bluuebunny/crossref_metadata_2025_split huggingface dataset:
Carboxyl-Terminal Repressor Domain of MBP-1 is Sufficient for Regression of Prostate Tumor Growth in Nude Mice
Authors: Ghosh Asish K. , Steele Robert , Ray Ratna B. 
Published: June 2022

Abstract
Prostate cancer is the most frequently diagnosed cancer in men and the second leading cause of male cancer death in the United States. Early detection and improved procedures for surgical intervention and radiation therapy have reduced the fatalities; however, there is no effective cure for men with advanced disease and additional therapy is urgently needed. We have previously shown that MBP-1 acts as a general transcriptional repressor and exerts an antiproliferative effect on several human cancer cells. MBP-1 possesses two repressor domains, located at the amino and carboxyl termini. In this study, we have examined the potential of the repressor domains of MBP-1 as a gene therapeutic candidate in regression of prostate tumor growth. Our results suggested that replication-deficient adenovirus-mediated delivery of amino-terminal (MBP-AR) or carboxyl-terminal (MBP-CR) repressor domain of MBP-1 exerted an antiproliferative effect, like the full-length MBP-1, and induced caspase-independent apoptosis in prostate cancer cells. Next, we investigated the therapeutic effectiveness of MBP-1 repressor domain on prostate tumors. When tested in human tumor xenografts in nude mice, MBP-CR suppressed prostate tumor growth more effectively than full-length MBP-1, whereas MBP-AR delayed prostate tumor growth. Together, these results suggested that MBP-CR expression has an antiproliferative effect in human prostate cancer cells, being more effective than the full-length MBP-1 in preventing tumor growth.
Genetic Linkage of Prostate Cancer Risk to the Chromosome 3 Region Bearing FHIT
Authors: Larson Garry P. , Ding Yan , Cheng Li S-C. , Lundberg Cathryn , Gagalang Virgil , Rivas Guillermo , Geller Louis , Weitzel Jeffrey , MacDonald Deborah , Archambeau John , Slater Jerry , Neuberg Donna , Daly Mary B. , Angel Irene , Benson Al B. , Smith Kimberly , Kirkwood John M. , O'Dwyer Peter J. , Raskay Barbara , Sutphen Rebecca , Drew Rosalind , Stewart James A. , Werndli Jae , Johnson David , Ruckdeschel John C. , Elston Robert C. , Krontiris Theodore G. 
Published: June 2022

Abstract
We conducted linkage analysis of 80 candidate genes in 201 brother pairs affected with prostatic adenocarcinoma. Markers representing two adjacent candidate genes on chromosome 3p, CDC25A and FHIT, showed suggestive evidence for linkage with single-point identity-by-descent allele-sharing statistics. Fine-structure multipoint linkage analysis yielded a maximum LOD score of 3.17 (P = 0.00007) at D3S1234 within FHIT intron 5. For a subgroup of 38 families in which three or more affected brothers were reported, the LOD score was 3.83 (P = 0.00001). Further analysis reported herein suggested a recessive mode of inheritance. Association testing of 16 single nucleotide polymorphisms (SNP) spanning a 381-kb interval surrounding D3S1234 in 202 cases of European descent with 143 matched, unrelated controls revealed significant evidence for association between case status and the A allele of single nucleotide polymorphism rs760317, located within intron 5 of FHIT (Pearson's χ2 = 8.54, df = 1, P = 0.0035). Our results strongly suggest involvement of germline variations of FHIT in prostate cancer risk.
CDKN2A Common Variants and Their Association with Melanoma Risk: A Population-Based Study
Authors: Dębniak Tadeusz , Scott Rodney J. , Huzarski Tomasz , Byrski Tomasz , Rozmiarek Andrzej , Dębniak Bogusław , Załuga Elżbieta , Maleszka Romuald , Kładny Józef , Górski Bohdan , Cybulski Cezary , Gronwald Jacek , Kurzawski Grzegorz , Lubinski Jan 
Published: June 2022

