tbuckley/cabot-search huggingface dataset:
Abstract 611: Reversion of mesenchymal features in NSCLC cells using M7824, a first-in-class bi-functional immunotherapeutic agent targeting PD-L1 and TGFβ1 (TGFβ TRAP)
Authors: Justin M. David, Jeffrey Schlom, Yan Lan, Claudia Palena
Journal: Cancer Research (2017)

Abstract Background: Evasion of antitumor immunity is widely regarded as a hallmark of cancer. Tumor cells can avoid immune destruction by upregulating the immune checkpoint molecule PD-L1, and antibodies targeting the PD-1/PD-L1 axis have demonstrated clinical efficacy in several tumor types. Antitumor immunity can also be suppressed by TGFβ, a pleiotropic cytokine that reduces innate and adaptive antitumor immune responses. Additionally, TGFβ impacts tumor cells by activating a differentiation program called epithelial-mesenchymal transition (EMT), in which tumor cells lose epithelial features and gain mesenchymal characteristics. The gain of mesenchymal traits is associated with metastasis, stemness, and resistance to multiple therapeutic modalities, including chemotherapy and radiation. The objective of this work is to investigate the therapeutic potential of M7824 in non-small cell lung cancer (NSCLC). M7824 is a first-in-class bi-functional immunotherapeutic agent designed to target two negative regulatory pathways in immunosuppression. It is a novel fusion protein comprised of the extracellular domain of human TGFβRII covalently linked to the C-terminus of the Fc domain of the fully human anti-PD-L1 IgG1 antibody avelumab. Methodology: In vitro assays were conducted using NSCLC cell lines treated with TGFβ1 alone or in combination with avelumab or M7824 to assess the ability of M7824 to revert features of tumor cell EMT, including molecular marker expression, cell proliferation, and response to various chemotherapies. The ability of M7824 to mediate antibody-directed cellular cytotoxicity (ADCC) of TGFβ1-treated cells in vitro was also assessed. Results: Treatment with TGFβ1 induced mesenchymal marker expression, reduced cell proliferation, and enhanced resistance to docetaxel, paclitaxel, and gemcitabine. Treatment with M7824, but not avelumab, was able to both prevent and revert these effects of TGFβ1. M7824 also exhibited the ability to mediate ADCC of TGFβ1-treated cells in vitro. Conclusions: M7824 effectively antagonizes TGFβ1-mediated tumor cell mesenchymalization, including resistance to chemotherapy. These results suggest that M7824 has the potential to relieve immunosuppression and block treatment-resistance induced by TGFβ1 in patients with NSCLC. Citation Format: Justin M. David, Jeffrey Schlom, Yan Lan, Claudia Palena. Reversion of mesenchymal features in NSCLC cells using M7824, a first-in-class bi-functional immunotherapeutic agent targeting PD-L1 and TGF&amp;#9461 (TGFβ&amp;#946 TRAP) [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 611. doi:10.1158/1538-7445.AM2017-611
Abstract 2837: Differential expression of Protocadherin-7 (PCDH7) in prostate cancer (PCa) cells: a direct association between PCDH7 and castrate resistant PCa
Authors: Gauri Shishodia, Sweaty Koul, Qin Dong, Hari K. Koul
Journal: Cancer Research (2017)

