bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 482: Recurrent glioma with lineage conversion from oligodendroglioma to astrocytoma: Another facet of glioma evolution during recurrence
Authors: Lee Kyung-Hwa , Jung Tae-Young , Jung Shin , Lee Jae-Hyuk , Kim Kyung-Keun , Kim Hangun , Moon Kyung-Sub
Published: August 2019

Background: Following the introduction of the molecular classification of gliomas by the WHO in 2016, molecularly-proven lineage conversion during glioma recurrence has never been reported.

Methods: We analyzed two cases of recurrent glioma that began as oligodendroglioma, both histologically and molecularly, but converted to astrocytoma over episodes of recurrence.

Results: The cases were initially diagnosed as oligodendroglioma with 1p/19q-codeletion and mutation of isocitrate dehydrogenase 1 (IDH1)-R132H. The recurrent tumors showed loss of alpha-thalassemia/mental retardation X-linked (ATRX) expression, strong P53 positivity, and 1p/19q-nondeletion. Next generation sequencing (NGS) analysis performed on the first case confirmed the transition of molecular traits from oligodendroglioma to astrocytoma. An IDH mutation of R132H was preserved in the episodes of recurrence, but ATRX and TP53 mutations were newly acquired and TERT promoter mutation C228T was lost at the most recent recurrence.

Conclusions: The issue in question for the presented cases is whether the original tumors were pure oligodendrogliomas that then transdifferentiated into astrocytomas, or whether the original tumor was an oligoastrocytoma having oligodendroglioma cells that outnumbered the astrocytoma cells and where the astrocytoma cells becoming more dominant over the episodes of recurrence. With the recognition of the possibility of lineage conversion, our study suggests that molecular examination should be performed to adjust therapeutic strategies in recurrent gliomas. Indeed, our observation of lineage conversion in glioma recurrence calls into question the current distinction drawn between oligodendroglioma, astrocytoma and oligoastrocytoma, rather than simply bidding “farewell to oligoastrocytoma”.

Citation Format: Kyung-Hwa Lee, Tae-Young Jung, Shin Jung, Jae-Hyuk Lee, Kyung-Keun Kim, Hangun Kim, Kyung-Sub Moon. Recurrent glioma with lineage conversion from oligodendroglioma to astrocytoma: Another facet of glioma evolution during recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 482.
Abstract 4853: M6123 is an ADCC-enhanced and selective monovalent antagonist of FGFR1 showing antitumor activity in preclinical lung cancer models
Authors: Esdar Christina , Iffland Christel , Zimmermann Astrid , Lim Angela , Sanderson Michael , Blaukat Andree
Published: August 2019

Despite the considerable progress made with immunotherapies and targeted therapies, lung cancer remains a devastating disease with a high medical need for more effective and safer therapeutic options. Targeted therapies have delivered meaningful benefit to subsets of lung adenocarcinoma patients harboring specific oncogenic driver alterations but have not yet been extensively explored in other lung cancer subtypes. In the case of lung squamous carcinoma and small-cell lung cancer, amplification and overexpression of FGFR1 have been described as potential oncogenic drivers.Several small molecule tyrosine kinase inhibitors of the FGFR family are in clinical development but initial reports have suggested limited therapeutic benefit of these agents when applied as monotherapy in FGFR1-amplified lung cancer patients. To overcome toxicities associated with pan-FGFR inhibition, such as dysregulation of FGF23-mediated phosphate homeostasis, M6123 was developed as an FGFR1-selective biological antagonist. An immunization campaign in OmniRats® led to the identification of the fully human, potent and highly selective FGFR1 antibody A08 which was converted into the monovalent FGFR1 antagonist M6123 based on the proprietary SEED platform. Furthermore, M6123 was engineered for enhanced ADCC effector function. In contrast to bivalent FGFR1 antibodies, M6123 was well tolerated in mice, with no signs of body weight loss. Of note, M6123 did not interfere with hormonal FGF23 signaling in mice, a severe side effect of FGFR kinase inhibitors. Concentration-dependent inhibition of FGFR1 auto-phosphorylation was demonstrated in FGFR1-overexpressing lung cancer cells both in vitro and in vivo. Moreover, M6123 monotherapy had strong antitumor activity in specific FGFR1-expressing cell line- and patient-derived xenograft models, whilst combination with chemotherapy significantly enhanced efficacy. In summary, M6123 is a unique and clearly differentiated selective FGFR1 antagonist which warrants further testing in preclinical models to refine a predictive biomarker strategy for selection of potentially sensitive lung cancer patients.

Citation Format: Christina Esdar, Christel Iffland, Astrid Zimmermann, Angela Lim, Michael Sanderson, Andree Blaukat. M6123 is an ADCC-enhanced and selective monovalent antagonist of FGFR1 showing antitumor activity in preclinical lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4853.
Abstract 4864: Targeted melanoma therapies as radiosensitizers
Authors: Smith Jessica L. , Chang Cecilia , Wang Tim , Rizos Helen , Shen Han , Carlino Matteo , Hau Eric
Published: August 2019

Introduction: In BRAFV600 mutant melanoma combination of BRAF and MEK inhibitors is associated with a rapid response in approximately 70% of patients, and an improvement in survival. Radiotherapy is used in the treatment of melanoma in multiple clinical settings including stereotactic radiosurgery for brain metastasis, oligo-metastatic extracranial disease and palliative radiotherapy to symptomatic lesions. Preclinical studies, and a small number of clinical case reports suggest the BRAF inhibitor vemurafenib and the MEK inhibitor trametinib leads to increased radiosensitivity.

