bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1076: Hormonal regulation of SEMA7A promotes therapeutic resistance in ER+ breast cancer
Authors: Crump Lyndsey S. , Wyatt Garhett L. , Rutherford Taylor R. , Richer Jennifer K. , Porter Weston W. , Lyons Traci R. 
Published: July 2021

Abstract
Background: The majority of all breast cancers (BC) are estrogen receptor positive (ER+). While ER-targeting endocrine therapies have improved patient survival, many tumors become drug resistant and recur within 20 years. Thus, novel targets are needed to treat recurrent ER+BC. Previous reports have described tumor-promotional effects of Semaphorin 7A (SEMA7A) in ER- disease; however, the role of SEMA7A in ER+ disease is not well-characterized.
Hypothesis: SEMA7A promotes cell survival and drug resistance in ER+ BC.
Methods: We measured expression of SEMA7A in drug resistant cells via immunoblotting. We then overexpressed SEMA7A and used ER-targeting drugs (fulvestrant and tamoxifen) to test how SEMA7A-expressing cells respond to endocrine therapy. In vitro, we utilized cell proliferation and survival assays. In vivo, we implanted ER+ BC cells, then treated the animals with fulvestrant to assess how SEMA7A affects primary tumor volume and metastasis. We also measured markers of “stemness” and multi-drug resistance via flow cytometry.
Results: We found that SEMA7A expression correlated with decreased relapse free survival in patients who received endocrine therapy for ER+BC (Kmplotter; p=0.042). We also observe that SEMA7A can be hormonally regulated in ER+BC, but expression did not consistently decrease with endocrine therapy. Instead, long term estrogen deprivation and ER-targeting treatments increased SEMA7A expression, likely through signaling via other hormone receptors such as the androgen receptor, which also increases with long term estrogen deprivation. Additionally, overexpression of SEMA7A promoted in vitro growth and survival of ER+ cells during estrogen-deprivation, tamoxifen, or fulvestrant treatments. In vivo, SEMA7A promoted fulvestrant resistance in the primary tumor and also induced lung metastases. Finally, we identified pro-survival signaling as a therapeutic vulnerability of ER+SEMA7A+ tumors.
Conclusion: These studies show that SEMA7A can promote drug resistance in ER+ BC. We suggest that targeting pro-survival signaling may prove efficacious for treating SEMA7A+ tumors, which are less likely be resistant to endocrine therapies.
Citation Format: Lyndsey S. Crump, Garhett L. Wyatt, Taylor R. Rutherford, Jennifer K. Richer, Weston W. Porter, Traci R. Lyons. Hormonal regulation of SEMA7A promotes therapeutic resistance in ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1076.
Abstract 114: Loss of BMPR1a in fibroblasts restricts breast cancer progression and alters the immune tumor microenvironment
Authors: Ihle Claire Louise , Provera Meredith D. , Karimpour Parvanee A. , Straign Desiree M. , Smith Erin , Owens Philip 
Published: July 2021

Abstract
The Bone Morphogenetic Protein (BMP) pathway is a member of the TGFβ signaling family and has complex roles in cancer. The dichotomous role of BMPs as both tumor promoters and suppressors appears to be largely context based in both the cancer cell and the surrounding microenvironment. Fibroblasts who are activated in the tumor microenvironment to become cancer associated fibroblasts (CAFs) also carry out diverse functions to support tumor progression, including matrix generation and remodeling as well as angiogenesis and immune cell regulation. We found that conditional deletion of the BMP signaling receptor BMPR1a in mammary fat pad derived fibroblasts (via FSP-Cre) restricts tumor progression in a C57BL/6 syngeneic mammary fat pad MMTV-PyMT breast cancer mouse model. Specific changes in the architecture of collagen were found in the tumors with loss of BMPR1a signaling in CAFs. We analyzed these mammary fat pad tumors using Vectra multiplexed immunohistochemistry (mIHC) to evaluate differential cell phenotypes, spatial distribution, and high-dimensional cell clustering dependent on BMP signaling in CAFs. Vectra mIHC panels were designed to perform tumor and stromal cell classification, immune cell profiling, immune cell function, cell signaling and vascular analysis. Based on Vectra mIHC, changes in myeloid cell populations and immune cell interactions in the tumors were observed with differential BMPR1a expression in CAFs. We profiled the secretome of mammary fat pad fibroblasts and found distinct chemokine and cytokine secretion was altered related on BMPR1a loss. These results indicate a unique necessity for BMP signaling in fibroblasts during tumor progression to influence the stroma, matrix, and immune components of the tumor microenvironment.
