tbuckley/cabot-search huggingface dataset:
Abstract 5147: Novel warheads for targeted therapies of cancer: The concept and design of proPBDs
Authors: Iontcho Vlahov, Longwu Qi, Spencer Hahn, Kevin Wang, Hari K. Santhapuram, Albert Felten, Paul Kleindl, Jeremy Vaughn, Christopher P. Leamon
Journal: Cancer Research (2017)

Abstract Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antibiotics, are a class of natural products produced by various actinomycetes bacteria. PBDs are sequence selective DNA-crosslinking alkylating compounds and are considerably more potent than systemic chemotherapeutic agents. Some PBDs have the ability to recognize and bond to specific sequences of DNA. After insertion in the minor groove, a covalent aminal bond is formed through nucleophilic attack of the N-2 of a guanine (G) base on the electrophillic C-11 imine of PBD. The end result is obstruction of tumor cell division without any significant distortion of the DNA’s helix, thus potentially avoiding the common phenomenon of drug resistance. In recent years, synthetic PBD-dimers have emerged as a promising class of payloads for conjugates in the field of targeted cancer therapies. Unfortunately, many PBD conjugates preserve the strongly alkylating imine moiety within their structural framework, which can react in a deleterious manner while in circulation on their way to their intended targets. As an elegant solution to this inherent problem we designed conjugated prodrugs lacking the imine moiety. Once the prodrug (proPBD) conjugate enters a targeted cell, cleavage of the linker system in the construct triggers the generation of a reactive intermediate possessing an aldehyde and aromatic amine. An intramolecular reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine, and as a result, the diazepine ring. In our proPBDs, we envision to mask the aldehyde as a hydrolytically sensitive oxazolidine moiety and to exploit its ring system as a part of an arsenal of self-immolative linker systems for conjugation. To prove the range of applications for this new class of latent DNA-alkylators, we designed and prepared a diverse variety of novel warheads, consisting of proPBD dimers, hybrids of proPBD with other powerful alkylating agents, as well as tethers of proPBDs with sequence-selective DNA minor groove binders. The utility of the so prepared novel warheads in the design of small molecule drug conjugates (SMDC) for targeted cancer therapies will be also discussed in the presented poster. Citation Format: Iontcho Vlahov, Longwu Qi, Spencer Hahn, Kevin Wang, Hari K. Santhapuram, Albert Felten, Paul Kleindl, Jeremy Vaughn, Christopher P. Leamon. Novel warheads for targeted therapies of cancer: The concept and design of proPBDs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5147. doi:10.1158/1538-7445.AM2017-5147
Abstract PD4-09: Combination FGFR4 and ER-targeted therapy for invasive lobular carcinoma
Authors: KM Levine, J Chen, MJ Sikora, N Tasdemir, N Priedigkeit, GC Tseng, SL Puhalla, RC Jankowitz, DJ Dabbs, PF McAuliffe, AV Lee, S Oesterreich
Journal: Cancer Research (2018)

