tbuckley/cabot-search huggingface dataset:
Abstract 542: Genomic and clonal characterization of immunogenic epitope landscape across The Cancer Genome Atlas
Authors: HoJoon Lee, Stephanie Greer, Susan M. Grimes, Jae-Ho Cheong, Hanlee P. Ji
Journal: Cancer Research (2017)

Abstract Recent advances in cancer immunotherapy and genomic sequencing technologies have created promising opportunities for precision cancer medicine. Somatic mutation in coding regions of cancer genomes may lead to amino acid alterations that generate immunogenic peptides, called neoantigens. These novel peptides are tumor-specific. An individual’s own MHC genotypes restricts the presentation of these tumor-specific peptides and thus there are a limited number of candidate epitopes for immune cellular recognition. Current studies have not comprehensively studied how MHC-restricted neoantigens are present across tens of thousands of cancer. Nor have these studies determined how somatic mutations and their associated neoantigens are represented among different subclonal populations existing within individual tumors. To address these limitations, we have mapped the complex immunogenomic topology of neoantigen epitopes across 8,000 tumors representing 18 different cancer types. This neoantigen landscape accounts for how neoepitope candidates are distributed among the various clonal subpopulations existing within any given tumor.Our study utilized genomic data from the Cancer Genome Atlas (TCGA). Our automated pipeline provides results from 8,000 samples from 18 cancer types that have somatic variant calls, copy number variation, whole exome sequence, and RNA-Seq data. Identification of somatic mutations that lead to highly immunogenic antigens involved five different steps; i) in-silico translation of identified mutations, ii) expression as measured per RNA-Seq, iii) patient’s own major histocompatibility complex genotype, iv) binding affinity specific to the MHC alleles for any given patient and v) occurrence of clonal subpopulations as demonstrated by intratumoral genetic heterogeneity. We mapped the neoantigen landscape with quantitative representation of the genetic clonal diversity existing within individual tumors. In average, 2% of missense mutations from a patient are detected in RNA-Seq, with binding affinity to own HLA genotypes, and from the dominant clonal subpopulation.In summary, our study demonstrates the various relationships among the number of optimal antigens, the number of clonal subpopulations, the number of mutations, and clinical phenotypes such as tumor stage. Our automated bioinformatics process facilitates the use of exome and RNA-Seq as potential diagnostic analytic process for precision immunotherapy. Citation Format: HoJoon Lee, Stephanie Greer, Susan M. Grimes, Jae-Ho Cheong, Hanlee P. Ji. Genomic and clonal characterization of immunogenic epitope landscape across The Cancer Genome Atlas [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 542. doi:10.1158/1538-7445.AM2017-542
Abstract 4895: CT20p as a therapeutic for lung cancer with elevated chaperoning containing TCP1 (CCT) expression levels
Authors: Ana C. Carr, Amr S. Khaled, Rania Bassiouni, Annette R. Khaled
Journal: Cancer Research (2017)

Abstract Lung cancer is the leading cause of cancer related fatalities worldwide and although there is a substantial effort in the development of improved, more specific, and less debilitating therapies, very little progress has been made accomplishing this goal. We propose the use of CT20p, a therapeutic peptide developed by our laboratory, as novel therapy for lung cancer. We have previously demonstrated that CT20p has tumor specific cytotoxicity in breast cancer cells and it induces tumor regression in xenograft models of breast cancer. We have also determined Chaperonin containing T-complex (CCT) to be the intracellular target of CT20p and that susceptibility to CT20p correlates with its expression levels, with tumor cells expressing high levels of CCT being the most susceptible. CCT is a large macromolecular complex composed of 8 subunits (CCTα, CCTβ, CCTγ, CCTδ, CCTϵ, CCTζ, CCTη, CCTθ). Immunoblot probing against four relevant CCT subunits (CCTβ, CCTγ, CCTδ, CCTϵ) was used to determine their relative expression level in five small cell lung cancer (SCLC) cell lines when compared to normal lung cells. We determined that the expression levels of the four probed CCT subunits varied amongst the five SCLC cell lines, however, the four CCT subunits were always expressed at higher levels when compared to normal lung cells. Immunohistochemistry staining for CCTβ was used on tissue microarray (TMA) of lung cancer progression. Results were interpreted on a scale of 1 to 4 (with 4 being the strongest staining). We determined that CCTβ levels increase with cancer severity and identified a significant correlation between CCTβ levels and cancer progression in both small cell lung carcinoma (SCLC) and Squamous cell lung carcinoma (SqCLC). Using The Cancer Genome Atlas (TCGA) database, we have found CCT gene alterations in clinical lung cancer cases range from 10% to 43%, however, only CCT4 gene amplification in SqCLC cases correlated with decreased survival. Altogether, these results suggest that CT20p has the potential for being a therapeutic for multiple types of lung cancer due to increased target expression. Citation Format: Ana C. Carr, Amr S. Khaled, Rania Bassiouni, Annette R. Khaled. CT20p as a therapeutic for lung cancer with elevated chaperoning containing TCP1 (CCT) expression levels [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 4895. doi:10.1158/1538-7445.AM2017-4895
Abstract 3851: Targeting HER2 in gastric cancer: Hints from a gastric PDX platform
Authors: Simona Corso, Cristina Migliore, Maria Apicella, Silvia Menegon, Eirini Pectasides, Tania Capeloa, Stefania Durando, Marilisa Cargnelutti, Paola Cassoni, Anna Sapino, Maurizio de Giuli, Adam Bass, Silvia Giordano
Journal: Cancer Research (2017)

Abstract Introduction: Gastric cancer is the 3rd leading cause of cancer mortality worldwide. Surgery is the only curative treatment strategy and conventional chemotherapy has shown limited efficacy. Trastuzumab (a HER2 mAb), is the only therapy targeting molecular alterations approved so far in gastric cancer, for HER2+ patients with advanced disease. However only a fraction (&amp;lt;20%) of HER2 amplified patients benefits from treatment. Methods: We have recently generated a molecularly annotated colony of gastro-esophageal PDXs (at the moment, &amp;gt; 70 PDXs). The platform also comprises primary cell lines and 3D-cultured organoids derived from gastric cancer PDXs. Results and Discussion: At present, we have identified several HER2+ PDXs and generated the corresponding in vitro derivatives. Four HER2+ PDXs, showing 3+ HercepTest score and HER2 amplification &amp;gt; 8 copies (thus theoretically sensitive to Trastuzumab), were selected to undergo ‘xenotrials’ with the following anti-HER2 drugs/combos: Trastuzumab (T); Pertuzumab (P, anti-HER2 mAb); Lapatinib (L, a dual HER2-EGFR tyrosine kinase inhibitor). According to RECIST-like criteria, T induced tumor regression in only 1 out of 4 HER2+ PDXs. Interestingly, in all the tumors but one the combos T+P and T+L were able to bypass resistance to T monotherapy and to induce tumor regression. One tumor was resistant to all the tested therapeutic approaches. Conclusion: We identified PDXs displaying HER2 gene amplification. Only a minor fraction of them benefited from the anti-HER2 mono-therapy, despite the presence of a strong HER2 gene amplification, while the association of two HER2 inhibiting drugs resulted in intense and prolonged response. This suggests that monotherapy with T might not be the most effective therapeutic approach in gastric cancer patients. We are currently investigating the cause of resistance to anti-HER2 drugs to identify mutations/CNV in tumors showing resistance to Trastuzumab. Note: This abstract was not presented at the meeting. Citation Format: Simona Corso, Cristina Migliore, Maria Apicella, Silvia Menegon, Eirini Pectasides, Tania Capeloa, Stefania Durando, Marilisa Cargnelutti, Paola Cassoni, Anna Sapino, Maurizio de Giuli, Adam Bass, Silvia Giordano. Targeting HER2 in gastric cancer: Hints from a gastric PDX platform [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 3851. doi:10.1158/1538-7445.AM2017-3851