Abstract Introduction: PCa is the most commonly diagnosed disease in American men and the second leading cause of death among them. Most of PCa deaths are a result of distant metastasis and due to emergence of castrate resistant PCa. Protocadherin-7 (PCDH7), a Cadherin superfamily transmembrane protein that is known to function in cell-cell recognition and adhesion, is reported to be overexpressed in breast cancer and non-small cell lung cancer (NSCLC). PCDH7 has been shown to mediate brain metastasis of breast cancer. Overexpression of PCDH7 was reported to be associated with poor clinical outcome of NSCLC. However, there is no report on involvement of PCDH7 in PCa tumorigenesis and metastasis. In the present study we evaluated expression of PCDH7 in androgen dependent and androgen independent PCa cells and in TCGA and Trento/Cornell/Broad 2016 clinical data sets. Materials and Methods: PCa cells- LNCaP, C4-2b, DU145, PC3, 22Rv1 and RWPE1 were used in this study. Protein expression was checked by Western Blotting. mRNA levels were checked by quantitative real time PCR. Results: Our data reveal high PCDH7 protein expression in PC3 cells and low levels of PCDH7 in LNCaP and RWPE1 cells. qRT-PCR confirmed an increased transcript level of PCDH7 in PC3 and low levels in LNCaP cells. We also observed elevated transcript levels for PCDH7 in castrate resistant and Enzalutamide refractory PCa (22Rv1) cells. These data suggest a direct relationship between castrate resistance and PCDH7 expression. Our results also show an inverse relationship between PCDH7 and E-Cadherin and a direct relationship between PCDH7 and EMT markers, indicating expression of PCDH7 is associated with tumor progression. Interestingly, there was no correlation between PCDH7 with tumor grade or metastasis from TCGA data, but analysis of NEPC (Trento/Cornell/Broad 2016) data set revealed amplification of PCDH7 in 9% of NEPC tumors. Collectively, these data suggest PCDH7 expression may be associated with advanced PCa in general and NEPC phenotype PCa in particular. Conclusion: Our results suggest direct association of PCDH7 expression and castrate resistance in PCa cell lines. Role of PCDH7 in castrate resistant PCa needs further evaluation. Citation Format: Gauri Shishodia, Sweaty Koul, Qin Dong, Hari K. Koul. Differential expression of Protocadherin-7 (PCDH7) in prostate cancer (PCa) cells: a direct association between PCDH7 and castrate resistant PCa [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 2837. doi:10.1158/1538-7445.AM2017-2837
Abstract 4240: Determination of normative patterns of gene expression levels and breast cancer risk biomarkers in human breast milk
Authors: Maria Ouzounova, Georgina Lewis, Raziye Piranlioglu, Tiana Curry-McCoy, Wonsuk Yoo, Nita Maihle, Sangmi Kim, Hasan Korkaya
Journal: Cancer Research (2017)

Abstract Parity and breastfeeding influence a woman’s risk of developing breast cancer. Understanding the underlying molecular changes in the breast will facilitate identification of additional factors during pregnancy and postpartum that modify breast cancer risk. Most prior studies in humans on this topic, however, have been cross-sectional studies comparing breast tissue samples from nulliparous versus post-pregnant women, and are limited in their ability to characterize longitudinal changes and within-person variations. Breast milk contains cells of the mature gland, and may have a potential as a noninvasive source for studying molecular characteristics of the pregnancy-associated changes in the breast and their impact on breast cancer risk. The objectives of this study were to (1) determine normative patterns of gene expression levels in longitudinally collected breast milk samples and (2) correlate gene expression data in relation to self-reported measures of psychosocial stress during pregnancy and postpartum period. Our preliminary results showed that the post-pregnancy gene expression levels in breast milk samples can be measured reproducibly over a short period of time. Whole-genome transcriptome analysis revealed that expression levels of the post-pregnancy genes are different in early (less than 3 month postpartum) and late lactation period (more than 6 month postpartum). Moreover cytokine expression profiling correlated expression of inflammatory cytokines with early versus late postpartum period. The unique contribution of this study is to capture longitudinal gene expression data from breast milk samples collected over the course of lactation, hence providing a valuable basis for future studies to identify differential dynamics associated with breast cancer susceptibility. Note: This abstract was not presented at the meeting. Citation Format: Maria Ouzounova, Georgina Lewis, Raziye Piranlioglu, Tiana Curry-McCoy, Wonsuk Yoo, Nita Maihle, Sangmi Kim, Hasan Korkaya. Determination of normative patterns of gene expression levels and breast cancer risk biomarkers in human breast milk [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 4240. doi:10.1158/1538-7445.AM2017-4240
Abstract 5164: A pyrrole-Imidazole polyamide conjugate targeting KRAS oncogenic mutations is a promising approach against KRAS mutated colorectal and pancreatic cancers
Authors: Hiroki Nagase, Atsushi Takatori, Takayoshi Watanabe, Nobuko Koshikawa, Jason Lin
Journal: Cancer Research (2017)

