bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 162: Overexpression of long noncoding RNA FTX was associated with colorectal cancer progression
Authors: Iwaya Takeshi , Sato Kei , Kume Kohei , Nishizuka Satoshi , Wakabayashi Go , Mimori Koshi 
Published: August 2015

Abstract
Increasing evidence suggests Long noncoding RNAs (lncRNAs) have crucial roles in cancer biology. Using public microarray database, we evaluated the association between the expression status of lncRNAs and colorectal cancer (CRC) prognosis. Among the candidate lncRNAs showed significant higher expression in CRC patients with poor prognosis, we focused on FTX on chromosome X. We validated FTX expression status in 128 primary tumor samples and corresponding normal tissues from CRC patients through quantitative real-time PCR (qRT-PCR) analysis. Primary tumor tissues exhibited higher FTX expression compared to corresponding normal tissues (p = 0.0008). In terms of overall survival, patients in the FTX high expression group (n = 74) had a significantly poorer prognosis than those in the FTX low expression group (n = 74). Multivaliate analysis of overall survival revealed that the level of FTX expression was a prognostic predictor. FTX knockdown inhibited tumor cell proliferation in CRC cell line, HT29. Our results indicate that overexpression of FTX may affect CRC progression.
Citation Format: Takeshi Iwaya, Kei Sato, Kohei Kume, Satoshi Nishizuka, Go Wakabayashi, Koshi Mimori. Overexpression of long noncoding RNA FTX was associated with colorectal cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 162. doi:10.1158/1538-7445.AM2015-162
Abstract 1635: Mechanistic investigation of neutropenia associated with palbociclib
Authors: Hu Wenyue , Sung Tae , Jessen Bart , Sacaan Aida 
Published: August 2015

Abstract
Bone marrow suppression, especially neutropenia, has been identified as one of the main dose-limiting toxicities for the selective CDK4/6 inhibitor, palbociclib, in the clinic. However, compared to chemotherapy-induced myelotoxicity, palbociclib-induced neutropenia is quickly reversible, uncomplicated and is proactively managed by a short duration treatment-free period between cycles, or reactively by dose delay or reduction. To aid in understanding the mechanism by which neutropenia occurs and to further differentiate it from chemotherapy- induced myelotoxicity, an in vitro bone marrow toxicity assay was utilized to evaluate the cellular mechanism and the reversibility of bone marrow suppression induced by palbociclib as a single agent or in combination with anti-estrogens.
This investigation has demonstrated that palbociclib-induced bone marrow suppression manifested through cell cycle arrest without apoptosis; by contrast, chemotherapeutic agents, including paclitaxel, doxorubicin, and carboplatin, primarily caused apoptotic cell death in the bone marrow. Following palbociclib treatment withdrawal in vitro, bone marrow cells resumed proliferation in the presence or absence of the anti-estrogen (fulvestrant); while breast cancer cells (MCF-7) remained arrested in the presence of fulvestrant. Bone marrow cells did not resume proliferation following chemotherapy treatment withdrawal. To further investigate the mechanism of reversibility, we evaluated the involvement of cellular senescence. Bone marrow cells did not enter senescence following treatment with palbociclib, anti-estrogen, or a combination of both agents. MCF-7 cells, on the other hand, became senescent following palbociclib or anti-estrogen treatment, and this effect was larger in the presence of both agents.
In summary, the current investigative work shed light on the mechanism of palbociclib- induced bone marrow suppression and clearly differentiated it from that induced by chemotherapeutic agents. These results potentially explain the quick reversibility of palbociclib-induced myelosuppression and its uncomplicated nature when compared to traditional cytotoxic agents. Moreover, the data supports the current dosing regimen in the clinic, which provides time for bone marrow cells to recover during the 1 week treatment-free period without impacting tumor efficacy. This investigative work provides valuable information to the clinicians in managing the neutropenia risk associated with breast cancer treatment.
This research was funded by Pfizer, Inc.
