bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3474: The effect of forced expression of k-ras mutation on gastrointestinal cancer cells and IGF-IR targeting therapy
Authors: Adachi Yasushi , Matsunaga Yasutaka , Sasaki Yasushi , Nosho Katsuhiko , Yamamoto Hiroyuki , Arimura Yoshiaki , Endo Takao , Kato Yasuo , Tokino Takashi , Carbone David P. , Shinomura Yasuhisa 
Published: August 2015

Abstract
Background & Aims: Mutation in k-ras plays important roles in both the progression and the resistance for anti-EGFR therapy in gastrointestinal tumors. Insulin-like growth factor-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of many tumors. We have previously shown successful therapy for gastrointestinal cancer cell lines with k-ras mutation using recombinant adenoviruses expressing dominant negative IGF-IR (IGF-IR/dn) and an anti-IGF-IR monoclonal antibody. In this study, we sought to evaluate the effect of k-ras mutation on gastrointestinal cancer cell lines and IGF-IR targeting therapies for those cells. Methods: We made stable transfectants of mutated k-ras in gastrointestinal cancer cell lines. We assessed the effect of forced expression of mutated k-ras on proliferartion, apoptosis induction, migration, and invasion in gastrointestinal cancer cell lines. Then we assessed the anti-tumor effect of IGF-IR/dn on mutated k-ras transfctomas. Results: Overexpression of mutated k-ras let gastrointestinal cancer cell lines be more agrressive phenotypes, such as more proliferative, more anti-apoptotic, more movable, and more invasive. IGF-IR/dn inhibited cell growth, colony formation, migration, and invasion, but induceed apoptosis of gastrointestinal cancer cells with or without mutated k-ras expression. Conclusions: K-ras mutation might be inportant for progressive phonotype in gastrointestinal cancers. IGF-IR might be a good molecular therapeutic target for gastrointestinal cancers even if k-ras is mutated.
Citation Format: Yasushi Adachi, Yasutaka Matsunaga, Yasushi Sasaki, Katsuhiko Nosho, Hiroyuki Yamamoto, Yoshiaki Arimura, Takao Endo, Yasuo Kato, Takashi Tokino, David P. Carbone, Yasuhisa Shinomura. The effect of forced expression of k-ras mutation on gastrointestinal cancer cells and IGF-IR targeting therapy. [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 3474. doi:10.1158/1538-7445.AM2015-3474
Abstract 3475: Diurnal suppression of EGFR signaling by glucocorticoids: implications for tumor progression and treatment
Authors: Lauriola Mattia , Enuka Yehoshua , Zeisel Amit , D'Uva Gabriele , Roth Lee , Carvalho Silvia , Solmi Rossella , Domany Eytan , Yarden Yosef 
Published: August 2015

Abstract
Signal transduction by receptor tyrosine kinases (RTKs) and nuclear receptors for steroid hormones is essential for body homeostasis, but the crosstalk between these receptor families is poorly understood. We observed that activation of GR, a steroid hormone receptor that binds glucocorticoids, inhibits the transcriptional response downstream to EGFR signaling, an RTK. The underlying mechanism entails suppression of EGFR's positive feedback loops, such as ligands and simultaneous triggering of negative feedback loops that normally restrain EGFR. Our animal studies reveal that the regulation of EGFR's feedback loops by glucocorticoids translates to circadian control of EGFR signaling: EGFR signals are suppressed by high glucocorticoids during the active phase, while EGFR signals are enhanced during the resting phase. Consistent with this pattern, treatment of animals bearing EGFR-driven tumors with a specific kinase inhibitor was more effective if administered during the resting phase of the day, when glucocorticoids are low. These findings support a circadian clock-based paradigm in cancer therapy.
Citation Format: Mattia Lauriola, Yehoshua Enuka, Amit Zeisel, Gabriele D'Uva, Lee Roth, Silvia Carvalho, Rossella Solmi, Eytan Domany, Yosef Yarden. Diurnal suppression of EGFR signaling by glucocorticoids: implications for tumor progression and treatment. [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 3475. doi:10.1158/1538-7445.AM2015-3475
Abstract 3476: Intermittent anti-androgen monotherapy: a possible treatment for androgen receptor-overexpressing prostate cancer
Authors: Oliver Tim , Berney Dan , Shaw Greg 
Published: August 2015

