bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2816: SB1703 has therapeutic effect on syngeneic mouse model as an immune modulator in TME
Authors: Kim Hyo Young , Kim Hee-Jung , Jung Jae Hoon , Jo So Young , Kim Ju Hee , Cho Wansang , Kim Mingi , Yim Junhyeong , Park Seung Bum 
Published: August 2019

Abstract
Although stage I melanoma is highly curable, the prognosis of late stage melanoma is poor and treatment options are limited to immune checkpoint modulators (ICMs). In this study, we synthesized a novel small molecule, SB1703, and identified high-mobility group box (HMGB) proteins as the direct binding target proteins. SB1703 inhibited melanoma growth in B16F10 syngeneic mouse model. To elucidate the tumor growth inhibitory mechanism, we determined the changes in myeloid-derived suppressor cell (MDSC) number during drug treatment. MDSCs expand in disease states such as cancer and have immune suppressive functions. Serum HMGB1 and interleukin (IL)-6 levels were increased in vehicle administered mice and decreased in SB1703 administered mice. We examined the possibility of combinatorial treatment with SB1703 and ICMs. SB1703 showed synergistic effect with ICMs. In conclusion, SB1703 exhibited therapeutic effects against melanoma in both single and combination treatments with ICMs, which might be due to modulation of myeloid cells such as MDSCs
Citation Format: Hyo Young Kim, Hee-Jung Kim, Jae Hoon Jung, So Young Jo, Ju Hee Kim, Wansang Cho, Mingi Kim, Junhyeong Yim, Seung Bum Park. SB1703 has therapeutic effect on syngeneic mouse model as an immune modulator in TME [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 2816.
Abstract 2827: Identification of chemotherapeutic resistant microbiota profile in colorectal cancer
Authors: Rao Shuyun , King Charles Hadley , Mazumder Raja , Gu Shoujun , Amdur Richard , Mishra Bibhuti , Mishra Lopa 
Published: August 2019

Abstract
Background: Emerging data shows a rise in CRC incidence in men and women under 55 years of age, with a potential new risk factors including alterations in the microbiome. While recent advances have significantly reduced CRC morbidity and mortality, such as screening and new therapeutic strategies, how the microbiome modulates CRC chemotherapy response remains understudied. This alarming trend presents an urgent need for further understanding of the molecular mechanisms and “signatures” of the gut microbiome in CRC patients. Key driving pathways in CRC include WNT, RAS, RAF, APC and TGF-β signaling. Modulating the gut immune response includes multiple mechanisms, including sensors through carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) that serve as receptors to microbes, and crosstalk with signaling pathways such as TGF-β signaling pathway. Interestingly, disruption of TGF-β leads to increased sensitivity to cisplatin and other DNA cross-linking agents.
Hypothesis and Aims: Our hypothesis is that the gut microbiome plays a key role in modulating the TGF-β pathway by CEACAMs binding to specific microbial species, thereby impeding the TGF-β pathway and altering chemotherapy response. Our aims are to explore TCGA genomics, and functional interactions between gut microbiota, CEACAMs, and TGF-β signaling in processing chemotherapy response.
Methods and Results: We first analyzed microbiome signatures in normal and CRC patients, and identified a signature pattern. TCGA analyses in 9,125 human cancers reveal alterations of TGF-β with CEACAM members in over 40% of CRC and correlate with a cancer stem cell signature. Mechanistic studies reveal that CEACAMs inhibit TGF-β tumor suppressor signaling by blocking TGFBR1, and promoting invasive CRC. Likewise, our TGF-β signaling-deficient mouse models spontaneously develop CRC, as well as metastases, likely modulated in part by the microbiome. Furthermore, key defects in the TGF-β pathway alter sensitivity to 5-FU and DNA cross-linking agents, such as cisplatin, through disruption of DNA repair pathways.
Conclusion: The TGF-β pathway is important in maintaining colon epithelial cell homeostasis potentially through interactions with CEACAMs and gut microbiota. When the pathway is disrupted, epithelial cells are more susceptible to transformation and invasion, potentially identifying specific populations that are more sensitive to chemotherapy such as cisplatin and 5FU.
Citation Format: Shuyun Rao, Charles Hadley King, Raja Mazumder, Shoujun Gu, Richard Amdur, Bibhuti Mishra, Lopa Mishra. Identification of chemotherapeutic resistant microbiota profile in colorectal 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 2827.
Abstract 2829: Pancreatic tumor microbiome and associated immune responses determine clinical outcomes
Authors: Riquelme Erick M. , Zhang Yu , Zhang Liangliang , Maria Montiel , Michelle Zoltan , Dong Wenli , Quesada Pompeyo , Sahin Ismet , Chandra Vidhi , Lucas Anthony San , Scheet Paul , Xu Hanwen , Hanash Samir M. , Feng Lei , Ajami Nadim , Petrosino Joseph , Peterson Christine B. , Nejman Deborah , Kim Michael P. , Sears Cynthia L. , Wood Laura D. , Maitra Anirban , Straussman Ravid , Katz Matthew , White James Robert , Jenq Robert , Wargo Jennifer , McAllister Florencia 
Published: August 2019

