tbuckley/cabot-search huggingface dataset:
Abstract 3551: Targeting glutamine addiction of PIK3CA mutant colorectal cancers
Authors: Yiqing Zhao
Journal: Cancer Research (2017)

Abstract Glutamine addiction is a major metabolic reprogramming event that occurs in cancer cells. Many tumors exhibit oncogene-dependent addiction to glutamine. PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase α, is the most frequently mutated oncogene in human cancers. However, whether PIK3CA mutations reprogram cancer metabolism is an important unaddressed question. Here we show that oncogenic PIK3CA mutations render colorectal cancers (CRCs) more dependent on glutamine to growth. As a metabolite, glutamine is first converted to glutamate by glutaminase (GLS) and then to α-ketoglutarate (α-KG) by either a transaminase or a glutamate dehydrogenase. Calithera Biosciences recently developed a potent GLS inhibitor called CB-839, which is currently in phase I clinical trials in cancer patients. Using isogenic colorectal cancer cell lines with either WT or mutant PIK3CA allele knockout, we demonstrated that CRCs with PIK3CA mutations are more sensitive to growth inhibition by CB-839. Remarkably, combination of CB-839 with 5-FU induces regression xenograft tumors in PIK3CA mutant CRC models, suggesting that this combinational therapy may be effective approach to treat CRC patients whose tumors harbor PIK3CA mutations. Mechanistically, mutant p110α up-regulates gene expression of glutamate pyruvate transaminase 2 (GPT2) through an AKT-independent PDK1-RSK2-ATF4 signaling axis, thereby facilitating conversion of glutamate to α-KG. Together, our data establish oncogenic PIK3CA mutations as a cause of glutamine addiction in CRCs and that targeting glutamine metabolism may be effective approach to treat CRCs with PIK3CA mutations. Citation Format: Yiqing Zhao. Targeting glutamine addiction of PIK3CA mutant colorectal 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 3551. doi:10.1158/1538-7445.AM2017-3551
Activity of paclitaxel in radiation induced and other secondary angiosarcomas
Authors: D. Pink, J. Rahm, D. Schoeler, T. M. Schoenknecht, P. Reichardt
Journal: Journal of Clinical Oncology (2009)

10578 Background: Angiosarcomas (AS) represent 1–2% of adult soft tissue sarcomas and can arise anywhere in the body. Major predisposing factors are therapeutic radiation and chronic lymphedema. Paclitaxel has shown an exceptionally high activity of 75–89% in angiosarcomas of the face and scalp and to a lesser and less consitent degree of 15–58% in other disease locations. We report on a retrospectice single center experience with chemotherapy in 17 patients (pts.) with secondary angiosarcomas (SAS). Methods: Data from 17 patients were analysed including 15 females and 2 males with a median age of 63 years (range 18–80 years). 12 female patients suffered from angiosarcoma of the breast/thoracic wall following operation and radiation + chemotherapy of a primary breast cancer with an interval of a median of 6 years (range 2–15 years). 1 patient developed a SAS 6 years after resection and radiation of a liposarcoma in the limb. 4 patients were diagnosed with SAS following chronic lymphedema (3 Steward-Treves-Syndrome, interval 8, 9 and 38 years, repectively and 1 connatal lymphedema, interval 18 years). Results: 14/17 pts. received surgery as first treatment for SAS. 10 pts. developed a locoregional recurrence, 1 pt. distant metastases. 3 pts. remain free of disease. 3 pts. were diagnosed with locally advanced/metastatic SAS. Surgery for local recurrence after primary surgery resulted in further recurrence in all cases. All 14 patients with recurrent/metastatic disease were treated with chemotherapy. 12 pts. received paclitaxel at a dose of 175 mg/m 2 q3w or 50–70 mg/m 2 q1w as first- or second-line therapy. Responses were 8 PR with a median PFS of 6 months (range 3–23 months), and 1 SD (PFS 4 months) with a disease control rate of 75%. 2 pts. are too early to evaluate, 1 pt. showed PD. In only 3/11 cases, pts. responded to Anthracycline-based chemotherapy. Conclusions: Paclitaxel shows high activity in SAS, comparable to the results in face and scalp angiosarcomas and can be considered a standard treatment option. No significant financial relationships to disclose.
Abstract 3478: Expression of the transcribed ultraconserved region Uc.63+ in prostate cancer
Authors: Yohei Sekino, Keisuke Goto, Ririno Honma, Yoshinori Shigematsu, Naoya Sakamoto, Kazuhiro Sentani, Naohide Oue, Jun Teishima, Akio Matsubara, Wataru Yasui
Journal: Cancer Research (2017)