Citation Format: Wenyue Hu, Tae Sung, Bart Jessen, Aida Sacaan. Mechanistic investigation of neutropenia associated with palbociclib. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1635. doi:10.1158/1538-7445.AM2015-1635
Abstract 1636: A model-based approach toward clinical pipeline optimization
Authors: Burton Jackson , Antebi William , Zopf Christopher J. , Bottino Dean , Teng Shu-Wen , Nolan Ryan , Chakravarty Arijit 
Published: August 2015

Abstract
Introduction
What is the optimal “shape” for a drug pipeline: A flute? A megaphone? A trumpet? In other words, what set of stringencies for passage of candidates to the next stage in development maximizes the value of the pipeline as a whole, and how do assays predicting drug quality influence this optimum?
Methods
A linear programming formulation was developed for four phases of a drug pipeline: Preclinical, Phase I, Phase II, and Phase III, with variables including: the total budget for the entire pipeline (B), and the number (Ni), cost (ci), and net present value (vi) of drugs in each phase (i). The model is subject to two constraints: (1) the pipeline must reduce in size with each subsequent phase (i.e. Npre≥ N1 ≥ N2 ≥ N3), and (2) the sum total of the cost times the number of drugs in each phase must be less than or equal to the total budget (i.e. cpreNpre + c1N1 + c2N2 + c3N3 ≤ B). The overall goal is to maximize the total value of drugs progressing through the pipeline (i.e. maximize vtot = vpreNpre + v1N1 + v2N2 + v3N3).
Additionally, pipeline evolution was modeled to evaluate the implications of a “predictive” drug quality assay. Hypothetical “drug quality scores” were drawn from normal distributions which reflect industry probabilities of success between phases. Drugs that are above a cutoff stringency advance forward, with the process repeated for all phases. The cost of each phase and value for successful drugs are recorded for each simulation. The process is repeated many times, with the expected value calculated at each iteration.
Results
Beginning with a pool of drug candidates, the optimal pipeline structure should approach equal sized pipeline widths as rapidly as possible.
Monte Carlo simulations demonstrated that increasing the stringency of a “quality assay” in Phase I results in a linear increase in expected value. Additionally, if the quality test is improved, e.g. by reducing the variability of the assay, the improvement in expected value will increase in an exponential manner.
Conclusions
The simulations predict that to maximize pipeline value, drug companies should: (a) pick the winners as early as possible (i.e. Preclinical or Phase I), (b) set stringent go/no-go criteria in Preclinical and Phase I development, and (c) perform prospective clinical trial simulations (Preclinical to Phase I, Phase I to Phase II, Phase II to Phase III) to improve the ability to predict winners.
Citation Format: Jackson Burton, William Antebi, Christopher J. Zopf, Dean Bottino, Shu-Wen Teng, Ryan Nolan, Arijit Chakravarty. A model-based approach toward clinical pipeline optimization. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1636. doi:10.1158/1538-7445.AM2015-1636
Abstract 1650: CYC065, a novel CDK2/5/9 inhibitor: detailed mechanistic studies, determinants of sensitivity and synergistic combinations
Authors: Saladino Chiara , Frame Sheelagh , Davis Susan , Blake David , Zheleva Daniella 
Published: August 2015

Abstract
Background: CYC065 is a novel, second generation aminopurine inhibitor highly selective for CDK2, CDK5 and CDK9 over other CDKs and non-CDK enzymes. CYC065 has completed IND-directed drug development and is ready for FIH studies. The unique target profile of CYC065 can be exploited in cyclin E-overexpressing tumors, including a trastuzumab-resistant Her2+ breast cancer model (Scaltriti et al, PNAS 2011; 9:3761).
The aim of this study was to gather key dosing information for this compound in advance of FIH studies, and provide understanding of the compound mechanism of action in additional key target indications.
CDK9 is a key regulator of mixed lineage leukemia (MLL)-driven leukemogenesis and Mcl-1-dependent survival and therefore represents a potential therapeutic target for AML and MLL leukaemia.