Aims: To determine if BRAF Inhibitors dabrafenib, vemurafenib and encorafenib, alone or in combination with their corresponding MEK Inhibitors, are radiation-sensitising in BRAF-mutant treatment naive melanoma cells.

Methods: Three melanoma cell lines harbouring a BRAF V600E mutation were studied: A375, SkMel28 and MM200. The half-maximal inhibitory concentration (IC50) for each cell line was determined by MTS assays for vemurafenib, dabrafenib, encorafenib, and the MEK inhibitors trametinib, binimetinib and cobimetinib. Clonogenic assays were conducted on each cell line. The optimal dose of BRAF and MEK inhibitors was determined from MTS assay and single drug clonogenic assays. Cells were treated with BRAF or MEK inhibitor alone and in combination. Cells were also treated with increasing doses of radiation (X-RAD 320 irradiator, PXI). The mode of cell death and changes in cell morphology were determined by live cell imaging (Wide Field Live Cell Observer, Ziess) for five days following the above treatments.

Results:Using Clonogenic assays, we confirmed that radiation sensitivity varies across different melanoma cell lines, with MM200 being significantly more sensitive to radiation then SKMel28. Clonogenic assays demonstrated that vemurafenib, dabrafenib, encorafenib, trametinib and binimetinib increased radiosensitivity across all three-cell lines. Further, the level of radiosensitsation was greater in combination across all three sets, than with either BRAF or MEK inhibitor alone. Using live cell imaging, we were able to confirm this increase in cell death, and visualise differences in the mode of cell death and morphology with these therapies.

Conclusions: Vemurafenib, dabrafenib, encorafenib, trametinib and binimetinib were shown in this study to be radiosensitisers in BRAFV600Emutant melanoma cell lines. Radiosensitisation was greatest with combined BRAF and MEK inhibition. Further studies are being conducted to determine if this sensitisation continues after BRAF resistance develops.

Citation Format: Jessica L. Smith, Cecilia Chang, Tim Wang, Helen Rizos, Han Shen, Matteo Carlino, Eric Hau. Targeted melanoma therapies as radiosensitizers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4864.
Abstract 4867: Radiosurgery consultation to treatment interval, additional brain metastases during the interim and outcomes after therapy
Authors: Ampil Federico , Caldito Gloria , Richards Troy
Published: August 2019

Background: Expediting the process of diagnosis and treatment should theoretically improve outcome. Delays in beginning therapy can cause anxiety to the patients and physicians who may be concerned about tumor progression before treatment is initiated. Treatment delays can be characterized as patient-generated or logistical medical infrastructure prolongations.

Objective: The goal of the present study was to determine the impact of stereotactic radiosurgery (RS) consultation to treatment interval (CTI) and the development of additional brain metastases (BRM) during the interim on outcomes after RS.

Methods: Between October 2014 and April 2018, 15 individuals developed more contrast-enhancing BRMs during the CTI. These patients were treated with gamma knife RS (including the six patients who underwent gross resection of metastatic intracranial neoplasm). The median duration of CTI was 19 days (range 5-61 days). A comparison of the ≤19 days CTI (eight patients) to the >19 days CTI (seven patients) was performed to assess the effects of the extent of delay to RS. The total number of BRM for RS was 68. The median target volume was 0.48 cm3, and the median margin dose was 24 Gy.

Results: Most (67%) of the subjects exhibited good performance status. The overall crude survival rate at two years was 27%; acute or late toxicity after RS was not observed. Comparison of the CTI groups revealed: i) A longer CTI was not associated with a poorer prognosis; ii) BRM recurrence after RS was less common in this patient subgroup; iii) Quality of life (QOL) was satisfactory even though the CTI was prolonged.

Conclusion: Acceptable longevity with minimal morbidity satisfying the QOL consideration was found in this audit of cases about CTI and the occurrence of more BRMs during the interim. Decreasing CTI in patients with BRM remains an important goal of quality improvement.

Citation Format: Federico Ampil, Gloria Caldito, Troy Richards. Radiosurgery consultation to treatment interval, additional brain metastases during the interim and outcomes after therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4867.
Abstract 4872: Disulfiam, a re-positioned aldehyde dehydrogenase inhibitor, enhances radiosensitivity of human glioblastoma cells in vitro
Authors: Koh Hyeon Kang , Seo Soo Yeon , Kim Jin Ho , Kim Hak Jae , Chie Eui Kyu , Kim Seung-Ki , Kim Il Han
Published: August 2019

Purpose : Glioblastoma, the most common brain tumor in adults, has poor prognosis. The purpose of this study was to determine the effect of disulfiram (DSF), an aldehyde dehydrogenase inhibitor, on in vitro radiosensitivity of glioblastoma cells with different methylation status of O6-methylguanine-DNA methyltransferase (MGMT) promoter and the underlying mechanism of such effect.