Abstract 1028: Genetic disruption of Kras sensitizes lung cancer cells to Fas-mediated apoptosis
Authors: Haiwei Mou, Jill Moore, Sunil Malonia, Yingxiang Li, Deniz Ozata, Soren Hough, Chunqing Song, Jordan Smith, Has Yin, Andrew Fisher, Daniel Anderson, Shipping Weng, Michael Green, Wen Xue
Journal: Cancer Research (2017)

Abstract Genetic lesions that activate KRAS account for ~30% of the 1.6 million annual cases of lung cancer. Despite clinical need, KRAS is still undruggable using traditional small molecule drugs/inhibitors. When oncogenic Kras is suppressed by RNA interference, tumors initially regress but eventually recur and proliferate despite suppression of Kras. Here we show that tumor cells can survive CRISPR-mediated knockout of oncogenic Kras, indicating the existence of Kras-independent survival pathways. Thus even if clinical KRAS inhibitors were available, resistance would remain an obstacle to treatment. Kras-independent cancer cells exhibit decreased colony formation in vitro but retain the ability to form tumors in mice. Comparing the transcriptomes of oncogenic Kras cells and Kras knockout cells, we identified 603 genes that were specifically upregulated in Kras knockout cells, including the Fas gene, which encodes a cell surface death receptor involved in physiological regulation of apoptosis. Antibodies recognizing Fas-receptor efficiently induced apoptosis of Kras knockout cells but not oncogenic Kras expressing cells. Increased Fas expression in Kras knockout cells was attributed to decreased association of repressive epigenetic marks at the Fas promoter. Concordant with this observation, treating oncogenic Kras cells with histone-deacetylase inhibitor and Fas-activating antibody efficiently induced apoptosis, thus bypassing the need to inhibit Kras. Our results suggest that activation of Fas could be exploited as an Achilles’ heel in tumors initiated by oncogenic Kras. Citation Format: Haiwei Mou, Jill Moore, Sunil Malonia, Yingxiang Li, Deniz Ozata, Soren Hough, Chunqing Song, Jordan Smith, Has Yin, Andrew Fisher, Daniel Anderson, Shipping Weng, Michael Green, Wen Xue. Genetic disruption of Kras sensitizes lung cancer cells to Fas-mediated apoptosis [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 1028. doi:10.1158/1538-7445.AM2017-1028
Abstract 2480: Suppression of homology-dependent DNA double-strand break repair induces PARP inhibitor sensitivity in <i>VHL</i>-deficient human renal cell carcinoma
Authors: Susan E. Scanlon, Parker L. Sulkowski, Peter M. Glazer
Journal: Cancer Research (2017)

Abstract The von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in the vast majority of human clear cell renal carcinomas. The pathogenesis of VHL loss is currently best understood to occur through stabilization of the hypoxia-inducible factors, activation of hypoxia-induced signaling pathways, and transcriptional reprogramming towards a pro-angiogenic and pro-growth state. However, hypoxia also drives other pro-tumorigenic processes, including the development of genomic instability via down-regulation of DNA repair gene expression. Here, we find that DNA repair genes involved in double-strand break repair by homologous recombination (HR) and in mismatch repair, which are down-regulated by hypoxic stress, are decreased in VHL-deficient renal cancer cells relative to wild type VHL-complemented cells. Non-homologous end joining (NHEJ) genes are not decreased in VHL-deficient cells, demonstrating specificity of the down-regulation and similarity to hypoxia. Functionally, this repression of HR genes is associated with impaired DNA double-strand break repair in VHL-deficient cells, as determined by the persistence of ionizing radiation-induced DNA double-strand breaks and reduced activity in a homology-dependent plasmid reactivation assay. Furthermore, VHL deficiency conferred increased sensitivity to the DNA crosslinking agent mitomycin C and PARP inhibitors, analogous to the synthetic lethality observed between hypoxia and these chemotherapeutic agents. Finally, we discovered a correlation between VHL inactivation and reduced HR, but not NHEJ, gene expression in a large panel of human renal carcinoma samples. Together, our data elucidate a novel connection between VHL-deficient renal carcinoma and hypoxia-induced down-regulation of DNA repair, and identify potential opportunities for targeting DNA repair defects in human renal cell carcinoma. Citation Format: Susan E. Scanlon, Parker L. Sulkowski, Peter M. Glazer. Suppression of homology-dependent DNA double-strand break repair induces PARP inhibitor sensitivity in VHL-deficient human renal cell carcinoma [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 2480. doi:10.1158/1538-7445.AM2017-2480
