bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-174: MicroRNA-126 (miR-126) and epidermal growth factor-like domain 7 (EGFL7) in Bevacizumab-treated patients with metastatic colorectal cancer
Authors: Nielsen Boye S. , Sorensen Flemming B. , Johnsson Anders , Jakobsen Anders , Hansen Torben F. 
Published: May 2015

Abstract
The miR-126 gene is located within intron 7 of the EGFL7 encoding gene, and therefore miR-126 expression is dependent on the transcription of the EGFL7 gene. It has been suggested that transcription is regulated by the VEGFR pathway through Ets1 transcription factor, that miR-126 itself negatively regulates the VEGF-R signaling pathway, and that EGFL7 itself regulates Notch signaling. In cancer therapeutic settings, VEGF or VEGF-R directed therapies are thus likely to affect expression of EGFL7 and miR-126. In colorectal cancer (CRC) tissue, miR-126 and EGFL7 are highly expressed in endothelial cells. In studies of XELOX-treated patients, we have previously reported that the miR-126 expression level measured by quantitative in situ hybridization (qISH) is related to poor response (Hansen et al, BMC Cancer 2012, 12:83). Here, we have analyzed miR-126 and EGFL7 expression by qISH and quantitative immunohistochemistry (qIHC), respectively, in 158 patients from two different cohorts with mCRC after treatment with anti-VEGF therapy (Bevacizumab) in combination with chemotherapy. We found that the EGFL7 vessel area (VA) in primary tumors was closely related to treatment response with a median EGFL7 VA in responding patients of 4 (95% CI 4-6) compared to 8.5 (95% CI 7-11) in non-responders, p&lt;0.001. This difference translated into a borderline significant difference in progression-free survival (PFS, p=0.06). Furthermore, a significant relationship between high EGFL7 VA and KRAS mutation was detected (p&lt;0.05). The results showed no significant relationship between the miR-126 VA and the clinical endpoints. Our study suggests a predictive value of EGFL7 in regard to first-line chemotherapy and bevacizumab in patients with mCRC. The strong predictive value of miR-126 found in mCRC patients treated with chemotherapy only was absent, suggesting that the anti-VEGF directed therapy is likely to have affected a key role of miR-126 in regulating the VEGFR pathway.
Citation Format: Boye S. Nielsen, Flemming B. Sorensen, Anders Johnsson, Anders Jakobsen, Torben F. Hansen. MicroRNA-126 (miR-126) and epidermal growth factor-like domain 7 (EGFL7) in Bevacizumab-treated patients with metastatic colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-174. doi:10.1158/1538-7445.AM2014-LB-174
Abstract LB-192: Circulating tumor cell clusters are precursors of breast cancer metastasis
Authors: Aceto Nicola , Bardia Aditya , Spencer Joel A. , Wittner Ben S. , Yu Min , Donaldson Maria C. , Pely Adam , Engstrom Amanda , Zhu Huili , Brannigan Brian W. , Kapur Ravi , Stott Shannon L. , Shioda Toshi , Ramaswamy Sridhar , Ting David T. , Lin Charles P. , Toner Mehmet , Haber Daniel A. , Maheswaran Shyamala 
Published: May 2015

Abstract
The metastatic spread of breast cancer, typically to bone, lung, liver and brain, accounts for the vast majority of cancer-related deaths. Breast cancer metastases are thought to be derived primarily from individual migratory cancer cells, reaching distant sites through the bloodstream and initiating proliferation within distant organs. In addition to these single circulating tumor cells (CTCs), CTC-clusters have been detected in the blood of patients with cancer. In patients with breast cancer, we find that presence of such CTC-clusters is correlated with decreased progression-free survival. To study their functional role, we used mouse models, demonstrating that breast cancer cells injected intravascularly as clusters are more prone to survive and colonize the lungs than similarly injected single cancer cells. Primary orthotopic mammary tumors comprised of differentially tagged cells give rise to oligoclonal CTC-clusters, with 40-fold increased metastatic potential to the lung, compared with single CTCs. Using in vivo flow cytometry, we show that CTC-clusters are rapidly cleared from peripheral vessels, consistent with their trapping in small capillaries. Together, our observations suggest that primary tumor cells break off into the vasculature as CTC-clusters, and exhibit greatly enhanced metastatic propensity.
Citation Format: Nicola Aceto, Aditya Bardia, Joel A. Spencer, Ben S. Wittner, Min Yu, Maria C. Donaldson, Adam Pely, Amanda Engstrom, Huili Zhu, Brian W. Brannigan, Ravi Kapur, Shannon L. Stott, Toshi Shioda, Sridhar Ramaswamy, David T. Ting, Charles P. Lin, Mehmet Toner, Daniel A. Haber, Shyamala Maheswaran. Circulating tumor cell clusters are precursors of breast cancer metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-192. doi:10.1158/1538-7445.AM2014-LB-192
Abstract LB-195: Penfluridol, an antipsychotic drug suppresses breast cancer metastasis to brain by inhibiting HER2/Akt/MMP signaling axis in a novel in vivo metastasis model
Authors: Ranjan Alok , Gupta Parul , Srivastava Sanjay K. 
Published: May 2015