Materials and Methods : Five human glioblastoma cells (U138MG, T98G, U251MG, U87MG, and U373MG) and one normal human astrocyte (NHA) cell were cultured and treated with DSF or 6MV x-rays (0, 2, 4, 6, 8 Gy). For combined treatment, cells were treated with DSF before irradiation. Surviving fractions fit from cell survival based on colony forming ability. Apoptosis, DNA damage repair, and cell cycle distribution were assayed by Western blot for cleaved caspase-3, γH2AX staining, and flow cytometry, respectively.

Results : DSF induced radiosensitization in most of the glioblastoma cells, especially, in the cells with radioresistance as wildtype unmethylated promoter (MGMT-wt), but did not in normal NHA cell. DSF augmented or induced cleavage of caspase-3 in all cells after irradiation. DSF inhibited repair of radiation-induced DNA damage in MGMT-wt cells, but not in cells with methylated MGMT promoter (MGMT-meth). DSF abrogated radiation-induced G2/M arrest in T98G and U251MG cells.

Conclusion : Radiosensitivity of glioblastoma cells were preferentially enhanced by pre-irradiation DSF treatment compared to normal cell, especially radioresistant cells such as MGMT-wt cells. Induction of apoptosis or inhibition of DNA damage repair may underlie DSF-induced radiosensitization. Clinical benefit of combining DSF with radiotherapy should be investigated in the future.

Citation Format: Hyeon Kang Koh, Soo Yeon Seo, Jin Ho Kim, Hak Jae Kim, Eui Kyu Chie, Seung-Ki Kim, Il Han Kim. Disulfiam, a re-positioned aldehyde dehydrogenase inhibitor, enhances radiosensitivity of human glioblastoma cells in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4872.
Abstract 4874: Incidental gallbladder cancer: Best step forward
Authors: Galodha Saurabh , Mahajan Puneet
Published: August 2019

Objective: There is a rising trend of Incidental Gall Bladder Cancer (IGBC) with increase in laparoscopic cholecystectomy. Objective of our study was to evaluate the efficacy of further management (completion surgery and adjuvant chemotherapy) in IGBC in terms of long-term survival (> 5 years).

Material and Method: Clinic-pathological and survival data of 145 IGBC patients was analysed from a prospectively maintained database of GBC. Patients investigated with triple phase CT abdomen and if required PET-CT. Diagnostic laparoscopy with Completion extended cholecystectomy performed in patients amenable for resection. Adjuvant therapy consisted of gemcitabine and cisplatin. Patients followed up with OPD visits and telephonic enquiry.

Results: 864 patients of GBC were treated during the period of January 1989 to December 2012. Out of these 145 patients were IGBC [113 women (77%), median age; 52 years)]. 96 patients were detected on histopathology while 49 were diagnosed intra-operatively. Open cholecystectomy was done in 88, laparoscopic in 45 while 12 underwent laparoscopic converted to open cholecystectomy. Commonest T stage was T3 (n=71). All patients were re-evaluated after diagnosis of IGBC. 80 patients (55%) were taken up for surgery of which, 50 (62.5%) underwent completion extended cholecystectomy (rest had metastases or locally advanced unresectable disease). Median time interval between index surgeries to re-exploration was 35 days (0-250). It was longer in patients who could not undergo completion extended cholecystectomy (70 days vs. 49 days). Overall 5-year survival in pT1b, pT2 and pT3 stage was 49.5%, 36.1% and 8.4% respectively, but was considerably better in patients who underwent completion extended cholecystectomy compared with those who did not undergo re-surgery [pT1; 62.5% vs. 29.1%, pT2; 52.2% vs. 15.9%, pT3; 22.6% vs. 7.2%, p<0.001]. Prognostic factors associated with poor prognosis were higher T stage, R1 resection, bile spillage during index surgery, no completion surgery and residual disease on re-exploration on univariate analysis. On multivariate analysis factors portending poor prognosis were higher T stage, R1 resection and residual disease.

Conclusion: Early recognition, early completion radical surgery and adjuvant therapy lends considerable survival benefit to patients of incidental carcinoma gall bladder. Residual disease and R1 resection portends a poorer survival. High index of suspicion should be kept in patients with thick walled GB to avoid missing a malignancy at index surgery.

Citation Format: Saurabh Galodha, Puneet Mahajan. Incidental gallbladder cancer: Best step forward [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4874.
Abstract 4876: Clinical significance of diffuse-type histological type coexistence in Stage II/III gastric cancer
Authors: Tanaka Hiroaki , Muguruma Kazuya , Tamura Tatsuro , Toyokawa Takahiro , Shibutani Masatsune , Fukuoka Tatsunari , Nagahara HIsashi , Ohira Masaichi
Published: August 2019

Background: Signet ring cell carcinoma (sig) and non-solid poorly differentiated adenocarcinoma (por2) are the histological forms of gastric cancer called diffuse type. They are considered to be a tissue type with a poor prognosis. Adjuvant chemotherapy using S-1 is standard therapy for stage II/III gastric cancer in Japan, however, clinical relevance of histological type to outcome of adjuvant therapy remains unclear.

Purpose: The purpose of the present study was to examine the impact of the coexistence of diffuse type on the prognosis of stage II/III gastric cancer.

Patients and Methods: We retrospectively analyzed the clinicopathologic data of 935 gastric carcinoma patients who underwent gastrectomy between 2007 and 2015 at our department.

