bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1992: Mesenchymal stem cell-derived interleukin-28 can drive the selection of apoptosis resistant bone metastatic prostate cancer
Authors: Mcguire Jeremy J. , Cook Leah , Frieling Jeremy , Muhammad Ayaz , Lawrence Harshani , Lawrence Nicholas , Lynch Conor 
Published: August 2019

Abstract
Bone metastatic prostate cancer is painful and incurable. We believe that understanding the interactions of tumor cells and the surrounding stromal cells may provide new therapeutic options. Bone metastatic prostate cancer promotes mesenchymal stem cell (MSC) recruitment and differentiation into osteoblasts, leading to the clinically often-observed osteogenic phenotype. However, the reciprocal roles of bone- marrow derived MSCs on prostate cancer cells are less explored. Here, we discovered that MSCs significantly suppress prostate cancer growth in vitro and in vivo. Mechanistically, we show that MSC-derived interleukin-28 (IL-28) promotes prostate cancer cell apoptosis via the IL-28 receptor alpha (IL-28Rα). However, chronic exposure to MSCs yields prostate cancer cell populations that are resistant to IL-28 induced apoptosis and therapeutics such as docetaxel. In vivo, we observed that MSC selected prostate cancer cells rather than being suppressed, grow at a significantly enhanced rate in bone. The increase in apoptosis resistance is accompanied by a shift in downstream signaling of the IL-28Rα from STAT1 to STAT3. Reduction of STAT3 levels or pharmacological inhibition (STI-201) significantly reduces the growth of MSC selected prostate cancer cells in vitro and in vivo. Collectively, these data shed light on how MSCs in the bone marrow microenvironment initially protect against prostate cancer cell establishment but in doing so, help select for aggressive, apoptosis resistant bone metastatic prostate cancer cells that are more aggressive. Given that the majority of prostate to bone metastases are positive for STAT3 expression and activity, our data provide rationale for the therapeutic targeting of STAT3 in bone metastatic prostate cancer.
Citation Format: Jeremy J. Mcguire, Leah Cook, Jeremy Frieling, Ayaz Muhammad, Harshani Lawrence, Nicholas Lawrence, Conor Lynch. Mesenchymal stem cell-derived interleukin-28 can drive the selection of apoptosis resistant bone metastatic prostate 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 1992.
Abstract 1999: As4O6 suppresses triple-negative breast cancer via inhibiting EGFR/mTOR mediated EMT in vitro and in vivo
Authors: Bae Illju , Lian Zenglin , Liu Ziyao , Wu Zhaoyan 
Published: August 2019

Abstract
Objective:The present study aimed to verify the anti-metastasis effects and its mechanisms of As4O6 on triple-negative breast cancer(TNBC)in vitro and in vivo.
Methods:MTT assay was used to evaluate cell proliferation. Wound healing assay and the invasion assay were carried out to investigate cell migration and invasion. The xenograft zebrafish model and orthotopic xenograft nude mouse model derived from MDA-MB-231-Green fluorescent protein (GFP) cells was established to analysis the anti-metastasis effect of As4O6in vivo. Western blot and immunohistochemistry were performed to analysis the metastasis-related proteins expression.
Result: MTT assay showed cell proliferation of TNBC cell MDA-MB-231 was inhibited in a dose-dependent manner by As4O6 treatment. Also, As4O6 suppressed cell migration and invasion by a Wound healing assay and the invasion assay, resulted in the reduction of MMP-2 and MMP-9 expression, especially for the inhibition of EGFR and mTOR phosphorylation. Meanwhile, As4O6 suppressed cancer metastasis in xenograft zebrafish model. The number of metastatic lesion in mouse lung was significantly reduced by the treatment of As4O6 in the orthotopic xenograft nude mouse model. The expression of p-mTOR, p-EGFR and EMT-related proteins such as Vimentin and E-cadherin were significantly reversed in As4O6 treated mouse lung tissues than that of non-treatment group. Furthermore, As4O6 treatment suppressed the expression of angiogenesis related proteins VEGF-a, VEGFR, CD34 and MMP2/9 in mouse lung tissues.
Conclusion:Thus, the data suggests that As4O6suppresses triple-negative breast cancer metastasis via inhibiting EGFR/mTOR mediated EMT in vitro and in vivo. As4O6 might be served as a potential useful agent for TNBC metastasis in the future.
Citation Format: Illju Bae, Zenglin Lian, Ziyao Liu, Zhaoyan Wu. As4O6 suppresses triple-negative breast cancer via inhibiting EGFR/mTOR mediated EMT in vitro and in vivo [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 1999.
Abstract 20: Pharmacology and metabolism of GLL398, an oral selective estrogen receptor degrader for endocrine therapy of breast cancer
Authors: Guo Shanchun , Zhang Changde , Mottamal Madhu , Hossain Ahamed , Liu Jiawang , Liu Jiawang , Wang Guangdi 
Published: August 2019