Abstract
A case report of a Gleason 4+4 patient who self-medicated on intermittent flutamide with 14 cycles of 3 months on 3 months off, surviving at 14 years.cast doubt on conventional wisdom that intermittently androgen blockade should include an LHRH blocking agent. Anti-androgen(aa) monotherapy was thought to be dangerous as on treatment testosterone rises. It was speculated that he had been Testosterone(T) deficient at diagnosis as in many patients with high grade tumours and had benefited from the blocking action of the aa to control tumour expansion while allowing the off period to allow T to differentiate the tumour possibly by suppressing an over expressed androgen receptor. Following this case others already on AA continuously were recruited to our then ongoing phase 1/2 study of intermittent hormone therapy(Lane 2004).
This abstract records their outcome and compares it with those treated with conventional GNRH monotherapy or maximum androgen blockade
Results: Between 1997 and 2007 111 patients sort advice about intermittent hormone therapy having started on some form of endocrine treatment. 46 MO patients received GNRH regime and 33 receive aa monotherapy (M0 = 31). Provided PSA was below 4 they were eligible for entry. Median pre-treatment PSA was 22 (range 0.4-237) compared to 22 (range 3.7-402) in MO GNRH groups. Over all survival was 87% ,at 5 year and 78% at 8 years and continuing to respond on protocol 66% at 5 yrs, 57% at 8 compared to 77/56% at 5 and 54/41% at 8 years in M0 GNRH treated group
Conclusion: Non-randomised selection in this cohort makes it difficult to draw strong conclusions. As overall survival is significantly better than with GNRH regimens, an exploratory randomised phase 2 trial comparing GNRH against aa monotherapy in patients presenting with over expression of androgen receptor and below normal age-corrected serum testosterone is under consideration
Citation Format: Tim Oliver, Dan Berney, Greg Shaw. Intermittent anti-androgen monotherapy: a possible treatment for androgen receptor-overexpressing prostate 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 3476. doi:10.1158/1538-7445.AM2015-3476
Abstract 3479: CPX-351 (cytarabine:daunorubicin liposome for injection) anti-leukemia activity is potentiated by Chk1 inhibition
Authors: Vincelette Nicole D. , Karnitz Larry M. , Karp Judith E. , Smith Douglas B. , Hess Allan D. , Mayer Lawrence D. , Kaufmann Scott H. 
Published: August 2015

