bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 983: Integrative analysis of androgen receptor regulated long non-coding RNA in prostate cancer
Authors: Malik Rohit , Zhang Yajia , Cieslik Marcin , Niknafs Yashar S. , Pitchiaya Sethuramasundaram , Hosono Yasuyuki , Subramaniam Shruthi , Yazdani Sahr , Cao Xuhong , Robinson Dan , Chinnaiyan Arul
Published: July 2016

Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer. AR regulates a large repertoire of genes; however, the effect of androgen signaling on the regulation of long non-coding RNAs (lncRNA) remains incompletely understood. Using transcriptome sequencing (RNA-seq) of AR-positive cell lines VCaP and LNCaP treated with dihydroxytestosterone (DHT), we identified genes, including lncRNAs, which were strongly regulated by AR. To confirm direct regulation by AR, we interrogated AR-ChIP-seq data from VCaP and LNCaP cells, identifying the lncRNAs with direct AR binding. Existence of these lncRNAs in prostate cancer tissue samples was confirmed by analysis of RNA-seq data from prostate tumors, and the degree of differential expression in prostate tumors (localized and castration resistant metastases) versus benign was determined. The most highly overexpressed lncRNA in this analysis was a 2.7kb multi-exonic transcript present on chromosome 16 called ARlnc1. RACE was utilized to determine the exact exon structure of this gene, and its expression levels in various prostate cancer cell lines as well as independent prostate cancer tissue cohorts was assessed. Further, knockdown of ARlnc1 in AR dependent cell lines inhibited cell proliferation and induced apoptosis. Knockdown of ARlnc1 affected molecular signatures related to cell cycle, mitosis and DNA damage. Interestingly, ARlnc1 knockdown also suppressed global androgen signaling as determined by Gene set enrichment analysis using AR gene signature. Upon investigation of the mechanism through which PRCAT47 regulate AR signaling, we discovered that ARlnc1 regulates AR at the level of translation. Taken together, our data suggests that many lncRNAs are regulated by androgen signaling, and we identify one such lncRNA that is involved in a protein-lncRNA positive feedback loop.

Citation Format: Rohit Malik, Yajia Zhang, Marcin Cieslik, Yashar S. Niknafs, Sethuramasundaram Pitchiaya, Yasuyuki Hosono, Shruthi Subramaniam, Sahr Yazdani, Xuhong Cao, Dan Robinson, Arul Chinnaiyan. Integrative analysis of androgen receptor regulated long non-coding RNA in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 983.
Abstract 989: A novel function of LncRNA AK023948—regulation of PI3K signaling
Authors: Koirala Pratirodh , Mo Yin Yuan
Published: July 2016

The human genome expresses a large number of long non-coding RNAs (lncRNAs) and increasing evidences suggest their physiological functions.However, the roles vast majority of lncRNAs are elusive in breast cancer. In the present study, we identified a set of lncRNAs that were differentially expressed in breast cancer tissues as compared to normal tissue. AK023948 is one of such lncRNAs which is up-regulated in breast cancer tissue and in breast cancer cell lines. Ectopic expression of AK023948 in breast cancer MCF-7 cells promotes proliferation and anchorage independent cell growth along with activation of AKT phosphorylation. On the other hand, knockdown or knockout of AK023948 in MCF-7 cells reduces the proliferation of cells and phosphorylation of AKT. Furthermore, there is a positive correlation between AK023948 and pAKT expression in breast cancer tissue microarray. To determine the underlying mechanism of AK023948-mediated activation of AKT, we performed RNA precipitation assays using biotin-labeled AK023948 RNA probe combined with mass spectrometry analysis and identified that ATP dependent RNA helicase A (RHA/DHX9) is AK023948. The interaction of AK023948 with DHX9 was confirmed by Western blot and RNA immunoprecipitation (IP), respectively. Co-IP indicated that DHX9 interacts with PI3K regulatory subunit p85. Further characterization revealed that AK023948 works as scaffold for p85-DHX9 interaction, which is essential for stability of p85 and AKT activity. Finally, we showed that AK023948 is essential to AKT activation induced by growth factors and acidosis, but it has no effect on activation of ERK phosphorylation, suggesting that AK023948 specifically regulate AKT signaling via PI3K. Together, these results suggest that AK023948 contributes to breast cancer pathogenesis by activating AKT and AK023948 may serve as a novel target for breast cancer therapy.

Citation Format: Pratirodh Koirala, Yin Yuan Mo. A novel function of LncRNA AK023948—regulation of PI3K signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 989.
Abstract 99: Ovarian cancer specific therapeutic vulnerability
Authors: Yoshihara Kosuke , Tamura Ryo , Suda Kazuaki , Ishiguro Tatsuya , Enomoto Takayuki
Published: July 2016

High-grade serous ovarian cancer comprises approximately 40% of epithelial ovarian cancer cases and is the most aggressive histologic type. Because this type of cancer usually presents as advanced stage disease at the time of diagnosis, the clinical outcome in patients with advanced stage ovarian cancer remains poor.