Abstract Prostate cancer (PCa) is the most prevalent cancer among men and the second leading cause of cancer related death in western world. Currently, there is a lack of effective treatment options for advanced PCa. Understanding the molecular mechanisms in prostate cancer development and progression would allow the identification of novel prognostic markers or therapeutic targets. The transcribed-ultraconserved regions (T-UCRs) are novel class of noncoding RNAs that are absolutely conserved (100%) between orthologous regions of the human, rat and mouse genomes. Some studies showed that T-UCRs exhibit distinct profiles in various human cancers. We examined the expression profile of representative 26 T-UCRs using qRT-PCR in 12 PCa tissues and 10 non-neoplastic prostate tissues, and found that the expression of Uc.63+ was higher in PCa tissues than that in non-neoplastic tissues. Further analysis revealed that the expression of Uc.63+ significantly correlated with higher PSA levels (p = 0.007) and higher Gleason score (p &amp;lt; 0.001). In order to verify biological function of Uc.63+ in PCa, we firstly transfected Uc.63+ expression vector into LNCaP cells expressing low level of Uc.63+. MTT assay and wound healing assay revealed that overexpression of Uc.63+ significantly increased the cell growth and migration. We also confirmed that downregulation of Uc.63+ using siRNA in DU145 and PC3 expressing high level of Uc.63+. Knockdown of Uc.63+ decreased the cell growth and migration. A recent report indicates that T-UCRs may act as endogenous competing RNA. miR-130b was found to have binding sites within the Uc.63+ using online software. We examined the expression of miR-130b by qRT-PCR in PCa tissues and non-neoplastic prostate tissues. We found a significant downregulation of miR-130b in PCa tissues compared with non-neoplastic prostate tissues, which figured out that there was a significant inverse correlation between Uc.63+ and miR-130b in PCa (p = 0.002). The expression of miR-130b in LNCaP was higher than that in DU145 and PC3. It has been shown that MMP2 is a direct target of miR-130b. Western blot analysis and qRT-PCR revealed that MMP2 expression was higher in LNCaP cells transfected with Uc.63+ expression than that in LNCaP cells transfected with empty vector. These results suggest that Uc.63+ may contribute to the progression of PC through miR-130b interaction. Citation Format: Yohei Sekino, Keisuke Goto, Ririno Honma, Yoshinori Shigematsu, Naoya Sakamoto, Kazuhiro Sentani, Naohide Oue, Jun Teishima, Akio Matsubara, Wataru Yasui. Expression of the transcribed ultraconserved region Uc.63+ in prostate 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 3478. doi:10.1158/1538-7445.AM2017-3478
Abstract 3432: microRNA expression reflects site specificity of metastatic colorectal cancer
Authors: Bastian Fromm, Eirik Høye, Diana Domanska, Christin Lund-Andersen, Annette Torgrund Kristensen, Vegar J. Dagenborg, Paul H. Boettger, Torveig W. Abrahamsen, Steinar Solberg, Stein G. Larsen, Bjørn Edwin, Eivind Hovig, Susanne Lorenz, Kjersti Flatmark
Journal: Cancer Research (2017)