Abstract
Background: Cytarabine and an anthracycline, the mainstay of AML therapy, affords a five-year survival below 30%. Accordingly, there is a continuing need for improved AML therapies. CPX-351 encapsulates within liposomes a fixed 5:1 molar ratio of cytarabine and daunorubicin that is synergistic (in vitro) and markedly improved in anti-leukemic activity (in vivo). Promising evidence of improved remission and survival rates with CPX-351 compared to standard of care treatments has also been observed clinically and a pivotal Phase 3 trial is currently ongoing. Because Chk1 inhibition has been shown to enhance the actions of both cytarabine and anthracyclines, there has been interest in assessing the effect of CPX-351 when combined with Chk1 inhibitors. Here we describe the evaluation of CPX-351 alone and in combination with the Chk1 inhibitors MK-8776 and LY2603618 in AML cell lines and in clinical AML samples ex vivo. Methods: Effects of CPX-351 on Chk1 phosphorylation and cell cycle distribution in the human AML lines U937 and HL-60 were analyzed by immunoblotting and flow cytometry. Effects of Chk1 inhibitors on CPX-351-induced apoptosis were assessed by flow cytometry after propidium iodide staining (DNA cleavage), Hoechst staining (nuclear fragmentation) and colony formation in soft agar (long-term survival). Effects CPX-351 ± MK-8776 on clinical AML samples were assayed using clonogenic assays. Results: Treatment of U937 cells with CPX-351 resulted in phosphorylation of Chk1 on Ser317 and Ser296 (sites of ATR-mediated phosphorylation and autophosphorylation, respectively) as well as S phase slowing consistent with Chk1 activation. Co-treatment of AML cell lines with Chk1 inhibitors + CPX-351 resulted in increased apoptotic morphological changes and DNA fragmentation as well as diminished clonogenic survival compared to CPX-351 alone. The CPX-351/MK-8776 combination displayed enhanced antiproliferative effects against some clinical AML isolates ex vivo compared to CPX-351 alone, with additional assays ongoing. Conclusions: Collectively, these results show that Chk1 inhibition enhances the cytotoxicity of CPX-351 in AML cell lines and some clinical AML samples, offering the possibility that CPX-351 may be well suited for combining with such molecularly targeted agents.
Citation Format: Nicole D. Vincelette, Larry M. Karnitz, Judith E. Karp, Douglas B. Smith, Allan D. Hess, Lawrence D. Mayer, Scott H. Kaufmann. CPX-351 (cytarabine:daunorubicin liposome for injection) anti-leukemia activity is potentiated by Chk1 inhibition. [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 3479. doi:10.1158/1538-7445.AM2015-3479
Abstract 3482: Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide
Authors: Tang Xiao-Han , Gudas Lorraine J. 
Published: August 2015

Abstract
We investigated the effects of bexarotene (a retinoid X receptor agonist), CD1530 (a retinoic acid receptor γ selective agonist), and the combination of these two drugs for the prevention of oral carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in a mouse model of human oral-cavity and esophageal squamous-cell carcinoma previously generated in our laboratory. We observed decreased numbers of neoplastic tongue lesions and reduced lesion severity in the 4-NQO plus CD1530 (4N+C) and 4-NQO plus bexarotene plus CD1530 (4N+B+C) groups compared with the 4-NQO group. RNA-Seq analyses showed increases in transcripts in cell proliferation/cell cycle progression pathways in the 4-NQO vs. the untreated group. In addition, β-catenin and matrix metallopeptidase 9 (MMP9) protein levels and reactive oxygen species (ROS), as assessed by 4-hydroxynonenal (4-HNE) staining, were elevated in tongue tissues 17 wk after the termination of the 4-NQO treatment. The 4N+B, 4N+C, and 4N+B+C groups showed dramatically lower levels of β-catenin, MMP9, and 4-HNE staining compared with the 4-NQO group. The major reduction in 4-HNE staining in the retinoid treatment groups suggests a novel mechanism of action, reduction of ROS, by which bexarotene and CD1530 inhibit carcinogenesis.
Citation Format: Xiao-Han Tang, Lorraine J. Gudas. Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide. [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 3482. doi:10.1158/1538-7445.AM2015-3482
Abstract 3487: A novel role of transient receptor potential vanilloid type 2 (TRPV2) for augmentation of chemotherapeutic drug efficacy in triple-negative breast cancer
Authors: Elbaz Mohamad M. , Nasser Mohd W. , Zhao Helong , Ganju Ramesh K. 
Published: August 2015

