bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3506: African-specific improvement of a polygenic hazard score to predict age of onset of prostate cancer
Authors: Karunamuni Roshan , Huynh-Le Minh-Phuong C. , Fan Chun C. , Mills Ian G. , Andreassen Ole A. , Dale Anders M. , Seibert Tyler M. ,   The PRACTICAL Consortium
Published: September 2020

Abstract
Introduction: Polygenic hazard models can be used in predicting age of onset of prostate cancer. A recently published model, PHS46, showed reduced performance in men with African genetic ancestry - the hazard ratio for aggressive prostate cancer in individuals with high values of PHS46 was approximately half as large for those with African genetic ancestry (2.4) as it was for those with European (5.6) or Asian (5.2) ancestry. We used a cross-validated search to identify SNPs that would add statistical value to a base model of PHS46 among African men and help bridge the performance gap in this population.
Material and Methods: Anonymized genotypic data were obtained from 6,253 men with African genetic ancestry from the PRACTICAL consortium. Ten iterations of a ten-fold cross-validation search were conducted, where SNPs were added greedily and stepwise to the PHS46 Cox proportional hazards model using age of onset of any prostate cancer as the dependent variable. Individuals without prostate cancer were censored at age of last follow-up. SNPs were selected for the final, enhanced-PHS46 model if they were selected in more than 50% of the folds. The predictive performances of PHS46 and enhanced-PHS46 were compared using the same cross-validated approach.
Results: Three SNPs (rs76229939, rs74421890, and rs5013678) were selected for inclusion in enhanced-PHS46 model. All three SNPs are located on chromosome 8q.24. Enhanced-PHS46 model showed substantial improvements in all performance metrics measured, including a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65 to 0.53), a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47 to 4.34) and a 95% increase in the relative hazard of those in the upper 2% compared to the middle 40% (2.1 to 4.1). Similar improvements were demonstrated using the age of onset of aggressive prostate cancer.
Conclusions: We identified three SNPs (rs76229939, rs74421890, and rs5013678) that substantially improved the performance of PHS46 in a dataset of men with African genetic ancestry. A strategy of building on established models might be applied to other groups generally under-represented in genome-wide association studies.
Citation Format: Roshan Karunamuni, Minh-Phuong C. Huynh-Le, Chun C. Fan, Ian G. Mills, Ole A. Andreassen, Anders M. Dale, Tyler M. Seibert, The PRACTICAL Consortium. African-specific improvement of a polygenic hazard score to predict age of onset of prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3506.
Abstract 3519: Genetically predicted plasma N-glycans and prostate cancer risk: Analysis of over 140,000 European descendants
Authors: Zhao Tianying , Zhu Jingjing , Wu Lang 
Published: September 2020

Abstract
Prostate cancer is the second most frequently diagnosed malignancy among males in many countries. There are critical needs to better understand its etiology and identifying effective biomarkers to improve its early detection. Many proteins are modified by glycans that bind to the proteins, a post-translational modification that are critical for normal physiological processes. Studies have linked dysregulation of glycosylation to several human diseases including prostate cancer. Multiple glycan alterations have been identified to be potentially related to prostate cancer, such as changes to PSA glycosylation, sialylation and core fucosylation, O-GlcNacylation, cryptic and branched N-glyans, as well as galectins and proteoglycans. Limited research, however, has been performed to comprehensively evaluate relationship between N-glycans and prostate cancer. To identify novel N-glycans that are potentially associated with prostate cancer risk, we performed a study using a highly novel and cost-efficient approach.
Using genetic variants reported to be associated with plasma N-glycan levels in large genome-wide associations studies as instruments, we evaluated associations between plasma N-glycans and prostate cancer risk, using the inverse variance weighted method (IVW). Data generated from 79,194 prostate cancer cases and 61,112 controls of European ancestry included in PRACTICAL/ELLIPSE consortia were used in this analysis, providing sufficient power for our research question of interest.
We observed associations between genetically predicted plasma levels of two N-glycans and prostate cancer risk at P&lt;0.05. The odds ratio (OR) and 95% confidence interval (CI) per one standard deviation increase in genetically predicted levels of glycans are: IGP17, 1.05 (1.01-1.10); and IGP41, 0.93 (0.88-0.99). However, these associations became insignificant after adjusting for multiple comparisons.