Abstract Colorectal Cancer (CRC) is one of the leading causes of cancer related deaths in the western world, and metastatic progression is the dominating cause of mortality. The primary site of CRC metastasis is the liver, followed by the lungs and peritoneal cavity, and prognosis for patients with metastatic CRC (mCRC) is poor, with only 10 % five-year survival. Although much is known about progression and metastasis of CRC; how primary CRC (pCRC) differs from mCRC on the molecular level and potential differences between metastases located in different organs are incompletely understood. This is important for our understanding of the disease, but also could have significant implications with respect to treatment. MicroRNAs have been shown to be key elements in cancer progression, but recent reports on CRC failed to consistently identify microRNA signatures of metastatic progression. We have addressed this using a smallRNA sequencing approach to analyze primary tumors and a set of liver, lung and peritoneal metastases, including corresponding adjacent tissue (colon, liver, lung, peritoneum). Further, we use the highly curated and updated microRNA reference MirGeneDB.org, the novel pipeline MirAthon - including a correction-algorithm of benign tissue microRNA signatures for tumor or metastatic samples, and we compare pCRC and site specific metastases separately. We are able to show that microRNA profiles of mCRC are distinct to pCRC in a site-specific manner. We identify a small panel of differentially expressed microRNAs including isoforms (isomiRs) hidden under a layer of benign signatures that we confirmed in other available datasets, too. Our findings will help better understand metastatic progression and site-specificity in CRC and could be potential biomarkers for mCRC. Our work identifies microRNA signatures of mCRC and suggest that microRNA signatures reflect mCRC site specificity. Furthermore, the results underline the importance of using a curated reference for microRNA studies, and to differentiate metastases based on their localization ab initio. Citation Format: Bastian Fromm, Eirik Høye, Diana Domanska, Christin Lund-Andersen, Annette Torgrund Kristensen, Vegar J. Dagenborg, Paul H. Boettger, Torveig W. Abrahamsen, Steinar Solberg, Stein G. Larsen, Bjørn Edwin, Eivind Hovig, Susanne Lorenz, Kjersti Flatmark. microRNA expression reflects site specificity of metastatic colorectal 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 3432. doi:10.1158/1538-7445.AM2017-3432
Abstract 4763: Metronomic chemotherapy prevents therapy-induced stromal activation and induction of cancer stem cells
Authors: Kelvin K. Tsai, Tze-Sian Chan, Chung-Chi Hsu, Vincent C. Pai, Shenq-Shyang Huang, Valerie M. Weaver
Journal: Cancer Research (2017)

Abstract Whilst traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. Treatment resistance and metastasis have been attributed to expansion of cancer stem-like cells (CSCs). Molecular analysis of the tumor stroma in neoadjuvant chemotherapy-treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximal tolerated dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts that induces the expression and secretion of ELR-motif-positive (ELR+) chemokines, which signal through CXCR-2 on carcinoma cells to trigger their phenotypic conversion into CSCs and promote their invasive behaviors, leading to paradoxical tumor aggression following the therapy. By contrast, the same total accumulated dose administered as a low-dose-metronomic chemotherapy regimen largely prevented the therapy-induced stromal ELR+-chemokine paracrine signaling for CSCs, thereby substantially enhancing treatment response and extending survival of mice carrying desmoplastic cancers (Chan et al, J. Exp. Med. 2016). These studies illustrate the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy. Note: This abstract was not presented at the meeting. Citation Format: Kelvin K. Tsai, Tze-Sian Chan, Chung-Chi Hsu, Vincent C. Pai, Shenq-Shyang Huang, Valerie M. Weaver. Metronomic chemotherapy prevents therapy-induced stromal activation and induction of cancer 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 4763. doi:10.1158/1538-7445.AM2017-4763
Uric acid and incident dementia over 12 years of follow-up: a population-based cohort study
Authors: Augustin Latourte, Aicha Soumaré, Thomas Bardin, Fernando Perez-Ruiz, Stéphanie Debette, Pascal Richette
Journal: Annals of the Rheumatic Diseases (2017)

