tbuckley/cabot-search huggingface dataset:
Abstract 5313: TT-00420, a novel multiple kinase inhibitor to treat TNBC
Authors: Peng Peng, Guoyu Li, Xiaoyan Qiang, Yuwei Tian, Qi Yu, Elisabetta Marangoni, Frank Wu
Journal: Cancer Research (2020)

Abstract TT-00420, a clinical stage spectrum-selective multiple kinase inhibitor, has been shown to be very efficacious against TNBC cell lines and in vivo models in our previous study. TT-00420 simultaneously inhibits Aurora A/B, RTKs involved in angiogenesis, JAK kinase family as well as CSF1R in kinase profiling assay. In breast cancer cell panel screening, TT-00420 specifically inhibits the proliferation across different subtypes of TNBC, while leaving ER/PR+ and Her2+ cells intact. Incubation of TNBC cell line HCC1806 with TT-00420 results in dose-dependent down-regulation of EGFR, TWIST1, SNAI2, FOSL1, and MYC, a cluster of genes collectively known as “Achilles cluster” essential for TNBC cell growth and proliferation. TT-00420 exhibits great in vivo efficacy in a panel of TNBC PDX models. In the mechanism study, we reveal that the inhibition of Aurora A or B lays the cornerstone of pan-TNBC inhibition capability of TT-00420, and the inhibition of angiogenesis pathway or JAK family or EGFR contributes to potency and activity of TT-00420 against TNBC at various degrees. Treatment of a mouse syngeneic TNBC model with TT-00420 normalizes the vessel conditions in tumors, which is consistent with TT-00420's capability to enhance the anti-tumor immune response both alone or combined with PD-1 blockade. Taken together, TT-00420 represents a novel synergistic inhibitory mechanism to treat TNBC. Citation Format: Peng Peng, Guoyu Li, Xiaoyan Qiang, Yuwei Tian, Qi Yu, Elisabetta Marangoni, Frank Wu. TT-00420, a novel multiple kinase inhibitor to treat TNBC [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 5313.
OC-057 Undetectable faecal immunochemical test for haemoglobin excludes colorectal cancer in symptomatic patients: a prospective uk study
Authors: MM Widlak, CL Thomas, MG Thomas, C Tomkins, S Smith, C Darby, N O’Connell, S Wurie, L Burns, C Harmston, C Evans, CU Nwokolo, B Singh, RP Arasaradnam
Journal: Gut (2017)

Introduction  The diagnosis of colorectal cancer (CRC) in primary care can be challenging as symptoms are variable with poor specificity. We investigated the diagnostic accuracies of faecal immunochemical test for haemoglobin (FIT) and faecal calprotectin (FCP) in symptomatic patients referred from primary care for urgent lower gastrointestinal investigations via the two-week wait colorectal pathway.  Method  1016 patients were prospectively recruited between January 2015 and September 2016. In total 612 patients returned stool samples, completed colonic investigations and were included in the final statistical analysis (51% women, median age 68 years, IQR: 57–76). FIT was performed on HM-JACKarc analyser (Kyowa Medex), and FCP by EliA Calprotectin immunoassay (Thermo Fisher Scientific). Any detectable FIT (detection limit 7 µg Hb/g faeces) and a cut-off of 50 µg/g for FCP were considered positive.  Results  37 (6%) patients were diagnosed with CRC. The negative predictive value (NPV) of FIT vs. FIT plus FCP was the same at 99% (95% CI 98% to 100%). The sensitivity and specificity of FIT was 84% and 89%, respectively. Whereas, it was 89% and 86% for FIT combined with FCP. The ROCs for FIT, FCP and both faecal biomarkers combined showed AUC 0.90, 0.73 and 0.91, respectively. Faecal chaemoglobin measurements were significantly higher in left-sided colonic lesions compared cwith the right side; 490 µg Hb/g faeces vs. 90 µg Hb/g faeces; p=0.007).  Conclusion  Undetectable FIT is sufficiently sensitive to exclude colorectal cancer, with higher values in left-sided lesions. FCP in combination does not appear to provide additional diagnostic information. Further studies to determine the health economic benefits of implementing FIT in primary care are required.  Disclosure of Interest  M. Widlak: None Declared, C. Thomas: None Declared, M. Thomas: None Declared, C. Tomkins Conflict with: Educational lectures on behalf of Thermo Fisher Scientific Ltd., S. Smith: None Declared, C. Darby: None Declared, N. O’Connell: None Declared, S. Wurie: None Declared, L. Burns: None Declared, C. Harmston: None Declared, C. Evans: None Declared, C. Nwokolo: None Declared, B. Singh: None Declared, R. Arasaradnam Conflict with: Educational lectures on behalf of Thermo Fisher Scientific Ltd.
Abstract 3963: Physical confinement induces malignant transformation in mammary epithelial cells
Authors: Yen-Chun Lu
Journal: Cancer Research (2020)