Abstract Background Invasive Lobular Carcinoma (ILC) is an understudied subtype of breast cancer that requires novel therapies in the advanced setting. Distinctive properties of ILC include growth patterns, metastatic behavior, and receptor status (almost universally estrogen receptor (ER) positive). Our lab recently generated six long-term estrogen deprivation (LTED) models of ILC cells and performed RNA-Sequencing to identify differentially expressed genes compared to their parental cells cultured with estrogen. We overlapped these results with a previously published microarray dataset and found that FGFR4 is the most consistently overexpressed gene in the setting of acquired resistance to endocrine therapy in ILC cells. Hypothesis FGFR4 is an important mediator of resistance to endocrine therapy in ILC. Methods To study the role of FGFR4 in vitro, we used multiple shRNAs and specific small molecule inhibition for growth assays of ILC cells. To study the role of FGFR4 in de novo resistance to endocrine therapy, we collected 129 well curated ER+ ILC tumor specimens and performed gene expression analysis on the pre-treatment samples using a custom NanoString panel. To study the role of FGFR4 in acquired resistance, we collected over 50 pairs of primary-metastatic ER+ tumors and performed exon capture based RNA-Sequencing. Results FGFR4 inhibition decreases parental and LTED ILC cell growth in classic 2D conditions, in the setting of ultra-low attachment, and in colony formation assays. The LTED cells, with higher FGFR4 expression, are more sensitive to its inhibition. For the parental cells, combination FGFR4 and ER-targeting drugs results in synergistic decreases in growth. In our database of primary ILC clinical samples, increased expression of FGFR4 is predictive of shorter time to distant recurrence. For our collection of 50 paired, primary-metastatic ER+ tissues, FGFR4 expression increases on average &amp;gt;2.5 fold in the metastatic setting, with large gains even in ductal carcinoma cases. Finally, in analyzing recently published cohorts of metastatic tumors, there is a significant enrichment of hotspot FGFR4 mutations in tumors originating in the breast, with &amp;gt;2% of metastatic ILC tumors containing such a mutation. Conclusion FGFR4 may play an important role in both acquired and de novo resistance to endocrine therapy in ILC. Citation Format: Levine KM, Chen J, Sikora MJ, Tasdemir N, Priedigkeit N, Tseng GC, Puhalla SL, Jankowitz RC, Dabbs DJ, McAuliffe PF, Lee AV, Oesterreich S. Combination FGFR4 and ER-targeted therapy for invasive lobular carcinoma [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD4-09.
Abstract 3050: Polymorphisms in the arntl2 promoter affect breast cancer metastasis susceptibility
Authors: Ngoc-Han Ha, Kent Hunter
Journal: Cancer Research (2017)

Abstract Breast cancer mortality is primarily due to metastatic lesions rather than primary tumors, yet relatively little is known regarding the mechanisms of metastatic breast cancer, making it difficult to identify patients who are at risk for metastatic disease. Our hypothesis suggests that inherited germline mutations contribute to metastatic disease and that these single nucleotide polymorphisms (SNPs) could be used to predict outcome in breast cancer patients. To investigate the effect of inherited SNPs on metastasis, we used a mouse genetics approach comparing strains with high (FVB) and low (MOLF) metastatic phenotypes and identified Arntl2, a circadian rhythm transcription factor, as a gene whose differential expression predicted outcome in breast cancer patients. To identify SNP differences in Arntl2 between MOLF and FVB, we performed whole genome sequencing of MOLF and compared it to the FVB genome. Overlapping the data with DNase hypersensitivity sites revealed 10 SNPs in the predicted promoter of Arntl2. To test the causative role of the SNPs on Arntl2 expression in vivo, metastatic cell lines were engineered using the CRISPR-Cas9 approach to specifically replace the FVB Arntl2 promoter with that of MOLF. In agreement with our hypothesis, substitution of the MOLF promoter reduced Arntl2 transcript levels and subsequently decreased lung metastases in orthotopic implantation assays. In vitro pulldown experiments with strain-specific promoter probes revealed potential differential binding of chromatin modifier proteins, demonstrating the significance of the SNPs in regulating Arntl2 transcription. Finally, analysis of SNPs associated with Arntl2 expression in a cohort of Chinese breast cancer patients revealed significant correlation of Arntl2 expression with overall survival, validating this gene as a marker in humans. Since Arntl2 is a transcription factor, current studies are focused on identifying Arntl2-regulated genes to investigate downstream pathways involved in metastasis. This study has important implications regarding the role of circadian rhythm in cancer progression and provides a potential mechanism to explain the increased risk of breast cancers in nightshift workers. Furthermore, this provides the first evidence that transcriptional control elements can be engineered using CRISPR-Cas9 to establish the causative role of SNPs in inherited susceptibility to cancer metastasis. Citation Format: Ngoc-Han Ha, Kent Hunter. Polymorphisms in the arntl2 promoter affect breast cancer metastasis susceptibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3050. doi:10.1158/1538-7445.AM2017-3050
Abstract 5269: Cryptotanshinone activate Nrf2 expression through microRNA regulations
Authors: Rachmad A. Dongoran, Tien-Yuan Wu
Journal: Cancer Research (2017)

