bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2641: Inhibition of Bcr-Abl in human leukemic cells with a coiled coil protein delivered by a leukemia-specific cell penetrating peptide
Authors: Bruno Benjamin J. , Lim Carol S. 
Published: August 2015

Abstract
The oncoprotein Bcr-Abl is the cause of chronic myeloid leukemia (CML). Current CML therapies target the tyrosine kinase domain of Bcr-Abl, but due to their non-curative nature, resistance to these drugs is common. Therefore, new treatments are needed for those patients refractive to available therapies. Bcr-Abl homo-oligomerization via its N-terminal coiled coil (CC) domain is required for tyrosine kinase activity. Our previous work has shown that it is possible to inhibit Bcr-Abl activity by targeting the CC domain with a altered version of the CC domain, known as CCmut3, delivered as a plasmid. In this study, CCmut3 is delivered to cells as a protein by utilizing a leukemia-specific cell-penetrating peptide (CPP). Here, recombinant CPP-CCmut3 was expressed, purified, and tested for its anti-oncogenic activity. CPP-CCmut3 was able to enter two leukemic cell lines (K562 and Ba/F3-P210) and inhibit Bcr-Abl activity as shown by induction of necrosis/apoptosis via 7-AAD/Annexin V staining, reduction of oncogenic potential in colony forming assays, reduction of cell proliferation, and inhibition of Bcr-Abl phosphorylation (kinase activity). Further, CPP-CCmut3 did not enter non-leukemic cell lines (HEK293 and MCF-7). While CPP-CCmut3 was able to enter the parental, non-leukemic Bcr-Abl- Ba/F3 pro-B cell line, it revealed no signs of activity in the assays performed, as expected. These results indicate the feasibility of using CPP-CCmut3 as a therapeutic against CML.
Citation Format: Benjamin J. Bruno, Carol S. Lim. Inhibition of Bcr-Abl in human leukemic cells with a coiled coil protein delivered by a leukemia-specific cell penetrating peptide. [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 2641. doi:10.1158/1538-7445.AM2015-2641
Abstract 2647: Anti-tumor activity of sHA8k, a HYAL1 hyaluronidase inhibitor, in bladder cancer cells
Authors: Jordan Andre R. , Chipollini Juan , Lopez Luis , Yates Travis , Lokeshwar Vinata 
Published: August 2015

