tbuckley/cabot-search huggingface dataset:
Abstract 5323: Chemical inhibitors of quiescin sulfhydryl oxidase (QSOX1) suppress tumor invasion and metastasis
Authors: Amber Fifield, Thai H. Ho, Douglas O. Faigel, Sergei Svarovsky, Eduard Sergienko, Thomas C. Chung, Douglas F. Lake
Journal: Cancer Research (2020)

Abstract Purpose: Quiescin Sulfhydryl Oxidase 1 (QSOX1) is an enzyme over-expressed by tumor cells. Our group and others have shown that QSOX1 is involved in invasion and metastasis. We previously reported that a small molecule, SBI-183, inhibited the enzymatic activity of QSOX1 and suppressed tumor cell invasion in vitro and metastasis of MDA-MB-231 breast tumor cells in vivo. In our current work we tested SPX-009, an analog of SBI-183 with increased potency, to suppress invasion and metastasis in vitro and in vivo. Methods: Commercially available analogs for SBI-183 were screened in a cell-free fluorescent screening assay for the ability to inhibit QSOX1. Analog compounds that inhibited QSOX1 in a concentration-dependent manner were then tested for the ability to inhibit growth and invasion of triple negative breast cancer (TNBC) cells (MDA-MB-231), sarcomatoid kidney cancer cells (RCJ-41T2) and pancreatic adenocarcinoma cells (MIAPaCa2). MTT assays were used to measure the effect of the compounds on tumor growth. 2D invasion assays and 3D tumor spheroid assays were employed to measure the effect of the analogs on invasion. One potent analog (SPX-009) was evaluated for the ability to suppress tumor growth and metastasis in mice bearing MDA-MB-231-luc breast cancer orthotopic xenografts. Results: Three of 53 analogs inhibited the enzymatic activity of QSOX1 at levels similar to the parent compound. However, one of those compounds, SPX-009, suppressed invasion of breast, kidney and pancreas tumor cells in 2D and 3D invasion assays at &amp;gt;10-fold lower concentrations than the parent compound (SBI-183). In a non-metastatic xenograft of kidney cancer SBI-183 suppressed primary kidney tumor growth by 51%, but in a metastatic xenograft breast cancer model (MDA-MB-231-luc TNBC), SBI-183 reduced lung metastasis by 76% compared to control. Human-mouse xenograft studies are ongoing with the more potent analog (SPX-009) and will also be presented. Conclusions: Chemical inhibitors of QSOX1 have a minor effect on tumor cell viability, but a major effect on tumor cell invasion in vitro and metastasis in vivo. This finding suggests that combining a QSOX1 inhibitor with a cytotoxic agent might provide a means to inhibit metastasis of cells that are resistant to cytotoxic agents. Citation Format: Amber Fifield, Thai H. Ho, Douglas O. Faigel, Sergei Svarovsky, Eduard Sergienko, Thomas C. Chung, Douglas F. Lake. Chemical inhibitors of quiescin sulfhydryl oxidase (QSOX1) suppress tumor invasion and metastasis [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 5323.
Abstract 5698: Novel conditionally active bispecific T cell engagers targeting solid tumors
Authors: Ana Paula G. Cugnetti, Haizhen Liu, Jing Wang, Charles Xing, Christina Wheeler, Matthew Lucas, Cathy Chang, Gerhard Frey, William J. Boyle, Jay M. Short
Journal: Cancer Research (2020)