Abstract Cryptotanshinone is a diterpene quinone derived from the roots of Salvia miltiorrhiza Bunge. An increasing number of studies have demonstrated that cryptotanshinone has the pharmacological activities such as anti-oxidative stress, anti-bacteria, anti-inflammation, and anti-cancer. Cryptotanshinone has been found to increase the ARE expression level induced by the Nrf2 and decrease Keap1 expression. This study investigated Nrf2 and Keap1-related microRNA to understand the mechanisms of cryptotanshinone in antioxidant activities. HepG2 cells were treated with cryptotanshinone 2.5 μM in DMEM medium with 1% FBS for 5 days. Total RNA was obtained for small RNA sequencing and real-time PCR analyses. The analyses revealed that Cryptotanshinone had the potential to inhibit miR-27a-5p, miR-142-5p, miR-28 and miR-93-5p levels, which subsequently increased the Nrf2 mRNA level. On the other hand, the Keap1 mRNA level was suppressed through up-regulation of miR-23a and down-regulation of miR-7-5p. Moreover, Nrf2 and its related downstream anti-oxidant enzymes such as NQO1 and UGT were increased and the Keap1 protein level was decreased. These findings suggest that cryptotanshinone possesses the cancer chemoprevention activity in up-regulation of Nrf2 mRNA and protein levels through the suppression of inhibitory microRNA. Future investigations that extend the current study can focus on pharmacological mechanism of cryptotanshinone as a cancer chemoprevention agent, and the safety of long-term uptake of cryptotanshinone for cancer prevention. Citation Format: Rachmad A. Dongoran, Tien-Yuan Wu. Cryptotanshinone activate Nrf2 expression through microRNA regulations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5269. doi:10.1158/1538-7445.AM2017-5269
Abstract 645: Immunological landscape of non-small cell lung cancer (NSCLC): PD-1 expression in lung TILs correlate with co-expression of other checkpoint inhibitor molecules
Authors: Se W. Jeong, Timothy Bullock
Journal: Cancer Research (2017)

Abstract Lung cancer is the leading cause of annual cancer related mortality in the United States. More than 150,000 people in the U.S. will die from lung cancer this year which will lead to roughly as many deaths as breast, prostate, colon, and pancreatic cancers combined. Lung cancer is also of global concern as tobacco and cigarette use, a significant known risk factor, in developing countries have risen significantly. Stage II and III non-small cell lung cancer (NSCLC) patients often have a 5-year disease free survival of less than 50% even after surgical resection and post-operative chemotherapy and a dismal 5% overall survival for patients with stage IV metastatic disease. Even with the advent of PD-1/PDL-1 checkpoint blockade immunotherapies, only about 20% of patients are responsive to the treatment. This limited scope of success may be due to our lack of understanding the immune landscape of NSCLCs. Therefore, we set out to characterize the immune composition from surgical lung resections via flow cytometry. We found that NSCLCs have a diverse set of checkpoint inhibitor and co-stimulatory molecules expressed by T cells, including PD-1, TIM-3, and TIGIT. Interestingly, even though PD-1 was elevated compared to a normal donor, the expression level was lower than either breast or melanoma tumor samples. We also discovered that PD-1 heavily correlates with co-expression of other checkpoint inhibitor molecules. In our regulatory T cell analysis, FoxP3+ populations have a profound presence in these lung tumors suggesting there is a highly suppressive environment for tumor infiltrating lymphocytes (TILs). Our lung resection screenings furthermore suggests a dynamic range of both frequency and proportion of CD3-CD56+ natural killer (NK) cells. Finally, our data indicates there is a large population of CD11b+CD33+ myeloid-derived suppressor cells (MDSCs) in the tumors, with varying degrees of arginase-1 expression, a functional marker for MDSCs. Altogether, these findings in concert suggest there are potential goldmine of opportunities to target molecules on different immune cell populations. This multi-modal approach, directing combination of immunotherapies that influences multiple immune compartments yet complement each other, may have significant implications for future clinical studies. Citation Format: Se W. Jeong, Timothy Bullock. Immunological landscape of non-small cell lung cancer (NSCLC): PD-1 expression in lung TILs correlate with co-expression of other checkpoint inhibitor molecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 645. doi:10.1158/1538-7445.AM2017-645
Abstract LB-163: Biological differences underlying racial disparity in breast cancer
Authors: Aditi Shendre, Yunlong Liu, Anna Maria Storniolo, Bryan P. Schneider, Jiali Han, Chunyan He
Journal: Cancer Research (2017)