Abstract Although a tremendous amount of studies has been made to directly target oncogenic drivers, such as RAS and MYC, no drug is clinically available because of difficulties to develop RAS- or Myc-targeted anti-cancer therapeutics due to the smooth 3D surface topology. One of major limitations of targeting the RAS pathway may be intrinsic or acquired resistance as seen in the other molecular target therapy. A new approach that directly target driver genes may provide a more direct route to help address unmet medical needs for refractory cancer conquest. We therefore synthesized the Pyrrole-Imidazole polyamide conjugate, KR12, specifically alkylated KRAS codon 12 mutant DNA (G12D or G12V). KR12 reduced expression of the mutated oncogenic-protein by RNA transcription inhibition and induced cancer cell death at low dose (1 to 50 nM). We also applied a novel enrichment-based sequencing and computational pipeline, which first identifies a PIP’s genomic binding sites through next-generation sequencing followed by gene expression microarray studies. The computational analysis suggested non-KRAS binding overall had little contribution to changes at the phenotypic level in colorectal cancer cell lines. We also the anti-cancer event is not only for colorectal but also pancreatic ductal adenocarcinoma (PDAC). Significant tumor reduction was observed in a mouse model of spontaneous PDAC (LSL-KrasG12D/+,Ptf1aCre/+,Tgfbr2flox/flox). In animal studies we also observed KR12 intakes and retentions in tumor but not any other organs 24 hours after I.V. administration. We will summarize the sequence-dependent alkylating approach using antibiotic mimics of alkylating PI-polyamide conjugates, may open a new strategy targeting the driver oncogene mutated DNA sequence. This approach should be used for medicine against variety of unfavorable KRAS mutated cancers. Note: This abstract was not presented at the meeting. Citation Format: Hiroki Nagase, Atsushi Takatori, Takayoshi Watanabe, Nobuko Koshikawa, Jason Lin. A pyrrole-Imidazole polyamide conjugate targeting KRAS oncogenic mutations is a promising approach against KRAS mutated colorectal and pancreatic cancers [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 5164. doi:10.1158/1538-7445.AM2017-5164
Abstract LB-005: Precise and rapid detection of gene fusions and microbial pathogens in next-generation sequencing data with sequence bloom trees
Authors: Erik D. Lehnert, Eric Freeman, Julia Salzman
Journal: Cancer Research (2017)

Abstract Public archives of sequencing data continue to grow at a rapid pace. (Re)analysis of large datasets can be both expensive and resource-intensive, and users are often only interested in the sample prevalence of a small subset of sequences. We have implemented a Sequence Bloom Tree data structure for the TCGA RNA-seq datasets, allowing researchers to rapidly test samples for the presence of sequences of interest. We demonstrate the ability to rapidly identify samples containing viral transcript sequences, estimate the sample prevalence of gene fusions and novel splice variants, and infer the presence of HeLa-cell contamination in a subset of TCGA data. We have implemented post-querying controls to mitigate false positives arising from the presence of genes with highly similar sequences. The tools are described using Common Workflow Language, allowing researchers to reproducibly generate and query the dataset. Citation Format: Erik D. Lehnert, Eric Freeman, Julia Salzman. Precise and rapid detection of gene fusions and microbial pathogens in next-generation sequencing data with sequence bloom trees [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-005. doi:10.1158/1538-7445.AM2017-LB-005
A proposed framework of supportive and palliative care for people with high-grade glioma
Authors: Jennifer Philip, Anna Collins, Caroline Brand, Vijaya Sundararajan, Carrie Lethborg, Michelle Gold, Rosalind Lau, Gaye Moore, Michael Murphy
Journal: Neuro-Oncology (2017)