Abstract
Selective estrogen receptor degrader (SERD) has proven clinically effective in treating advanced or metastatic breast cancer since the approval of fulvestrant by FDA in 2002. Recent expansion of indications as a first line monotherapy and as combination therapy with CDK4/6 inhibitors further demonstrates its clinical utility as an efficacious breast cancer endocrine regimen. However, the poor pharmacokinetic properties of fulvestrant and its injection-only administration route has driven continued efforts to develop orally bioavailability SERD that could potentially improve clinical response to SERD treatment. GLL398, a boron-modified GW5638 analog, showed superior oral bioavailability while retaining both antiestrogenic activity and ER degrading efficacy at a potency level comparable to the more active metabolite of GW5638, GW7604. Here we report further studies on the pharmacology, pharmacokinetics, and metabolism of GLL398. Consistent with GLL398’s robust activities in breast cancer cells that are tamoxifen resistant or express constitutively active, mutant ESR1 (Y537S), it was found to bind the mutant ERY537S at a high affinity. Molecular modeling of the binding mode of GLL398 to ER also found its molecular interactions consistent with the experimentally determined high binding affinity towards WT ER and ERY537S. To test if the superior oral bioavailability can be translated to potent efficacy in vivo, mice bearing MCF-7 derived xenograft breast tumors and patient derived xenograft (PDX) tumors harboring ERY537S were treated with GLL398 which potently inhibited tumor growth in mice. Finally the metabolism of GLL398 was also investigated to elucidate the biotransformation of the drug and its potential contribution to the superior oral bioavailability over GW7604.
Citation Format: Shanchun Guo, Changde Zhang, Madhu Mottamal, Ahamed Hossain, Jiawang Liu, Jiawang Liu, Guangdi Wang. Pharmacology and metabolism of GLL398, an oral selective estrogen receptor degrader for endocrine therapy of 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 20.
Abstract 2002: Computational drug repositioning identifies bortezomib as a novel metastatic inhibitor of lung cancer
Authors: Kwon Ok-Seon , Lee Haeseung , Kim Wankyu , Cha Hyuk-Jin 
Published: August 2019

Abstract
Although many molecular targets for cancer therapy have been discovered, they often show poor druggability, which is a major obstacle to develop targeted drugs. As an alternative route to drug discovery, we adopted an in silicodrug repositioning (in silicoDR) approach based on large-scale gene expression signatures, with the goal of identifying inhibitors of lung cancer metastasis. Our analysis of clinicogenomic data identified GALNT14, an enzyme involved in O-linked N-acetyl galactosamine glycosylation, as a putative driver of lung cancer metastasis leading to poor survival. To overcome the poor druggability of GALNT14, we leveraged Connectivity Map approach, an in silicoscreening for drugs that are likely to revert the metastatic expression patterns. It leads to identification of bortezomib (BTZ) as a potent metastatic inhibitor, bypassing direct inhibition of poorly druggable target, GALNT14. The anti-metastatic effect of BTZ was verified in vitroand in vivo. Notably, both BTZ treatment and GALNT14knockdown attenuated TGFβ-mediated gene expression and suppressed TGFβ-dependent metastatic genes, suggesting that BTZ acts by modulating TGFβsignaling. Taken together, these results demonstrate that our in silicoDR approach is a viable strategy to identify a candidate drug for undruggable targets, and to uncover its underlying mechanisms.
Citation Format: Ok-Seon Kwon, Haeseung Lee, Wankyu Kim, Hyuk-Jin Cha. Computational drug repositioning identifies bortezomib as a novel metastatic inhibitor of lung 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 2002.
Abstract 2007: Validation of a preclinical model for bone metastatic triple negative breast cancer
Authors: Zdrojewska Justyna , Suominen Mari I. , Fagerlund Katja M. , Halleen Jussi M. , Bernoulli Jenni , Zimmermann Johann 
Published: August 2019