Abstract
Breast tumor metastasis is primary cause of cancer-related deaths. Metastasis is a complex process involving cell migration and invasion of tumor cells to distant organs from primary sites. Brain metastasis is a frequent cause of reduced survival of breast cancer patients. In the current study, we evaluated the anti-metastatic effects of penfluridol, a first generation highly potent antipsychotic drug in a novel murine model of breast tumor metastasis to brain. 4T1 breast tumor cells with stable luciferase expression were injected into the left ventricle of mouse heart. The migration of cells to brain was monitored using a non-invasive IVIS bio-luminescent live animal imaging system. To evaluate the anti-metastatic effects, 10mg/kg penfluridol was administered orally to mice every day for 12 days after intra-cardiac injection of tumor cells. The growth rate of metastasized tumors cells in control and treated mice was determined by measuring the luminescence in the brain area in each mouse at different time points. Our results demonstrate that the growth of metastatic brain tumors was reduced by 82% in the mice treated with penfluridol. In addition, treatment of 4T1, MCF-7 or MDA-MB-231 cells with 10µM Penfluridol for 24 hours resulted in the significantly reduced migration and 30-40% reduced invasion of cells, as evaluated by wound healing and Boyden's transwell invasion assay respectively. Penfluridol treatment also reduced the expression of HER2, AKT and MMP-2, 9 in these cells. Interestingly, overexpression of HER2 led to the phosphorylation of Akt, which in turn is known to regulate MMPs. Taken together, our results indicate that the anti-metastatic effects of penfluridol were associated with down regulation of HER2, AKT and MMPs. To the best of our knowledge, our study for the first time demonstrates the anti-metastatic effects of penfluridol in vivo in a novel breast tumor metastasis model. Most importantly, penfluridol is already in clinical use with an established safety record; therefore any positive findings from our studies can be rapidly translated to the clinics for undertaking a clinical trial to treat advanced metastatic breast cancer patients. [Supported in part by R01 grant CA 129038 awarded by National Cancer Institute, NIH]
Citation Format: Alok Ranjan, Parul Gupta, Sanjay K. Srivastava. Penfluridol, an antipsychotic drug suppresses breast cancer metastasis to brain by inhibiting HER2/Akt/MMP signaling axis in a novel in vivo metastasis model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-195. doi:10.1158/1538-7445.AM2014-LB-195
Abstract LB-196: Preventing breast cancer metastases with an anti-angiogenic and anticancer RGD-bearing nanomedicine
Authors: Eldar-Boock Anat , Ben-Shushan Dikla , Sanchis Joaquin , Lupu Ruth , Vicent Maria J. , Satchi-Fainaro Ronit 
Published: May 2015