Methods: A panel of acute leukemia cell lines with different MLL status (WT, MLL translocations and MLL PTD) was used in this study. Resazurin and flow cytometry-based annexin V assays were used to determine cell viability and apoptosis induction. PI staining was used to examine cell cycle distribution. Protein levels were quantified by Western blotting and quantitative imaging. Combinations were studied using the Chou and Talalay method. The in vivo activity of CYC065 was studied in murine xenograft models.
Results: CYC065 rapidly decreased phosphorylation of Ser2 -RNAP II and expression of proteins involved in cell cycle control, survival and leukemogenesis (such as Mcl-1, Cyclin E, PNUTS, Hoxa9 and Meis 1), leading to robust and early induction of apoptosis (within 4 h). Time- and dose-dependent studies indicated that 6 h pulse treatment at 0.5-1 μM CYC065 was sufficient to cause ≥ 90% cell death in sensitive cell lines. Cell lines with MLL rearrangements were highly sensitive to CYC065, whilst sensitivity of AML cell lines with WT MLL correlated with the level of Bcl-2 family proteins. Cell lines with reduced sensitivity to CYC065 could be effectively targeted by exposure to longer, 10 h pulse treatments with CYC065, or in combination with short pulses of Bcl-2 inhibitors. In vivo, CYC065 achieved &gt;90% TGI at well tolerated dose levels in HL60 (WT MLL) and EOL-1 (MLL PTD) xenograft models.
Conclusion: CYC065 has therapeutic potential for AML and MLL leukemia. MLL status and the levels of Bcl-2 family proteins might be useful patient stratification markers for predicting sensitivity/resistance.
Citation Format: Chiara Saladino, Sheelagh Frame, Susan Davis, David Blake, Daniella Zheleva. CYC065, a novel CDK2/5/9 inhibitor: detailed mechanistic studies, determinants of sensitivity and synergistic combinations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1650. doi:10.1158/1538-7445.AM2015-1650
Abstract 1691: SL-401 activity against AML blasts correlates with CD123 levels and does not down-regulate CD123 expression
Authors: Mani Rajeswaran , Gopalakrishnan Bhavani , Mo Xiaokui , Brooks Chris , Blum William , Lozanski Gerard , Vasu Sumithira , Muthusamy Natarajan 
Published: August 2015

Abstract
Despite the progress, the current therapies for acute myeloid leukemia (AML) are not curative partly due to failure to eradicate the leukemic stem cells (LSCs) that repopulate the leukemia. CD123 is the alpha-chain of interleukin-3 receptor (IL-3R) that is expressed on AML and AML LSCs, while it is undetectable in normal hematopoietic stem cells. We report here time and dose dependent cytotoxic activity of SL-401(Stemline Therapeutics, Inc), a diphtheria toxin interleukin-3 fusion protein which is designed to selectively bind, internalize and induce apoptosis of CD123+ primary AML cells isolated from patients.
AML blasts were obtained from leukapheresis of patients and cultured in RPMI1640 with 20% fetal bovine serum and antibiotics and supplemented with growth factors GM-CSF and SCF (10ng/ml) overnight before treatment with increasing concentrations of SL-401. CD123 expression of AML blasts was analyzed using multicolor flow cytometry before and 24 hours after treatment with SL-401. The viability of the cells before and after treatment with increasing concentrations of SL-401 was measured by annexinV-FITC and propidium iodide staining.
SL-401 induced dose-dependent (SL-401: 10, 100, 1000ng/ml) cytotoxicity in primary AML in nanomolar range (trend p = 0.0002 at 48hr), which correlated with surface expression levels of CD123. AML CD34+CD33+ blasts showed high CD123 expression levels and were susceptible to cytotoxicity with SL-401 (P&lt;0.0001,1000ng/ml at 48hr). CD34−CD33+ committed leukemic cells were also CD123+ and responded to SL-401. To determine if SL-401 modulated CD123 levels after exposure, AML blasts pre-treated with SL-401 for 24hr were analyzed by flow cytometry for receptor expression. Importantly, SL-401 treatment after 24 hours did not down-regulate CD123 expression on primary AML blasts indicating a lack of an escape mechanism for malignant cells.