In conclusion, our agnostic analysis does not identify novel N-glycans whose genetically predicted levels in plasma are associated with prostate cancer risk. Further studies are needed to better characterize the relationship between N-glycans and prostate cancer.
Citation Format: Tianying Zhao, Jingjing Zhu, Lang Wu. Genetically predicted plasma N-glycans and prostate cancer risk: Analysis of over 140,000 European descendants [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3519.
Abstract 3760: HH2710, a highly potent and selective erk1/2 inhibitor for the treatment of mapk mutant tumors
Authors: Li Lei , Huang Min , Li Leping , Chen Yi , Tang Shuai , Su Yi , Dong Ruiping , Ding Jian , Geng Meiyu 
Published: September 2020

Abstract
The mitogen-activated protein kinases (MAPK) pathway, often known as the RAS-RAF-MEK-ERK signal cascade, is the most frequently mutated signal pathway in cancer, which makes the components of this pathway attractive targets for anticancer drug development. The MAPK pathway is aberrantly activated in more than 30% of human cancers through a high frequency of genetic alteration. BRAF mutation has been identified in colorectal (10%), thyroid (∼50%) and melanoma (60%) tumors, whereas RAS is mutated in melanoma (20%), colorectal (50%) and pancreatic (90%) tumors. Thus far, inhibitors targeting the upstream BRAF and MEK have been the focus of past decades and achieved great clinical successes, but remained being challenged by the acquired resistance due to genetic alterations in RAS, BRAF or MEK. Therefore, targeting the downstream ERK is believed to exhibit potential advantages in both effectively shutting down MAPK signaling cascade and overcoming the resistance to upstream targets. Toward that end, we developed a novel ERK1/2 inhibitor, HH2710, which is a highly potent and selective inhibitor of ERK1 and ERK2 with IC50 of 4.5, 4.9 nM, respectively. HH2710 significantly inhibited the downstream RSK phosphorylation in a dose-dependent manner in both BRAF and RAS mutant cancer cell lines. HH2710 strongly inhibited the proliferation of most BRAF mutated cancer cell and a proportion of RAS mutated cells, with IC50s ranging from 0.2 to 4.5 μM. In tumor xenograft models, HH2710 showed significant antitumor activity at the doses of 15, 30, and 60 mg/kg (twice per day, given orally) with the relative tumor volume at the endpoint (T/C value) of 51.0%, 18.1%, and 11.7% respectively, exhibiting improved efficacy over the front runner molecule in clinical development. Summary of pharmacokinetic parameters are listed in Table 1. The full in vitro and in vivo preclinical characterizations of HH2710 will be presented. Table 1, Pharmacokinetic parameters of HH2710 in mouse, SD rats and Beagle dogs
ParametersnCmax*nAUC0-t*t1/2TmaxFµg/mLµg•h/mLhh(%)Mouse, PO0.5031.811.12.065Rat, PO0.2691.773.02.068Dog, PO0.3381.642.01.573*nCmax: Cmax/dose; nAUC0-t : AUC0-t/dose
Citation Format: Lei Li, Min Huang, Leping Li, Yi Chen, Shuai Tang, Yi Su, Ruiping Dong, Jian Ding, Meiyu Geng. HH2710, a highly potent and selective erk1/2 inhibitor for the treatment of mapk mutant tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3760.
Abstract 3859: CXCL17 modulates macrophage polarization and immune cell infiltrate in cutaneous squamous cell carcinoma
Authors: Khandelwal Alok R. , Paralikar Ameesha A. , Soleja Rafay Q. , Temple Zachary B. , Robert Madison M. , Alam Maksudul , Nathan Cherie-Ann O. 