Abstract
Overcoming drug resistance, emerging either on recurring cancer or metastasis, is a major challenge of cancer treatments. The combination of anti-angiogenic agents with chemotherapeutic ones offers a promising therapeutic approach. Such combination can be achieved exploiting the multivalency of polymer therapeutics. We have recently showed that polymer conjugation of paclitaxel (PTX), a potent cytotoxic and anti-angiogenic drug, improved its pharmacokinetic profile. We hypothesized that actively targeting PTX to αvβ3-integrin, presents an attractive therapeutic strategy for breast cancer. Interestingly, overexpression of αvβ3-integrin, occurring on tumor endothelial and some epithelial cells during tumor growth, invasion, and metastasis, was found to correlate with PTX-resistance of breast cancer cells.
We designed and synthesized a novel polyglutamic acid (PGA)-PTX-E-[c(RGDfK)2] nano-sized conjugate. Polymer conjugation converted PTX to a water-soluble macromolecule, which passively targeted the tumor tissue exploiting the enhanced permeability and retention (EPR) effect. The E-[c(RGDfK)2] was utilized as an additional active targeting moiety to αvβ3 integrin. PGA is enzymatically-degradable by cathepsin B, leading to PTX release. PGA-PTX-E-[c(RGDfK)2] displayed a potent anti-angiogenic activity, determined by several well-established in vitro assays. Preferential tumor accumulation of the RGD-bearing conjugate in orthotopic mammary tumors inoculated in mice, lead to enhanced antitumor efficacy and a marked decrease in toxicity compared with free PTX. We found that metastasis establishment was dependent on αvβ3-integrin expression as determined in vitro and ex vivo. PGA-PTX-E-[c(RGDfK)2] conjugate inhibited metastatic growth in an experimental breast cancer metastases model in mice.
Taken together, inclusion of an active targeting moiety to integrin expressing-cells has the potential to decrease breast cancer metastases establishment by displaying an anti-angiogenic and anticancer activity.
Citation Format: Anat Eldar-Boock, Dikla Ben-Shushan, Joaquin Sanchis, Ruth Lupu, Maria J. Vicent, Ronit Satchi-Fainaro. Preventing breast cancer metastases with an anti-angiogenic and anticancer RGD-bearing nanomedicine. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-196. doi:10.1158/1538-7445.AM2014-LB-196
Abstract LB-2: TRIM28 is overexpressed in breast cancer and regulates the expression of multiple cancer-associated genes
Authors: Addison Joseph , Koontz Colton , McLaughlin Sarah , Livengood Ryan , Pugacheva Elena , Chen Dongquan , Creighton Chad , Ivanov Alexey V. 
Published: May 2015

Abstract
The transcriptional regulator TRIM28 plays an important role in development, stem cells self-renewal, chromatin organization and DNA damage response. KAP1 is an essential co-repressor for KRAB zinc finger proteins (KRAB-ZNFs). Though KRAB-ZNFs represent the largest family of human transcription factors, their biological functions are largely unknown. We showed that KAP1 and certain KRAB-ZNFs were overexpressed in breast tumors and breast cancer cell lines at both mRNA and protein levels. More significantly, an active SUMOylated form of KAP1 was markedly increased in breast cancer cells. KAP1 depletion in several breast cancer cell lines slowed cell proliferation and inhibited primary tumor growth and metastasis of MDA-MB-231LN xenografts, while KAP1 overexpression conversely stimulated cell proliferation and tumor growth. KAP1 knockdown led to down-regulation of PTGS2/COX2, EREG, CD44, MMP1, MMP2 and ID transcription factors, previously implicated in cancer progression and metastasis. These results indicate that KAP1 and KRAB-ZNFs are up-regulated in breast cancer cells and contribute to increased cell proliferation, tumor growth and metastasis.
Citation Format: Joseph Addison, Colton Koontz, Sarah McLaughlin, Ryan Livengood, Elena Pugacheva, Dongquan Chen, Chad Creighton, Alexey V. Ivanov. TRIM28 is overexpressed in breast cancer and regulates the expression of multiple cancer-associated genes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-2. doi:10.1158/1538-7445.AM2014-LB-2
Abstract LB-200: Potent antitumor activity of MLN0128, an investigational selective mTORC1/2 kinase inhibitor, in preclinical models of rhabdomyosarcoma
Authors: Slotkin Emily , Patwardhan Parag , Deraje Shyamprasad Vasudeva , Schwartz Gary , William Tap 
Published: May 2015