Patients with malignant high-grade glioma (HGG) have significant supportive and palliative care needs, yet few tailored guidelines exist to inform practice. This study sought to develop an HGG framework of supportive and palliative care informed by needs reported by patients, families, and health care professionals (HCPs). This study integrates a mixed-methods research program involving: (i) exploring experiences through systematic literature review and qualitative study (10 patients, 23 carers, and 36 HCPs); and (ii) an epidemiological cohort study (N = 1821) describing care of cases of HGG in Victoria, Australia using linked hospital datasets. Recommendations based on these studies were developed by a multidisciplinary advisory committee for a framework of supportive and palliative care based on the findings of (i) and (ii). Key principles guiding framework development were that care: (i) aligns with patient/family caregiver needs according to illness transition points; (ii) involves continuous monitoring of patient/family caregiver needs; (iii) be proactive in response to anticipated concerns; (iv) includes routine bereavement support; and (v) involves appropriate partnership with patients/families. Framework components and resulting activities designed to address unmet needs were enacted at illness transition points and included coordination, repeated assessment, staged information provision according to the illness transition, proactive responses and referral systems, and specific regular inquiry of patients' and family caregivers' concerns. This evidence-based, collaborative framework of supportive and palliative care provides an approach for patients with HGG that is responsive, relevant, and sustainable. This conceptual framework requires evaluation in robust clinical trials.
<sup>11</sup>C-Methionine-PET in Multiple Myeloma: A Combined Study from Two Different Institutions
Authors: Constantin Lapa, Maria J. Garcia-Velloso, Katharina Lückerath, Samuel Samnick, Martin Schreder, Paula Rodriguez Otero, Jan-Stefan Schmid, Ken Herrmann, Stefan Knop, Andreas K. Buck, Hermann Einsele, Jesus San-Miguel, Klaus Martin Kortüm
Journal: Theranostics (2017)

11C-methionine (MET) has recently emerged as an accurate marker of tumor burden and disease activity in patients with multiple myeloma (MM). This dual-center study aimed at further corroboration of the superiority of MET as positron emission tomography (PET) tracer for staging and re-staging MM, as compared to 18F-2`-deoxy-2`-fluoro-D-glucose (FDG). 78 patients with a history of solitary plasmacytoma (n=4), smoldering MM (SMM, n=5), and symptomatic MM (n=69) underwent both MET- and FDG-PET/computed tomography (CT) at the University Centers of Würzburg, Germany and Navarra, Spain. Scans were compared on a patient and on a lesion basis. Inter-reader agreement was also evaluated. In 2 patients, tumor biopsies for verification of discordant imaging results were available. MET-PET detected focal lesions (FL) in 59/78 subjects (75.6%), whereas FDG-PET/CT showed lesions in only 47 patients (60.3%; p<0.01), accordingly disease activity would have been missed in 12 patients. Directed biopsies of discordant results confirmed MET-PET/CT results in both cases. MET depicted more FL in 44 patients (56.4%; p<0.01), whereas in two patients (2/78), FDG proved superior. In the remainder (41.0%, 32/78), both tracers yielded comparable results. Inter-reader agreement for MET was higher than for FDG (κ = 0.82 vs κ = 0.72). This study demonstrates higher sensitivity of MET in comparison to standard FDG to detect intra- and extramedullary MM including histologic evidence of FDG-negative, viable disease exclusively detectable by MET-PET/CT. MET holds the potential to replace FDG as functional imaging standard for staging and re-staging of MM.
Abstract 5682: Circulating tumour DNA following decompression using selfexpandable metallic stent
Authors: Goro Takahashi, Takeshi Yamada, Takuma Iwai, Kohki Takeda, Michihiro Koizumi, Seiichi Shinji, Yasuyuki Yokoyama, Keisuke Hara, Hiroyasu Furuki, Atsushi Watanabe, Keiichro Ohta, Eiji Uchida
Journal: Cancer Research (2017)