Abstract
The population frequencies of the CDKN2A variants remain undetermined. In Poland there are three common variants of CDKN2A: an alanine to threonine substitution (A148T), Nt500c&gt;g and Nt540c&gt;t, which have been detected in other populations. To establish if they are associated with an increased malignant melanoma (MM) risk we did an association study based on genotyping 471 patients with MM and 1,210 random control subjects from the same Polish population. We found a significantly increased frequency of the A148T variant among patients with MM (7.0%) in comparison with the general population (2.9%). The incidence of the A148T variant remained greater in both unselected and familial melanoma subgroups. A statistically significant positive association was seen for unselected MM (odds ratio, 2.529; P = 0.0003), especially in patients diagnosed under 50 years of age (odds ratio, 3.4; P = 0.0002). The A148T carrier population (heterozygous G/A alleles) was more likely to have a relative with malignancy compared with the noncarrier population (57% versus 36%, respectively; P = 0.03). Further examination of the CDKN2A promoter sequence done in 20 melanoma patients with the A148T change (heterozygous G/A alleles) and 20 patients with MM without this alteration identified it was in linkage disequilibrium with a polymorphism in the promoter region at position P-493. We found no statistically significant overrepresentation of the Nt500c&gt;g and the Nt540c&gt;t polymorphisms in the Polish melanoma population. In conclusion, the A148T variant of the CDKN2A gene seems to be associated with an increased risk of development of MM. Additional studies are required to confirm whether this particular change is associated with increased risk of other nonmelanoma malignancies.
Tissue Inhibitor of Metalloproteinase-1 Protects Human Breast Epithelial Cells from Extrinsic Cell Death: A Potential Oncogenic Activity of Tissue Inhibitor of Metalloproteinase-1
Authors: Liu Xu-Wen , Taube Marcus E. , Jung Ki-Kyung , Dong Zhong , Lee Yong J. , Roshy Stefanie , Sloane Bonnie F. , Fridman Rafael , Kim Hyeong-Reh Choi 
Published: June 2022

Abstract
Tissue inhibitors of metalloproteinases (TIMPs) inhibit matrix metalloproteinases and some members of a disintegrin and metalloproteinase domain (ADAM) family. In addition, recent studies unveiled novel functions of TIMPs in the regulation of apoptosis. TIMP-1 inhibits intrinsic apoptosis by inducing TIMP-1 specific cell survival pathways involving focal adhesion kinase (FAK). TIMP-3, however, was shown to enhance extrinsic cell death by inhibiting the shedding of the cell surface death receptors mediated by tumor necrosis factor-α converting enzymes (TACE/ADAM-17). Here, we examined whether TIMP-1, an inhibitor of some of the ADAM family members, enhances the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)–induced extrinsic apoptotic pathway. Surprisingly, we found that TIMP-1 effectively protects human breast epithelial cells from TRAIL-induced apoptosis, demonstrating opposite roles of TIMP-1 and TIMP-3 for the regulation of extrinsic apoptosis. TIMP-1 inhibition of TRAIL-induced apoptosis does not depend on its ability to inhibit matrix metalloproteinases or ADAM activities and is unrelated to its ability to stabilize active or decoy death receptors. Importantly, inhibition of PI 3-kinase signaling by wortmannin and down-regulation of FAK expression using siRNA significantly diminish TIMP-1 protection of human breast epithelial cells against TRAIL-induced extrinsic apoptosis. In addition, the in vitro three-dimensional culture studies showed that TIMP-1 inhibits lumen formation and apoptosis during morphogenesis of MCF10A acini. Taken together, these studies suggest that TIMP-1 may exert oncogenic activity in breast cancer through inhibition of both intrinsic and extrinsic apoptosis involving the FAK survival signal transduction pathway.
Spontaneous Feline Mammary Carcinoma Is a Model of HER2 Overexpressing Poor Prognosis Human Breast Cancer
Authors: De Maria Raffaella , Olivero Martina , Iussich Selina , Nakaichi Munekazu , Murata Tomoaki , Biolatti Bartolomeo , Di Renzo Maria Flavia 
Published: June 2022