Abstract 4461: Detection of somatic mutations in exosomal RNA from human oral squamous cell carcinoma cells
Authors: Norihiko Tokuzen, Koh-ichi Nakashiro, Hiroyuki Hamakawa
Journal: Cancer Research (2017)

Abstract Exosomes are small vesicles, ranging from 30 to 100 nm in size, secreted from most types of cells. They contain proteins, lipids, and nucleic acids (e.g. DNA, mRNA, and microRNA) and are thought to play an important role in cell proliferation, invasion, and metastasis in human malignancies. Recently, circulating exosomes have also been of interest as a source for liquid biopsies. In this study, we examined the usefulness of exosomal RNA as a biomarker and attempted to detect the tumor-specific gene mutations from exosomal RNA derived from human oral squamous cell carcinoma (OSCC) cells. We used 3 human OSCC cells (HSC2, KT-T, KT-N). KT-T and KT-N cells were established from the lower gingival tumor and lymph node metastasis, respectively. First, we detected the somatic mutations in genomic DNA extracted from these cells by next-generation sequencing (NGS) with the use of HaloPlex Cancer Research Panel (Agilent Technologies). PIK3CA H1047R mutation was identified in all OSCC cells, and KT-N cells had the additional HRAS Q61R mutation. We confirmed these mutations of PIK3CA and HRAS in OSCC cells by TaqMan® SNP Genotyping Assays (Thermo Fisher Scientific). Subsequently, we evaluated the gene mutations in exosomal RNA from these OSCC cells. Exosomal RNA was isolated from the conditioned medium using exoRNeasy Serum/Plasma Maxi Kit (Qiagen) according to the manufacture’s protocol. In exosomal RNA, we found the PIK3CA H1047R mutation from all OSCC cells and HRAS Q61R mutation from KT-N cells by genotyping assays. Furthermore, we assessed the detection of these mutations in tumor xenograft mouse models. KT-T and KT-N cells (5 x 106) complexed with Matrigel® (BD) in 100-µl aliquots were injected subcutaneously space in the flank of male athymic nude mice. Exosomal RNA was isolated from the serum of tumor-bearing nude mice using exoRNeasy Serum/Plasma Midi Kit (Qiagen). By genotyping assays using serum exosomal RNA, PIK3CA H1047R mutation was observed in both types of xenograft mice and HRAS Q61R mutation was positive in KT-N xenograft mice. Cancer cell-derived exosomal RNA had the same gene mutations in those cells, and could be detected in the serum of tumor-bearing nude mice. These results suggest that exosomal RNA is useful for detecting somatic mutations in OSCC cells. Citation Format: Norihiko Tokuzen, Koh-ichi Nakashiro, Hiroyuki Hamakawa. Detection of somatic mutations in exosomal RNA from human oral squamous cell carcinoma cells [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 4461. doi:10.1158/1538-7445.AM2017-4461
Abstract 5904: Stiffness of extracellular matrix regulates breast cancer progression by stimulating mesenchymal stem cells
Authors: Seiichiro Ishihara, David R. Inman, Wan-Ju Li, Suzanne M. Ponik, Patricia J. Keely
Journal: Cancer Research (2017)

Abstract The tumor microenvironment contains cancer cells, non-cancerous cells, and extracellular components such as extracellular matrix (ECM). Previous studies have demonstrated that interactions between the cells and the microenvironment contribute to cancer progression via chemical stimuli, such as growth factors, and mechanical stimuli, such as stiffness of the ECM. Recently, it has been reported that mesenchymal stem cells (MSCs) differentiate into cancer associated fibroblasts (CAFs) in response to chemical stimuli from cancer cells and thereby promote cancer progression. However, the contribution of mechanical stimuli to