Abstract
INTRODUCTION AND OBJECTIVE: Tumor cell-derived hyaluronidase HYAL1, which degrades hyaluronic acid (HA) into angiogenic fragments, promotes tumor growth and metastasis. HYAL-1 is an independent prognostic marker for predicting metastasis. Small molecular mass sulfated hyaluronic acid (sHA) derivatives (sHA8k) inhibit HYAL1 activity through a mixed inhibition mechanism. Antitumor activity of sHA8k and mechanism of action was evaluated in BCa models..
METHODS: Effect of sHA8k (0-40 ug/ml) on cell proliferation and apoptosis was examined in BCa cells (253J-Lung, HT1376, UMUC-3, T24, RT4) by cell counting and Cell Death ELISA kit. Matrigel invasion and Boyden chamber assays were used to test the effect of sHA8k on invasive activity. Effect of sHA on signaling, apoptosis cascade, HA receptor (CD44, RHAMM), EMT markers (β-catenin, E-cadherin, Snail, Twist) levels, was evaluated by Q-pCR and immunoblotting assays. Angiogenic fragment addition and mAkt transfection were performed to elucidate mechanism of action. Athymic mice bearing 253J-Lung xenografts were treated with sHA (25 and 50 mg/kg) by i.p. injection.
RESULTS: sHA8k inhibited proliferation, motility and invasion in BCa cells that expressed HYAL-1. At IC50 for HAase activity inhibition (∼ 20-μg/ml), sHA induced &gt; 3-fold apoptosis and inhibited invasive activity of BCa cells. sHA8k induced caspase-3, -8, -9 activation, up-regulation of Fas, Fas-L, FADD, DR4, DR5 and E-cadherin. sHA8k downregulated CD44, RHAMM, bcl-2, phospho(p)-Akt, pGSK3β, pβcatenin(ser552), snail and Twist expression. Effect of sHA8k were attenuated by angiogenic HA fragments or overexpression of m-Akt and downregulation of CD44 and RHAMM mimicked sHA8k effects. sHA significantly inhibited 253J-Lung xenograft growth. The majority of the animals did not form palpable tumors at 50-mg/kg dose. No weight loss or serum and organ toxicity was observed in sHA treated animals. Biochemical analysis of tumors also showed the same alterations in Akt and EMT pathways as observed cell culture.
CONCLUSION: This is the first study that shows sHA8k, a small molecular mass HYAL-1 inhibitor has potent antitumor activity.
Support: R01 CA 72821-14 (VBL)
Citation Format: Andre R. Jordan, Juan Chipollini, Luis Lopez, Travis Yates, Vinata Lokeshwar. Anti-tumor activity of sHA8k, a HYAL1 hyaluronidase inhibitor, in bladder 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 2647. doi:10.1158/1538-7445.AM2015-2647
Abstract 2649: Inhibition of mTOR, but not PI3K, is required for the anti-tumor efficacy in breast cancer of dual PI3K/mTOR inhibitors given in combination with MEK inhibitors
Authors: Smith Aleisha M. , Xiong Jessie , Hunter Lucas , Jordan Jamie , Clark Kelly , Darr David B. , Norman Sharpless , Perou Charles M. , Kim William Y. 
Published: August 2015

Abstract
Background: The mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways are deregulated in many cancers including breast cancer. Additionally, studies have shown that significant crosstalk exists between these pathways; often making single pathway inhibition ineffective. While, combined PI3K/mTOR and MEK inhibition appears highly active in pre-clinical models, the combination has been reported to be toxic in human use. In an effort to produce a more targeted regimen, we examined whether both PI3K and mTOR inhibition are required for pre-clinical anti-tumor efficacy in combination with a MEK inhibitor.
Methods: In vivo studies assessed overall survival and best tumor response upon administration of dual PI3K/mTOR (BEZ235 and GSK806) versus allosteric mTOR inhibition (Everolimus) in combination with MEK inhibition (AZD244 and GSK212) in genetically engineered murine models (GEMM) of breast cancer [T11 and C(3)Tag]. Activation and response of the PI3K/mTOR and MEK/ERK pathways to dual PI3K/mTOR, allosteric mTOR inhibition, and MEK inhibition were assessed in vitro in murine cell lines derived from the above GEM models.
Results: Single agent regimens of MEK, allosteric mTOR, or dual PI3K/mTOR inhibition were minimally effective in C(3)Tag or T11 tumors in vivo. As previously reported, combined PI3K/mTOR and MEK inhibition showed potent pre-clinical activity in both the T11 and C3Tag models, prolonging overall survival relative to both vehicle or single-agent treated mice. Surprisingly, combinations of MEK inhibitors with allosteric mTOR inhibitors were as active as the MEK/PI3K/mTOR combination. In vitro studies in cell lines derived from these tumor models showed that mTORC1 inhibition, but not PI3K inhibition, resulted in compensatory activation of MEK.
Conclusions: Combined targeting of the mTOR and MEK pathways results in improved response and survival in faithful GEM models of breast cancer. The combination of dual PI3K/mTOR catalytic inhibitors with MEK inhibition does not afford benefit over combined allosteric mTOR and MEK inhibition
Citation Format: Aleisha M. Smith, Jessie Xiong, Lucas Hunter, Jamie Jordan, Kelly Clark, David B. Darr, Sharpless Norman, Charles M. Perou, William Y. Kim. Inhibition of mTOR, but not PI3K, is required for the anti-tumor efficacy in breast cancer of dual PI3K/mTOR inhibitors given in combination with MEK inhibitors. [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 2649. doi:10.1158/1538-7445.AM2015-2649
Abstract 2674: Activity of BAY1082439, a balanced PI3Kα/β inhibitor, in gastric cancer
Authors: Hung Huynh T. , Ong Richard , Haike Katja , Petrova Elissaveta , Chong Mei Ling , Loh Marie , Bhattacharya Bhaskar , Soong Richie , Liu Ningshu 
Published: August 2015