Abstract
Most patients diagnosed with pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a very small subset of patients survive longer. The factors that determine the long-term survivorship remain elusive. Recently, studies have shown that bacteria can be found in PDAC which may influence therapy responses. In this study, we aimed to determine if the tumor microbiome, and its associated immune responses, can guide long-term survivorship in resected PDAC patients. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition and immunoprofile in PDAC patients who survived less than 5 years (short term survivors, STS) versus those who survived more than 5 years (long term survivors, LTS) in two independent cohorts of patients from two institutions (MD Anderson Cancer Center and Johns Hopkins University). We found higher alpha-diversity in the tumor microbiome from LTS compared to STS PDAC patients. Additionally, we found greater densities of immune cells in the LTS compared to STS, with significant correlation with alpha-diversity. Taken together, our study demonstrates that the PDAC microbiome composition may influence the host immune response and the natural history of the disease.
E.R. and Y.Z. contributed equally to this work.
Citation Format: Erick M. Riquelme, Yu Zhang, Liangliang Zhang, Montiel Maria, Zoltan Michelle, Wenli Dong, Pompeyo Quesada, Ismet Sahin, Vidhi Chandra, Anthony San Lucas, Paul Scheet, Hanwen Xu, Samir M. Hanash, Lei Feng, Nadim Ajami, Joseph Petrosino, Christine B. Peterson, Deborah Nejman, Michael P. Kim, Cynthia L. Sears, Laura D. Wood, Anirban Maitra, Ravid Straussman, Matthew Katz, James Robert White, Robert Jenq, Jennifer Wargo, Florencia McAllister. Pancreatic tumor microbiome and associated immune responses determine clinical outcomes [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 2829.
Abstract 2837: Fusobacterium nucleatum and T cells in colorectal cancer liver metastasis
Authors: Sakamoto Yuki , Mima Kosuke , Daitoku Nobuya , Hiyoshi Yukiharu , Imai Katsunori , Iwatsuki Masaaki , Ishimoto Takatsugu , Baba Yoshifumi , Iwagami Shiro , Miyamoto Yuji , Yamashita Yoichi , Yoshida Naoya , Baba Hideo 
Published: August 2019

Abstract
Background: Accumulating evidence links the intestinal microbiota and colorectal carcinogenesis. Fusobacterium nucleatum has been shown to promote colorectal tumor growth and inhibit antitumor immune responses. Emerging evidence demonstrates an enrichment of Fusobacterium species in colorectal cancer live metastasis (CRLM).
Aim: To test the hypothesis that higher amount of Fusobacterium nucleatum is associated with lower density of CD8+ T-cells in CRLM.
Method: Genomic DNA was extracted from CRLM and adjacent normal liver tissues. We measured the amount of Fusobacterium nucleatum DNA in 164 CRLM tissues using a quantitative polymerase chain reaction assay. The density of CD8+ T-cells in CRLM was determined by immunohistochemical staining.
Result: Fusobacterium nucleatum was detected in 8 (4.9%) of 164 CRLM cases. A higher density of CD8+ T-cells in CRLM was significantly associated with better relapse-free survival (P =0.036). Fusobacterium nucleatum-negative cases, Fusobacterium nucleatum-positive cases were inversely associated with the density of CD8+T-cells (P =0.020).
Conclusions: The presence of Fusobacterium nucleatum is inversely associated with CD8+ T-cells density in CRLM. Upon validation, our data may have implications for preventing the formation of liver metastases in colorectal cancer through targeting intestinal microflora.
Citation Format: Yuki Sakamoto, Kosuke Mima, Nobuya Daitoku, Yukiharu Hiyoshi, Katsunori Imai, Masaaki Iwatsuki, Takatsugu Ishimoto, Yoshifumi Baba, Shiro Iwagami, Yuji Miyamoto, Yoichi Yamashita, Naoya Yoshida, Hideo Baba. Fusobacterium nucleatum and T cells in colorectal cancer liver metastasis [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 2837.
Abstract 2845: The role of PSAT1 in triple negative breast cancer metastasis
Authors: Metcalf Stephanie , Kruer Traci , Dougherty Susan , Biyik-Sit Rumeysa , Klinge Carolyn , Clem Brian 
Published: August 2019