These results provide evidence that time- and dose-dependent activity of SL-401 against CD123+ AML blasts correlates with CD123 expression. Moreover, treatment does not down-regulate IL-3R expression. Clinical studies of SL-401 in patients with relapsed/refractory AML with evaluation of CD123 expression and blastic plasmacytoid dendritic cell neoplasm (BPDCN) are ongoing.
Citation Format: Rajeswaran Mani, Bhavani Gopalakrishnan, Xiaokui Mo, Chris Brooks, William Blum, Gerard Lozanski, Sumithira Vasu, Natarajan Muthusamy. SL-401 activity against AML blasts correlates with CD123 levels and does not down-regulate CD123 expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1691. doi:10.1158/1538-7445.AM2015-1691
Abstract 1707: PACE4-dependent cellular uptake and retention of the Multi-Leucine peptide inhibitor into cancer cells
Authors: Couture Frédéric , Ly Kevin , Levesque Christine , Kwiatkowska Anna , Desjardins Roxane , Guérin Brigitte , Day Robert 
Published: August 2015

Abstract
The proprotein convertase PACE4 is strongly overexpressed in prostate cancer and plays an important role in tumor progression by promoting cell proliferation and tumor angiogenesis. Because the high expression levels and the necessity of this enzyme for cancer progression, we have developed a peptide-based inhibitor known as the Multi-Leucine (ML) peptide, which is a PACE4-specific inhibitor. Just like PACE4-downregulation through stable shRNA transfections, this compound displays anti-proliferative properties when applied on cancer cells. We showed its target-specific uptake into prostate cancer xenografts by positron emission tomography, which allowed clear tumor visualization.
The ML-peptide has potent effects to block the further progression of prostate cancer cells, however, the uptake mechanism of this peptide is not clear and whether it is PACE4-dependent. We therefore tested the uptake and efflux rates of the ML-peptide peptide in prostate cancer cells and correlated these with PACE4 expression levels in wild type and stable PACE4-knockdown cell lines. In addition to prostate cancer cell lines LNCaP, DU145 and PC3, we tested HepG2, Huh7 and HT1080 cells, which also express PACE4. To measure peptide uptake, the ML peptide was modified through the addition a 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) moiety to strongly chelate radiometal such as 64Cu. Our study shows that uptake of the ML-peptide is correlated with expression levels, but more importantly can be blocked in PACE4-knockdown cell lines, demonstrating a PACE4-dependant uptake mechanism. We also correlated uptake with the anti-proliferative effects of the ML-peptide and showed that entry into these cell lines predicted the effects of the ML-peptide on the growth of these cells.
These results confirm the notion that ML-peptide entry within cell is an important requirement to exert growth inhibition properties, and further provide a mechanism for that entry. This study demonstrates further support for the use of the ML-peptide or its analogs as potential drugs in prostate cancer, as well as any other PACE4-dependent tumors. These indications of peptide uptake within tumor could allows PACE4-status to be determined by positron emission tomography and may be of great theranostics uses in the context of pharmacological intervention with PACE4 inhibitors.
Citation Format: Frédéric Couture, Kevin Ly, Christine Levesque, Anna Kwiatkowska, Roxane Desjardins, Brigitte Guérin, Robert Day. PACE4-dependent cellular uptake and retention of the Multi-Leucine peptide inhibitor into cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1707. doi:10.1158/1538-7445.AM2015-1707
Abstract 1710: Xanthohumol suppresses estrogen-signaling in endocrine resistant breast cancer through the specific inhibition of BIG3-PHB2 interactions
Authors: Katagiri Toyomasa 
Published: August 2015

Abstract
Estrogen-receptor-α (ERα) plays a pivotal role in the development and progression of breast cancer. The current endocrine therapies for breast cancer are mainly based on targeting ERα signaling using selective ERα modulators, ERα downregulators, and aromatase inhibitor (AI)1-3. However, tamoxifen treatment often fails, and patients succumb to recurrent, endocrine-resistant tumors. Moreover, some patients who have undergone AI treatment still relapse. The precise molecular events that determine alterations in the effectiveness of these endocrine therapies remain unknown.