Abstract The physical microenvironment of tumor cells plays an important role in cancer initiation and progression. Here, we present evidence that confinement - a new physical parameter that is apart from matrix stiffness - can also induce malignant transformation in mammary epithelial cells. We discovered that MCF10A cells, a benign mammary cell line that forms growth-arrested polarized acini in Matrigel, transforms into cancer-like cells within the same Matrigel material following confinement in alginate shell hydrogel microcapsules. The confined cells exhibited a range of tumor-like behaviors, including uncontrolled cellular proliferation and invasion. Additionally, 4-6 weeks after transplantation into the mammary fad pads of immunocompromised mice, the confined cells formed large palpable masses that exhibited histological features similar to that of carcinomas. Taken together, our findings suggest that physical confinement represents a previously unrecognized mechanism for malignancy induction in mammary epithelial cells and also provide a new, microcapsule-based, high throughput model system for testing new breast cancer therapeutics. Citation Format: Yen-Chun Lu. Physical confinement induces malignant transformation in mammary epithelial 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 3963.
Abstract CT186: HEPANOVA: Interim safety analysis from a phase 2 study of Tumor Treating Fields (TTFields, 150 kHz) concomitant with sorafenib in advanced hepatocellular carcinoma (HCC)
Authors: Eleni Gkika, Thomas Brunner, Robert Thimme, Anca-Ligia Grosu
Journal: Cancer Research (2020)

Abstract Background: Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, utilizing low intensity alternating electric fields delivered non-invasively to the tumor using a portable medical device. TTFields are approved by the FDA for the treatment of glioblastoma and malignant pleural mesothelioma. In vitro and invivoTTFields at 150 kHz reduced the proliferative potential of hepatocelluar carcinoma (HCC) cell lines. Most HCC patients are not amenable to curative therapies and are treated with systemic chemotherapy following failure of local treatment options. The HEPANOVA Phase II trial (NCT03606590) is a prospective, single-arm study investigating the safety and efficacy of TTFields as a treatment option for advanced HCC concomitant with sorafenib in 25 patients. We present the interim saftey data of the HEPANOVA trial. Methods: Incidence and severity of adverse events of the first nine patients who have been enrolled in the HEPANOVA Phase II trial were analyzed based on the MedDRA body system (system organ class) and preferred terms. Results: The median age was 70 (range 63-85), all the patients were male, 3 (33.3%) patients had an ECOG score of 0. The median number of prior treatments was 2 (0-6) and median time from diagnosis was 9 (0-56) months. Five (55.6%) patients had Barcelona Clinic Liver Cancer (BCLC) stage B disease. The median treatment duration was 2 months for sorafenib and 3 months for TTFields. The total TTFields treatment duration for all nine patients was 29.1 months. Six (66.7%) patients had severe AEs (grade 3-4) and 3 (33.3%) had serious adverse events (SAE), none of which were related to TTFields. Mild-moderate skin toxicity was the only TTFields-related AE, reported in seven (78%) patients. Conclusions: No unanticipated serious adverse device effects have been reported to date in the HEPANOVA study. The majority of AEs reported to date were expected and associated with the disease or chemotherapy. The most common adverse event reported was the expected TTFields-related dermatitis. In summary, these results emphasize the tolerably and safety of TTFields (150 kHz) concomitant with sorafenib in advanced hepatocellular carcinoma. Citation Format: Eleni Gkika, Thomas Brunner, Robert Thimme, Anca-Ligia Grosu. HEPANOVA: Interim safety analysis from a phase 2 study of Tumor Treating Fields (TTFields, 150 kHz) concomitant with sorafenib in advanced hepatocellular carcinoma (HCC) [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 CT186.
Abstract 1037: Orally available small molecule CD73 inhibitor reverses immunosuppression through blocking of adenosine production
Authors: Xiaohui Du, Brian Blank, Brenda Chan, Xi Chen, Yuping Chen, Frank Duong, Lori Friedman, Tom Huang, Melissa R. Junttila, Wayne Kong, Todd Metzger, Jared Moore, Daqing Sun, Jessica Sun, Dena Sutimantanapi, Natalie Yuen, Tatiana Zavorotinskaya
Journal: Cancer Research (2020)