Abstract The use of CD3/target bispecific molecules has great therapeutic potential in oncology. This potential, however, is diminished due to serious on-target drug-related toxicities, restricting the development of bispecific T cell engagers to targets that have limited expression in normal tissues. Conditionally Active Biologic (CAB) technology is a proprietary platform that generates antibodies which have no or very little binding to the target antigen in healthy tissue (normal physiological conditions), but have strong binding in the context of diseased tissues (tumor microenvironment) based on the glycolytic tumor metabolism (including Warburg effect). Using our CAB technology, we have developed CD3/target bispecific antibodies that bind to recombinant CD3 and to CD3 expressing cells under in vitro tumor microenvironment conditions, but not in physiologic conditions (CAB CD3). CAB CD3 bispecific antibodies were generated against various well-established tumor associated antigens (TAA), including EpCAM, B7-H3, HER-2 and EGFR. All of these molecules play important roles in cancer biology and are attractive targets for the development of therapeutic bispecific antibodies. In addition, we have also developed CAB TAA / CAB CD3 bispecific antibodies. In vitro and in vivo efficacy data as well as toxicology studies in non-human primates for CAB-T cell engagers will be presented. Our data demonstrates that CAB bispecific antibodies are efficacious in vivo and have lower toxicity comparing to non-CAB bispecific antibodies. The CAB technology will allow the generation of a new class of T-cell engagers with increased safety margin and therapeutic index in the clinic. Citation Format: Ana Paula G. Cugnetti, Haizhen Liu, Jing Wang, Charles Xing, Christina Wheeler, Matthew Lucas, Cathy Chang, Gerhard Frey, William J. Boyle, Jay M. Short. Novel conditionally active bispecific T cell engagers targeting solid 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 5698.
Abstract 1470: UGP2 is a critical regulator of protein glycosylation in pancreatic cancer
Authors: Andrew L. Wolfe, Jacqueline Galeas, Eneda Toska, Qing Zhou, Angel Ku, Richard P. Koche, Sourav Bandyopadhyay, Carlito B. Lebrilla, Maurizio Scaltriti, Frank McCormick, Sung Eun Kim
Journal: Cancer Research (2020)

Abstract UDP-glucose pyrophosphorylase 2 (UGP2) is a lynchpin metabolic enzyme that rests at the convergence of multiple metabolic pathways regulating both glycogen synthesis and glycosylation modifications. Here we elucidated the essential role of UGP2-mediated glycosylation in the maintenance of KRAS-driven cancer using both in vitro and in vivo models. A key effector of KRAS oncogenic function is the transcription factor YAP. We identified the YAP/TEAD transcription factor complex as a major regulator of UGP2 mRNA expression and enzymatic activity using genomic perturbations, correlative protein immunohistochemistry in PDAC samples, and ChIP-seq and targeted ChIP-qPCR at the UGP2 promoter. Loss of YAP or UGP2 leads to a decrease in glycogen and defects in key glycosylation targets such as EGFR. In murine xenograft models using pancreatic cancer lines, knockdown of UGP2 prevented tumor growth and decreased expression of the critical glycosylation target EGFR. This essential role for UGP2 in cancer maintenance may lead to new avenues of therapy in otherwise intractable KRAS-driven cancers. Citation Format: Andrew L. Wolfe, Jacqueline Galeas, Eneda Toska, Qing Zhou, Angel Ku, Richard P. Koche, Sourav Bandyopadhyay, Carlito B. Lebrilla, Maurizio Scaltriti, Frank McCormick, Sung Eun Kim. UGP2 is a critical regulator of protein glycosylation in pancreatic 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 1470.
Abstract 4165: Stable <i>RUNX1p.(Leu56Ser)</i> kinetics during the course of myeloid neoplasms disagree with putative RUNX1 poor prognosis status
Authors: Lena Rai, Sai Phyo, Elisabeth Nacheva
Journal: Cancer Research (2020)