We previously reported that the oncoprotein brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) and tumor suppressor prohibitin 2 (PHB2) complex play a pivotal role in E2 signaling modulation in ERα-positive breast cancer. Namely, BIG3 binds PHB2, thereby inhibiting the E2-dependent suppressive ability of PHB2 and resulting in constitutive ERα activation. Considering these findings, strategies utilising the tumour suppressive activity of PHB2 upon its release from BIG3 by inhibitors of protein-protein interaction may represent novel therapies for breast cancer. Accordingly, we focus on whether XN potentially binds to the tumor suppressor protein PHB2, forming a novel natural anti-tumor compound targeting the BIG3-PHB2 complex and acting as a pivotal modulator of E2 /ERα signaling in breast cancer cells. XN treatment effectively prevented the BIG3-PHB2 interaction, thereby releasing PHB2 to directly bind to both nuclear- and cytoplasmic ERα. This event led to the complete suppression of the E2-signaling pathways and ERα-positive breast cancer cell growth both in vitro and in vivo, but did not suppress the growth of normal mammary epithelial cells. Our findings suggest that XN may be a promising natural compound to suppress the growth of luminal-type breast cancers, especially endocrine resistant breast cancers.
Citation Format: Toyomasa Katagiri. Xanthohumol suppresses estrogen-signaling in endocrine resistant breast cancer through the specific inhibition of BIG3-PHB2 interactions. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1710. doi:10.1158/1538-7445.AM2015-1710
Abstract 1711: SLC6A15, a novel potential metabolic target for non-small cell lung cancer
Authors: SRIVASTVA PALLEVI , Yoo Hyuntae 
Published: August 2015

Abstract
Current therapeutic targets for non-small cell lung cancer consist only of signaling pathways targeting VEGF, EGFR or ALK. Recent researches have put focus on understanding cancer metabolism (such as 2-hydroxyglutarate accumulation in gliomas with mutant IDH1) and have opened a new avenue in cancer therapeutics which can complement the current practices. Here we introduce a new potential metabolic target for non-small cell lung cancer, SLC6A15. It is a trans-membrane protein known to facilitate uptake of branched chain amino acids (BCAA) (leucine, isoleucine and valine) and proline into the cells. BCAA was recently reported to increase cellular proliferation by regulating m-TOR in normal cells like beta-pancreatic cells. Here we show that these BCAA are highly enriched in lung tumor cell lines (H1299 & H460) as well as in human lung tumor tissues as a result of overexpression of SLC6A15. We performed a transient knockdown of this transporter using siRNA for SLC6A15 and observed its effect on reduced clonogenicity of the two cancer cell lines by 3.3 and 1.6 fold, respectively. Further, gas chromatography mass spectrometry (GC-MS) analysis of the cells treated with si(SLC6A15) revealed selective reduction of BCAA levels by 1.3 to 1.5 fold but not in Proline, which can be synthesized in the cells unlike BCAA. These results support the role of these amino acids in tumor cell proliferation. Overexpression of SLC6A15 protein was confirmed by western blot analysis in 8 NSCLC cell lines and is indicative of its tumor specific nature. This finding is also supported by SLC6A15 gene expression data available on TCGA (The Cancer Genome Atlas), where 6 out of 10 patients show high expression of this gene. Therefore, we conclude that SLC6A15 is a new candidate of therapeutic target for NSCLC. Targeted inhibition may open new possibilities to specific reduction of tumor cell proliferation and possibly, increase life expectancy of patients suffering from NSCLC.
Citation Format: PALLEVI SRIVASTVA, Hyuntae Yoo. SLC6A15, a novel potential metabolic target for non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1711. doi:10.1158/1538-7445.AM2015-1711