AbstractCompanion animal spontaneous tumors are suitable models for human cancer, primarily because both animal population and the tumors are genetically heterogeneous. Feline mammary carcinoma (FMC) is a highly aggressive, mainly hormone receptor–negative cancer, which has been proposed as a model for poor prognosis human breast cancer. We have identified and studied the feline orthologue of the HER2 gene, which is both an important prognostic marker and therapeutic target in human cancer. Feline HER2 (f-HER2) gene kinase domain is 92% similar to the human HER2 kinase. F-HER2–specific mRNA was found 3- to 18-fold increased in 3 of 3 FMC cell lines, in 1 of 4 mammary adenomas and 6 of 11 FMC samples using quantitative reverse transcription-PCR. Western blot showed that an anti-human HER2 antibody recognized a protein comigrating with the human p185HER2 in FMC cell lines. The same antibodies strongly stained 13 of 36 FMC archival samples. These data show that feline HER2 overexpression qualifies FMC as homologous to the subset of HER2 overexpressing, poor prognosis human breast carcinomas and as a suitable model to test innovative approaches to therapy of aggressive tumors.
Novel Roles of Unphosphorylated STAT3 in Oncogenesis and Transcriptional Regulation
Authors: Yang Jinbo , Chatterjee-Kishore Moitreyee , Staugaitis Susan M. , Nguyen Hannah , Schlessinger Karni , Levy David E. , Stark George R. 
Published: June 2022

Abstract
Signal transducer and activator of transcription 3 (STAT3) is phosphorylated on tyrosine residue 705 in response to growth factors or cytokines to form activated homodimers that drive gene expression. Because the stat3 promoter has a binding site for STAT3 dimers, the amount of STAT3 protein increases when STAT3 is activated (e.g., in response to interleukin 6). Unphosphorylated STAT1 is known to drive the expression of certain genes. To explore the possibility of a similar role for the induced expression of unphosphorylated STAT3, we overexpressed either Y705F STAT3, which can not be phosphorylated on residue 705, or wild-type STAT3 in normal human mammary epithelial cells or STAT3-null mouse cells. The levels of many mRNAs were affected strongly by high levels of either form of STAT3. Some genes whose expression was increased by overexpressed STAT3, but not by activated STAT3 dimers, encode well-known oncoproteins (e.g., MRAS and MET). In many tumors, STAT3 is activated constitutively, and thus the unphosphorylated form is likely to be expressed highly, driving oncogene expression by a novel mechanism. In addition, expression of the stat3 gene is increased strongly in response to interleukin 6, and the high levels of unphosphorylated STAT3 that result drive a substantial late phase of gene expression in response to this cytokine. Thus, unphosphorylated STAT3, which activates gene expression by a novel mechanism distinct from that used by STAT3 dimers, is very likely to be an important transcription factor both in cancer and in responses to cytokines.
Silencing of CXCR4 Blocks Breast Cancer Metastasis
Authors: Liang Zhongxing , Yoon Younghyoun , Votaw John , Goodman Mark M. , Williams Larry , Shim Hyunsuk 
Published: June 2022

Abstract
RNA interference technology, silencing targeted genes in mammalian cells, has become a powerful tool for studying gene function. For the first time in cancer research, we show that direct injection of a pool of naked small interfering RNA (siRNA) duplexes can prevent tumorigenesis in an animal model, suggesting a novel preventive and therapeutic strategy for cancer management. As a model system, we used siRNA duplexes of CXCR4 to block breast cancer metastasis. Here, we show that blocking CXCR4 expression at the mRNA level by a combination of two siRNAs impairs invasion of breast cancer cells in Matrigel invasion assay and inhibits breast cancer metastasis in an animal model. Targeting more than one site of the target gene may be important to overcome the functional redundancy of other variants of a single gene, especially in in vivo experiments. Moreover, our studies confirm the necessity of CXCR4 in breast cancer metastasis.
Ras Inhibition in Glioblastoma Down-regulates Hypoxia-Inducible Factor-1α, Causing Glycolysis Shutdown and Cell Death
Authors: Blum Roy , Jacob-Hirsch Jasmine , Amariglio Ninette , Rechavi Gideon , Kloog Yoel 
Published: June 2022

Abstract
Active Ras and phosphatidylinositol-3-kinase–dependent pathways contribute to the malignant phenotype of glioblastoma multiformes (GBM). Here we show that the Ras inhibitor trans-farnesylthiosalicylic acid (FTS) exhibits profound antioncogenic effects in U87 GBM cells. FTS inhibited active Ras and attenuated Ras signaling to extracellular signal-regulated kinase, phosphatidylinositol-3-kinase, and Akt. Concomitantly, hypoxia-inducible factor 1α (HIF-1α) disappeared, expression of key glycolysis pathway enzymes and of other HIF-1α–regulated genes (including vascular endothelial growth factor and the Glut-1 glucose transporter) was down-regulated, and glycolysis was halted. This led to a dramatic reduction in ATP, resulting in a severe energy crisis. In addition, the expression of E2F-regulated genes was down-regulated in the FTS-treated cells. Consequently, U87 cell growth was arrested and the cells died. These results show that FTS is a potent down-regulator of HIF-1α and might therefore block invasiveness, survival, and angiogenesis in GBM.
The Kinetics and (Dys)kinetics of Cancer Chronotherapy
Authors: Field Jeffrey M. , Sehgal Amita 
Published: June 2022