Abstract Compared to European American (EA) women, African American (AA) women have higher rates of estrogen receptor negative (ER-) breast cancer, more specifically triple-negative (TN) subtype, and show poorer prognosis and survival. Increasing evidence suggests biological differences may contribute to the observed racial disparity. Studies evaluating racial differences in gene expression in breast tumor tissue have reported inconsistent results. Study of normal breast tissue in healthy women may provide new insight into biological mechanisms for cancer development prospectively before tumor occurrence. However, racial influence on gene expression in normal breast tissue has not been extensively studied. In this study, we evaluated racial differences in gene expression in normal breast tissue obtained from 23 healthy women as well as tumor tissue obtained from 108 breast cancer patients. We analyzed RNA-sequencing data and performed differential expression analysis between AA and EA women. We found that differentially expressed genes in normal breast tissue between AA and EA women were enriched in biological pathways related to amino acid metabolism, immune response and signaling, lipid and protein biosynthesis, and cell proliferation and survival. Many of these biological differences persist in tumor tissue between EA and AA women in a subtype-specific manner. For example, in ER- breast cancer, racial differences in gene expression were enriched in amino acid metabolism, cell proliferation and survival pathways, with particular enrichment in immune response and signaling and lipid metabolism pathways in TN breast cancer. For ER+ breast cancer, we did not find any major biological pathway enrichment. In addition, we identified several microRNAs differentially expressed in normal breast tissue between EA and AA women. They may be involved in racial differences in breast carcinogenesis but their potential downstream effects are yet to be determined. Future studies are needed to validate our findings and understand racial-specific biological mechanisms in breast cancer development. Citation Format: Aditi Shendre, Yunlong Liu, Anna Maria Storniolo, Bryan P. Schneider, Jiali Han, Chunyan He. Biological differences underlying racial disparity in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-163. doi:10.1158/1538-7445.AM2017-LB-163
Abstract 1534: The significance of a p53 gain-of-function mutation in the acquisition of metastatic traits in the SW13 cell line
Authors: McKale Montgomery, Elizabeth Hull
Journal: Cancer Research (2017)

Abstract The therapeutic potential of histone deacetylase inhibitors (HDACi), shown to epigenetically regulate a variety of genes, has yet to be fully realized due to their documented pleiotropic effects in vivo. Currently, four HDACi are FDA-approved for the treatment of hematological malignancies, but their effectiveness against other types of cancers have been shown to be limited at best and, as a result, most of these clinical trials have failed. A comprehensive review of the recent literature has identified that approximately 50% of all cell lines treated with an HDACi demonstrate an increase in metastatic potential as measured by increases in migration and invasion. Of these cell lines that respond with increased metastatic potential to HDACi treatment, 60% have a gain-of-function mutation within p53 (p=0.03). As HDACi have been shown to destabilize mutant p53, they have been used in studies to examine the effects of HDACi treatment on cancers with an identified p53 mutation. This is concerning as the specific p53 mutation in these cancers is not always known, and thus treatment could potentially result in an increase in cancer cell growth. Previous work in our lab demonstrates that the human SW13 adrenal adenocarcinoma cell line, which harbors a homozygous H193Y gain-of-function mutation, does have an HDACi-induced metastatic phenotype; treated cells demonstrate significant increases in MMP activity and ~50% reduction in p53 protein expression compared to untreated cells. To investigate the role that a decrease in mutant p53 expression plays in the acquisition of metastatic characteristics we utilized stable shRNA plasmids to knock-down p53 expression in the SW13 cell line. HeLa cells, which possess a wild-type p53 gene, were used as a positive control. We found that a decrease in p53 expression alone was not sufficient to induce changes in SW13 growth or invasiveness. In fact, even though p53 expression was knocked down by ~70% in the shRNA lines, HDAC inhibition still induced the acquisition of metastatic properties in these cells. Intriguingly, while the DNA binding activity of mutant p53 was correlated with protein expression and was significantly decreased following HDAC inhibition, the same response was not observed in HeLa cells. These findings suggest that p53 status may be an important determinant of therapeutic response to HDAC inhibition. Note: This abstract was not presented at the meeting. Citation Format: McKale Montgomery, Elizabeth Hull. The significance of a p53 gain-of-function mutation in the acquisition of metastatic traits in the SW13 cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1534. doi:10.1158/1538-7445.AM2017-1534
Abstract 625: Eradication of cancer cells by T-cell receptor-engineered T cells targeting neoantigens/oncoantigens
Authors: Tatsuo Matsuda, Taigo Kato, Yuji Ikeda, Matthias Leisegang, Sachiko Yoshimura, Tetsuro Hikichi, Makiko Harada, Makda Zewde, Jae-Hyun Park, Hans Schreiber, Kazuma Kiyotani, Yusuke Nakamura
Journal: Cancer Research (2017)