Results: We observed that there were 62 cases (17%) with sig mixed (dominant 12 cases, inferiority 50 cases) and 104 cases (30%) with por 2 mixed (dominant 19 cases, inferiority 85 cases). The patients with por2 or sig had more peritoneum dissemination compared with intestinal types. In Stage III, the recurrence rate was high in the case with sig mixed, the 3-year relapse-free survival rate was 36% in the mixed case and 55% in the non-mixed case. However, we found no correlation of sig mixture to prognosis of patients with Stage II. Among the patient who received the S-1 adjuvant chemotherapy, the prognosis of sig mixture was relatively poor.

Conclusion: In the case of stage III gastric cancer in which there was mixed signet ring cell carcinoma in the tissue, the recurrence rate was high and the prognosis was poor. Our findings suggested that it should be needed to treat sig mixed cases as a high risk group in the future postoperative adjuvant chemotherapy for gastric cancer.

Citation Format: Hiroaki Tanaka, Kazuya Muguruma, Tatsuro Tamura, Takahiro Toyokawa, Masatsune Shibutani, Tatsunari Fukuoka, HIsashi Nagahara, Masaichi Ohira. Clinical significance of diffuse-type histological type coexistence in Stage II/III gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4876.
Abstract 4882: Expression atlas of FGF and FGFR genes in pan-cancer uncovered predictive biomarkers for FGFR inhibition response in clinical trials
Authors: Li Yuan , Wu Long , Cheng Yanlei , Tao Weiping , Wu Dawei , Ma Fei , Li Ning
Published: August 2019

Genomic variation of FGFR has been intensively investigated in cancer for years, however, clinical trials on the basis of FGFR mutation or amplification as a druggable target of FGFR inhibitors have produced disappointing clinical outcomes. Therefore, the identification of predictive biomarkers for FGFR-targeted agents has remained a crucial issue. Expression profiles of FGF and FGFR in 8,111 patients with 24 types of solid tumors and 879 tumor cell lines along with drug sensitivity data were obtained from public databases. Differential expression, survival and correlation analyses were performed to uncover the clinical relevance of FGF and FGFR genes expression in pan-cancer. As results, FGF and FGFR were frequently dysregulated in pan-cancer. Moreover, almost all the FGF and FGFR were significantly associated with overall survival in at least two cancer types, however, mixed prognostic values were seen in pan-cancer. More importantly, tumor cell lines with high FGFR1/3 expression were more sensitive to FGFR inhibitor PD173074, especially in breast cancer, liver cancer, lung squamous cell carcinoma and ovarian cancer. The predicted positive ratios of FGFR1/2/3/4 were generally over 10% in most tumor types, especially in squamous cell carcinoma. High positive FGFR1 or 3 expression ratio were predicted in cholangiocarcinoma (58%), followed by bladder cancer (42%), endometrial carcinoma (35%), ovarian cancer (34%) and head and neck squamous cell carcinoma (34%). FGFR expression were promising predictive biomarkers for FGFR inhibition response in clinical trials and different combination of FGFR genes should be used in screening for patients in certain tumor types.

Citation Format: Yuan Li, Long Wu, Yanlei Cheng, Weiping Tao, Dawei Wu, Fei Ma, Ning Li. Expression atlas of FGF and FGFR genes in pan-cancer uncovered predictive biomarkers for FGFR inhibition response in clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4882.
Abstract 4924: High ALDH1 expression in colorectal carcinoma could predict early onset of the disease
Authors: Vermani Litika , Kumar N Senthil , Talukdar Anuradha , Deka Monoj , Kannan Ravi , Kumar Rajeev
Published: August 2019

Background: Worldwide there is an increase in the trend of early onset of colorectal carcinoma in individuals who are less than 45 years of age. The composition of young age colorectal cases ranges from 35% to 40% in India. Currently, we do not have the access to any molecular marker that could predict early onset of the disease and its clinical course. Aldehyde dehydrogenase 1 (ALDH1), Twist, E Cadherin and Vimentin are markers for cancer stem cells and epithelial mesenchymal transition. However, there is paucity of data on their clinical significance in terms of their impact on early onset of colorectal carcinoma. This lack of data prompted us to investigate their role in the early onset of the colorectal cancer.

Methods: Immunohistochemisty of ALDH1, Twist, E Cadherin and Vimentin was performed in pre treatment biopsy samples collected from 103 colorectal patients who were further divided into 2 groups: viz, less than or equal to 45 years and more than 46 years.

Results: Over expression of ALDH1, Twist, E Cadherin and Vimentin was observed in 75.7%, 90.3%, 92.2% and 2.9% of pre treatment colorectal carcinoma tissue specimens respectively. ALDH1 expression was found to have strong correlation with early onset of the disease (patients who were less than or equal to 45 years of age (P=0.003). Women patients were found predominantly non smokers (P=0.001) and non tobacco chewers (P=0.004) with respect to men.

Conclusion: High ALDH1 expression correlates with the early onset of colorectal cancer. None of other markers could reach statistical significance with the early or late onset of colorectal cancer.

Note: This abstract was not presented at the meeting.