Abstract
Breast cancer is the number one diagnosed cancer type among women in the United States (NCI). This disease can be stratified into different molecular subtypes, including triple negative breast cancer (TNBC), each of which can have different therapeutic options, patient prognosis, and survival outcomes. TNBC disease readily metastasizes and different processes have been implicated in the development of metastatic disease. The serine synthesis pathway (SSP) is responsible for de novo production of serine and consists of three enzymes, including phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). PSAT1 catalyzes the second step in this pathway, is elevated in more aggressive tumor types such as basal breast cancer (Pollari, 2011) and has clinically been associated with poorer distant metastatic free survival and overall survival (unpublished from KMPlotter) in breast cancer patients. These prior studies combined with our own preliminary data underscores the hypothesis that PSAT1 promotes the metastatic potential of triple negative breast cancer. This hypothesis was first evaluated through immunohistochemistry examination of patient samples which demonstrated that expression of PSAT1 increases with TNBC tumor grade. In vitro assays of proliferation showed no difference upon loss of PSAT1, however, metastasis (migration and invasion) was significantly inhibited upon PSAT1 suppression. In a tail-vein experimental metastasis model, suppression of PSAT1 significantly inhibited the formation of tumor nodules. Mechanistically, the relevance for de novo serine synthesis pathway was examined in vitro via suppression of PHGDH. Decreased PHGDH did not affect proliferation or the metastatic capability of either cell line. Further, addition of exogenous serine could not rescue metastatic deficiencies upon loss of PSAT1. Our results suggest that PSAT1 does contribute to metastasis in TNBC and that this affect appears to be independent of its metabolic role in serine synthesis. While studies are ongoing, this points to the potential of a non-canonical function of PSAT1 being a therapeutic target for patients with TNBC that are currently lacking treatments options.
Citation Format: Stephanie Metcalf, Traci Kruer, Susan Dougherty, Rumeysa Biyik-Sit, Carolyn Klinge, Brian Clem. The role of PSAT1 in triple negative breast cancer metastasis [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 2845.
Abstract 2888: Targeting the fatal pediatric brain tumors AT/RT and DIPG with the DNA binding agent quinacrine
Authors: Kaur Harpreet , Guo Huizi , Green Peter , Akhtarkhavari Sepehr , Shah Smit , Eberhart Charles G. , Raabe Eric H. 
Published: August 2019