Abstract Background: Decompression using selfexpandable metallic stent (SEMS) has been reported to improve short-term outcomes in patients with malignant large bowel obstruction (MLBO). However, some reports suggest that SEMS worsen long-term survival. Conversely, trans-anal drainage tubes (TDT), which are similar to the ileus tubes widely used in Japan for MLBO, have had no reports suggesting reduced survival. SEMS worsen long-term survival by compressing tumor continuously and induce tumor cell death which can lead production of various types of mediator which could negatively affect prognosis. In this study, we investigated tumor cell death induced by decompression procedure by using circulating tumour DNA (ctDNA). Methods: Plasma samples were obtained before and 1, 3 and 7 days after decompression. First, we purified circulating cell free DNA (ccfDNA) from 1 mL of plasma and measured the concentration using fluorometer. Second, we measured mutated fragment of ccfDNA (circulating tumour DNA) which is derived from tumor cell. Mutational analysis from the main tumour was performed using Ion PGM™ Sequencer following library preparation with Ampliseq CHPver.2 (Thermo Fisher Scientific). Each mutant fragment in ccfDNA was quantified using digital PCR (QuantStudio 3D® digital PCR system). Results: We enrolled 30 patients (22 SEMS and 8 TDT). CcfDNA levels on day7 was significantly increased in the SEMS group (before; 623ng/ml, day7; 1455ng/ml, p=0.006) but TDT group. Sequencing result revealed that the average number of mutation per tumor was 3.7 (e.g. APC, TP53, and KRAS) out of 50 genes. Mutant fragments (ctDNA) were detected in the ccfDNA in all cases. Mutant fragment also increased after decompression in SEMS group(before; 6.2copies/μl, day3; 22.6copies/μl, p=0.03)but in TDT group. Conclusion: SEMS insertions increased plasma levels of not only ccfDNA but also ctDNA in patients with MLBO. This indicated that SEMS would induce massive cancer cell death. This tumor cell death can drain various mediators, including DAMPs, into blood flow and may worsen prognosis of patients with MLBO. Conversely, TDT may not induce massive tumor cell death. Citation Format: Goro Takahashi, Takeshi Yamada, Takuma Iwai, Kohki Takeda, Michihiro Koizumi, Seiichi Shinji, Yasuyuki Yokoyama, Keisuke Hara, Hiroyasu Furuki, Atsushi Watanabe, Keiichro Ohta, Eiji Uchida. Circulating tumour DNA following decompression using selfexpandable metallic stent [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 5682. doi:10.1158/1538-7445.AM2017-5682
Abstract 1084: Combination of eribulin and AURKA inhibitor prevents metastatic colonization and eradicates established metastases in breast cancer
Authors: Elena N. Pugacheva, Varvara Kozyreva, Anna Kiseleva, Ryan Ice, Brandon Jones, Yuriy Loskutov
Journal: Cancer Research (2017)

Abstract The majority of cancer-related deaths (90%) are happened due to metastasis from the primary tumor site to distant organs. MLN8237 is a small, highly selective molecule inhibitor of Aurora A kinase (AURKA), which results in disruption of the mitotic spindle, chromosome segregation collapse, and inhibition of cell proliferation. Numerous studies have showed that levels of AURKA are elevated in many types of cancer, including breast cancer. Our previous studies indicated that MLN8237 is extremely potent against pulmonary metastasis, but not the primary tumor in orthotropic xenograft model. To further enhance MLN8237 based regiment, its combination with other therapeutic compounds can be used. As a potential partner we chose eribulin - fully synthetic macrocyclic analogue of the marine natural product halichondrin B. Eribulin belong to the class of non-taxane microtubule destabilizing molecules, currently used in clinic to treat taxol resistant metastatic breast cancer. In present study we have investigated the effect of MLN8237 and eribulin against breast cancer in vivo and in vitro. The results showed that combination of drugs possess a synergistic effect on both primary tumor and metastases, through inducing cytotoxic autophagy and apoptosis. This data clearly indicate great potential behind the MLN8237 based therapies and introduce a new hope for the eradication of metastatic breast cancer. Citation Format: Elena N. Pugacheva, Varvara Kozyreva, Anna Kiseleva, Ryan Ice, Brandon Jones, Yuriy Loskutov. Combination of eribulin and AURKA inhibitor prevents metastatic colonization and eradicates established metastases 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 1084. doi:10.1158/1538-7445.AM2017-1084