Abstract
Metastatic breast cancer (MBC) is the most advanced stage of breast cancer, diagnosed as stage IV. Typically, MBC metastases occur in the bones, liver, brain, and lungs. Bone metastases cause significant morbidity and mortality in late-stage breast cancer patients. At present, there is no efficient curative or preventive treatment for bone metastases. Therefore, establishment and validation of well characterized in vivo models of breast cancer bone metastasis is of utmost importance. The aim of this study was to validate an intracardiac model of bone MBC utilizing GFP tagged triple negative (estrogen receptor; ER, progesterone receptor; PR and human epidermal growth factor receptor 2; HER2 negative) human breast cancer cells, which could be used to study efficacy of new potential treatments. Female athymic nude mice (Hsd: Athymic Nude-Foxn1nu) were used in this study. Bone seeking MDA-MB-231(SA)-GFP human breast cancer cells were inoculated into the left cardiac ventricle of 4-6 weeks old female mice. Allocation to treatment groups (n=15) was performed by stratification procedure based on animal weight prior to the beginning of the study. To validate the model, the current standard-of-care (SOC) treatment (Paclitaxel) was administered between study days 13-17 at the therapeutic dose. Serum bone biomarker TRACP5b was measured before cancer cell inoculation and at sacrifice. Planar X-ray of hind limbs and ex vivo fluorescence imaging of the whole body were performed at sacrifice. The observed tumor take rate was 100%. 33% of mice in the vehicle group were cachectic, but mice treated with SOC exhibited only mild and temporary weight loss. Tumors were observed mainly in skeletal sites but also in soft tissues. The SOC treatment decreased both total and skeletal tumor burden. Based on X-ray images, tumor induced osteolytic bone lesions were smaller in the SOC treated group compared to vehicle though no differences were observed in total bone lesion area. Serum TRACP5b was increased in the vehicle group as a result of osteolytic lesions, and decreased with the SOC treatment. In conclusion, an intracardiac model of MBC was successfully validated with the SOC treatment paclitaxel that efficiently inhibited disease progression. Therefore, this intracardiac model provides a promising tool for testing new treatments against bone and soft tissue MBC in vivo.
Citation Format: Justyna Zdrojewska, Mari I. Suominen, Katja M. Fagerlund, Jussi M. Halleen, Jenni Bernoulli, Johann Zimmermann. Validation of a preclinical model for bone metastatic 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 2007.
Abstract 2010: SKI-G-801, an AXL kinase inhibitor, blocks metastasis and induces anti-tumor immune responses in various syngeneic cancer models
Authors: Xin Chun-Feng , Kim Sung Eun , Pyo Kyoung-Ho , Jo Ha Ni , Cho Jae Seok , Kim Jae Hwan , Lee Wongeun , Lee Hee Kyu , Kim Jung-Ho , Song Ho-Juhn , Koh Jong Sung , Cho Byoung Chul 
Published: August 2019