A recent study has identified that homozygous deleted essential-redundant genes generate therapeutic vulnerabilities in glioblastoma multiforme. On the other hand, a pan-cancer analysis of somatic copy number alterations demonstrates that ovarian cancer has high frequent somatic copy number alterations compared to other tumor types including glioblastoma. Therefore, we hypothesized that ovarian cancer has also therapeutic vulnerabilities leading to development of new therapeutic strategies. To discover ovarian cancer specific vulnerability, we used DNA copy number and mRNA expression data submitted to the Cancer Genome Atlas. First, we performed GISTIC 2.0 to detect copy number alterations and found 4107 genes with homozygous deletion in at least 1% of 562 ovarian cancer samples. Of them, 3060 genes had at least one paralogue gene defined by Ensembl. We focused on metabolism pathway to extract 182 metabolism-related genes. By comparing gene expression between homozygous deletion samples and others using unpaired t-test, we identified 73 genes that were significantly down-regulated in homozygous deletion samples (p < 0.05). Next, we used copy number data submitted to Cancer Cell Line Encyclopedia to discover 41 candidate genes that were homozygously deleted in at least one ovarian cancer cell line. These findings suggest that cancer specific vulnerability exists not only glioblastoma multiforme but also other tumor types including ovaryan cancer and that further functional validation of 41 candidate genes might lead to development of new therapeutic strategies in ovarian cancer in the near future.

Citation Format: Kosuke Yoshihara, Ryo Tamura, Kazuaki Suda, Tatsuya Ishiguro, Takayuki Enomoto. Ovarian cancer specific therapeutic vulnerability. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 99.
Abstract 992: Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1
Authors: Taniue Kenzui , Takeda Yasuko , Akiyama Tetsu
Published: July 2016

Increasing evidence suggests that lncRNAs play critical roles in a diverse set of biological processes, including proliferation, differentiation, embryogenesis, neurogenesis and stem cell pluripotency. It has been reported that many lncRNAs regulate gene expression and various post-transcriptional processes, including splicing, transport, translation and degradation of mRNA. Furthermore, recent studies have shown that Many lncRNAs play critical roles in tumor development and progression.

We attempted to identify lncRNAs critical for the tumorigenicity of colon tumor cells. We have found that a lncRNA termed UPAT is required for the survival and tumorigenicity of colorectal cancer cells. We also show that UPAT interacts with and stabilizes the epigenetic factor UHRF1 by interfering with its β-TrCP-mediated ubiquitination. UHRF1 plays key roles in multiple biological processes, including proliferation and development. Moreover, UHRF1 is overexpressed in various tumors, including colon cancer, and plays a critical role in the proliferation and survival of tumor cells. Furthermore, we demonstrate that UHRF1-UPAT complex upregulate SCD1 and SPRY4, which play critical roles in the survival and proliferation of colon cancer cells.

Our findings suggest that UPAT-mediated stabilization of UHRF1 is critical for the proliferation and tumorigenicity of colon tumor cells. Our results suggest that UHRF1-UPAT axis may be a promising molecular target for colon cancer therapies.

Citation Format: Kenzui Taniue, Yasuko Takeda, Tetsu Akiyama. Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 992.
Abstract CT033: Phase 1b study of heat shock protein 90 inhibitor onalespib in combination with paclitaxel in patients with advanced, triple-negative breast cancer (NCT02474173)
Authors: Wesolowski Robert , Lustberg Maryam B. , Mrozek Ewa , Layman Rachel , Reinbolt Raquel , Poi Ming , Osman Nadia , Lively Andrea , Stephens Julie , Grever Michael , Ramaswamy Bhuvaneswari
Published: July 2016

Background: Heat shock protein 90 (HSP90) is a molecular chaperone that is required for proper folding and stabilization of proteins. Client proteins of HSP90 include many mediators of signal transduction known to be over-activated in triple negative breast cancer such as AKT, EGFR, members of RAS/MAPK signaling pathways and androgen receptor. Expression of HSP90 has been found to be upregulated in multiple triple negative breast cancer cell lines and associated with poor outcome of breast cancer patients. In addition, over-expression of HSP90 client proteins such as AKT and c-RAF has been implicated in paclitaxel resistance. Onalespib (AT13387) is a synthetic non-ansamycin small molecule that acts as an inhibitor of HSP90 by binding to the amino terminal of the protein and has dissociation constant (Kd) of 0.71 nM.

Materials and Methods: Patients with inoperable or metastatic triple negative or weakly hormone receptor positive breast cancer are treated with onalespib and paclitaxel on days 1, 8, 15 every 28 days. Paclitaxel is given at a standard dose of 80 mg/m2 while the dose of onalespib is gradually increased using standard 3+3 design (see table). In order to assess the effect of each drug on pharmacokinetics of the other drug, onalespib is given on day -7 prior to cycle 1 and skipped on day 1 of cycle 1 during which paclitaxel in administered alone. The primary objective of the study is to determine recommended phase 2 dose and assess the toxicity profile of the combination. The secondary objectives include effect of onalespib on pharmacokinetics of paclitaxel and effect of paclitaxel on pharmacokinetics of onalespib. Overall response rate, response duration and progression-free survival will also be assessed. Dose Escalation ScheduleDose LevelDoseOnalespib (mg/m2 IV on days 1, 8, 15)Paclitaxel (mg/m2 IV on days 1, 8, 15)Level -110080Level 112080Level 215080Level 320080Level 426080

Conclusion: The study opened to accrual on January 15, 2016 and is currently enrolling the first 3 patients to dose level 1.