Abstract
Circadian rhythms are the daily cycles that time almost all aspects of physiology, but treatments of the clock or by the clock are rarely tested in the clinic. We develop a framework for identifying interventions that may benefit from administration at the appropriate time of day (chronotherapy). Typically, pharmacokinetics is an important consideration for chronotherapy, with short half-life drugs deemed optimal for such treatments. However, recent data suggest long-lived antibodies can show time-of-day specific effects. Examples include both tumor-targeted antibodies as well as immunotherapies with antibodies that activate T cells. Clues to the immunotherapy mechanism come from animal vaccination studies, which demonstrate circadian responses of T cells to a single dose that leads to long-lasting T-cell activation. Conversely, some studies have challenged the efficacy of chronotherapy, underscoring the need to rigorously investigate its application for each drug and tumor type.
Abstract 6293: Genomic characteristics of nivolumab/ipilimumab with or without CBM-588 supplementation in patients with metastatic renal cell carcinoma
Authors: Castro Daniela V. , Dizman Nazli , Zengin Zeynep B. , Malhotra Jasnoor , Meza Luis A. , Muddasani Ramya , Govindarajan Ameish , Chawla Neal S. , Chehrazi-Raffle Alex , Hsu JoAnn , Bergerot Paulo G. , Bergerot Cristiane D. , Dorff Tanya B. , Lyou Yung , Pal Sumanta K. 
Published: June 2022

Abstract
Background: In a previous randomized phase I trial, addition of CBM-588 to the nivolumab/ipilimumab (N/I) regimen showed improved objective response rate, clinical benefit rate, and progression free survival compared to N/I alone in patients (pts) with metastatic renal cell carcinoma (mRCC; Meza et al., ASCO 2021). Furthermore, genomic alterations such as PBRM1 have been associated with clinical benefit to anti-PD-1 monotherapy in patients with mRCC (Miao et al., Science 2018). The primary aim of this study was to investigate tumor genomic characteristics according to treatment arms.
Methods: We retrospectively identified pts with mRCC who received N/I alone or with CBM-588 supplementation along with whole exome and transcriptome sequencing (Ashion Analytics). Responses were measured according to RECIST v1.1. A two-tailed Fischer’s exact test was performed to compare genomic characteristics across arms.
Results: In this study, 29 mRCC pts were randomized to receive N/I +/- CBM-588 and 21 (72%) pts (71% in N/I with CBM-588 arm and 29% N/I arm) had available genomic data. Within this cohort, the median age was 66.8 (range 46-90) and 71% of pts were male. Eleven (52.4%) pts had clear-cell histology and 10 (47.6%) pts had sarcomatoid features; 15 pts received N/I with CBM-588 and 6 pts received N/I alone. The most commonly mutated genes in the overall cohort were VHL (61.9%), PBRM1 (42.9%), and SETD2 (33.3%). Alterations in VHL, PBRM1, and SETD2 were seen in 66.7% vs. 73.3% (p=0.115), 50.0% vs. 40.0% (p=0.523) and 33.3% vs. 33.3% (p=0.686), in N/I vs. N/I with CBM-588 arm, respectively.
Conclusions: There was no significant difference observed in clinically relevant genomic features across study arms. The clinical benefit from CBM-588 appears to be independent of tumor genomic characteristics. More extensive investigations are needed to characterize the determinants of benefit from CBM-588 supplementation.
Citation Format: Daniela V. Castro, Nazli Dizman, Zeynep B. Zengin, Jasnoor Malhotra, Luis A. Meza, Ramya Muddasani, Ameish Govindarajan, Neal S. Chawla, Alex Chehrazi-Raffle, JoAnn Hsu, Paulo G. Bergerot, Cristiane D. Bergerot, Tanya B. Dorff, Yung Lyou, Sumanta K. Pal. Genomic characteristics of nivolumab/ipilimumab with or without CBM-588 supplementation in patients with metastatic renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6293.
Abstract ND14: Pharmacological profile and anti-tumor properties of FHD-286: A novel BAF inhibitor for the treatment of transcription factor-driven cancers
Authors: Hentemann Murphy 
Published: June 2022