Abstract
Introduction: Aberrant AXL expression plays a critical role in cancer cell migration, metastasis and drug resistance. Researchers have revealed that AXL signaling is also over expressed on cells associated with tumor microenvironment. These findings highlight AXL as an attractive drug candidate for targeting tumor evasion and metastasis. Here we present SKI-G-801, a small molecule inhibitor that targets phosphorylation of AXL (IC50 = 20 nM) and its downstream signals.
Methods: Inhibitory effects of SKI-G-801 on cancer viability (MTT and colony formation assay), invasion and migration (trans-well invasion assay) were examined in AXL high-expressing lung cancer cells in vitro. LLC2 lung and 4T1 breast cancer bearing mouse models were established. in addition, C57BL/6 mice were injected intravenously with B16F10 melanoma cells to establish lung metastasis model. Mice were administrated with 30 mg/kg of SKI-G-801 orally before (metastasis model) or after (syngeneic model) tumor injection. To elucidate the involvement of AXL inhibitor on tumor microenvironment, the population of T cells and myeloid cells was analyzed by flow cytometry from the LLC2 tumor.
Results: Treatment of SKI-G-801 showed strong inhibition of cancer migration and invasion, when its direct killing effect on cancer cells was modest. These results were reproduced in vivo test that pretreatment of SKI-G-801 significantly reduced metastatic burden in B16F10 model (p &lt; 0.05). LLC2 and 4T1 tumors were decreased in SKI-G-801 treatment group (p &lt; 0.05), but not in anthemic nude mice. CD3+CD8+ T cell population and memory Tc cells were increased in SKI- G-801 treatment group (p &lt; 0.05). Especially, granzyme B+ Tc and gp70+ tumor specific Tc were increased (p &lt; 0.05). SKI-G-801 increase the helper T cell population; CD3+CD4+ (p &lt; 0.05), and CD44+ memory Th cells (p &lt; 0.01).
Conclusion: SKI-G-801 demonstrates great potential in anti-cancer activity though immune responses. The anti-cancer effects lead to a reversal of the metastatic phenotype in animal model. Our results suggest that SKI-G-801 is a promising drug for prevention against metastatic cancer.
Citation Format: Chun-Feng Xin, Sung Eun Kim, Kyoung-Ho Pyo, Ha Ni Jo, Jae Seok Cho, Jae Hwan Kim, Wongeun Lee, Hee Kyu Lee, Jung-Ho Kim, Ho-Juhn Song, Jong Sung Koh, Byoung Chul Cho. SKI-G-801, an AXL kinase inhibitor, blocks metastasis and induces anti-tumor immune responses in various syngeneic cancer models [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 2010.
Abstract 202: STAT1 regulates B7H3 mediated angiogenesis in medulloblastoma
Authors: Purvis Ian J. , Avilala Janardhan , Guda Maheedhara R. , Venkataraman Sujatha , Vibhakar Rajeev , Tsung Andrew J. , Velpula Kiran K. , Asuthkar Swapna 
Published: August 2019

Abstract
B7-H3 (CD276), an immune checkpoint member of the B7/CD28 family, plays a key role in the repression of the immune response by cancer cells. B7-H3 is overexpressed on tumor and tumor-associated cells, making it an interesting therapeutic target. B7-H3 also appears to play a role outside of immune evasion, contributing to the progression of cancer via invasion/migration, angiogenesis, and metastasis. Our previous data has confirmed the presence of B7-H3 in highly aggressive Myc+ medulloblastoma (MB) tumors. Data-mining studies revealed that B7-H3 is correlated with Myc expression in Group 3 and 4 MBs, and is associated with worse patient outcomes. miR-29, a tumor suppressor, has been shown downregulating the expression of B7-H3 in various cancers. We have shown that miR-29 can reduce the angiogenesis abilities of D283 and D425 cells by downregulating B7-H3 in vitro. Subsequent RNA-sequencing analysis of miR-29-transfected D283 cells revealed upregulation of STAT1 activity. Immunoblot analysis and real-time PCR of D283 and D425 cells demonstrated increased expression of p-STAT1, when transfected with miR-29 plasmid. Treatment with all-trans retinoic acid induced p-STAT1 expression, with a concomitant decrease in the expression of B7-H3 and MMP-9. This preliminary data revealed a novel role for STAT1 in potentially regulating B7-H3, and consequently, angiogenesis and metastasis in MB. To date, the role of STAT1 in MB progression has not been fully investigated, and so our results provide a new avenue for developing potential treatments for aggressive MB tumors.
Citation Format: Ian J. Purvis, Janardhan Avilala, Maheedhara R. Guda, Sujatha Venkataraman, Rajeev Vibhakar, Andrew J. Tsung, Kiran K. Velpula, Swapna Asuthkar. STAT1 regulates B7H3 mediated angiogenesis in medulloblastoma [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 202.
Abstract 2024: Obesity induces breast cancer cell invasion through stromal secretion of IGF-1
Authors: Hillers Lauren , D'Amato Joseph , Chamberlin Tamara , Paderta Gretchen , Arendt Lisa 
Published: August 2019