Citation Format: Robert Wesolowski, Maryam B. Lustberg, Ewa Mrozek, Rachel Layman, Raquel Reinbolt, Ming Poi, Nadia Osman, Andrea Lively, Julie Stephens, Michael Grever, Bhuvaneswari Ramaswamy. Phase 1b study of heat shock protein 90 inhibitor onalespib in combination with paclitaxel in patients with advanced, triple-negative breast cancer (NCT02474173). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT033.
Abstract CT075: Tumor mutation status will predict metabolic response to metformin in lung cancer treated with stereotactic body radiation therapy (SBRT)
Authors: Skinner Heath D. , Guerrero Thomas , Hobbs Brian , Court Laurence , Nitsch Paige L. , Heymach John
Published: July 2016

At present, there are over 100 clinical trials examining the role of metformin in malignancy, either alone or in combination with chemotherapy. However, despite significant preclinical data, trials examining the role of metformin as a radiosensitizer are few. Moreover, the effects of endogenous tumor mutations on response to metformin are unknown, as some data suggests that certain mutations (eg. TP53, STK11) may confer sensitivity to this agent. Finally, the effects of metformin on FDG-uptake in solid tumors is far from clear, as this agent can actually lead to an increased uptake of FDG in normal bowel. Because of these questions, we have designed an imagining-guided trial of 70 patients, randomized 6:1 in favor of metformin treatment in patients with non-small cell lung cancer to be treated with stereotactic body radiotherapy (SBRT). Patients receive either placebo or metformin at a loading dose of 1,000 mg per day for one week followed by 1-2 weeks of metformin at 2,000 mg per day. Prior to study entry, an FDG-PET scan is performed which is then repeated after 2-3 weeks of metformin treatment. Metformin or placebo is maintained throughout SBRT and the standard daily cone-beam CTs are taken. Metformin or placebo stops at the end of SBRT followed by an additional FDG-PET scan 6 months after completion of therapy. All tumors with available tissue will be subjected to targeted sequencing. The primary outcome is FDG-PET response following initial metformin or placebo monotherapy as well as at 6 months. Secondary outcomes include the effect of common mutations (TP53, STK11, Kras) on metformin FDG-PET response. Currently, 14 patients have been registered for this trial. We anticipate that this study will provide a unique insight on how metformin affects FDG-PET response, if this response is affected by tumor mutation status, and provide preliminary data on the clinical efficacy of metformin in the setting of SBRT.

Citation Format: Heath D. Skinner, Thomas Guerrero, Brian Hobbs, Laurence Court, Paige L. Nitsch, John Heymach. Tumor mutation status will predict metabolic response to metformin in lung cancer treated with stereotactic body radiation therapy (SBRT). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT075.
Abstract CT091: A neoadjuvant co-clinical trial in triple-negative breast cancer patients with genomic discovery analysis
Authors: Ademuyiwa Foluso O. , Li Shunqiang , Luo Jingqin , Skinner Tracy , Hoshower Jason , Ma Cynthia X. , Weilbaecher Katherine , Naughton Michael , Hernandez-Aya Leonel , Mardis Elaine R. , Ellis Matthew J.
Published: July 2016

Background: Patients with TNBC who do not achieve a pathologic complete response (pCR) or near pCR have high rates of relapse, due to chemotherapy resistance, within the first few years after their diagnosis. Molecular biomarkers predictive for chemotherapy sensitivity are lacking. This ongoing trial is evaluating carboplatin and docetaxel in the neoadjuvant setting to determine whether these drugs will increase the pCR rate compared to historical controls. Correlative studies include exome and transcriptome sequencing on samples acquired from patients as a means to decipher the genomic architecture and clonal evolution of those who achieved a pCR compared to those who did not. The simultaneous development of patient derived xenografts (PDX) from host tumors is also planned.

Methods: Patients with clinical stage 2 or 3 histologically confirmed TNBC will receive six cycles of neoadjuvant carboplatin AUC 6 and docetaxel 75 mg/m2 every 3 weeks, followed by definitive surgery. Forty-one eligible patients will be treated according to this protocol, permitting us to attain a power of 83% to detect our expected pCR rate of 54% compared to the historical 35% rate, based on a two-sided exact binomial test at the 4.8% significance level. Eligibility: tumor size at least 2 cm, adequate organ and bone marrow function, no bilateral or inflammatory breast cancer, no invasive cancer within 5 years, ECOG performance status of ? 2, no prior sentinel lymph node biopsy. Tissue collection for xenografting and correlative studies will occur at baseline, at cycle 1 day 3, and at surgery. The primary objective is to determine the pCR rate, defined as the absence of invasive cancer in breast or nodes at definitive surgery. Secondary and exploratory objectives include xenografting rates, evaluation of mutational signatures of chemotherapy resistance and response, and comparison of chemotherapy responses between patients and their xenografts. The study was activated on 7/7/2014 and is still recruiting. Twenty (48.8% of planned 41) patients have been enrolled and have had baseline tissue banked. Fourteen patients have completed protocol therapy. Three patients have tissue at all 3 time points (9 samples), and are presently being studied by exome and transcriptome sequencing.