Objectives In patients with gout, maintaining too low serum uric acid (SUA) level with urate-lowering therapy is a concern because uric acid is thought to be neuroprotective. However, the relation between SUA and dementia remains debated. This study aimed to investigate the impact of SUA level on the incidence of dementia. Methods We assessed the longitudinal association between SUA level and incident dementia (Diagnostic and Statistical Manual of Mental Disorders Version IV (DSM-IV) criteria) in a large cohort of healthy older people from the community (Three-City Dijon cohort). Additionally, we investigated the relation between SUA level and MRI markers of brain ageing (white matter hyperintensity volume (WMHV), lacunes and hippocampal volume). Results The study sample comprised 1598 people (mean (SD) age 72.4(4.1) years, 38.3% male). During the 13,357 person-years of follow-up (median duration: 10.1 years), dementia developed in 110 participants (crude incidence rate: 8.2/1000 person-years). After multiple adjustments, the multivariate HR with the highest (≥75th percentile) versus lowest SUA level was 1.79 (95% CI 1.17 to 2.73; p=0.007). The association was stronger with vascular or mixed dementia (HR=3.66 (95% CI 1.29 to 10.41), p=0.015) than Alzheimer’s disease (HR=1.55 (95% CI 0.92 to 2.61), p=0.10). There was a non-significant trend towards an association between high SUA level and extensive WMHV (p=0.10), a biomarker of small vessel disease, but not hippocampal volume (p=0.94) or lacunes (p=0.86). The association between SUA level and vascular or mixed dementia might be affected by interim strokes. Conclusions Risk of dementia, especially vascular or mixed dementia, may be increased with high SUA levels in elderly people.
Abstract 3063: Predicting efficacy of c-Met targeting therapy in autocrine and paracrine tumor cell lines
Authors: Veronica S. Hughes, Dietmar W. Siemann
Journal: Cancer Research (2017)

Abstract Tumor cells frequently harbor abnormalities in signaling pathways, leading to increased migration, invasion, survival, angiogenesis, and proliferation. C-Met is one such commonly aberrant pathway. Because of its effects on tumor cells, c-Met has been a target of interest for anti-metastatic therapies. Clinical trials of c-Met inhibition select patients based on total Met expression, or amplification of the Met gene. However, c-Met inhibitors target the activated pathway. We therefore predict that phospho-Met will be a better marker for patient sensitivity to, and hence selection for, c-Met inhibitor trials. C-Met is activated by the endogenous ligand Hepatocyte Growth Factor (HGF). In order to mimic the paracrine signaling during in vitro experiments, many studies add exogenous HGF at concentrations of 25-50 ng/mL. However, these concentrations may not be representative of in vivo conditions. HGF serum levels of healthy humans is 0.4 ng/mL. While HGF levels do rise in cancer patients, it is unusual to see serum levels higher than 1 ng/mL. Conditioned media from several cell lines (MDA-MB-231, PC-3, DU145, LNCaP, OS156, OS521, U87, U118, RKO, KHT, SCC7, and RIF) was collected to analyze for secretion of HGF in conditioned media. These cells were then examined for basal phosphorylation of Met. The cell lines that secreted HGF also had higher levels of phospho-Met in comparison to non-HGF-secreting cell lines. Importantly, levels of total Met did not predict for levels of phospho-Met. In migration and invasion assays, the HGF-secreting cell line KHT was found to be sensitive to the c-Met inhibitor BMS-777607.The non-HGF-secreting cell line DU145 only became sensitive to the inhibitor when high, non-physiologic exogenous levels of HGF (25-50 ng/mL) were added.These results suggest that autocrine activation of the c-Met pathway may be a factor in predicting sensitivity to c-Met inhibition. This may indicate the existence of a subset of patients most likely respond to c-Met inhibition therapy. Furthermore, consideration of exogenous HGF concentration should be considered when conducting preclinical trials of c-Met inhibitors, as addition of exogenous HGF may change the apparent efficacy of the inhibitor. Citation Format: Veronica S. Hughes, Dietmar W. Siemann. Predicting efficacy of c-Met targeting therapy in autocrine and paracrine tumor cell lines [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 3063. doi:10.1158/1538-7445.AM2017-3063
Abstract 145: PIK3CB inhibitors selectively block the survival of glioblastoma cells
Authors: Lamvy Le, Zhi Sheng
Journal: Cancer Research (2017)