Published: September 2020

Abstract
Cutaneous squamous cell carcinoma (cSCC), a keratinocyte-derived invasive and metastatic tumor of the skin, is the second most common form of skin cancer. Exposure to UltraViolet B (UVB) radiation represent a unique risk factors for cSCC development, and the immune system plays a key role in modulating the response. Immunosuppressed patients are at a considerably increased risk for cSCC-induced morbidity and mortality due to its enhanced recurrence and metastatic potential. Novel mechanism-based therapeutics are needed to prevent UVB-induced cSCC. Chemokines are a group of small chemotactic cytokines that can exert extensive and complex effects on cancer via interaction with their receptors. Chemokine (C-X-C motif) ligand 17 (CXCL17) is the latest member of the chemokine family, and recent studies have identified both a causative and suppressive role of CXCL17 and its cognate receptor GPR35 in tumorigenesis. The purpose of the study was to investigate the role of CXCL17 in modulating tumor immune cell infiltrate with primary focus on macrophages. Further, the effect of CXCL17 on macrophage polarization and function was also assessed. Treatment of RAW 264.7 and bone marrow-derived macrophages (BDMC) with CXCL17 increased chemotaxis and polarized the cells towards an M2 phenotype with significant increase in transcriptional levels of Arginase, Fizz and Ym2. Interestingly, CXCL17 also increased transcript level of TNF-alpha in both RAW and BDMC's suggesting a “mixed” M1/M2 phenotype population that may potentially maintain a certain degree of flexibility and adaptability in facilitating tumor survival and resistance to biologic therapies. This “mixed” phenotype is also expected to promote a variety of pro-tumor functions. To further translate our in vitro studies in an in vivo mouse syngeneic cSCC model, SCCB cells were deleted for CXCL17 and injected into the flank of FVB mice. Tumors were collected and subjected to flow cytometry analysis for tumor cell infiltrate. Deletion of CXCL17 significantly decreased macrophage infiltration at the tumor site. Further, decrease in CXCL17 was associated with a reduction in immunosuppressive cells such as Tregs and MDSC suggesting a role for CXCL17 in tumor immune evasion. Our studies underscore the importance of CXCL17 signaling in cSCC and provide a novel target for the treatment of non-melanoma skin cancer.
Citation Format: Alok R. Khandelwal, Ameesha A. Paralikar, Rafay Q. Soleja, Zachary B. Temple, Madison M. Robert, Maksudul Alam, Cherie-Ann O. Nathan. CXCL17 modulates macrophage polarization and immune cell infiltrate in cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3859.
Abstract 3993: 'Educated' osteoblasts suppress osteoclastogenesis and bone resorption in a bone mimetic microenvironment
Authors: Kolb Alexus D. , Bussard Karen M. 
Published: September 2020

Abstract
Breast cancer (BC) preferentially disseminates to bone. During BC progression in bone, BC cells communicate with osteoblasts (OBs), osteoclasts (OCs), and other stromal cells to shape the bone-tumor niche. Recently, our lab discovered two distinct subpopulations of OBs in the bone-tumor niche based on protein marker expression. One group ‘educated' osteoblasts (EOs) have engaged in crosstalk with disseminated BC cells, whereas another group, ‘uneducated' osteoblasts (UOBs) have not. We have new evidence that EOs suppress osteoclastogenesis and reduce bone resorption associated with BC cell metastatic progression in bone. Culture supernatant of EOs and OBs was analyzed for soluble protein expression of receptor activator of nuclear factor-kappa β ligand (RANKL) and osteoprotegerin (OPG) via ELISA. EOs were co-cultured with pre-osteoclasts to determine OC maturation and resorption. EOs and pre-osteoclasts were co-cultured on a mimetic bone matrix in the presence of soluble RANKL to assess for OC resorption and pit formation. In addition, pre-osteoclasts were tri-cultured with EOs plus either human metastatic triple negative or estrogen receptor positive (ER+) BC cells to assess the effect of BC cells on the formation of OCs. The culture supernatant of EOs expressed reduced amounts of RANKL and OPG soluble protein compared to UOB supernatant. OCs formed in the presence of EOs were approximately half the size of those formed in the presence of UOBs as visualized by TRAP stain. Furthermore, we found up to a 66% reduction in the number of OCs formed in the presence of EOs when compared to the number of OCs formed in the presence of UOBs. When pre-osteoclasts were co-cultured on a mimetic bone matrix, up to 45% reduction was observed in the number of resorptive pits formed upon co-culture with EOs versus UOBs. Moreover, the tri-cultures of pre-osteoclasts, EOs, and human metastatic BC cells yielded up to a 28% reduction in the number of mature, multi-nucleated OCs formed, as opposed to the number of mature, multi-nucleated OCs formed in tri-cultures of pre-osteoclasts, UOBs, plus human metastatic BC cells. Overall, these data suggest that EOs suppress osteoclastogenesis and reduce bone resorption on a bone mimetic surface. These data imply that EOs provide a protective effect against bone resorption during bone metastatic BC progression. These data underscore the importance of investigating EOs as mediators of bone remodeling during BC progression in bone. Supported by NIH R00 CA178177 and Commonwealth of Pennsylvania-Department of Health SAP 4100072566 for KMB.