Citation Format: Claire Louise Ihle, Meredith D. Provera, Parvanee A. Karimpour, Desiree M. Straign, Erin Smith, Philip Owens. Loss of BMPR1a in fibroblasts restricts breast cancer progression and alters the immune tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 114.
Abstract 1153: Targeting CA125 transcription for ovarian cancer treatment
Authors: Yue Er , Yang Guangchao , Yao Yuanfei , Wang Guangyu , Zhang Yanqiao , Wang Edward W. 
Published: July 2021

Abstract
CA125 coded by MUC16 gene is highly expressed in most ovarian cancer cells and serves as a tumor marker to monitor disease progression or response to treatment of ovarian cancer patients. However, targeting CA125 for ovarian cancer treatment has never been successful. We performed multiple steps of high-fidelity PCR and obtained a 4.2kb DNA fragment upstream of the human MUC16 gene, which included a region upstream from the transcription start site (TSS) and a region downstream from the TSS that contains both the 5' untranslated region and the first 136bp of the open reading frame. Reporter assays showed that this DNA fragment possesses strong transactivation activity in CA125-high cancer cells, but not in CA125-low cells, indicating that the DNA fragment we cloned contains the transactivation region that controls specific expression of MUC16 gene in ovarian cancer cells. We further refined the promoter and found a 1040bp fragment with similar transcriptional activity and specificity. We used this refined MUC16 promoter to replace the E1A promoter in the adenovirus type 5 genome DNA to control expression of E1A, an essential gene for adenovirus replication, and successfully generated a conditionally replication-competent adenovirus that can replicate in and lyse CA125-high-expressing cancer cells, including CAOV3, Kuramochi, MADH2774, OVCAR3, OVCAR4, and TOV112D cells, but not in CA125-low or -negative cancer cell lines, such as A2780, OVCAR5, PEO4, or SKOV3 cells. In vivo studies showed that intraperitoneal virus injection prolonged survival of NSG mice inoculated intraperitoneally with MADH2774 cells. Preliminary experiment showed that a mouse ovarian cancer cell line, ID8, infected with the virus might elicit a protective immune response to rechallenge of parental cancer cells. Our data indicate that targeting MUC16 transactivation for ovarian cancer treatment by conditionally replicative adenovirus development is feasible and practical.
Citation Format: Er Yue, Guangchao Yang, Yuanfei Yao, Guangyu Wang, Yanqiao Zhang, Edward W. Wang. Targeting CA125 transcription for ovarian cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1153.
Abstract 1155: Subcutaneous intratumoral administration of a novel oncolytic virus leads to eradication of peritoneal disseminated pancreatic cancer in nude mice
Authors: Zhang Zhifang , Yang Annie , Chaurasiya Shyambabu , Kim Sang-In , Park Anthony K. , Lu Jianming , Warner Susanne G. , Fong Yuman , Woo Yanghee 
Published: July 2021

Abstract
Introduction: We investigated a novel oncolytic virus, CF33-hNIS-antiPDL1, which has shown robust preclinical activity against numerous solid tumors, for its ability to track and kill distant peritoneal metastases after local virus administration in vivo.
Methods: In this study, we used CF33-hNIS-antiPDL1, a replication competent orthopoxviral chimera engineered to express the human sodium iodine symporter (hNIS) and anti-human programmed death ligand 1 (PD-L1) antibody. To create our mouse model, we inoculated the human pancreatic cell line - AsPC1-ffluc (5x106 cells/site) in both the subcutaneous space and the peritoneum in nude mice. After confirming presence of tumor, the mice were divided into two groups; and treated with either 1) three doses of intratumoral (IT) CF33-hNIS-antiPDL1 (3x105 plaque forming units; (n=8) or 2) PBS (n=4). Each mouse was assessed for the following: tumor burden (bioluminescence imaging); CF33-hNIS-antiPDL1 tracking and replication in tumors (124I based PET imaging); and survival (time to death).