Abstract CD73 has emerged as an attractive target for cancer immunotherapy. CD73 (ecto-5-nucleotidase) is a glycosyl phosphatidyl inositol (GPI)-anchored cell surface protein and catalyzes the hydrolysis of AMP into immunosuppressive adenosine and inorganic phosphate. CD73 is widely overexpressed in tumor microenvironments (TME) of many cancers, resulting in elevated levels of extra cellular adenosine (ADO). ADO plays a critical role in tumor progression through immune suppression, chemotherapy resistance, metastasis and angiogenesis. Therefore, reducing the level of adenosine via inhibition of CD73 has become a potential strategy for treating cancers. Here we report our medicinal chemistry efforts in developing orally available small molecule CD73 inhibitors. Based on the binding mode of adenosine 5'-(α,β-methylene)diphosphate (APCP) with CD73, we designed a novel series of monophosphate CD73 inhibitors, which are highly potent and orally bioavailable. In preclinical studies, OP-5244 inhibited ADO production completely in human cancer cells and CD8+ T cells. It also showed dose-dependent inhibitory effects on CD73 activity in various tumors ex vivo. Furthermore, OP-5244 showed PK/PD efficacy through lowering of ADO/AMP ratio and reversal of immunosuppression in vivo. Citation Format: Xiaohui Du, Brian Blank, Brenda Chan, Xi Chen, Yuping Chen, Frank Duong, Lori Friedman, Tom Huang, Melissa R. Junttila, Wayne Kong, Todd Metzger, Jared Moore, Daqing Sun, Jessica Sun, Dena Sutimantanapi, Natalie Yuen, Tatiana Zavorotinskaya. Orally available small molecule CD73 inhibitor reverses immunosuppression through blocking of adenosine production [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 1037.
Abstract 5963: NGS-based murine pan-cancer gene expression panel for immuno-oncology and tumor microenvironment studies
Authors: Xiaobo Chen, Jia Xue, Qixiang Li, Sheng Guo
Journal: Cancer Research (2020)