Citation Format: Alexus D. Kolb, Karen M. Bussard. 'Educated' osteoblasts suppress osteoclastogenesis and bone resorption in a bone mimetic microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3993.
Abstract 4058: TheraT - a highly versatile arenavirus based vector platform for intravenous and intratumoral cancer immunotherapy
Authors: Raguz Josipa , Schmidt Sarah , Kleisner Theresa , Zerbs Manuel , Bekic Goran , Feher Sonja , Oeler Daniel , Stemeseder Felix , Berka Ursula , Kiefmann Bettina , Schulha Sophie , Matushansky Igor , Lauterbach Henning , Orlinger Klaus 
Published: September 2020

Abstract
The unprecedented success of checkpoint blockade therapies clearly demonstrates the power of the immune system to fight cancer. Yet, only a minority of cancer patients respond with long-term control of the tumor or even cure, necessitating the development of other treatment modalities. Hookipa Pharma developed a novel attenuated, replication-competent viral vector platform (TheraT) that induces powerful cytotoxic T lymphocyte responses against foreign and self-antigens. In a preclinical model for human papilloma virus 16 (HPV16) associated cancer (TC-1), we evaluated immunogenicity and efficacy upon systemic and intratumoral application of TheraT vectors based on the arenaviruses lymphocytic choriomeningitis virus (LCMV) and pichinde virus (PICV). Both HB-201 (LCMV) and HB-202 (PICV) product candidates encode a non-oncogenic but highly antigenic E6/E7 fusion protein from HPV16. Independent of the route of administration, single administration of HB-201 or HB-202 induced potent peripheral E7-specific CD8+ T cell responses and led to efficient tumor growth control. Survival of TheraT treated animals was significantly longer compared to buffer treated animals. Similarly, single systemic as well as intratumoral application of HB-201 or HB-202 induced major infiltration of CD8+ T cells into the tumor microenvironment. Combination of intravenous HB-201 and anti-PD1 was well tolerated but did not further enhance efficacy in this model, implicating the presence of other immune evasion factors. In conclusion, replication-attenuated TheraT is safe, highly immunogenic and shows excellent therapeutic efficacy after single intravenous and intratumoral application. These data underline the potential and versatility of this novel vector platform. Mechanistic studies in various mouse tumor models are underway. Phase 1/2 clinical trial initiation of HB-201 monotherapy is planned for end of 2019 and preparations for an IND filing for a combination trial of HB-201 and HB-202 in H1 2020 have been initiated.
Citation Format: Josipa Raguz, Sarah Schmidt, Theresa Kleisner, Manuel Zerbs, Goran Bekic, Sonja Feher, Daniel Oeler, Felix Stemeseder, Ursula Berka, Bettina Kiefmann, Sophie Schulha, Igor Matushansky, Henning Lauterbach, Klaus Orlinger. TheraT - a highly versatile arenavirus based vector platform for intravenous and intratumoral cancer immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4058.