Citation Format: Foluso O. Ademuyiwa, Shunqiang Li, Jingqin Luo, Tracy Skinner, Jason Hoshower, Cynthia X. Ma, Katherine Weilbaecher, Michael Naughton, Leonel Hernandez-Aya, Elaine R. Mardis, Matthew J. Ellis. A neoadjuvant co-clinical trial in triple-negative breast cancer patients with genomic discovery analysis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT091.
Abstract CT115: Pharmacokinetics of standard versus short high-dose dexamethasone therapy in childhood acute lymphoblastic leukemia: results from the UKALL 2011 trial
Authors: Jackson Rosanna K. , Irving Julie AE , Veal Gareth J.
Published: July 2016

Dexamethasone (Dex) is a key component of ALL therapy, with glucocorticoid sensitivity strongly linked to prognosis. However, it also contributes to life threatening toxicities. The ongoing UKALL 2011 trial is investigating a new schedule of Dex (10mg/m2 × 14 days vs 6mg/m2 × 28 days), in an attempt to bring about a more rapid cytoreduction whilst limiting toxicities associated with long term steroid exposure. There are limited data regarding Dex pharmacokinetics, however large variability has been reported in children with ALL (Yang et al. 2008).

For Dex pharmacokinetic studies, blood samples were collected up to 8h post oral administration on one of the first and last three days of induction chemotherapy. Plasma Dex levels were analysed using a validated LC-MS method, with a range of 5-250ng/ml, and non-compartmental pharmacokinetic analysis was performed.

Pharmacokinetic parameters from day one sampling are shown below. Exposure, as defined by AUC0-12h, and Cmax were significantly higher on the short arm (p = 0.0002 and 0.0007, respectively). However there was substantial overlap between the two arms, with a number of patients on the standard arm exhibiting higher exposures than those on short therapy, despite having a longer duration of treatment. This is reflected in the AUC0-12h ranges observed on the two arms (short: 202-1606; standard: 38-1009 hr*ng/mL). Pharmacokinetic profiles also differed between the two days of treatment, with AUC0-12h being significantly higher at the end of induction chemotherapy (n = 37, study day 1: 655 ± 322; study day 2: 894 ± 496 hr*ng/mL, p = 0.003).

Based on these preliminary data it will be important to consider pharmacokinetic variability when analysing the results generated from the UKALL 2011 trial. Further evaluation of relationships between pharmacokinetic variation, dose scheduling and clinical outcome may enable better stratification of Dex therapy for future patients. Dexamethasone pharmacokinetics in short and standard therapy arms following day one samplingPharmacokinetic parameters (mean ± SD)Half life (hr)Tmax (hr)Cmax(ng/mL)Clearance(L/hr/m2)AUC0-12h(hr*ng/mL)Short (n=43)3.96 ± 3.21.9 ± 1.0128 ± 558.1 ± 5.3692 ± 325Standard (n=33)3.68 ± 2.11.7 ± 1.187 ± 419.2 ± 12.7443 ± 202

Citation Format: Rosanna K. Jackson, Julie AE Irving, Gareth J. Veal. Pharmacokinetics of standard versus short high-dose dexamethasone therapy in childhood acute lymphoblastic leukemia: results from the UKALL 2011 trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT115.
Abstract CT120: Radiotherapy in pediatric patients with atypical teratoid rhabdoid tumor of the central nervous system
Authors: Frick Melissa , Minturn Jane , Li Yi-Mei , Hill-Kayser Christine
Published: July 2016

Atypical teratoid/rhabdoid tumor (ATRT) of the CNS is a rare, highly malignant tumor of early childhood. Current protocols favor multimodality treatment, but practice guidelines differ with regard to radiotherapy. The aim of this study was to evaluate outcomes and prognostic factors in pediatric ATRT receiving multimodality treatment including postoperative radiation. Pediatric subjects with CNS ATRT treated at our institution between 2000 and 2014 were evaluated. Kaplan Meier method was used to estimate progression free survival (PFS) and overall survival (OS) over time and log-rank tests were used to examine associations of demographic and treatment factors with PFS and OS. 20 pediatric subjects (median age 23.5 months; range 4-99 months) with CNS ATRT treated at our institution between 2000 and 2014 were retrospectively evaluated. All underwent surgical resection, adjuvant radiotherapy, and aggressive multi-agent chemotherapy. PFS at 1-year was 63.3% (95% CI, 38.1% - 80.6%) and 2-years was 46.1% (95% CI, 22.9% - 66.5%). OS at both 1- and 2-years was 73.0% (95% CI, 46.7% - 87.8%). Infratentorial disease, lack of metastatic disease at diagnosis, and gross total tumor resection were identified as beneficial prognostic factors in PFS and OS. Progressive disease after radiation was identified as a poor prognostic factor in OS. Radiation modality (proton versus x-ray) did not affect disease-related outcomes. Modern treatment for ATRT with aggressive multimodality therapy including radiotherapy results in a significant portion of subjects with long-term disease control. Prognosis appears to be improved in subjects with localized, completely resected disease.

