase in migration when M12 cells were exposed to M2 cells.
Conclusions and relevance: We demonstrate in vitro evidence to support the current hypothesis of the role of the immune system in prostate cancer metastasis. Overall, our results demonstrate that immune cells, including M2 macrophages, may create a tumor microenvironment that promotes prostate cancer metastasis.
Citation Format: Jared HL Hara, Stephen R. Plymate, Cynthia T. Sprenger. The role of immune cells and androgen receptor splice variant 567 exon-skipping in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C11.
Abstract C14: Foxf1 transcription factor reprograms pulmonary endothelial cells to promote metastasis
Authors: Cai Yuqi , Le Tien , Malewski David , Bolte Craig , Goda Chinmayee , Kalin Tanya V. 
Published: October 2016

Abstract
The ability to form a metastatic niche is a unique feature of tumor cells. The niche provides signals for tumor cells extravasation, survival, dormancy or proliferation, ultimately leading to the formation of metastasis. Endothelial cells of metastatic niche become activated and play a key role in tumor cells extravasation and establishing inflammatory microenvironment that supports metastatic outgrowth. Although multiple signaling pathways have been implicated in formation of metastatic niche, the transcriptional network which controls reprogramming of normal endothelial cells (EC) into activated endothelial cells of the metastatic niche (aEC) are poorly understood. Screening for multiple regulators of the endothelial reprogramming, we identified Forkhead Box F1 (Foxf1) transcription factor, which is highly expressed in normal pulmonary ECs and is down-regulated in aECs within mouse and human lung metastases. Tamoxifen-regulated inactivation of both Foxf1 alleles in EC of adult Pdgfb-CreER/Foxf1fl/fl mice caused lung inflammation and edema, leading to respiratory insufficiency and uniform mortality. Deletion of a single Foxf1 allele from mouse ECs was sufficient to increase the number and size of pulmonary metastases in the spontaneous orthotopic mouse model of breast cancer. Increased lung metastasis in Foxf1-deficient mice was associated with increased recruitment of macrophages to the metastatic niche. The genomic signature of Foxf1 deletion from purified lung ECs indicated increased expression of cell adhesion molecules and pro-inflammatory chemokines, as well as reduced expression of genes critical for maintenance of adherence junctions in ECs. Foxf1 knockdown in vitro and in vivo disrupted adherence junctions, increased endothelial permeability and decreased mRNA and protein levels of VE-cadherin, a key regulator of endothelial barrier function. Foxf1 directly bound to and induced transcriptional activity of the VE-cadherin (Cdh5) promoter through -788/-775 bp Cdh5 promoter region. Altogether, Foxf1 transcription factor controls reprogramming of normal pulmonary ECs into aECs of the metastatic niche by regulating expression of endothelial genes critical for recruitment of macrophages and extravasation of tumor cells through endothelial barrier.
Citation Format: Yuqi Cai, Tien Le, David Malewski, Craig Bolte, Chinmayee Goda, Tanya V. Kalin. Foxf1 transcription factor reprograms pulmonary endothelial cells to promote metastasis. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C14.