Abstract Cytotoxic T lymphocytes (CTLs) play critical roles in cancer-immune responses, and functional characterization of CTLs and their cancer-specific antigens will facilitate cancer immunotherapies. Immunogenic peptides, which can be derived from oncogenic proteins specifically expressed in cancer cells but not expressed in normal organs except testis (oncoantigens), or from peptides with somatic nonsynonymous mutations (neoantigens), are known as good targets for CTLs to eradicate cancer cells. In this study, we aimed to establish a method to efficiently identify oncoantigen/neoantigen-specific CTLs. Firstly, we screened candidate HLA-A2402-restricted oncoantigen/neoantigen peptides by in silico prediction of their binding affinity to MHC class I molecules. We conducted an in-vitro stimulation of CD8 lymphocytes carrying HLA-A24:02 allele by each peptide, and then confirmed clonal expansion of the peptide-specific CTLs by TCR repertoire sequencing analysis, interferon-γ enzyme-linked immunospot (ELISPOT) and/or peptide-HLA multimer assays. After identification of TCR alpha-beta pairs, we conducted retroviral transduction and prepared the TCR-engineered T cells to evaluate their cytotoxic activities against cancer cells. As oncoantigens, we isolated the CTLs for FOXM1 and UBE2T from healthy donors, and found these CTLs showed strong cytotoxicity against HLA-A2402-positive cancer cells expressing target proteins, but not against HLA-unmatched cancer cells. Similarly, the TCR-engineered T cells for FOXM1 and UBE2T showed killing effects for only HLA-A2402-positive cancer cells. Neoantigen-specific TCR-engineered CTLs also exhibited the mutated peptide-specific response, but did not cross-react to the nonmutated peptide. In addition, neoantigen-specific cytotoxicity was observed against HLA-A2402-positive cancer cells expressing the proteins with target somatic mutations. In conclusion, we developed the pipeline to screen possible onconatigens/neoantigens and establish antigen-specific TCR-engineered CTLs from peripheral blood lymphocytes. Our approach provides a promising strategy to develop personalized immunotherapies using onconatigen/neoantigen-reactive TCR-engineered T cells to treat cancer. Citation Format: Tatsuo Matsuda, Taigo Kato, Yuji Ikeda, Matthias Leisegang, Sachiko Yoshimura, Tetsuro Hikichi, Makiko Harada, Makda Zewde, Jae-Hyun Park, Hans Schreiber, Kazuma Kiyotani, Yusuke Nakamura. Eradication of cancer cells by T-cell receptor-engineered T cells targeting neoantigens/oncoantigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 625. doi:10.1158/1538-7445.AM2017-625
The Importance of a Valid Comparison Group—Reply
Authors: Florian Walter, Carsten B. Pedersen, Roger T. Webb
Journal: JAMA Psychiatry (2017)

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