Citation Format: Melissa Frick, Jane Minturn, Yi-Mei Li, Christine Hill-Kayser. Radiotherapy in pediatric patients with atypical teratoid rhabdoid tumor of the central nervous system. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT120.
Abstract CT126: Single arm study of neoadjuvant chemotherapy without taxane for BRCAness cases in triple-negative breast cancer
Authors: Ishikawa Takashi , Teraoka Saeko , Kaise Hiroshi , Yamada Kimito , Hosonaga Mari , Ueda Ai , Kawai Yoko , Okazaki Miki , Oba Mari S. , Sato Eiichi
Published: July 2016

BACKGROUND: BRCA1 impaired cancers are sensitive to DNA damage. This is associated with the defective homologous recombination (HR) pathway in these tumors. In contrast, these tumors are resistant to mitotic poisons, because BRCA1 protein activates the mitotic spindle checkpoint and triggers apoptosis in microtubule damage. Both preclinical evidence and clinical evidence have shown that the single-agent taxane is not active for BRCA1 mutated breast cancers.

It is reported that BRCA1 function may be impaired in approximately 60% of triple negative breast cancer (TNBC) without mutation. This is called ‘BRCAness’. Previous studies have demonstrated that BRCAness identified tumors with HR deficiency. Thus, taxane may not be necessary for all TNBC cases, although combined treatments of anthracycline and taxane are standard at present.

STUDY PROTOCOL: We have launched a single arm study of neoadjuvant chemotherapy (NAC) for TNBC to confirm that taxane is unnecessary in BRCAness cases.

For the study protocol, TNBC cases requiring NAC are enrolled. Four cycles of an anthracycline-based regimen (FEC 100 or dose-dense EC) are started and BRCAness is examined simultaneously in core-needle specimens. BRCAness is determined by Multiple Ligation-dependent Probe Amplification (MLPA) methods (FALCO Biosystems), which consist of 2 steps. These include copy number analysis in 34 loci specific to BRCA1 mutant and scoring with prediction analysis for microarray. If BRCAness is determined by MLPA, surgery is performed without proceeding to taxane. The primary endpoint is a pathological complete response (pCR) in surgical specimens. The expected pCR and threshold pCR are estimated at 55% and 40%, respectively, based on our previous randomized phase II trial comparing docetaxel plus cyclophosphamide with epirubicin plus cyclophosphamide followed by docetaxel for hormone receptor-negative breast cancer (Ishikawa T. ASCO 2013). With a one-sided significance of 5%, 70 BRCA cases are required.

This study was approved in September 2015 and has been started. Interim analysis is planned when 30 cases are completed.

Citation Format: Takashi Ishikawa, Saeko Teraoka, Hiroshi Kaise, Kimito Yamada, Mari Hosonaga, Ai Ueda, Yoko Kawai, Miki Okazaki, Mari S. Oba, Eiichi Sato. Single arm study of neoadjuvant chemotherapy without taxane for BRCAness cases in triple-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT126.
Abstract CT155: The effect of perioperative probiotics treatment for colorectal cancer: short-term outcomes of a randomized controlled trial
Authors: Ma Yanlei , Wei Qing , Yang Yongzhi , Qin Huanlong
Published: July 2016

This study was designed to mainly evaluate the anti-infective effects of perioperative probiotic treatment in patients receiving confined colorectal cancer (CRC) respective surgery. From November 2011 to September 2012, a total of 60 patients diagnosed with CRC were randomly assigned to receive probiotic (n = 30) or placebo (n = 30) treatment. The operative and post-operative clinical results including intestinal cleanliness, days to first - flatus, defecation, fluid diet, solid diet, duration of pyrexia, average heart rate, length of intraperitoneal drainage, length of antibiotic therapy, blood index changes, rate of infectious and non-infectious complications, postoperative hospital stay, and mortality were investigated. The patient demographics were not significantly different (p > 0.05) between the probiotic treated and the placebo groups. The days to first flatus (3.63 versus 3.27, p = 0.0274) and the days to first defecation (4.53 versus 3.87, p = 0.0268) were significantly improved in the probiotic treated patients. The incidence of diarrhea was significantly lower (p = 0.0352) in probiotics group (26.67%, 8/30) compared to the placebo group (53.33%, 16/30). There were no statistical differences (p > 0.05) in other infectious and non-infectious complication rates including wound infection, pneumonia, urinary tract infection, anastomotic leakage, and abdominal distension. In conclusion, for those patients undergoing confined CRC resection, perioperative probiotic administration significantly influenced the recovery of bowel function, and such improvement may be of important clinical significance in reducing the short-term infectious complications such as bacteremia.