Citation Format: Litika Vermani, N Senthil Kumar, Anuradha Talukdar, Monoj Deka, Ravi Kannan, Rajeev Kumar. High ALDH1 expression in colorectal carcinoma could predict early onset of the disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4924.
Abstract 4938: Identification of a subtype of hepatocellular carcinoma with poor prognosis based on expression of genes within the glucose metabolic pathway
Authors: Zhang Xiaoli , Ghoshal Kalpana , Li Lang
Published: August 2019

Hepatocellular carcinoma (HCC) is the most prevalent primary cancer and a highly aggressive liver malignancy. Liver cancer cells reprogram their metabolic pathways to meet their needs for rapid proliferation and generation of the biomass for tumor growth. The accelerated aerobic glycolysis in tumor has been considered one of the hallmarks that distinguish cancer cells from normal cells. In the present study, liver hepatocellular cancer dataset of the Cancer Genome Atlas (LIHC TCGA) and datasets from Gene Expression Omnibus (GEO) were used to investigate the alterations in expressions of the genes involved in the glucose metabolic pathways as well as their association with the patient clinical stage and survival in liver cancer. In this study, 97 genes including glucose and lactate transporters, the enzymes involved in glucose metabolism (glycolysis, gluconeogenesis, regulation of glucose metabolism, tricarboxylic acid cycle (TCA), pentose phosphate pathway), and glycogen metabolism (glycogen synthesis, glycogen degradation, regulation of glycogen metabolism) were included. The results showed that the expressions of around 50% of genes involved in the glucose metabolic pathway are altered in liver tumors compared to the corresponding normal tissues (p-values<0.005 and fold change≥1.5). More importantly, the differentially expressed genes are associated with advanced AJCC (American Joint Committee on Cancer) clinical stage (p-values<0.05), and reduced overall survival (OS) and recurrence-free survival (RFS) as determined by multivariate Cox proportional hazard models (p-values<0.05). Unexpectedly but interestingly, supervised clustering with the differentially expressed genes of the LIHC TCGA data identified a subgroup of patients with worse OS compared to those patients that clustered with the normal samples (p-value=0.00015, and 5-year median survival time (months) is 25.50 with 95% CI (20.90, 42.37) vs. 47.43 with 95% CI (40.33, NA)). This group of patients had decreased activation (p-values<0.0001) of FXR/RXR and LXR/RXR involved in lipid, cholesterol and glucose metabolism, but had increased atherosclerosis and leukocyte extravasation signaling (p-values<0.0001) activated during inflammation. This indicates those patients had decreased metabolism and increased inflammation which may contribute to the worse OS. Collectively, this study indicates that expressions of the glucose metabolic genes could be used as potential prognostic markers as well as therapeutic targets for liver cancer.

Citation Format: Xiaoli Zhang, Kalpana Ghoshal, Lang Li. Identification of a subtype of hepatocellular carcinoma with poor prognosis based on expression of genes within the glucose metabolic pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4938.
Abstract 4940: The clinical significance of MRE11 expression based on location of primary tumor in colorectal cancer patients: an integrative analysis of multi-center data
Authors: Fan Chuanwen , Kopsida Maria , Liu Youbin , Zhang Hong , Gao Jingfang , Arbman Gunnar , Cao Siyuwei , Li Yuan , Zhou Zongguang , Sun Xiaofeng
Published: August 2019

MRE11 plays an important role in DNA damage response for maintenance of genome stability and is becoming a prognostic marker. Its role, however, remains controversial in colorectal cancer (CRC) as it we don’t know if this difference is caused by the different locations of primary cancer. To figure out the prognostic heterogeneity of MRE11 in CRC, 207 primary CRC samples from Swedish, as well as 596 primary CRC samples from TCGA data were included in present study. The associations of MRE11 expression against tumor-infiltrating inflammatory cells (TIICs) and microsatellite status with overall survival in right-sided CRC (RSCRC) and left-sided CRC (LSCRC) were assessed. The weighed gene co-expression network analysis and ClueGO were adopted to further analyze the different signaling of MRE11-related in RSCRC and LSCRC. The results showd that either high MRE11 expression alone (HR = 0.37, 95% CI = 0.18-0.76, P = 0.007) or the combination of high MRE11 expression with high TIICs was related to a favorable prognosis (HR = 0.150, 95% CI = 0.043-0.524, P = 0.003) in LSCRC. High MRE11 expression associated with a favorable prognosis in LSCRC with microsatellite stability (HR = 0.23, 95% CI = 0.09-0.55, P = 0.001). The relationships furnished above were adjusted for TNM stage, differentiation and/or TIICs, and no such evidence was present in RSCRC. Further analysis of the biological functions and the pathway involving MRE11 was associated with cell cycle process and DNA repair in both RSCRC (cor = 0.55, P = 0.55e-46) and LSCRC (cor = 0.62, P = 3e-64), whereas, activation of the immune response, necrotic cell death specifically correlated with LSCRC (cor = 0.5, P = 8e-38). In Conclusions, High MRE11 expression is associated with a favorable prognosis and the enhanced prognostic potency of combining high MRE11 with high TIICs in LSCRC. The prognostic heterogeneity of MRE11 in CRC may be due to the differential cell signals activated by MRE11 in RSCRC and LSCRC. The prognostic heterogeneity of MRE11 provides a novel rationale for stratifying patients accordingly, in order to obtain a better personalized prognostic evaluation for CRC patients.