Abstract
Pharmacological profile and anti-tumor properties of FHD-286, a novel BAF inhibitor for the treatment of transcription factor-driven cancersMartin Hentemann, Rishi G. Vaswani, Lan Xu, Richard C. Centore, Luis M. M. Soares, Kana Ichikawa, Zhifang Li, Hong Fan, Jeremy Setser, David L. Lahr, Laura Zawadzke, Xueying Chen, Kimberly D. Barnash, Jordana Muwanguzi, Sarah Reilly, Neville Anthony, Gabriel J. Sandoval, Katharine Feldman, Ammar Adam, David Huang, Shawn Schiller, Kevin Wilson, Liyue Huang, Jessica Piel, Johannes Voigt, David S. Millan, Ho Man Chan, Ryan G. Kruger, Carl P. Decicco, Samuel Agresta, Steven F. BellonFoghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, MA 02139The BRG/Brahma-associated factors (BAF) family of chromatin remodeling complexes (also referred to as the mSWI/SNF complex) regulates the chromatin landscape of the genome. Through its ATP-dependent chromatin remodeling activity, BAF regulates the accessibility of gene-control elements, allowing for the binding of transcription factors. Thus, BAF is a major regulator of lineage- and disease-specific transcriptional programs. We have discovered and developed a compound that potently and selectively inhibits the ATPase components of the BAF complex, SMARCA4 and SMARCA2 (also called BRG1 and BRM, respectively). Mutational, structural, and biochemical studies demonstrated that this SMARCA4/SMARCA2 inhibitor acts through a unique allosteric mechanism. Pharmacologic inhibition of the BAF complex resulted in lineage-specific changes in chromatin accessibility in cancer cell lines from diverse origins. Phenotypic screening of cancer cell lines showed that uveal melanoma and hematological cancer cell lines were exquisitely sensitive to BAF inhibition. FHD-286 is orally bioavailable and demonstrates robust efficacy in multiple cell line and primary human tumor derived xenograft models at well-tolerated doses. In preclinical efficacy and toxicology studies, this first in class molecule demonstrates an acceptable therapeutic index which should allow for flexibility in clinical designs. FHD-286 is currently in two Phase I trials for both relapsed refractory AML and MDS, and metastatic uveal melanoma.
Citation Format: Murphy Hentemann. Pharmacological profile and anti-tumor properties of FHD-286: A novel BAF inhibitor for the treatment of transcription factor-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND14.
Abstract PL01-03: From population to personalized prevention: Lessons from Barrett's esophagus
Authors: Fitzgerald Rebecca 
Published: June 2022

Abstract
Cancer medicine is undergoing a radical shift away from a reactive approach in patients presenting with symptomatic disease towards a more proactive approach aimed at early diagnosis, including at the pre-cancerous stage. Oesophageal adenocarcinoma develops gradually from the pre-malignant condition Barrett’s oesophagus which presents an opportunity to radically improve outcomes from this highly aggressive cancer. Work to unravel the: clinical-demographic and inherited risk factors; the cell of origin of this disease; and the molecular landscape of Barrett’s samples over time and space, in patients with different outcomes, is shedding light on the disease pathogenesis. Our improved understanding of the disease can be used to develop novel approaches to risk-based population screening and personalised prevention. One emerging paradigm is a triage system that comprises a risk assessment, followed by targeted screening using novel non-endoscopic detection devices coupled with molecular biomarkers to identify individuals at high risk of invasive cancer needing monitoring or preventative treatment. In patients with a Barrett’s lesion undergoing monitoring, molecular strategies can further distinguish between those with indolent disease versus those likely to progress. As we redesign clinical pathways for this disease we must be sure to maximise patient and clinician acceptability, affordability and ease of access to a given technology while balancing the risks for over-diagnosis and over-treatment.
Citation Format: Rebecca Fitzgerald. From population to personalized prevention: Lessons from Barrett's esophagus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr PL01-03.