Results: By week 2, the animals in the CF33-hNIS-antiPDL1 treated group compared to the PBS treated group had significantly decreased tumor burden both in the peritoneal tumors (2.5e9±2.498e9 %/ID/cc versus 1.6e10 ±1.3e10 %/ID/cc, respectively; p&lt;0.05) and SC tumors (5.2e8 ±4.3e8 %/ID/cc versus 2.6e9 ±2.6e9 %/ID/cc; p&lt;0.05). With a median survival of 35 days, all PBS treated mice died from disease between 21 to 47 days. In the CF33-hNIS-antiPDL1 treated group, the median survival was 49 days; and two out of eight mice were still alive at 220 days (p&lt;0.05). These two surviving animals had no evidence of cancer; there was complete eradication of SC and peritoneal tumors. At one week after the first CF33-hNIS-antiPDL1 administration, significantly increased PET avidity for 124I uptake in the SC tumors (6.4±1.5 photons/second of regions of interest) and PC tumors (3.5±0.14 photons/second of regions of interest) were visible in the CF33-hNIS-antiPDL1 treated mice.
Conclusion: After local SC tumor injection, CF33-hNIS-antiPDL1 can efficiently kill local tumor and kill distant peritoneal metastases to improve survival. Successful therapy of SC and peritoneal tumors using CF33-hNIS-antiPDL1 can be visualized by 124I-based PET imaging.
Citation Format: Zhifang Zhang, Annie Yang, Shyambabu Chaurasiya, Sang-In Kim, Anthony K. Park, Jianming Lu, Susanne G. Warner, Yuman Fong, Yanghee Woo. Subcutaneous intratumoral administration of a novel oncolytic virus leads to eradication of peritoneal disseminated pancreatic cancer in nude mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1155.
Abstract 1160: SAM competitive PRMT5 inhibitor PF06939999 demonstrates antitumor activity in splicing dysregulated NSCLC with decreased liability of drug resistance
Authors: Jensen-Pergakes Kristen , Tatlock John , Maegley Karen , McAlpine Indrawan , McTigue Michele , Xie Tao , Dillon Christopher , Wang Yuli , Yamazaki Shinji , Spiegel Noah , Shi Manli , Nemeth Amy , Miller Natalie , Hendrickson Eleanore , Lam Hieu , Sherrill John , Liu Wei , Deng Ya-Li , Chung Chi-Yeh , McMillan Elizabeth A. , Palde Prakash , Brooun Alexei , Braganza John , Kephart Susan E. , Kumpf Robert , Patman Ryan , Rui Eugene , Scales Stephanie , Tran-Dube Michelle , Wang Fen , Wythes Martin , Paul Thomas 
Published: July 2021

Abstract
Protein arginine methyltransferase 5 (PRMT5) overexpression in hematological and solid tumors promotes symmetrical di-methyl arginine (SDMA) on cellular proteins involved in important cancer functions including cell cycle regulation, mRNA splicing, cell differentiation, cell signaling, and apoptosis. PRMT5 methyltransferase function has been linked with high rates of tumor cell proliferation and decreased overall survival, and PRMT5 inhibitors are currently being explored as an approach for targeting cancer-specific dependencies due to PRMT5 catalytic function. Here we describe the discovery of potent and selective S-adenosylmethionine (SAM) competitive PRMT5 inhibitors, including the clinical candidate PF-06939999. Acquired resistance mechanisms were explored through the development of drug resistant cell lines. Our data highlight compound-specific resistance mutations in the PRMT5 enzyme that demonstrate structural constraints in the co-factor binding site that prevent emergence of complete resistance to SAM site inhibitors. PRMT5 inhibition by PF-06939999 treatment reduced proliferation of NSCLC cancer cells, with dose-dependent decreases in SDMA levels and changes in alternative splicing of numerous pre-mRNAs. Drug sensitivity associates with cancer pathways including MYC, cell cycle and splicing. Translation of efficacy in mouse tumor xenograft models with splicing mutations provides rationale for therapeutic use of PF-06939999 for treatment of splicing dysregulated NSCLC.