Abstract
Phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) axis regulates growth and homeostasis, and is often dysregulated in rhabdomyosarcoma. Agents that target mammalian target of rapamycin complex 1 (mTORC1), one of the two multi-protein complexes comprising the serine-threonine kinase mTOR, have been disappointing in clinical trials, and novel therapeutics are urgently needed to treat patients with relapsed, refractory, or metastatic alveolar (ARMS) and embryonal (ERMS) rhabdomyosarcoma. It is hypothesized that modest clinical results with mTORC1 only inhibitors may be attributed to the lack of inhibition of the second mTOR complex, mTORC2, and its downstream effectors, as well as release of mTOR-mediated negative feedback of the pathway that leads to activation of receptor tyrosine kinases and feedback activation of AKT. In the present preclinical study, MLN0128, a selective and highly potent inhibitor of both mTORC1 and mTORC2, was tested for its antitumor activity in vitro and in a mouse xenograft model. Data suggest that the anti-proliferative effect of MLN-0128 was superior to rapamycin, a selective mTORC1 inhibitor, in a broad panel of ERMS and ARMS cell lines where it was found to be highly effective at low concentrations from 5 to 175 nanomolar. Western immunoblot analysis of treated cells showed inhibition of phosphorylation of mTORC1 and mTORC2 targets including phosphorylated S6 ribosomal protein (pS6), phospho-p70-S6K, phospho-AKT-S473, phospho-AKT-T308, and phospho-4E-BP1. Apoptosis in both ERMS and ARMS cell lines was confirmed by the presence of cleaved poly ADP ribose. Additionally, MLN0128 was found to have superior anti-tumor effect in a xenograft model of rhabdomyosarcoma without significant toxicity when compared with rapamycin. These pre-clinical studies support further research of MLN0128 as a potential therapeutic approach for patients with ARMS and ERMS.
Citation Format: Emily Slotkin, Parag Patwardhan, Shyamprasad Vasudeva Deraje, Gary Schwartz, Tap William. Potent antitumor activity of MLN0128, an investigational selective mTORC1/2 kinase inhibitor, in preclinical models of rhabdomyosarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-200. doi:10.1158/1538-7445.AM2014-LB-200
Abstract LB-208: Targeting resistance pathways in BRAF-mutant pediatric gliomas
Authors: Yao Tsun-Wen (Sheena) , Yoshida Yasuyuki , Zhang Jie , Ozawa Tomoko , James David , Nicolaides Theodore 
Published: May 2015

Abstract
Mutational activation of BRAF is a common finding in pediatric gliomas. As many as 14% of pediatric high grade glioma and up to 66% of certain low grade pediatric glioma subtypes contain the BRAFV600E mutation. Small molecule inhibitors that selectively target BRAFV600E are FDA approved for melanoma and have shown significant efficacy in treating BRAFV600E glioma in pre-clinical trials. Despite showing initial efficacy, drug resistance significantly limits the use of BRAFV600E inhibitors in clinical settings. Here, we identified the molecular mechanisms of BRAFV600E inhibitor resistance in glioma and also provide strategies to over come drug resistance.
We have generated multiple BRAFV600E inhibitor resistant glioma cell lines and murine models to study the mechanisms of drug resistance in glioma. The BRAFV600E inhibitor resistant AM38 and DBTRG-05MG cells are insensitive to BRAF inhibitor induced MAP kinase inhibition, reduced cell viability and cell cycle arrest. Also, the BRAFV600E inhibitor resistant glioma xenografts do not respond to drug induced suppression of tumor growth, resulting in poor animal survival. By phospho-receptor tyrosine kinase array and gene expression array, we found that certain receptor tyrosine kinases, including EGF and Axl receptors, and pro-survival pathways such as Wnt signaling, are hyperactivated in BRAFV600E inhibitor resistant gliomas. We further showed that pharmacological and genetic inhibition of those pathways significantly reduces the viability of those drug resistant cells.
In conclusion, we have discovered mechanisms of BRAFV600E inhibitor resistance in glioma. We showed that BRAFV600E inhibitor resistant cells acquire drug dependency by upregulating pro-survival pathway, such as Wnt, and hyperactivating receptor tyrosine kinases, including EGFR and Axl, to bypass the insult from the drug. Our data suggests novel therapeutic strategies to BRAFV600E -mutant pediatric glioma in which no effective treatment is available.
Citation Format: Tsun-Wen (Sheena) Yao, Yasuyuki Yoshida, Jie Zhang, Tomoko Ozawa, David James, Theodore Nicolaides. Targeting resistance pathways in BRAF-mutant pediatric gliomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-208. doi:10.1158/1538-7445.AM2014-LB-208
Abstract LB-214: The RAC1 P29S hotspot mutation in melanoma confers resistance to pharmacological inhibition of RAF
Authors: Watson Ian R. , Li Liren , Cabeceiras Peter K. , Mahdavi Mozhdeh , Fang Zhuangna , Stemke-Hale Katherine , Mills Gordon B. , Chin Lynda 
Published: May 2015