Abstract
Obese women diagnosed with breast cancer have an increased risk for metastasis, and the underlying mechanisms are not well established. Within the mammary gland, adipose stromal cells (ASCs) are a group of heterogeneous cells with the capacity to differentiate along multiple mesenchymal lineages. ASCs are recruited and activated within tumors, but it is unknown how obesity may influence ASCs in both normal and cancerous tissue. To study the effects of obesity on ASCs, we isolated the stromal vascular fraction from the mammary glands of mice fed either a control diet (CD) or high fat diet (HFD) to induce obesity and plated the cells to select for adherent growth. We observed that obesity increased ASCs proliferation, decreased differentiation potential, and upregulated expression of α-smooth muscle actin, a marker of activated fibroblasts, compared to ASCs from lean mice. To determine how ASCs from obese mice impacted tumor growth, we mixed ASCs isolated from CD- or HFD-fed mice with mammary tumor cells, Met-1 cells, and transplanted them into the mammary glands of lean FVB female mice. Tumors cells mixed with ASCs from obese mice grew significantly larger tumors and had increased invasion into surrounding adipose tissue than tumor cells mixed with control ASCs. To study the effects of factors secreted by ASCs on tumor cell behavior, we collected conditioned media (CM) from lean and obese ASCs and treated Met-1 cells. Compared with lean ASCs, obese ASCs expressed higher levels of insulin-like growth factor-1 (IGF-1), which has been implicated in tumor cell invasion. Met-1 cells treated with recombinant IGF-1 were more invasive than vehicle-treated cells. In addition, Met-1 cells treated with obese ASCs CM supplemented with an IGF-1 neutralizing antibody had significantly reduced invasion, compared to controls. Weight loss induced in obese mice significantly decreased expression of IGF-1 from ASCs and reduced the ability of the ASCs to induce an invasive phenotype. Together, these results suggest that obesity enhances local invasion of breast cancer cells through increased expression of IGF-1 by mammary ASCs, and weight loss may reverse this tumor-promoting phenotype.
Citation Format: Lauren Hillers, Joseph D'Amato, Tamara Chamberlin, Gretchen Paderta, Lisa Arendt. Obesity induces breast cancer cell invasion through stromal secretion of IGF-1 [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 2024.
Abstract 2027: Understanding the role and regulation of newly synthesized Annexin A2 in the progression of breast cancer
Authors: Mahdi Amira F. , Malacrida Beatrice , Nolan Joanne , McGourty Kieran , Lowery Aoife J. , Kiely Patrick A. 
Published: August 2019

Abstract
In Ireland, almost three thousand women are diagnosed with invasive breast cancer every year. This makes it the most common form of malignant tumour found in Irish females and accounts for 17% of all female cancer deaths. Although treatment for breast cancer when diagnosed early is highly effective, for those who develop late stage and metastatic breast cancer, survival rates decline rapidly. As a result, a large effort is being made to understand the mechanisms involved in the progression of breast cancer and identifying the changes that take place during the in-situ to metastatic transition.
Using 2-D and 3-D in vitro models of cancer metastasis, we conducted a mass spectrometry screen to identify proteins that are newly synthesised by breast cancer cells as they migrate towards a growth factor gradient. From this screen, we identified Annexin A2 as a newly synthesised protein. Annexin A2 is a calcium-ion regulated, phospholipid-binding protein, which is involved in cell trafficking, cell-to- cell contact, cell motility and regulation of the cytoskeletal structure. Annexin A2 has been reported to be overexpressed in a range of cancers including breast cancer and has also been reported to contribute to cancer-associated processes such as proliferation, migration and chemoresistance.
While investigating the role of Annexin A2 in the progression of breast cancer, our findings suggest that through modulation of the cell culture environment, subjecting cells to stress conditions and altering growth factor supplementation, that the intracellular expression of Annexin A2 remains relatively constant. However, in breast cancer patients we see dysregulation of Annexin A2 expression at a gene level, which correlates with disease progression. We are currently investigating how alterations in the composition of the extracellular environment, particularly the extracellular matrix, regulates Annexin A2 expression and cellular location.
We believe that delineating the function of newly synthesised proteins such as Annexin A2 has the potential to direct novel anti-cancer therapies aimed specifically at halting the progression of breast cancer. Ultimately, these insights may lead to improvements in survival rates for those affected with this disease.
Citation Format: Amira F. Mahdi, Beatrice Malacrida, Joanne Nolan, Kieran McGourty, Aoife J. Lowery, Patrick A. Kiely. Understanding the role and regulation of newly synthesized Annexin A2 in the progression of 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 2027.