Abstract
Background: Activation of the p110α and p110β subunits of PI3K by PIK3CA mutation (7% of cancers), PIK3CA amplification (36-60%) and/or PTEN loss (33-47%) is a frequent oncogenic event in gastric cancer. Here, we report on the activity, mode of action and biomarker analysis of BAY1082439, a balanced PI3Kα/β inhibitor, in cell lines and xenografts from Asian and Caucasian gastric cancer patients.
Methods: Twenty cell lines were screened in vitro for the sensitivity to BAY1082439 using cell proliferation, cell cycle, migration and invasion assays. In vivo activity and mode of action of BAY 1082439 were further assessed by pathway inhibition, tumor growth inhibition, and effects on tumor stromal cells. Molecular features were assessed by Oncocarta analysis, gene expression arrays, and immunohistochemistry.
Results: Seven cell lines were sensitive to BAY1082439, which included 6/7 cell lines with PIK3CA mutations and/or PTEN loss. In vivo study with 15 PDX and 2 cell line models revealed that tumors with genetic alteration of PIK3CA and PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression were more sensitive to BAY 1082439 (tumor growth inhibition &gt;90%), while tumors harboring KRAS mutation and/or overexpressing EGFR were insensitive or less responsive to BAY 1082439. Interestingly, BAY1082439 did not inhibit proliferation of MKN45 cells in-vitro (IC50&gt;10μM), however it induced tumor stasis in this highly vascularized MKN45 xenografts. The anti-angiogenic activity BAY 1082439 was also demonstrated in patient derived gastric cancer models assessed by CD31 immunohistochemistry. BAY1082439 was also active in many tumors resistant to standard-of-care chemotherapy. Synergistic or additive effects on tumor growth and apoptosis were observed for BAY1082439 in combination with paclitaxel, 5-FU, and capecitabine/oxaliplatin.
Conclusions: The PI3Kα/β balanced inhibitor BAY1082439 showed considerable anti-tumor activity including tumor regression in gastric cancer models with genetic alteration or activation of PI3Kα/β and/or PI3Kα/β as single agent or in combination.
Citation Format: Huynh T. Hung, Richard Ong, Katja Haike, Elissaveta Petrova, Mei Ling Chong, Marie Loh, Bhaskar Bhattacharya, Richie Soong, Ningshu Liu. Activity of BAY1082439, a balanced PI3Kα/β inhibitor, in gastric 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 2674. doi:10.1158/1538-7445.AM2015-2674
Abstract 2681: Stromal neuregulin-1 promotes adaptive resistance in mutant BRAF melanoma
Authors: Capparelli Claudia , Rosenbaum Sheera , Berger Adam , Aplin Andrew E. 
Published: August 2015