Abstract
Atypical teratoid/rhabdoid tumors (AT/RT) and diffuse intrinsic pontine glioma (DIPG) are incurable pediatric brain tumors. Developing new targets and novel therapeutics are urgently needed. We have previously shown that multiple primary brain tumors and cell lines express increased amounts of the epigenetic modifier high mobility group AT-hook 2 (HMGA2). HMGA2 is a DNA-binding oncoprotein that regulates transcription during normal embryogenesis and in cancer stem cells. Targeting HMGA2 using short hairpins significantly decreased AT/RT and glioma growth and increased survival of xenografted mice. We hypothesized that pharmacological inhibition of HMGA proteins using DNA minor-groove binding drugs like quinacrine will decrease AT/RT and DIPG growth due to displacement of HMGA proteins from the DNA. We used quinacrine in ten patient-derived cell lines: five AT/RT (BT37, CHLA-05, CHLA-06, BT-12, CHLA-266) and five DIPG (JHHDIPG1, SUDIPGXIII, JHHDIPG16A, SF7761, HSJD-007). Quinacrine has been used in millions of humans to treat malaria and parasitic infections, has a well-known safety profile and can penetrate the brain. Using quinacrine fluorescence as a surrogate, we can achieve therapeutically efficacious micromolar concentration of quinacrine in the mouse and zebrafish brain after oral administration without overt toxicity. In both tumor cell lines, quinacrine causes a dose-dependent reduction in growth (MTS) and proliferation (BrdU) compared to vehicle-treated cells (P&lt;0.01). Treatment of both tumor lines with quinacrine significantly increased apoptosis (cleaved caspase-3 and cleaved PARP) compared to control cells (P&lt;0.01). Quinacrine had no effect on growth of normal hindbrain cells. Our results suggest that minor groove binding drugs like quinacrine are a viable potential treatment strategy for these lethal tumors. Ongoing studies include validating the in vivo efficacy of quinacrine using zebrafish and mouse models of AT/RT and DIPG. Future studies are aimed at investigating the mechanism of quinacrine in these devastating tumors.
Citation Format: Harpreet Kaur, Huizi Guo, Peter Green, Sepehr Akhtarkhavari, Smit Shah, Charles G. Eberhart, Eric H. Raabe. Targeting the fatal pediatric brain tumors AT/RT and DIPG with the DNA binding agent quinacrine [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 2888.
Abstract 2898: Stochastic variation in gene expression is selected during clonal evolution of spontaneous mouse mammary tumors
Authors: Felts Sara J. , Tang Xiaojia , Keulen Virginia P. Van , Kalari Krishna R. , Pease Larry R. 
Published: August 2019

Abstract
Molecular and cellular diversity in cancer cells enables evolutionary processes that govern tumor progression and contributes to treatment failures, but the mechanisms governing this variability remain incompletely understood. We previously described tumor-specific epigenetic alterations in DNA devoid of canonical CpG methylation sites throughout the genomes of spontaneous breast tumors which arise in genetically uniform, yet heterozygous, [FVB X BALB/c MMTV-NeuT+] F1 mice. Those changes were detected in purified tumor DNA using a template-assisted quantitative ligation assay employing locus-specific and SNP-specific oligonucleotide genotyping probes, and the assay was subsequently shown to be sensitive to epigenetic modifications of the templates. We now describe losses of heterozygosity similarly distributed throughout the transcriptomes of tumors in this same model. We quantified expressed alleles across a population of clonal tumors and tested each expressed variant for the occurrence of allelic ratio outliers. The results revealed variegated patterns of expression in hundreds of genes, highly significantly enriched in pathways typically co-opted by tumors (Molecular Mechanisms of Cancer, P &lt; 10-10, IPA analysis). An astounding 87% (2634 of 3044) of expressed genes that could be measured using this approach were represented in at least one tumor. Furthermore, the frequency of these outliers in any one individual tumor was found to correlate strongly with the transcriptional repression of an additional large set of non-polymorphic genes. These findings reveal underappreciated, latent mechanisms driving sporadic errors in epigenetic programming that promote repression of a multiple cis-linked transcripts. This genome-wide molecular chaos presents as dysregulated cellular homeostasis and is the foundation for heritable diversity as tumors evolve.
Citation Format: Sara J. Felts, Xiaojia Tang, Virginia P. Van Keulen, Krishna R. Kalari, Larry R. Pease. Stochastic variation in gene expression is selected during clonal evolution of spontaneous mouse mammary tumors [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 2898.
Abstract 2912: The impact of primary tumor sidedness on the effect of regorafenib in refractory metastatic colorectal cancer
Authors: Yoon Sang Eun , Hur Joon Young , Lee Su Jin , Lee Jeeyun , Park Se Hoon , Park Joon Oh , Lim Ho Yeong , Kang Won Ki , Park Young Suk , Kim Seung Tae 
Published: August 2019