Abstract INTRODUCTION: Cancer is a heterogeneous disease and highly related to the immunological system. The significance of fully understanding the interactions between cancer and immunity in cancer therapeutics has been broadly noted, particularly for immunotherapies. Experimental murine models derived from a variety of biological technologies are essential preclinical model systems utilized before clinical studies. Molecular pathology techniques, such as gene expression biomarkers, are widely used to systematically profile and characterize these models. So far, however, there has been no robust and cost-effective assay designed for murine clinical immuno-oncology (I/O) research to characterize tumor-immune interactions at a gene expression level. METHODS: Marker genes were identified by combining public and in-house reference genomic data for non-tumor bearing mice as well as tumor mouse models. Oligonucleotide-based hybridization/capture techniques analogous to exome sequencing, targeting specific regions are well established on Illumina Novaseq and BGI MGIseq platforms. These methods were applied to the murine I/O panel assay, with accuracy and reproducibility verified across these two sequencing platforms. The results were further qualified using a PCR array platform. RESULTS: A mouse gene panel involving 1080 genes that encompass surface markers and transcriptomic biomarkers for the immune system, key pathways at the interface of the tumor, tumor microenvironment (TME), and immune response, as well as internal reference genes for data normalization has been established. By combining advanced NGS technologies and specific bioinformatic pipelines, we were able to detect and distinguish various immune and stromal cells involved in the complex interaction between the tumor and its microenvironment, allowing for a multifaceted characterization of disease biology and the interrogation of immune response and evasion. We validated the sensitivity, specificity, and repeatability of the panel by qPCR experiments. CONCLUSIONS: We have established a murine-I/O NGS panel involving 1080 genes to characterize tumor-immune interactions more efficiently and in a cost-effective manner for preclinical studies. This provides an enhanced insight into the TME, with high-content data that has the potential to translate more effectively to the clinic as well as for early identification of immunotherapy companion diagnostics. Citation Format: Xiaobo Chen, Jia Xue, Qixiang Li, Sheng Guo. NGS-based murine pan-cancer gene expression panel for immuno-oncology and tumor microenvironment studies [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 5963.
Abstract 5892: Whole-exome and RNA sequencing reveals chromosomal rearrangements associated with the recurrence of pulmonary carcinoid
Authors: Akihiko Miyanaga, Mari Masuda, Noriko Motoi, Koji Tsuta, Yuka Nakamura, Nobuhiko Nishijima, Shun-ichi Watanabe, Hisao Asamura, Akihiko Tsuchida, Masahiro Seike, Akihiko Gemma, Tesshi Yamada
Journal: Cancer Research (2020)

Abstract Background: The majority of pulmonary carcinoid (PC) tumors can be cured by surgical resection alone, but a significant proportion of patients experience recurrence. As PC is insensitive to conventional chemotherapy and a significant proportion of patients develop metastases, further clarification of the molecular mechanisms of metastasis is needed in order to develop targeted therapeutics. Material and Method: We performed comprehensive whole-exome sequencing (WES) of primary tumors and corresponding normal lung tissues from 14 PC patients (including 4 patients who developed postsurgical distant metastasis) and RNA sequencing of primary tumors from 6 PC patients (including 4 patients who developed postsurgical distant metastasis). Exon array-based gene expression analysis was performed in 25 cases of PC. Results: We identified a total of 139 alterations in 136 genes. MUC6 and SPTA1 were recurrently mutated at a frequency of 21% (3/14) and 14% (2/14), respectively. Mucin protein family genes including MUC2, MUC4 and MUC6 were mutated in a mutually exclusive manner in 36% (5/14). Pathway analysis of the mutated genes revealed enrichment of genes involved in mitogen-activated protein kinase (MAPK) signaling, regulation of the actin cytoskeleton and focal adhesion, and transforming growth factor (TGF)-β signaling. RNA sequencing revealed a total of 8 novel fusion transcripts including one derived from a chromosomal translocation between the TRIB2 and PRKCE genes. All of the 8 fusion genes were detected in primary PCs that had developed metastasis after surgical resection. We identified 14 genes up-regulated in 5 PCs that had relapsed after surgical resection. Conclusions: In this study we identified novel somatic mutations and chromosomal rearrangements in PC by examining clinically aggressive cases that had developed postsurgical metastasis. It will be essential to validate the clinical significance of these genetic changes in a larger independent patient cohort. Citation Format: Akihiko Miyanaga, Mari Masuda, Noriko Motoi, Koji Tsuta, Yuka Nakamura, Nobuhiko Nishijima, Shun-ichi Watanabe, Hisao Asamura, Akihiko Tsuchida, Masahiro Seike, Akihiko Gemma, Tesshi Yamada. Whole-exome and RNA sequencing reveals chromosomal rearrangements associated with the recurrence of pulmonary carcinoid [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 5892.
Abstract 2094: Improving cancer cytogenetic case review with a new machine learning system
Authors: Megan Roytman, Viren Wasnikar, Paul An, Raja Kashevan, Shalini Verma, Soheil Shams
Journal: Cancer Research (2020)