MSCs in cancer is poorly understood. In this study, we revealed that MSCs showed CAF phenotypes and promote mammary cancer progression in response to mechanical stimuli. On a stiff substrate, MSCs treated with conditioned media from cancer cell culture expressed increased levels of alpha smooth muscle actin (alpha-SMA), a marker of CAFs, compared to the MSCs cultured on a soft substrate. MSCs grown on a stiff substrate displayed higher expression and activity of YAP and increased phosphorylation of myosin light chain (MLC) compared to MSCs grown on a soft substrate. In addition, knockdown of YAP by shRNA decreased the expression of alpha-SMA and phosphorylation of MLC in MSCs on a stiff substrate. Pharmacological inhibition of MLC phosphorylation by H1152 treatment also reduced expression of alpha-SMA and activity of YAP in MSCs. Cell-cell communication between MSCs and carcinoma cells was bi-directional, as conditioned medium from MSCs cultured on a stiff substrate, but not a soft substrate, increased growth of mammary carcinoma cells. The soluble factor prosaposin was highly secreted by the MSCs on a stiff substrate, and the addition of recombinant prosaposin increased proliferation and survival of mammary carcinoma cells. Furthermore, secretion of prosaposin was promoted in YAP-overexpressed MSCs on a soft substrate. Mammary carcinoma cells treated with prosaposin showed increased level of phosphorylation in Akt at T308. In addition, inhibition of phosphorylation of Akt at T308 prevented proliferation and survival in mammary carcinoma cells. These results suggest that increased stiffness of the ECM in the tumor microenvironment induces differentiation of MSCs to CAFs via YAP and actomyosin contractility, secretion of prosaposion from MSCs, and as a result, trigger progression of mammary cancer via phosphorylation of Akt at T308. Citation Format: Seiichiro Ishihara, David R. Inman, Wan-Ju Li, Suzanne M. Ponik, Patricia J. Keely. Stiffness of extracellular matrix regulates breast cancer progression by stimulating mesenchymal stem cells [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 5904. doi:10.1158/1538-7445.AM2017-5904
Abstract 3818: Identification of a <i>FGFR3-TACC3</i> fusion in esophageal cancer
Authors: Takuro Mizukami, Kazuko Sakai, Saeko Naruki, Tomoko Taniyama, Yoshiki Horie, Naoki Izawa, Takashi Tsuda, Takashi Fujino, Narikazu Boku, Hiroshi Yasuda, Tetsu Fukunaga, Takako Eguchi Nakajima, Kazuto Nishio
Journal: Cancer Research (2017)

Abstract Aberrant activation of fibroblast growth factor (FGF) signaling has been found to contribute to carcinogenesis. Recently, activating FGFR fusions are detected in several malignancy. However, limited information is available regarding the existence of FGFR fusions in esophageal squamous cell cancer (ESCC) and gastric cancer (GC). In this report, we explored major FGFR1, FGFR2, and FGFR3 fusion transcripts in ESCC and GC specimens (n = 74 and 114, respectively) using a most comprehensive next-generation sequencing panel. We detected a targetable fusion between exon 18 of FGFR3 and exon 11 of TACC3 at a frequency of 1.4% (1/74) in ESCC, whereas other FGFR fusions were not detected in the ESCC or GC specimens analyzed. Furthermore, split FGFR3 signals were apparent in this specimen by fluorescence in situ hybridization (FISH) with break-apart probes. The patient, a 64-year-old man with unresectable T4bN3M1 poorly differentiated ESCC of stage IV, was treated with palliative chemoradiotherapy followed by taxane chemotherapy. The patient died of cancer progression, with his overall survival time having been 9.5 months. Our results provide sequence information that should prove useful for development of simple and cost-effective diagnostic assays as an alternative to FISH for patients with ESCC harboring the FGFR3-TACC3 fusion. Citation Format: Takuro Mizukami, Kazuko Sakai, Saeko Naruki, Tomoko Taniyama, Yoshiki Horie, Naoki Izawa, Takashi Tsuda, Takashi Fujino, Narikazu Boku, Hiroshi Yasuda, Tetsu Fukunaga, Takako Eguchi Nakajima, Kazuto Nishio. Identification of a FGFR3-TACC3 fusion in esophageal 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 3818. doi:10.1158/1538-7445.AM2017-3818