Abstract Objective: To explore the divergent role of PI3K isoforms in glioblastoma Background: Glioblastoma multiforme is the most malignant brain tumor in adults. Despite aggressive treatments, the median survival and five-year overall survival of glioblastoma patients remains low (14.6 months and 4.7%, respectively). Nearly 90% of patients experience recurrence within two years, leaving patients with few treatment options. Recently, PI3K pan inhibitors have been used to treat recurrent glioblastoma and achieved modest effect in the clinic. PI3K has four catalytic isoforms (PIK3CA, B, D, and G); hence, it is possible that these isoforms may have different roles in glioblastoma and need to be selectively targeted. This idea is further supported by our recent results, in which we have shown that elevated expression of PIK3CB, but not other PI3K isoforms, significantly correlated with higher rate, risk, and poor prognosis of recurrent glioblastomas. Hence, we hypothesize that PIK3CB-selective inhibitors are more effective for glioblastoma. Design/Methods: We used a panel of glioblastoma cells with different levels of PIK3CB, treated them with PI3K-isoform-selective inhibitors, and compared them to pan PI3K inhibitors. We measured cell viability using the MTS cell viability assay. Normal human astrocytes were used as controls to determine toxicity. Results: We found that PIK3CB inhibitors TGX-221 and GSK2636771 significantly blocked the proliferation of PIK3CB-high U87MG and SF295 cells, while it had no effect on the viability of PIK3CB-low A172 and LN229 cells. In contrast, other PI3K inhibitors and pan inhibitors either non-selectively blocked or had no effect on these cells. Importantly, these compounds, but not PIK3CB inhibitors, blocked the growth of astrocytes. Conclusions: Selective blockade of PIK3CB, but not other PI3K isoforms, is an effective therapy for glioblastoma with a low toxicity to normal tissues. Citation Format: Lamvy Le, Zhi Sheng. PIK3CB inhibitors selectively block the survival of glioblastoma 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 145. doi:10.1158/1538-7445.AM2017-145
Screening of 181 Patients With Antibody Deficiency for Deficiency of Adenosine Deaminase 2 Sheds New Light on the Disease in Adulthood
Authors: Johanna Schepp, Michele Proietti, Natalie Frede, Mary Buchta, Katrin Hübscher, Jessica Rojas Restrepo, Sigune Goldacker, Klaus Warnatz, Jana Pachlopnik Schmid, Andrea Duppenthaler, Vassilios Lougaris, Ignacio Uriarte, Susan Kelly, Michael Hershfield, Bodo Grimbacher
Journal: Arthritis & Rheumatology (2017)

We aimed to test the relevance of deficiency of adenosine deaminase 2 (DADA2) in patients with antibody deficiency and describe the clinical picture of the disease in adulthood.We screened for DADA2 in a cohort of 181 patients with antibody deficiency with or without vascular lesions using next-generation sequencing and targeted Sanger sequencing. All mutations were confirmed by determining the ADA2 enzymatic activity levels in dried plasma spots. Clinical data and laboratory values were collected in a standardized format.Following the diagnosis of 2 siblings in the index family, we identified 9 additional affected patients with compound heterozygous or homozygous CECR1 mutations, containing 6 novel and 4 previously published mutations. The patients' age at evaluation ranged from 13 to 51 years, with a median age of 22 years. Clinically, we saw a broad phenotype, ranging from isolated antibody deficiency to recurrent strokes. All but 1 patient had low numbers of memory B cells. Moreover, B cell function seemed to correlate with inflammation.Taken together, our findings indicate that DADA2 presents not only with vasculopathy but also with an immunodeficiency of the B cell compartment. Therefore, patients with antibody deficiency should be screened for DADA2. Anti-tumor necrosis factor treatment might improve immunologic features over time and might be considered in patients without vascular manifestations but with elevated inflammation markers. Conservative management has so far proven to be the choice for our less severely affected adolescent and adult DADA2 patients; however, in patients with severe cytopenias and bone marrow failure, hematopoietic stem cell transplantation should be considered.