Citation Format: Chuanwen Fan, Maria Kopsida, Youbin Liu, Hong Zhang, Jingfang Gao, Gunnar Arbman, Siyuwei Cao, Yuan Li, Zongguang Zhou, Xiaofeng Sun. The clinical significance of MRE11 expression based on location of primary tumor in colorectal cancer patients: an integrative analysis of multi-center data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4940.
Abstract 4943: Leveraging single-cell sequencing to discover novel exhaustion markers of CD8 T cells
Authors: Shi Xiaoshan , Jayaram Savita , Lee Kayla , Bhojak Keshav , Kode Vasumathi , Chaudhary Mridul , Patil Ashwini , Gupta Ravi , Chaudhuri Amit , Chakraborty Papia
Published: August 2019

Therapeutic revival of tumor-specific exhausted T cells using checkpoint blockade antibodies has improved clinical outcomes in cancer significantly. Notwithstanding a high overall response rate to these drugs, long-term benefit is realized by a small fraction of the treated patients. A mechanistic explanation of relapse comes from the recent findings that in both murine and human cancers intratumoral T cells exist in a wide spectrum of functional states – from fully functional at one end of the spectrum, to fully dysfunctional at the other end. Therefore, tumor response to checkpoint inhibitors is determined by the ratio of functional to dysfunctional state of T cells, which in turn is modulated by a wide array of immune-suppressive signals present within the tumor microenvironment. Dissecting the T cell functional states can significantly enhance our understanding of patient responses to immunotherapy drugs and can be used to develop targeted and personalized strategies for restoring antitumor immunity. A key challenge to this problem is that the transcriptional signatures of dysfunctional exhausted T cells are closely intertwined with the activated/effector CD8+ T cell states. This is not surprising, since T cell dysfunction arises following chronic T cell activation. Developing unique markers of T cell exhaustion from in vivo models has not been successful. In this study, we present data to show how single cell transcriptomics on a 10x Genomics platform can identify T cell functional states following antigen-stimulation in an ex vivo T cell activation system. In particular, we identified functional gene clusters and molecular networks that are unique to CD8+ T cell exhausted state. The combined expression of our T cell exhaustion gene signature correlated with poor prognosis when applied to TCGA data of over 1500 tumors from many different cancers. Furthermore, the molecular pathways identified in this study provide opportunities to develop novel therapeutic interventions specially targeting dysfunctional T cells in cancers thereby enhancing the efficacy of checkpoint inhibitors.

Citation Format: Xiaoshan Shi, Savita Jayaram, Kayla Lee, Keshav Bhojak, Vasumathi Kode, Mridul Chaudhary, Ashwini Patil, Ravi Gupta, Amit Chaudhuri, Papia Chakraborty. Leveraging single-cell sequencing to discover novel exhaustion markers of CD8 T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4943.
Abstract 4944: Differential expression of complex immune biology in MSI and MSS colorectal tumor microenvironments using high-plex spatial resolution
Authors: Fuhrman Kit , Church Sarah , Zolligner Daniel , Reeves Jason , Hinerfeld Doug , Bailey Christina , Warren Sarah
Published: August 2019

Spatial characterization of the tumor microenvironment (TME) including cancer cells, stroma and immune cells is essential for understanding tumor progression and discovering prognostic and predictive biomarkers. However, it has proven difficult to perform such studies in a highly multiplexed manner using limited sample quantity. GeoMx™ Digital Spatial Profiling (DSP) has been developed as an integrated research use platform for hi-plex spatial profiling of mRNA and protein using an optical-barcode read-out without the need for on-tissue molecular biology. In this study, we combined both bulk gene expression analysis using the NanoString PanCancer IO360™ panel and the spatial analysis of 40 proteins and 78 RNAs to characterize microsatellite stable (MSS) or instable (MSI) colorectal tumors to evaluate active and suppressive immune mechanisms in both immune dense regions and tumor versus stroma.

Comparing colorectal tumors characterized by MSS, spatial analysis of RNA and protein expression by DSP was able to differentiate immune hot and cold regions of the tumors despite MSS status. Furthermore, comparison of immune-enriched hot-spots, measured by CD45 dense regions of interest, showed that MSS immune hot tumors had decreased macrophage and tumor proliferation markers compared to MSI immune hot tumors, elucidating potential therapeutic targets. Since there is a subset of patients with MSS colorectal cancer that still responds to immunotherapy, this suggests DSP could ultimately be used to identify unique spatial biology and immune characteristics that might further expand beyond MSS and MSI status and tradition gene signatures to help predict patients' response to mono- or combination therapy.

Citation Format: Kit Fuhrman, Sarah Church, Daniel Zolligner, Jason Reeves, Doug Hinerfeld, Christina Bailey, Sarah Warren. Differential expression of complex immune biology in MSI and MSS colorectal tumor microenvironments using high-plex spatial resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4944.
Abstract 4948: T helper 2 cells block breast cancer promotion
Authors: Boieri Margherita , Malishkevich Anna , Steidl Lauren , Ngo Kenneth , Iyer Sowmya , Awad Mary , Kreuzer Johannes , Haas Wilhelm , Rivera Miguel , Demehri Shadmehr
Published: August 2019