Abstract
Transient receptor potential vanilloid type 2 (TRPV2) is a non-selective cation channel that is triggered by agonists like cannabidiol (CBD). Chemotherapeutic drugs such as doxorubicin (DOX) and paclitaxel (PAC) are routinely used for treatment of Triple negative breast cancer (TNBC) patients however, these drugs are usually resisted and show limited efficacy and more side effects at higher doses. In the present study, we analyzed the ability of TRPV2 activation in enhancing the chemotherapeutic efficacy in TNBC cells. Interestingly, we found that TRPV2 is significantly up regulated in primary and metastatic breast tumor tissues compared to normal breast tissues using tissue microarray analysis. In addition, using publically available Kaplan Miere Plotter datasets, we found that estrogen receptor (ER) negative patients with higher TRPV2 expression levels and committed to anti-tumor chemotherapy have significantly higher survival than patients committed to anti-tumor chemotherapy but have lower TRPV2 expression levels. Our in vitro studies showed that TNBC cells subjected to combination treatment of CBD and DOX show enhanced proliferation inhibition compared to cells treated with DOX only . Analysis of molecular mechanisms showed higher levels of cleaved PARP and cleaved Caspase-3 in combination treatment compared to Dox alone. Further studies revealed that CBD activates more uptake of DOX into TNBC cells. This increased uptake was abrogated upon treatment with specific TRPV2 blocker. Furthermore, TRPV2 blocker inhibited the increased levels of cleaved PARP and cleaved caspase-3 in the combination treatment. By using two orthotopic mouse model, we showed that mice treated with CBD in combination with doxorubicin have significantly less tumor weight, fewer Ki67 and CD31 positive cells, and significantly higher level of cleaved caspase 3 and cleaved PARP compared to the mice treated with CBD or DOX alone. This study suggests the use of TRPV2 agonists as an adjuvant therapy to improve the anti-tumor chemotherapeutic efficacy especially in TNBC patients.
Citation Format: Mohamad M. Elbaz, Mohd W. Nasser, Helong Zhao, Ramesh K. Ganju. A novel role of transient receptor potential vanilloid type 2 (TRPV2) for augmentation of chemotherapeutic drug efficacy in triple-negative breast 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 3487. doi:10.1158/1538-7445.AM2015-3487
Abstract 3490: Topotecan synergizes with CHEK1 inhibitor to induce apoptosis in ovarian cancer cells
Authors: Kim Marianne K. H. , James Jana , Annunziata Christina 
Published: August 2015

Abstract
Background
Topotecan is a therapeutic option for women with platinum-resistant or -refractory ovarian cancer. However, the dose-limiting toxicity of topotecan is myelosuppression. This led us to seek a combination treatment to augment topotecan anti-cancer activity in a cancer-targeted manner. Ovarian serous cancers, a major subtype, show dysregulated DNA repair pathway and often display a high level of CHEK1, a cell cycle regulator and DNA damage sensor. CHEK1 inhibitors are a novel approach to treatment, and have been used as single agents or in combination chemotherapy in many cancers.
Methods
We evaluated the cellular effects of topotecan in a panel of high grade serous (HGS) and non-HGS ovarian cancer cells. We then determined IC50s of topotecan in the absence and presence of suboptimal concentrations of CHEK1 inhibitor, PF477736. Synergism between topotecan and PF477736 was calculated based on cellular viability assays. Cytotoxic effect of the combined treatment was compared with apoptotic activities by Caspase3/7 activity assay and Western blotting of cleaved-PARP1 and γH2A.X.
Results
Non-HGS ovarian cancer cells were generally more sensitive to topotecan treatment compared to HGS ovarian cancer cells. When combined with suboptimal concentrations of CHEK1 inhibitor, topotecan potently and synergistically inhibited the proliferation of HGS ovarian cancer cells. This dramatic synergism in cellular toxicity was consistent with increases in markers of apoptosis.
Conclusions
Our findings suggest that the addition of CHEK1 inhibitor increases the response of ovarian cancer cells to topotecan. Furthermore, reduced dosages of both drugs achieved maximal cytotoxic effects by combining topotecan with CHEK1 inhibitor. This strategy would potentially minimize side effects of the drugs for extended clinical benefit.
Citation Format: Marianne K. H. Kim, Jana James, Christina Annunziata. Topotecan synergizes with CHEK1 inhibitor to induce apoptosis in ovarian 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 3490. doi:10.1158/1538-7445.AM2015-3490
Abstract 3492: Metformin inhibits salivary gland tumor growth through cell cycle arrest and apoptosis
Authors: Guo Yuqi 
Published: August 2015