Trial Registrations: ChiCTR-TRC-13003332 (http://www.chictr.org/en/)

Citation Format: Yanlei Ma, Qing Wei, Yongzhi Yang, Huanlong Qin. The effect of perioperative probiotics treatment for colorectal cancer: short-term outcomes of a randomized controlled trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT155.
Abstract LB-002: Methylation of the EGF receptor regulates signaling and therapeutic response
Authors: Liao Hsin-Wei , Hsu Jung-Mao , Xia Weiya , Hung Mien-Chie
Published: July 2016

Epidermal growth factor receptor (EGFR)-targeted monoclonal antibody, cetuximab, is one of the most effective ways of controlling colorectal cancer progression. However, resistance to cetuximab has been observed in clinical setting. Here, we report a mechanism contributing to cetuximab resistance in which protein arginine methyltransferase 1 (PRMT1) methylates the extracellular domain of EGFR at R198 and R200, leading to an increase in the binding affinity between EGF and methylated EGFR, and subsequently receptor dimerization, downstream signaling activation, and cell proliferation in vitro. R/K mutation of the EGFR methylation sites reduces tumor growth in mouse orthotopic xenograft model. Increased EGFR methylation retains its signaling activation and cell proliferation in the presence of cetuximab. Importantly, EGFR methylation level is correlated with higher recurrence rate after cetuximab treatment and poor overall survival, suggesting that the methylation status of EGFR has the potential to predict resistance to cetuximab treatment in colorectal cancer and head and neck cancer patients.

Citation Format: Hsin-Wei Liao, Jung-Mao Hsu, Weiya Xia, Mien-Chie Hung. Methylation of the EGF receptor regulates signaling and therapeutic response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-002.
Abstract LB-005: TRIP13/PCH2 is a novel regulator of EGF-mTOR signaling promoting hepatocellular carcinoma development
Authors: Meissburger Bettina , Chan Jessica , de Guia Roldan , Herzig Stephan , Berriel Diaz Mauricio
Published: July 2016

Hepatocellular carcinoma (HCC) is currently the third most common cause of cancer-related mortality with limited treatment options and bleak prognosis. The main risk factors for HCC have been linked to hepatitis infection, alcoholic liver injury, non-alcoholic fatty liver disease (NAFLD) and metabolic diseases. Current therapeutic options are limited, which could be due to the lack of understanding of the key cellular players and signalling pathways in HCC.

In order to find novel regulators of HCC development, we surveyed expression data of human hepatocellular carcinoma (E-GEOD-25097) and found the AAA-ATPase Thyroid Hormone Receptor Interactor 13 (TRIP13) to be upregulated in tumorous tissue compared to non-tumorous tissue. Consistently, using a mouse model for HCC by injection of Diethylnitrosamine (DEN), we observed induced expression of TRIP13 in liver tumors compared to healthy liver tissue. Additionally, in a model of liver regeneration by partial hepatectomy, induction of TRIP13 coincided with a peak in cell proliferation in the regenerating liver. Strinkingly, Adeno-associated virus (AAV)-mediated hepatocyte-specific knockdown of TRIP13 impeded liver regeneration upon partial hepatectomy, suggesting an important role of TRIP13 in liver cell proliferation. Indeed, knockdown (KD) of TRIP13 severely impaired cell growth and proliferation in different human and murine HCC cell lines in vitro.

To investigate the oncogenic potential of TRIP13 in vivo, we injected lentiviral infected cells subcutaneously into mice and measured tumor growth. Remarkably, knockdown of TRIP13 in Hepa1-6 cells led to the development of smaller tumors compared to control cells, whereas TRIP13-deficient Huh7 cells did not form any tumors.

Interestingly, shRNA knockdown of TRIP13 in HCC cell lines showed decreased phosphorylation of key players in the mTOR signalling pathway and reduction of the downstream Cyclin D1 levels. Concurrently, the mRNA and protein expression of EGF receptor was also downregulated in TRIP13 KD-cells.

Taken together, we identified a novel role of TRIP13 during hepatocyte proliferation both in liver regeneration and HCC. Additionally, our findings also support an oncogenic function of TRIP13 through the regulation of the EGFR-mTOR signalling axis.

Citation Format: Bettina Meissburger, Jessica Chan, Roldan de Guia, Stephan Herzig, Mauricio Berriel Diaz. TRIP13/PCH2 is a novel regulator of EGF-mTOR signaling promoting hepatocellular carcinoma development. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-005.
Abstract LB-020: IP3 3-kinase B suppresses B-cell lymphoma by antagonizing PI3K/mTOR in B cells
Authors: Sauer Karsten , Conche Claire , Jin Hyun-Yong , Bethel Kelly , Rigaud Stephanie , Westernberg Luise , Siegemund Sabine , Xiao Changchun
Published: July 2016

Accounting for ∼4% of all cancers in the US, Non-Hodgkin Lymphoma (NHL) is the most prevalent blood cancer. Diffuse large B-cell Lymphoma (DLBCL) is the most common and aggressive type of NHL. Here, we identify inositol-trisphosphate (IP3) 3-kinase B (Itpkb) as a novel tumor suppressor whose deficiency triggers DLBCL in mice. We found that aging Itpkb-/- mice die prematurely with anemia and splenomegaly. 15% of these mice showed multiorgan-infiltration with neoplastic germinal-center phenotype B cells reminiscent of DLBCL. Itpkb-/- B cell lymphomas are mono-or oligoclonal, transplantable, and constitutively hyperactivate the oncogenic phosphoinositide 3-kinase (PI3K) signaling pathway. Growth of Itpkb-/- B cell lymphoma xenografts in immunodeficient mice is sensitive to treatment with PI3K or mTOR inhibitors. In humans, subsets of DLBCL patients carry Itpkb missense mutations, deletions or copy number reductions. Additionally, Itpkb expression is altered in several other hematopoietic and non-hematopoietic human cancers. We propose that Itpkb suppresses tumors by producing inositol-tetrakisphosphate (IP4), a soluble analog of the PI3K product phosphatidylinositol-trisphosphate (PIP3). We and others have previously shown that IP4 antagonism with PIP3 for Akt effector kinase binding prevents excessive Akt/mTORC1 signaling in hematopoietic cells. Our new results suggest that this mechanism prevents oncogenic PI3K signaling in the B cell lineage and possibly in other cell types. Thus, Itpkb might be a novel biomarker for tumor aggressiveness or prognosis, and Itpkb activating drugs or IP4 might have therapeutic potential.