New immune-based strategies for cancer treatment including the activation of tumor-infiltrating CD8+ cytotoxic T lymphocytes (CTLs) have led to effective therapeutics against late-stage disease. However, the function of the immune system in combating the early-stage cancers remains uncertain. To establish a mechanism that activates immune cells against early carcinogenesis, we have studied the role of an epithelial-derived cytokine, thymic stromal lymphopoietin (TSLP), in early stages of breast cancer development. We have previously discovered that TSLP blocks breast carcinogenesis through the activation of CD4+ T cells that heavily infiltrate the sites of developing cancer in the breast gland without affecting the normal tissue.To investigate the mechanism by which TSLP-stimulated CD4+ T cells suppress spontaneous breast cancer development, we used MMTV-PyMT transgenic mouse models (PyMTtg) that spontaneously develop breast tumors and resemble the human luminal breast cancer. These mice were crossed into TSLP transgenic mice that produce TSLP under the promoter of a skin-specific keratin 14 promoter (K14-TSLPtg), plus additional knockouts including TSLPR-/- and IL4rα;-/-. Tumor development was arrested in K14-TSLPtg;PyMTtg mice compared to PyMTtg counterparts as their tumors failed to progress to high grade. The tumor suppressive mechanism of CD4+ T cells was mediated by a block in cancer cell proliferation, but not by cytotoxicity. Polarization of CD4+ T cells into T helper 2 (Th2) subtype was essential for blocking breast tumor development, and the tumor suppression was achieved by CD4+ T cells in the absence of CD8+ T and B cells. Finally, we found the basal levels of TSLP released by premalignant breast epithelial cells to be protective against the early phases of breast cancer development.In conclusion, we demonstrate that CD4+ Th2 cells block early stages of breast carcinogenesis. TSLP stimulated CD4+ Th2 cells induce an arrest in cancer cell proliferation, which represents a novel mode of immunity with great potential for the prevention and treatment of breast cancer.

Citation Format: Margherita Boieri, Anna Malishkevich, Lauren Steidl, Kenneth Ngo, Sowmya Iyer, Mary Awad, Johannes Kreuzer, Wilhelm Haas, Miguel Rivera, Shadmehr Demehri. T helper 2 cells block breast cancer promotion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4948.
Abstract 4951: Obesity-induced changes in baseline immune responses to pre-clinical breast cancer
Authors: Gibson Justin , Nagareddy Prabhakara , Norian Lyse
Published: August 2019

Obesity is known to increase morbidity and mortality in breast cancer patients; however, the immunological contributions to such changes remain incompletely understood. Our long-term goal is to investigate the broad impact of obesity on anti-tumor immunity, with a particular focus on understanding the mechanisms underlying obesity-induced immune alterations and how these alterations may influence the use of immunotherapeutics in breast cancer patients. For our studies, we utilized a diet-induced model of obesity (DIO) in which mice were fed either a high-fat or low-fat diet to generate DIO or age-matched lean controls, respectively. Animals were then challenged with the syngeneic E0771 mammary carcinoma cell line. Tumor outgrowth was quantified by caliper measurements, bioluminescent imaging (BLI) via firefly luciferase-expressing E0771 (E0771-fLUC) cells, and endpoint tumor weights. Whole tumor immunogenetic gene expression profiles were evaluated using nanoString and immune populations were assessed via multi-parameter flow cytometry. All measures of tumor outgrowth reveal that obesity significantly increases primary tumor outgrowth and induces a variety of alterations to the immunogenetic profile. Additionally, obesity significantly alters the frequency of intra-tumoral immune populations, including decreases in CD4+ and CD8+ T cells, increases in granulocytic myeloid-derived suppressor cells (G-MDSCs) and myeloid dendritic cells (mDCs), and a trending decrease in total CD45+ tumor infiltrating leukocytes. These alterations are specific to the tumor environment, as they are not present in the spleens of tumor-bearing mice. Collectively these data implicate obesity as a causal agent in impairing anti-tumor immune responses to murine mammary tumors. Furthermore, they suggest several cellular candidates for future mechanistic investigations into obesity-induced alterations in breast cancer immunity.

Citation Format: Justin Gibson, Prabhakara Nagareddy, Lyse Norian. Obesity-induced changes in baseline immune responses to pre-clinical breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4951.
Abstract 4999: Characterization of myeloid derived suppressor cells after capecitabine and nivolumab combination treatment
Authors: Lin Qing , Wang Tienan , Yan Wenjun , Wu Ranran , Nie Lun , Miao Chensi , Wang Xing , Wang Feng , Zhang Jie , Shi Weilin , Yuan Yanping , Shi Tingting , Li Ao , Dong Wei , Chen Xu , Sun Jingying , Ji Qunsheng
Published: August 2019

Capecitabine, a widely used oral chemotherapeutic agent, only functions in its active form, 5-FU. The metabolism of capecitabine to 5-FU frequently occurs in tumor tissues with high expression of thymidine phosphorylase, enzyme responsible for converting capecitabine. Extensive studies have demonstrated that capecitabine functions to inhibit growth of tumors, especially for metastatic breast and colorectal tumors, by impairing DNA synthesis and metabolism. However, effects of capecitabine on myeloid derived suppressor cell (MDSC) in the tumor microenvironment are poorly understood. In fact, conflicting results were reported that capecitabine either reduced CD11bhigh/Gr1high MDSC and enhanced T cell functions, or failed to alter the number and function of MDSC or the levels of GM-CSF/IL6 in blood. In this study, we established an optimized in-vitro MDSC suppressive assay and take the advantage of this system to investigate the function of capecitabine on MDSC-mediated T cell suppression. Myeloid cells in tumor environment acquire the expression of PD-L1, suggesting that blocking the PD1-PD-L1 axis might revert the function of MDSC. Therefore, we further explored the combination effect of capecitabine and nivolumab, a PD-1 antibody, on the function of MDSC in human PBMC cells.