Abstract
Recently, the sidedness of the primary tumor (right versus left) has been investigated for its ability to prognosticate and predict outcomes. We evaluated the effect of regorafenib based on KRAS mutation status and the sidedness of the primary tumor in patients with metastatic colorectal cancer (mCRC). We analyzed 135 patients with refractory metastatic colorectal cancer (mCRC) being treated with regorafenib at Samsung Medical Center, between January 2014 and January 2018. Primary tumors originating in the splenic flexure, descending colon, sigmoid colon, rectum, or proximal third of the transverse colon were defined as left-sided CRC (LC). Primary tumors originating in the appendix, cecum, ascending colon, hepatic flexure, or distal two-thirds of the transverse colon were defined as right-sided CRC (RC). Among all 135 patients, 100 (74.1%) had left sided colon cancer and 35 (25.9%) had right-sided colon cancer. No patients achieved a complete response, but four achieved a partial response, revealing a response rate (RR) of 3.0%. Thirty-seven patients had stable disease, yielding a disease control rate (DCR) of 30.4%. There was no difference in RR or DCR according to the location of the primary tumor (LC vs. RC). A significant difference in progression free survival (PFS) with regorafenib was observed between the LC and RC groups (2.6 months; 95% CI, 2.0 to 3.1 vs. 1.9 months; 95% CI, 1.6 to 2.3; P = 0.04, respectively). In a subpopulation with wild type KRAS, PFS with regorafenib was also significantly different between the LC and RC groups (2.9 months; 95% CI, 1.5 to 4.3 vs. 2.1 months; 95% CI, 0.6 to 3.6; P= 0.04). On multivariate analysis, the sidedness of the primary tumor (LC vs. RC) and the number of metastatic sites (≤1 vs. 2&gt;) had a prognostic effect on PFS (P = 0.01 and P = 0.01, respectively). Regorafenib is a current standard treatment for CRC, but treatment outcomes may be improved if regorafenib is administered based on the appropriate biomarker.
Citation Format: Sang Eun Yoon, Joon Young Hur, Su Jin Lee, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Ho Yeong Lim, Won Ki Kang, Young Suk Park, Seung Tae Kim. The impact of primary tumor sidedness on the effect of regorafenib in refractory metastatic colorectal 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 2912.
Abstract 2917: Inhibition of Annexin A6 sensitizes triple negative breast cancer cells to radiation
Authors: Nangami Gladys N. , Sakwe Amos , Ochieng Josiah 
Published: August 2019

Abstract
Introduction: Despite vast evidence that tumor genetics play a dominant role in determining radiosensitivity and ultimate benefit from radiation therapy (RT), current RT delivery algorithms have not successfully incorporated tumor biology. Instead, clinical decisions regarding the use of RT are still based on features of tumor aggressiveness such as stage, grade, degree of metastasis and type of surgery. We provide evidence showing that most aggressive basal-like TNBC cells characteristically expresses low levels of the Ca2+-dependent membrane-binding tumor suppressor Annexin A6 (AnxA6) as compared to mesenchymal-like TNBC cell lines. We have also shown that depletion of AnxA6 in TNBC cells induced severe morphological changes from the slow growing mesenchymal-like to rapidly growing basal-like phenotypes and that this was not only associated with enhanced anchorage independent cell proliferation, but significantly inhibited cell adhesion, motility and invasiveness. Given that rapidly proliferating cells are more radiosensitive, we hypothesized that the expression status of AnxA6 in triple negative breast cancer cells underlies their response to RT.
Materials and Methods: For clonogenic assay, cells were grown to 70-80% confluency then were allowed to settle and attach for 8 hours before being exposed to irradiation at various doses. Dishes were then incubated at 37oC in 5% CO2 in a humidified incubator to form colonies for 14 days. Colonies (50 cells or more) were stained with crystal violet and enumerated under a Fisher Stereomaster II 10X stereoscopic microscope. Radiation induced cell cycle arrest was assessed by flow cytometry.
Results: Our studies show that depletion of AnxA6, significantly increased the sensitivity of triple negative breast cancer cells via up-regulation of cell cycle pathways as demonstrated by lack of G2/M cell cycle arrest in cells with low level of AnxA6. Additionally, we demonstrate that knockdown of AnxA6 enhanced radiation induced DNA damage.
Conclusions: Our findings demonstrate that reduced expression of AnxA6 enhances radiation sensitivity of triple negative breast cancer cells.
Note: This abstract was not presented at the meeting.
Citation Format: Gladys N. Nangami, Amos Sakwe, Josiah Ochieng. Inhibition of Annexin A6 sensitizes triple negative breast cancer cells to radiation [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 2917.