Citation Format: Kristen Jensen-Pergakes, John Tatlock, Karen Maegley, Indrawan McAlpine, Michele McTigue, Tao Xie, Christopher Dillon, Yuli Wang, Shinji Yamazaki, Noah Spiegel, Manli Shi, Amy Nemeth, Natalie Miller, Eleanore Hendrickson, Hieu Lam, John Sherrill, Wei Liu, Ya-Li Deng, Chi-Yeh Chung, Elizabeth A. McMillan, Prakash Palde, Alexei Brooun, John Braganza, Susan E. Kephart, Robert Kumpf, Ryan Patman, Eugene Rui, Stephanie Scales, Michelle Tran-Dube, Fen Wang, Martin Wythes, Thomas Paul. SAM competitive PRMT5 inhibitor PF06939999 demonstrates antitumor activity in splicing dysregulated NSCLC with decreased liability of drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1160.
Abstract 1179: MSH2 is necessary for temozolomide-induced ATR activation in MGMT-methylated cancers
Authors: Ganesa Sachita , Sule Amrita D. , Jackson Christopher B. , Sundaram Ranjini K. , Bindra Ranjit S. 
Published: July 2021

Abstract
The methylation status of the O6-methyl guanine methyltransferase (MGMT) gene promoter is a prognostic biomarker for treatment with the alkylator, temozolomide (TMZ) in many solid tumors including gliomas and colorectal cancers. It is well established that patients with a methylated MGMT promoter (MGMT-) who are treated with the TMZ have a better overall survival than patients with an unmethylated MGMT promoter (MGMT+). The enzyme produced by the MGMT gene is responsible for removing cytotoxic O6-methylguanine (O6-meG) lesions formed by TMZ. In the MGMT- setting, the O6-meG lesion activates the mismatch repair (MMR) pathway which functions to remove the damage. Published work from our group reported differential activation of the ataxia telangiectasia and RAD3 related protein (ATR) in MGMT- and MGMT+ glioblastoma multiforme (GBM) cells in response to TMZ treatment, as demonstrated through the phosphorylation of CHK1. Though it is known that MMR proteins are involved in ATR activation, the specific MMR proteins required for ATR activation by TMZ-induced alkyl lesions remain unknown in the MGMT- setting. Here, we demonstrate that the MMR protein MSH2 plays a role in ATR activation in the presence of O6-meG lesions. We show that there is potent synergy with ATRi and TMZ in the MGMT- MSH2-proficient GBM cell line, which is abrogated in an shMSH2 MGMT- GBM cell line. Additionally, we observe decreased levels of pCHK1 in the shMSH2 MGMT- setting compared to the MGMT- MSH2-proficient cells, suggesting that MSH2 is integral in the activation of ATR upon TMZ treatment. This study elucidates a potential role for MSH2 in ATR activation. Mechanistic understanding of how the MMR system is involved in ATR activation by TMZ can ultimately be exploited for therapeutic gain.
Citation Format: Sachita Ganesa, Amrita D. Sule, Christopher B. Jackson, Ranjini K. Sundaram, Ranjit S. Bindra. MSH2 is necessary for temozolomide-induced ATR activation in MGMT-methylated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1179.
Abstract 1474: Antitumor activity of belvarafenib in melanoma brain metastasis and NRAS mutation melanoma models
Authors: Bae Inhwan , Kim Yu-Yon , Kim Jisook , Park Hyunjin , Song Taehyun , Byun Joo-Yun , Lim Semi , Kim Young Hoon , Ahn Young Gil , Suh Kwee Hyun 
Published: July 2021

Abstract
Over the past decade, BRAF inhibitors, either alone or in combination with MEK inhibitors, have set a new milestone in the treatment of patients with BRAF V600 mutation melanoma, which accounts for about 50% of melanomas. More recently, anti-PD-(L)1 therapies such as nivolumab or pembrolizumab and atezolizumab have been approved as very useful treatments for patients with melanoma. Nevertheless, metastases to the brain in melanoma patients, which are highly aggressive and associated with poor outcomes, still require better treatment. Also, to date, no targeted therapy has been developed for patients with NRAS mutations, which account for about 20% of melanoma.
Previously, we reported that belvarafenib (HM95573 or GDC5573) strongly inhibits the growth of various cancer cell lines harboring BRAF, NRAS or KRAS mutations and demonstrates remarkable anticancer efficacy in preclinical animal models. Belvarafenib, currently in Phase 1 clinical trials, is a potent and selective pan-RAF kinase inhibitor showing strong inhibition activities for BRAF WT, BRAF V600E and CRAF.