Citation Format: Qing Lin, Tienan Wang, Wenjun Yan, Ranran Wu, Lun Nie, Chensi Miao, Xing Wang, Feng Wang, Jie Zhang, Weilin Shi, Yanping Yuan, Tingting Shi, Ao Li, Wei Dong, Xu Chen, Jingying Sun, Qunsheng Ji. Characterization of myeloid derived suppressor cells after capecitabine and nivolumab combination treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4999.
Abstract 5022: iGRAMMy: Cloud-based characterization of microbial landscape in colorectal cancers
Authors: Xia Li C. , Ai Dongmei , Guo Man , Ji Hanlee
Published: August 2019

Many studies have identified pervasive tumor-infiltrating bacteria in colon, gastric, kidney, and other tumors. Infiltrating bacteria have functional significance, affecting the immune system state, affecting a tumor’s ability to metastasize, and modifying patient’s response to therapies. Only a few tools can infer infiltrating bacteria based on the RNA-and DNA-Seq data of tumor samples. These tools are not optimized for cloud-based computation, where large public datasets such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) now reside. Here, we present a novel cloud-based bioinformatics tool - iGRAMMy, that accurately, efficiently, and robustly estimate microbial relative abundance in sequenced tumor and matched normal samples. We developed iGRAMMy by integrating read filtering, remapping, and relative abundance estimation steps of whole genome (WGS-seq) and/or transcriptome (RNA-seq) based microbiome analysis. We validated iGRAMMy by comparing estimated abundance to positive and negative controls of a published dataset as golden standard. We applied iGRAMMy to study all colorectal cancer samples within the TCGA cohort and reported the microbial landscape of these tumors. We identified a significantly higher abundance of overall bacterial infiltration in tumor as compared to normal samples. We found species like Bacteroides fragilis, Bacteroides dorei and Fusobacterium nucleatum were significantly higher in tumors, which were corroborated by previous reports. We uniquely identified Bacteroides intestinalis was also significantly more abundant in tumor samples. We released iGRAMMy and the entire analysis as a workflow pipeline on cancer genomics cloud, where researchers can easily replicate the study and use the tool for their own data.

Citation Format: Li C. Xia, Dongmei Ai, Man Guo, Hanlee Ji. iGRAMMy: Cloud-based characterization of microbial landscape in colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5022.
Abstract 5024: Treatment with synthetic RIG-I agonist triphosphate RNA leads to local and systemic anti-tumor effects in a mouse melanoma tumor model
Authors: Helms Mike W. , Parmantier Eric , Jahn-Hofmann Kerstin , Gnerlich Felix , König Lars , Metz-Weidmann Christiane , Braun Monika , Dietert Gabriele , Grandien Kaj , Theilhaber Joachim , Cao Hui , Wagenaar Tim , Schnurr Max , Endres Stefan , Wiederschain Dmitri , Scheidler Sabine , Rothenfusser Simon , Brunner Bodo
Published: August 2019

RIG-I is a highly important cytosolic pattern recognition receptor (PRR) involved in sensing RNA virus infection and inducing interferon (IFN) production. RIG-I’s natural ligand, triphosphate RNA (ppp-RNA), is proposed to be a valuable addition to the growing arsenal of cancer immunotherapy treatment options. This study validates the use of intratumoral treatment with synthetic RIG-I agonist ppp-RNA for the therapy of human cancer, with melanoma as potential entry indication amenable to intratumoral treatment. Firstly, we demonstrate that RIG-I expression is closely correlated to cellular and cytokine immune activation in a wide variety of tumor types. Secondly, cellular models of human melanoma confirm susceptibility of cancer cells to ppp-RNA treatment, revealing unexpected heterogeneity between cell lines in their selectivity for RNA features, including sequence, secondary structures and presence of triphosphate. Cellular RNA treatment responses (type I IFN, FasR, MHC-I, cytotoxicity) were demonstrated to be RIG-I dependent using RIG-I KO cells. Thirdly, we show that ppp-RNA treatment of a mouse melanoma tumor model, leads to significant local and systemic anti-tumor effects and survival benefits, associated with a type I IFN response, tumor cell apoptosis and innate and adaptive immune cell activation. For the first time, we demonstrate systemic presence of tumor antigen specific CTLs following treatment with RIG-I agonist. Overall our study demonstrates that ppp-RNA or analogs thereof have the potential to play an important role for cancer treatment in the next wave of immunotherapy. However, potential challenges in the generation and formulation of potent RIG-I agonists remain to be solved.

Citation Format: Mike W. Helms, Eric Parmantier, Kerstin Jahn-Hofmann, Felix Gnerlich, Lars König, Christiane Metz-Weidmann, Monika Braun, Gabriele Dietert, Kaj Grandien, Joachim Theilhaber, Hui Cao, Tim Wagenaar, Max Schnurr, Stefan Endres, Dmitri Wiederschain, Sabine Scheidler, Simon Rothenfusser, Bodo Brunner. Treatment with synthetic RIG-I agonist triphosphate RNA leads to local and systemic anti-tumor effects in a mouse melanoma tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5024.