Abstract
Human salivary gland cancer (SGC) is one of the common malignancies found in the head and neck area. The limitation of the treatment and poor prognosis are calling for more investigations into novel intervention to improve the treatment modality in SGCs. Metformin as a widely used anti-type-2 diabetes medicine had demonstrated its anti-tumor potential in many different types of cancers. Our previous work demonstrated that metformin effectively targeted c-Myc oncogene to prevent the initiation and progression of prostate cancer. Interestingly, the overexpression of c-Myc has also been shown in some SGCs, such as salivary gland adenoid cystic carcinoma. Therefore, it is intriguing to explore metformin's anti-neoplastic efficacy of metformin in SGC. In this study, we used a human salivary adenocarcinoma cell line, HSY cell line as a model for salivary gland tumor. Our in vitro results show metformin prominently suppresses the growth of HSY cell through stimulation of cell cycle arrest and apoptosis. Meanwhile, metformin significantly down-regulates cMyc expression and rescues p53 tumor suppressor gene expression. Considering that mTOR inhibitors resistance could occur when tumors over-express cMYC. PP242, a novel and potent mTOR inhibitor was used in combination with metformin to inhibit HSY cell growth. As expected, metformin enhanced the inhibitory effects of PP242 associated with reduced c-MYC levels in vitro. Further in HSY xenograft tumors, massive necrotic areas were observed inside the tumors from metformin treated mice while only limited necrotic area in the core of tumors from PBS treated mice. Staining of proliferation marker Ki-67 confirmed lower proliferation rate in tumors from metformin treated group compare to that from the PBS group. In conclusion, our novel finding of metformin efficacy in SGC not only proves metformin plays a pivotal role in suppressing SGCs through cell cycle arrest and apoptosis, but also suggest that a combination treatment using metformin and mTOR inhibitors together may yield better inhibitory efficacy.
Citation Format: Yuqi Guo. Metformin inhibits salivary gland tumor growth through cell cycle arrest and apoptosis. [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 3492. doi:10.1158/1538-7445.AM2015-3492
Abstract 3499: Improving therapeutic efficacy of Docetaxel in breast cancer
Authors: King Jeronay , Mir Hina , Kapur Neeraj , Singh Shailesh 
Published: August 2015

Abstract
Chemotherapy is the preferred choice for treatment of advance breast cancer (BrCa). In most cases, cytotoxic drugs are used at or near a maximum tolerated dose (MTD) to achieve maximum response and eradicate the neoplastic cells, at the same time MTD doses are often toxic and have severe side effects. Lower dose i.e. “optimal biological response modifier dose” (OBRMD) provides potentially beneficial responses, but is not capable of achieving optimal clinical response. Hence, the focus of this study was to achieve the optimal therapeutic outcome of Docetaxel (DTX) at a lower dose by using it in combination with Apigenin (API), a dietary flavonoid present in fruits and vegetables. Effect of DTX and API, either alone or in combination on BrCa cells viability and apoptosis was determined by MTT assay and flow cytometry, respectively. We further investigated the mechanism of enhanced efficacy of DTX using western blot analysis and real time qPCR. Significant decrease in cell viability was observed when cells were treated with low dose DTX in combination with API as compared to either of the agent used individually in MDA-MB-231, MDA-MB-468 and MCF 10A cells. Real time analysis showed that API up regulates pro-apoptotic molecules and down regulates anti-apoptotic molecules when using in combination with DTX. These findings suggest that Apigenin is capable of reducing the effective dose of docetaxel. Hence, this new modality may have better therapeutic outcome with minimal or no toxicity.
Citation Format: Jeronay King, Hina Mir, Neeraj Kapur, Shailesh Singh. Improving therapeutic efficacy of Docetaxel in breast 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 3499. doi:10.1158/1538-7445.AM2015-3499