Here, we present the results of preclinical model studies suggesting that belvarafenib could be effective in treating melanoma patients with metastases to the brain as well as NRAS mutation melanoma patients. First, belvarafenib was found to be able to accumulate in the brain of mice and rats following oral administration. The exposure of belvarafenib in the brain was similar to that in plasma (approximately 100% brain to plasma ratio). This level of brain penetration of belvarafenib differs significantly from currently approved BRAF inhibitors that are known to have low brain penetration. Belvarafenib showed excellent anti-tumor activity in an orthotopic brain tumor model using melanoma cells. Belvarafenib significantly increased the overall survival of mice implanted intracranially with BRAF V600E A375SM melanoma cells. Overall, our data demonstrated that belvarafenib has therapeutic potential to treat NRAS mutation melanoma patients. In fact, in the NRAS G13D K1735 murine melanoma cell syngeneic mice model, the combination of belvarafenib with atezolizumab (anti-PD-L1) significantly inhibited tumor growth and effectively induced infiltration of cytotoxic T-cells into tumor tissues. These effects of belvarafenib identified in the above preclinical studies need to be immediately warranted through appropriate clinical trials.
Citation Format: Inhwan Bae, Yu-Yon Kim, Jisook Kim, Hyunjin Park, Taehyun Song, Joo-Yun Byun, Semi Lim, Young Hoon Kim, Young Gil Ahn, Kwee Hyun Suh. Antitumor activity of belvarafenib in melanoma brain metastasis and NRAS mutation melanoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1474.
Abstract 1525: Enhancing potency of antigen presenting cells via signal 2/3 mRNA engineering through Cell Squeeze® technology
Authors: Ozay Emrah Ilker , Dunbar Paul , Volk Kelly , Maloney Michael F. , Yee Christian , Mosaheb Mubeen , Trumpfheller Christine , Umana Pablo , Seidl Katherine J. , Bernstein Howard , Loughhead Scott M. 
Published: July 2021

Abstract
Antigen-specific CD8+ T cells are critical effectors of the immune system that help limit persistence of tumors and virally infected cells. During priming, T cells integrate three signals which determine the magnitude and quality of response generated. Signal one is T cell receptor(TCR) and peptide-MHC (pMHC) engagement, which determines the specificity of the response.Signal two is cell surface costimulation by antigen presenting cells (APCs). Signal three is provided through the local cytokine milieu at the time of priming. Here, we use microfluidic CellSqueeze® technology to deliver mRNAs encoding antigen (signal 1), costimulatory molecules(signal 2), and chimeric membrane-tethered cytokines (signal 3) to the cytosol of human peripheral blood mononuclear cells (PBMCs), generating antigen presenting cells (APCs) with multiple enhanced functions. We demonstrate that microfluidic squeezing enables delivery and expression of single or multiple mRNAs encoding signal 1 (various antigens), signal 2 (CD70 orCD86) and/or signal 3 (membrane-tethered form of IL-2) by the major subsets of PBMCs (T cells, B cells, NK cells, and monocytes). While unsqueezed PBMCs showed no to minimal expression of signal 2 and no expression of signal 3 molecules, expression of delivered signal 2and 3 mRNAs in squeezed PBMCs could be observed on the cell surface for several days post squeeze delivery - a timeframe that could potentially support improved T cell priming. When these signal 2/3 molecules were delivered alone or in combination, antigen-specific CD8+ T cell responses could be increased as much as ten-fold compared to delivery of antigen alone.Therefore, microfluidic cell squeezing enables us to efficiently deliver mRNA antigens that have potential to generate multiple immune epitopes in an HLA agnostic manner. Moreover,multiplexing these antigens with signal 2/3 mRNAs enhances the antigen presenting potency ofSQZ APCs inducing stronger antigen-specific CD8+ T cell responses. The potential to deliver numerous materials simultaneously and engineer compound signals via mRNA could allow for applications for HLA-agnostic patient population in oncology and infectious disease areas.
Citation Format: Emrah Ilker Ozay, Paul Dunbar, Kelly Volk, Michael F. Maloney, Christian Yee, Mubeen Mosaheb, Christine Trumpfheller, Pablo Umana, Katherine J. Seidl, Howard Bernstein, Scott M. Loughhead. Enhancing potency of antigen presenting cells via signal 2/3 mRNA engineering through Cell Squeeze® technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1525.