This work was supported by NIH grants AI070845 and GM100785 to KS, The Leukemia & Lymphoma Society Scholar Award 1440-11 to KS, the AAI Careers in Immunology Fellowship Program to SR, DFG Fellowship SI 1547/1-1 to SS, and an ARC fellowship to CC.

Citation Format: Karsten Sauer, Claire Conche, Hyun-Yong Jin, Kelly Bethel, Stephanie Rigaud, Luise Westernberg, Sabine Siegemund, Changchun Xiao. IP3 3-kinase B suppresses B-cell lymphoma by antagonizing PI3K/mTOR in B cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-020.
Abstract LB-021: LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of triple-negative/basal-B breast cancer cells
Authors: Yokdang Nucharee , Hatakeyama Jason , Wald Jessica , Simion Catalina , Tellez Joseph , Chang Dennis , Swamynathan Manojit , Chen Mingyi , Murphy William , Carraway Kermit , Sweeney Colleen
Published: July 2016

LRIG1, a member of the LRIG family of transmembrane leucine rich repeat-containing proteins, is a negative regulator of receptor tyrosine kinase signaling and a tumor suppressor. LRIG1 expression is broadly decreased in human cancer and in breast cancer, low expression of LRIG1 has been linked to decreased relapse-free survival. Recently, low expression of LRIG1 was revealed to be an independent risk factor for breast cancer metastasis and death. These findings suggest that LRIG1 may oppose breast cancer cell motility and invasion, cellular processes which are fundamental to metastasis. However, very little is known of LRIG1 function in this regard. In this study, we demonstrate that LRIG1is down-regulated during epithelial to mesenchymal transition (EMT) of human mammary epithelial cells, suggesting that LRIG1 expression may represent a barrier to EMT. Indeed, depletion of endogenous LRIG1 in human mammary epithelial cells expands the stem cell population, augments mammosphere formation and accelerates EMT. Conversely, expression of LRIG1 in highly invasive triple-negative/Basal B breast cancer cells provokes a mesenchymal to epithelial transition accompanied by a dramatic suppression of tumorsphere formation and a striking loss of invasive growth in three-dimensional culture. LRIG1 expression perturbs multiple signaling pathways and represses markers and effectors of the mesenchymal state. Furthermore, LRIG1 expression in MDA-MB-231 breast cancer cells significantly slows their growth as tumors, providing the first in vivo evidence that LRIG1 functions as a growth suppressor in breast cancer.

Citation Format: Nucharee Yokdang, Jason Hatakeyama, Jessica Wald, Catalina Simion, Joseph Tellez, Dennis Chang, Manojit Swamynathan, Mingyi Chen, William Murphy, Kermit Carraway, Colleen Sweeney. LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of triple-negative/basal-B breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-021.
Abstract LB-022: The E3-ligase CHIP negatively regulates the expression and function of the tumor suppressor TAp63 through ubiquitination and subsequent proteasome-mediated degradation
Authors: Armstrong Stephen R. , Wang Benfan , Abuetabh Yasser , Leng Roger
Published: July 2016

The p53 tumor suppressor family is comprised of three members: p53, p63, and p73. These transcription factors can negatively regulate cell proliferation by inducing the expression of proteins related to apoptosis (ex. bax) and cell cycle arrest (ex. p21). Isoforms of the p63 protein can be divided into two major groups, the transcriptionally active TAp63 variants, and the dominant-negative ΔNp63 variants. The TAp63 variants are considered to be tumor suppressor proteins that can cooperate with p53 and p73 to prevent cancer development. Unlike p53, which is frequently mutated in cancer, TAp63 is rarely mutated, and its transcription function is primarily regulated at the protein level. One such method of regulation at this level is proteasome-mediated degradation, initiated by tagging the substrate protein with a poly-ubiquitin chain recognized by the proteasome. This ubiquitination is mediated by E-3 ligases such as Mdm2 and AIP4, two previously characterized regulators of the p53 family. In this study, we report that CHIP, an E-3 ligase involved in protein chaperoning during the heat shock response is a negative regulator of TAp63. The purpose of this study was to characterize CHIP as a TAp63-interacting protein that negatively regulates TAp63 expression and function. Using transient transfection assays, we found that CHIP can bind to, ubiquitinate, and reduce the expression of TAp63 in H1299 lung carcinoma cells. Stably knocking down CHIP expression in these cells using anti-CHIP shRNA restores endogenous p63 expression. This negative regulation of TAp63 by CHIP is associated with a decrease in p21 promoter transcription (measured by a luciferase reporter assay), cell cycle arrest and cellular apoptosis (measured by flow cytometry), and accompanied by an increase in cell survival (measured by colony forming assay) and invasive capacity (measured by a cell scattering assay). An immunoblot analysis of carcinoma cell lines and invasive prostate cancer tissue samples also demonstrates a negative correlation between CHIP and TAp63 expression levels. We conclude that CHIP is a negative regulator of TAp63 expression and function, and, therefore, has an oncogenic role in context with TAp63.