Abstract ‘De novo Acute Myeloid Leukemia (AML) with mutated RUNX1' is a provisional WHO entity with poor prognosis. Missense variant, RUNX1c.167T&amp;gt;C, NP_001745.2:p.(Leu56Ser), with COSMIC reference and FATHMM score of 0.90 suggests it is ‘Pathogenic'; while dbSNP reference and population frequencies of &amp;gt;1.5% suggests ‘Benign'. To address this discrepancy, we studied RUNX1p.(L56S) kinetics in patients with primary or secondary Myeloid neoplasms receiving varied chemotherapy regimen. Bone marrow (BM) samples received were subjected to routine diagnostic algorithm including targeted next-generation sequencing. ¶Out of 227 patients with RUNX1 mutated Myeloid neoplasms, 75 (33%) had RUNX1p.(L56S) making it the most frequent RUNX1 variant (Table-1). RUNX1p.(L56S) was present at ≈55% (46.6%-62.4%) Variant Allele Frequency (VAF) in all cases except one where VAF was 99%. Paired T-test (95% CI) analysis of RUNX1p.(L56S) VAF at diagnosis and remission (p-value=0.89) or relapse/AML transformation (p-value=0.7017) showed no significant difference; similar to that of single nucleotide polymorphisms (SNPs) identified in these cases (remission samples, p-value=0.15; disease evolution, p-value=0.79). In contrast, VAF of other coexisting gene variants was significantly different between diagnostic and remission (p-value=0.02) or relapse/transformation (p-value=0.01) samples, largely owing to acquisition or loss of pathogenic variants. RUNX1p.(L56S) VAF remained stable in sequential samples despite variable BM blasts; nor was it significantly different amongst patients with adverse risk cytogenetics versus those with favourable or intermediate risk (p-value=0.60). In the MDS cohort, RUNX1p.(L56S) was not associated with morphological subtypes. ¶Our data demonstrates RUNX1p.(Leu56Ser) kinetics remain stable during Myeloid disease course, similar to co-occurring SNPs. Our data strongly recommend considering clinical relevance of individual variant when assessing gene mutation-based disease entities. Table-1:Patient characteristics [includes only those with RUNX1p.(Leu56Ser)]AML (1o or 2o) [No./Median (Range)]MDS (1o or 2o)/MPN [No./Median (Range)]Fisher Exact (2-tailed; 95% CI)No. of patients1758No. of samples76105Genderp-value=0.27Male631Female1127Age (years)57.5 (13.6- 71.4)65 (20.8- 88.2)Cytogenetic risk groupp-value=1.00Favourable228Intermediate1215Adverse33Unavailable012Clinical outcomep-value= 0.24No. of patients in remission (immunophenotypic)79No. of patients with relapse/transformation63Time to event (months)21.0 (8-68)24.0 (10-49) Citation Format: Lena Rai, Sai Phyo, Elisabeth Nacheva. Stable RUNX1p.(Leu56Ser) kinetics during the course of myeloid neoplasms disagree with putative RUNX1 poor prognosis status [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 4165.
Abstract 5402: Inhibition of RET via BLU-667 in an <i>in vitro</i> model of neuroblastoma
Authors: Jessica Gutierrez, Sean Flynn, Yuchen Huo, Jacqueline Lesperance, Peter Zage
Journal: Cancer Research (2020)

Abstract Neuroblastoma is the most common extracranial solid tumor of childhood. Despite aggressive treatment, outcomes in patients with high-risk disease remains poor and new therapeutics are needed to address their needs. Rearranged during Transfection (RET) is a tyrosine kinase that is a known oncogenic driver of multiple human tumors. RET is expressed on neural crest derived cells, including neuroblastoma cells, and has been shown to play a role in neuroblastoma proliferation and survival as well. Recent studies have shown RET inhibition to be a promising new therapeutic target in neuroblastoma. BLU-667 is a selective RET inhibitor with a higher potency and specificity for RET than the current inhibitors that have been previously tested. We hypothesize that this increased potency and specificity will result in greater efficacy against neuroblastoma in preclinical models with fewer off target effects. Thus, to investigate this we evaluated BLU-667 at different concentrations against a panel of established human neuroblastoma cell lines to assess its effects on neuroblastoma cell proliferation, differentiation, and viability. We found that inhibition of RET resulted in a significant decrease in cell proliferation and viability in vitro. Further, given the increased specificity of BLU-667 to RET, we hope to use western blot protein analysis to establish the specific downstream pathways through which RET inhibition leads to decreased neuroblastoma cell survival, potentially revealing further therapeutic targets. Citation Format: Jessica Gutierrez, Sean Flynn, Yuchen Huo, Jacqueline Lesperance, Peter Zage. Inhibition of RET via BLU-667 in an in vitro model of neuroblastoma [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 5402.
Abstract 4087: ALDH1A1 inhibitor induces cell cycle arrest and reduces cell proliferation of cisplatin-resistant ovarian cancer cells
Authors: Ilangovan Ramachandran, Sivakumar Ramadoss, Selvendiran Karuppaiyah, Lauren Nathan, R. Ileng Kumaran, Gautam Chaudhuri
Journal: Cancer Research (2020)