Abstract 4188: The ERK1/2 inhibitor, JSI-1187, demonstrates preclinical efficacy in tumor models with MAPK pathway mutations
Authors: Li Ao , Jian Shanzhong , Yuan Xia , Song Fengge , Yang Shengwei , Du Chengyi , Tao Yue , Wang Liucheng , Pan Mingming , Dong Penghui , Zhou jiajun , Ge Zhengkang , Zhu Qinghong , Hao Wenshan , Xu Wen , Zhang Jintao , Li Qun , Wang Shaohui 
Published: September 2020

Abstract
The MAPK pathway, via RAS-RAF-MEK-ERK, is one of the most important pathways for relaying signals from cell surface receptors for cell survival, proliferation, and differentiation. Many mutations were identified in this pathway and intensely studied, resulting in a number of therapeutics for various cancers (for example, EGFR mutant inhibitors, BRAF V600 mutant inhibitors and MEK inhibitors). A common mechanism of resistance to these therapeutics has emerged to be the reactivation of ERK1/2, the terminal kinase in this pathway. Inhibition of ERK1/2 activity could therefore be instrumental in various mutations in the MAPK pathway, either as single therapy or in combination with other compounds. Through internal effort, we discovered a novel ERK1/2 small molecule inhibitor, JSI-1187, which reversibly inhibited ERK2 with a Ki of less than 1 nM. In anti-proliferation assays, JSI-1187 had IC50 of 37 NM in the BRAF V600E melanonma cell line A375 and 48 NM in the BRAF V600E CRC cell line COLO 205. For cell lines with KRAS mutations, JSI-1187 had anti-proliferation IC50 of 130 NM in the CRC cell line HCT116 and 150 NM in the NSCLC cell line Calu-6. Furthermore, JSI-1187 inhibited the phosphorylation of the ERK substrate RSK1 in these cell lines. We also tested JSI-1187 using mouse CDX models. JSI-1187 showed tumor growth inhibition in a dose dependent manner in the xenograft models of A375, COLO 205, HCT116, and Calu-6. In the COLO 205 model, JSI-1187 caused tumor regression at the dose of 20 mg/kg QD. In the Calu-6 model, BID and QD dosing schedules were compared, with the result that 10 mg/kg BID and 20 mg/kg QD inhibit xenograft tumor growth similarly. Moreover, in the HCT116 model, JSI-1187 concentrations in plasma and tumor were measured, as well as phopspho-RSK1 levels in tumor. A PK/PD correlation was observed. In addition to being tested alone, JSI-1187 was also tested in combination with the BRAF inhibitor dabrafenib in the COLO 205 xenograft model. JSI-1187 and dabrafenib demonstrated synergistic efficacy in tumor growth inhibition. In conclusion, JSI-1187 can be potentially used for treatment of cancer with MAPK pathway mutations.
Citation Format: Ao Li, Shanzhong Jian, Xia Yuan, Fengge Song, Shengwei Yang, Chengyi Du, Yue Tao, Liucheng Wang, Mingming Pan, Penghui Dong, jiajun Zhou, Zhengkang Ge, Qinghong Zhu, Wenshan Hao, Wen Xu, Jintao Zhang, Qun Li, Shaohui Wang. The ERK1/2 inhibitor, JSI-1187, demonstrates preclinical efficacy in tumor models with MAPK pathway mutations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4188.
Abstract 4228: PLAP (placental alkaline phosphatase)-CAR-T cells specifically target colorectal cancer
Authors: Golubovskaya Vita M. , Berahovich Robert , Zhou Hua , Liu Xianghong , Li Feng , Xu Shirley , Wei Yuehua , Ouaret Djamila , Bodmer Walter , Wu Lijun 
Published: September 2020

Abstract
Placental alkaline phosphatase, PLAP encoded by ALPP gene in humans is mainly expressed in placenta and testis, and not expressed in any other normal tissues. PLAP is overexpressed in a proportion of colorectal cancers which makes it an attractive target for CAR (chimeric antigen receptor)-T cell therapy. PLAP mRNA expression was detected in 21.4% (25 out of 117) of colorectal cancer cell lines and this expression was confirmed by FACS at the protein level. In addition, IHC staining on primary colorectal cancer tumors demonstrated PLAP expression in &gt;20% of colorectal cancer tumors. We generated mouse and humanized PLAP ScFv-CAR-T cells and demonstrated high specificity against PLAP-positive colon cancer cells using RTCA (real-time cytotoxicity assay) and IFN-gamma secretion. In addition, humanized-CAR-T cells significantly decreased Lovo xenograft tumor growth in vivo. The combination of hPLAP-CAR-T cells with PD-1, PDL-1 or LAG-3 checkpoint inhibitors significantly increased the activity of hPLAP-CAR-T cells.
Significance: This study demonstrates ability of novel PLAP-CAR-T cells to kill colorectal cancers and that the extent of killing can be increased by combination with checkpoint inhibitors. These preclinical results suggest that PLAP-CAR-T cells combined with checkpoint inhibitors may be developed into an effective clinical therapy for PLAP expressing colorectal and other cancers.
Citation Format: Vita M. Golubovskaya, Robert Berahovich, Hua Zhou, Xianghong Liu, Feng Li, Shirley Xu, Yuehua Wei, Djamila Ouaret, Walter Bodmer, Lijun Wu. PLAP (placental alkaline phosphatase)-CAR-T cells specifically target colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4228.