Citation Format: Stephen R. Armstrong, Benfan Wang, Yasser Abuetabh, Roger Leng. The E3-ligase CHIP negatively regulates the expression and function of the tumor suppressor TAp63 through ubiquitination and subsequent proteasome-mediated degradation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-022.
Abstract LB-024: PIM kinase inhibitors selectively kill hypoxic cancer cells by reducing Nrf2 activity and increasing reactive oxygen species
Authors: Sainz Alva G. , Song Jin H. , Kraft Andrew S. , Warfel Noel A.
Published: July 2016

Prostate cancer (PCa) is the leading cause of cancer death in men worldwide. Patients diagnosed with metastatic prostate cancer initially respond to androgen deprivation therapy, but this response is not durable, and all patients develop hormone-refractory disease that ultimately leads to death. Current treatment options for metastatic PCa patients are limited (e.g., cytotoxic chemotherapy or radiation), and the response to these agents is invariably temporary and does not improve survival. A significant obstacle to the successful treatment of advanced PCa is tumor hypoxia. While hypoxia is toxic to normal cells, cancer cells take particular advantage of their ability to adapt to these harsh conditions by increasing the expression of proteins that promote angiogenesis and survival. Therefore, elucidating the molecular mechanisms controlling survival in hypoxia is important for the development of effective therapeutic strategies to selectively kill hypoxic tumor cells.

The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases represent a pro-survival pathawy that is upregulated in response to hypoxia in a HIF-1 independent manner. We demonstrate that pharmacological or genetic inhibition of PIM kinases is significantly more toxic toward cancer cells in hypoxia versus normoxia. Xenograft studies confirm that PIM kinase inhibitors impede tumor growth and selectively kill hypoxic tumor cells in vivo. Experiments show that PIM kinases enhance the ability of tumor cells to adapt to hypoxia-induced oxidative stress by increasing the nuclear localization and activity of Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), which functions to increase the expression of antioxidant genes. Small molecule PIM kinase inhibitors reduce the ability of Nrf2 to enter the nucleus and block the transcrption of cytoprotective genes, leading to the accumulation of intracellular reactive oxygen species (ROS) to toxic levels in hypoxic tumor cells. This toxic effect of PIM inhibitors can be succesfully blocked by ROS scavengers, including N-acetyl cystine and superoxide dismutase. Thus, inhibition of PIM kinases has the potential to oppose hypoxia-mediate therapeutic resistance and induce cell death in the hypoxic tumor microenvironment.

Citation Format: Alva G. Sainz, Jin H. Song, Andrew S. Kraft, Noel A. Warfel. PIM kinase inhibitors selectively kill hypoxic cancer cells by reducing Nrf2 activity and increasing reactive oxygen species. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-024.
Abstract LB-034: Tcf7: an essential mediator in Notch-induced T-ALL
Authors: Koch Ute , Sugrue Tara , Dubey Christelle , Radtke Freddy
Published: July 2016

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer caused by the malignant transformation of immature thymocytes. Notch1 gain-of-function mutations are present in >50% of T-ALL cases and result in the constitutive activation of Notch1 intracellular domain (N1ICD) in mutated cells. The mechanisms by which deregulated Notch1 signalling leads to T-ALL development are currently unresolved and stringently investigated. T cell factor-1 (TCF-1) is a transcription factor encoded by Tcf7. Not only playing crucial roles in Wnt signalling, Tcf7 is (i) a direct Notch1 target gene and (ii) required for driving early T lineage commitment of hematopoietic progenitors. Together, these findings suggest that Tcf7 may play a role in Notch1-driven T-ALL. Herein, we show that the conditional loss of Tcf7 in hematopoietic progenitors prevents T-ALL development in both genetic- and retroviral-based mouse models of N1ICD over-expression. However, T-ALL development was unaffected by conditional loss of the Wnt signalling mediator, β-catenin. Interestingly, conditional Tcf7 deficiency partially restored the B lineage potential of N1ICD over-expressing bone marrow progenitors. Similar to Tcf7-/- mice, conditional Tcf7 deficiency in bone marrow progenitors abrogated T cell development in adult thymi. However, unexpectedly, Tcf7-deficient hematopoietic progenitors adopted a B cell fate in these thymi, a phenotype that was found to be comparable to conditional loss of Notch1. Overall, our results indicate that Tcf7 is an important mediator of Notch1-driven T-ALL. Furthermore, our data suggests that, in addition to promoting T lineage commitment, Tcf7 may also function as a Notch1-dependent transcriptional repressor of B lineage commitment in adult hematopoiesis. We performed RNAseq to identify the molecular players involved in Tcf7-mediated lineage repression and complement this approach with CHIP_Seq.

Citation Format: Ute Koch, Tara Sugrue, Christelle Dubey, Freddy Radtke. Tcf7: an essential mediator in Notch-induced T-ALL. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-034.