Abstract A novel machine learning system trained on The Cancer Genome Atlas (TCGA) data has been designed to help with classification, prognostic measures, and monitoring treatment responses in cancer management. The utility of this system will be demonstrated using a set of retrospective samples. Cytogenetic analysis has long been utilized in clinical cancer care with conventional cytogenetic methods such as chromosomal banding and FISH still standard protocols for hematologic malignancies. With the advent of microarrays, smaller and more complex variants have been discovered in cancer samples but identifying the potential impact of many alterations such as copy number variation (CNV) and loss of heterozygosity (LOH) has not been fully exploited. A typical cancer cytogenetic report can list many tens of variants with unclear clinical implications. To bridge this gap and assist with determining the clinical implications of such alterations, we have developed a novel machine learning system that has been trained using data from The Cancer Genome Atlas (TCGA). The TCGA data has been processed using the SNP-FASST2 segmentation algorithm followed by manual review for ploidy adjustment yielding high quality regions of CNV and LOH for over 6000 cases across 29 cancer types. Our novel neural network used this processed data to arrange samples based on their CNV and LOH profile across a two-dimensional map. The proximity of one sample to another on this map corresponds to its similarity in terms of CNV and LOH profile. To apply this system in a clinical setting, we have designed a case review system that aligns a new case with the learned cancer map to provide information on the similarity of the case with ones in TCGA. This enables rapid verification of tumor type or detection of a different origin for the sample than the one reported. In addition, the system can create a prognostic score using clinical survival data for the samples in TCGA. Here we will demonstrate the utility of the system in classifying new cases against the learned cancer map and estimating prognostic measures. Citation Format: Megan Roytman, Viren Wasnikar, Paul An, Raja Kashevan, Shalini Verma, Soheil Shams. Improving cancer cytogenetic case review with a new machine learning system [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 2094.
Abstract 440: Dual role of epithelial MyD88 in<i>Apc</i>-mutant intestinal tumors
Authors: Rie Kajino-Sakamoto, Teruaki Fujishita, Makoto Mark Taketo, Masahiro Aoki
Journal: Cancer Research (2020)

Abstract Mutational activation of the Wnt/β-catenin signaling plays essential roles in initiating the adenoma-carcinoma sequence for the majority of colorectal cancers (CRCs) as well as in maintaining the transformed phenotypes of progressed CRCs. However, the Wnt/β-catenin signaling itself is not easy to target for therapy. Here we addressed the roles of MyD88, a critical adaptor protein in the interleukin (IL)-1β and Toll-like receptor (TLR) pathways, in intestinal epithelial cells (IECs) during intestinal tumor formation in Apc+/Δ716 mice, a mouse model of familial adenomatous polyposis as well as the early-stage spontaneous colorectal cancer. Conditional knockout of MyD88 in IECs significantly reduced the number of intestinal tumors in Apc+/Δ716 mice. Although suppression of tumor formation in Apc mutant mice by IEC-specific knockout of MyD88 was previously reported by others, our mechanistic studies uncovered the downstream molecular pathways of MyD88 involved in tumor formation. (1) IEC-specific MyD88 loss induced inactivation of the JNK/mTORC1 signaling, a pathway we previously demonstrated to be essential in the growth of Apc+/Δ716 tumors, leading to decreased proliferation of tumor cells in vivo. (2) IEC-specific MyD88 loss reduced the level of NF-κB p65 and attenuated the Wnt/β-catenin signaling, leading to apoptosis of intestinal tumor cells in vivo. (3) Induction of MyD88 deletion in the intestinal tumor-derived organoids, but not in the normal IEC-derived organoids, caused apoptotic cell death and suppressed their growth in vitro. (4) Knockdown of MYD88 in colorectal cancer cell lines harboring mutations in the Wnt/β-catenin signaling reduced their proliferation and induced apoptosis. These results demonstrate a novel mechanism by which epithelial MyD88 contributes to intestinal tumorigenesis, and also suggest synthetic lethality between MyD88 deficiency and mutations in the Wnt/β-catenin signaling in CRCs. Citation Format: Rie Kajino-Sakamoto, Teruaki Fujishita, Makoto Mark Taketo, Masahiro Aoki. Dual role of epithelial MyD88 inApc-mutant intestinal 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 440.