Abstract Introduction: Ovarian cancer is one of the most common malignancies among women that causes severe mortality in USA and globally. Despite advances in cancer treatments in the last few decades, there is no substantial improvement in the survival rates of patients with advanced ovarian cancers. This is mainly attributed to drug resistance and tumor recurrence. Most patients develop resistance to platinum compounds, which are often used as the first-line therapy. Several studies have shown that aldehyde dehydrogenase (ALDH1A1) plays an important role in cancer stemness and confers resistance to cell death induced by platinum compounds used to treat ovarian cancers. Therefore, in this study, we determined the effect of a small-molecule inhibitor of ALDH1A1 (A37) in cisplatin-resistant ovarian cancer cells and assessed it's molecular mechanism of action. Experimental methods: The cisplatin-resistant ovarian cancer cells (A2780-CR) were exposed to various concentrations of ALDH1A1 inhibitor (A37) and then the cell proliferation by water-soluble tetrazolium salt (WST-1) assay, cell cycle analysis by flow cytometry and oxygen consumption rate (OCR) by Seahorse extracellular flux analysis (Seahorse XFe24 Analyzer) were performed. Furthermore, the protein expression of critical signaling molecules that modulate the proliferation of ovarian cancer cells was assessed by western blot analysis. Results: A37 treatment drastically decreased the proliferation of A2780-CR cells at 24 and 48 h. In addition, cell cycle analysis revealed a significant increase in G1 phase and dramatic decrease in S phase of the cell cycle upon A37 treatment. Interestingly, A37 suppressed the basal OCR, an indicator of mitochondrial respiration. Furthermore, A37 reduced the protein expression of mammalian target of rapamycin (mTOR), which plays a critical role in cancer cell cycle and proliferation. Conclusions: Our findings indicate that the ALDH1A1 inhibitor (A37) induces cell cycle arrest and suppresses the cell proliferation of cisplatin-resistant ovarian cancer cells, possibly through downregulation of mTOR signaling. Most importantly, A37 affects the cancer cell metabolism by reducing the mitochondrial respiration. Taken together, our study highlights the importance of potential therapeutic implication of ALDH1A1 inhibitor towards the treatment of chemoresistant-ovarian cancers. Citation Format: Ilangovan Ramachandran, Sivakumar Ramadoss, Selvendiran Karuppaiyah, Lauren Nathan, R. Ileng Kumaran, Gautam Chaudhuri. ALDH1A1 inhibitor induces cell cycle arrest and reduces cell proliferation of cisplatin-resistant ovarian cancer cells [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 4087.
Abstract 3493: Interactions between adiponectin pathway polymorphisms and obesity on breast cancer risk among African American postmenopausal women
Authors: Gina E. Nam, Zuo-Feng Zhang, Jianyu Rao, Hua Zhou, Su Yon Jung
Journal: Cancer Research (2020)