Abstract
Following recurrent mutations in BRAF and NRAS, the RAC1 c.85C &gt; T single nucleotide variant encoding P29S amino acid change represents the next most frequently observed hotspot mutation in melanoma. However, the biological and clinical relevance of the RAC1 P29S somatic mutation in approximately 4-9% of patients is not entirely clear. Here, we demonstrate that melanoma cell lines possessing the RAC1 hotspot variant are resistant to RAF inhibitors (dabrafenib and vemurafenib). Enforced expression of RAC1 P29S in sensitive BRAF mutant melanoma cell lines resulted in increased viability and in vivo tumor growth upon treatment with RAF inhibitors compared to controls. Conversely, knockdown of endogenous RAC1 P29S in a melanoma cell line with a co-occurring BRAF V600 mutation increased sensitivity to dabrafenib and vemurafenib. Our results suggest that RAC1 P29S status in melanoma may be an important predictor of RAF inhibitor resistance in patients, and consequently should be evaluated as a predictive biomarker to such therapies in the clinic.
Citation Format: Ian R. Watson, Liren Li, Peter K. Cabeceiras, Mozhdeh Mahdavi, Zhuangna Fang, Katherine Stemke-Hale, Gordon B. Mills, Lynda Chin. The RAC1 P29S hotspot mutation in melanoma confers resistance to pharmacological inhibition of RAF. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-214. doi:10.1158/1538-7445.AM2014-LB-214
Abstract LB-221: PI3K-independent, Rheb-mediated mTOR activation promotes lapatinib resistance
Authors: Brady Samuel W. , Zhang Jian , Tsai Ming Horng , Yu Dihua 
Published: May 2015

Abstract
Acquired resistance to HER2 kinase inhibitors, such as lapatinib, presents an unmet clinical need among the 20% of breast cancers with HER2 amplification. To identify mechanisms of lapatinib resistance, we generated a lapatinib resistance model by extended exposure of the AU565 HER2-amplified breast cancer cell line to lapatinib (AU565 LapR cell line), which was highly resistant to lapatinib compared to AU565 parental cells. AU565 LapR cells maintained mTORC1 activation (indicated by p-P70 S6K and p-S6) after lapatinib treatment, whereas mTORC1 was completely inhibited in lapatinib-treated parental cells. Moreover, HER2 was inhibited equally well by lapatinib in parental and LapR cells, suggesting that mTORC1 activation in LapR cells was HER2-independent. Interestingly, mTORC1 activation in LapR cells was PI3K/Akt-independent, as p-Akt was completely inhibited by lapatinib in parental and LapR cells, while mTORC1 activation was maintained in LapR cells only. LapR cells were sensitive to mTORC1 and mTORC1/2 inhibition, but not to PI3K inhibition. Knockdown of the GTPase Rheb, which is known to promote mTORC1 activation, abolished mTORC1 activity in lapatinib-treated LapR cells, indicating that Rheb was required for mTOR activation in LapR cells. Surprisingly, several known mediators of Rheb/mTOR activation, such as TSC1/2, AMPK, the β-catenin pathway, and PRAS40, were not altered in their activation status in LapR cells compared with parental cells. This suggests that a potentially novel mechanism of mTOR activation may promote lapatinib resistance. These findings suggest the use of mTOR inhibitors in lapatinib-resistant breast cancers, and also may lead to novel basic mechanistic insights into mTOR signaling, which is commonly dysregulated in cancer.
Citation Format: Samuel W. Brady, Jian Zhang, Ming Horng Tsai, Dihua Yu. PI3K-independent, Rheb-mediated mTOR activation promotes lapatinib resistance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-221. doi:10.1158/1538-7445.AM2014-LB-221