Abstract Purpose: A decreased circulating adiponectin concentration is associated with obesity and an increased breast cancer risk among postmenopausal women. Yet, the interplay between adiponectin-associated genetic variants, obesity, and breast cancer risk is unclear in African American (AA) postmenopausal women. We examined adiponectin pathway polymorphisms for their association with breast cancer risk among AA postmenopausal women. We also explored a gene-environment interaction between adiponectin pathway polymorphisms and obesity for the risk of breast cancer. Method: Using the Women's Health Initiative SNP Health Association Resource Study, we identified 37 single-nucleotide polymorphisms (SNPs) in relation to the adiponectin pathway. Body-fat distributions were determined using three independent indices including body mass index (BMI), waist-to-hip ratio (WHR), and waist circumference (WC). We used multiple Cox proportional hazards regression models to estimate hazard ratios and 95% confidence intervals (CIs) for the association with breast cancer. Obesity-stratified analysis and tests for the joint effects with the SNPs were conducted. Results: Of 7,991 AA postmenopausal women, 402 reported of having an invasive breast cancer with a mean follow-up of 14.5 years. The majority were obese, had low WHR (&amp;lt; 0.85), and had high WC (&amp;lt; 88 cm). Of 37 adiponectin pathway-related SNPs, 3 SNPs were significantly associated with breast cancer risk (KCNK9 rs2468677, OR8S1-LALBA rs11168618, and EIF4A2 rs266719). Among women who have under or normal bodyweight, the minor allele GG genotype of NMU rs13434995 had an elevated risk of postmenopausal breast cancer compared to those with the major allele AA genotype. Women who carry the heterozygous TC genotype of OR8S1-LALBA rs11168618 and are obese jointly increased the risk of breast cancer (relative excess risk due to interaction = 0.58, 95% CI = 0.35, 0.80). Conclusion: Our findings revealed the association between the previously confirmed adiponectin pathway-related SNPs and breast cancer risk among AA postmenopausal women. We also demonstrated that obesity plays an important role as an effect modifier in the relationship between the SNPs and breast cancer, suggesting 1) the potential use of metabolic and genetic biomarkers for identifying a greater risk for breast cancer and 2) support for the research to promote interventions to those with risk genotypes, thus reducing breast cancer risk. Citation Format: Gina E. Nam, Zuo-Feng Zhang, Jianyu Rao, Hua Zhou, Su Yon Jung. Interactions between adiponectin pathway polymorphisms and obesity on breast cancer risk among African American postmenopausal women [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 3493.
Ihsanul Haq Mian
Authors: Safoora Mian-Cudmore, Saira Risdale
Journal: BMJ (2020)

The appointment of Ihsanul Haq Mian (“Ihsan”) as consultant psychiatrist in 1976 was the culmination of a journey that took Ihsan across two continents, three countries, and three universities.

What followed was a distinguished career of selfless dedication and tireless commitment to improving the lives of people with mental illness and their carers.

Born in India before partition, Ihsan moved with his family at the age of 11 to the newly founded Pakistan. Despite a five mile journey to school, usually on foot, occasionally by bicycle or horse, he exhibited from an early age a drive to work hard, succeed, and to make something of himself.

Having completed his medical degree in Bahawalpur, he first worked in rural Pakistan as an assistant medical officer. In 1961, he travelled to the UK for …
Abstract 5051: RenMab Mouse: A leading platform for fully human antibody generation
Authors: Gary Ng, Huizhen Zhao, Yabo Zhang, Lili Liu, Hui Lu, Shuwen Huang, Yuelei Shen
Journal: Cancer Research (2020)

Abstract With the development of immune-oncology, therapeutic antibodies have been proven to be extraordinarily effective for cancer treatment. Conventional human antibody discovery process can be divided into steps including target selection, target validation, screening preparation, hits generation, leads selection, lead optimization, and clinical candidate selection. To accelerate antibody development process, Biocytogen has developed RenMab Mouse, a fully human antibody mouse whose entire variable regions were replaced by human Ig heavy chain and κ light chain through Biocytogen's unique Mb-scale chromosome engineering technology. RenMab Mouse provides a remarkably efficient therapeutic antibody discovery platform for fully human antibody generation, characterization, and rapid in vivo efficacy screening. We have characterized RenMab Mouse with the following features. 1. The entire mouse variable regions were replaced with complete human genome DNA in situ for complete human &amp; mouse regulatory elements. The gene regulation of RenMab mouse is highly consistent with that of human. 2. Mouse constant region remains to ensure normal immune cell population, development and maturation. Immune system of RenMab Mouse has been proven to be almost identical to that of wild type mice. RenMab Mouse showed normal antibody immune responses to antigens. 3. RenMab Mouse generates a highly diverse repertoire of fully human antibody variable regions through V(D)J recombination. This capability can lead to improved hit rates in antibody drug discovery. In conclusion, RenMab Mouse, a fully human antibody mouse developed by Biocytogen's chromosome engineering technology, has been proven to exhibit normal immune cell profile and rapid immune response. Combined with existing inventory of single, double or triple target humanized mouse models and a world-leading proprietary gene editing platform, Biocytogen is dedicated to providing a one-stop solution for antibody discovery and development from target validation to IND application. Citation Format: Gary Ng, Huizhen Zhao, Yabo Zhang, Lili Liu, Hui Lu, Shuwen Huang, Yuelei Shen. RenMab Mouse: A leading platform for fully human antibody generation [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 5051.