Abstract
RAF inhibitors are first-line treatments for melanomas that harbor BRAF V600E/K mutations; however, patients invariably progress on these targeted therapies. While durable resistance is mediated frequently by stable alterations intrinsic to the tumor cells leading to ERK1/2 pathway reactivation, the compensatory activation of growth factor receptor tyrosine kinases (RTKs) modulates the level of initial response. The composition of the tumor microenvironment likely plays a key role in these compensatory/adaptive responses to targeted inhibitors. In this study, we demonstrate that NRG1 is expressed in fibroblasts, as well as cancer associated fibroblasts (CAFs) isolated from a mutant BRAF melanoma. Fibroblast derived-NRG1 was able to mediate the enhanced ErbB3 pathway activation in RAF-inhibited mutant BRAF melanoma cells. Furthermore, conditioned medium from fibroblasts and CAFs limits RAF inhibitor cytotoxicity in V600 BRAF-harboring melanomas. Importantly, ErbB3 and ErbB2 targeting antibodies partially reverse the protective effects of fibroblast-derived medium on ErbB3 pathway activation and cell growth properties of mutant BRAF-inhibited melanoma cells. Together, these data demonstrate a requirement for a paracrine-produced factor in the tumor microenvironment to promote resistance to RAF inhibitor in mutant BRAF melanoma and reinforce the idea that targeting ErbB3/ErbB2 signaling may improve the efficacy of RAF inhibitors.
Citation Format: Claudia Capparelli, Sheera Rosenbaum, Adam Berger, Andrew E. Aplin. Stromal neuregulin-1 promotes adaptive resistance in mutant BRAF melanoma. [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 2681. doi:10.1158/1538-7445.AM2015-2681
Abstract 2683: Simultaneous inactivation of TP53 and loss of PTEN diminish response to targeted therapy in V600EBRAF mutant melanoma
Authors: Galvani Elena , Brooks Kelly , Baenke Franziska , Girotti Maria Romina , Gremel Gabriela , Kumar Mandal Amit , Viros Amaya , McManus Clare , Smith Matthew , Lim Kok Haw Jonathan , Lee Rebecca , Fusi Alberto , Lorigan Paul , Marais Richard 
Published: August 2015

Abstract
Numerous cancers are driven by mutationally activated kinases, many of which can be employed to define subsets of cancers and therefore patients most likely to benefit from treatment with rationally designed targeted therapies. Defining the landscape of genetic alterations that participate in cancer transformation provides insight into the diversity of clinical responses observed to targeted treatments. Here, we identified concurrent mutational inactivation of the tumor suppressors TP53 and PTEN as a mechanism of resistance to BRAF inhibitors in melanomas harboring mutant V600EBRAF.
Defects in TP53 function and PTEN loss occur in 17% and 12% of malignant melanomas respectively, rendering cells dependent on CHK1 to maintain normal cell cycle progression. We demonstrate that CHK1 inhibition increases sensitivity to a variety of alkylating agents and targeted therapies in V600EBRAF mutant, TP53/PTEN deficient cell lines and patient derived xenografts. Inhibition of CHK1 concurrently with the induction of either DNA damage or replication stress leads to ‘‘mitotic catastrophe’’ and cell death in our in vitro and in vivo models of TP53/PTEN deficient tumors. In the case of externally applied cellular stress from chemotherapeutics, our results suggest CHK1 inhibition may sensitise this genetically defined subset of melanomas to such treatments.
Our results provide some insight into the heterogeneity of clinical outcomes observed when treating BRAF mutant melanomas with BRAF inhibitor and suggest a need for comprehensive screening of TP53 and PTEN inactivation in these patients.
Citation Format: Elena Galvani, Kelly Brooks, Franziska Baenke, Maria Romina Girotti, Gabriela Gremel, Amit Kumar Mandal, Amaya Viros, Clare McManus, Matthew Smith, Kok Haw Jonathan Lim, Rebecca Lee, Alberto Fusi, Paul Lorigan, Richard Marais. Simultaneous inactivation of TP53 and loss of PTEN diminish response to targeted therapy in V600EBRAF mutant melanoma. [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 2683. doi:10.1158/1538-7445.AM2015-2683
Abstract 270: Preclinical assessment of combination therapy with selumetinib and CTLA-4 for cancer
Authors: Mullins Stefanie R. , Poon Edmund , Watkins Amanda , Smith Paul D. , Leishman Andrew , Stewart Ross , Wilkinson Robert 
Published: August 2015

Abstract
Immune mediated therapies for Cancer (IMT-C), such as anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal antibodies (mAb), are showing promise in the treatment of solid tumors. However, although these treatments demonstrate clinical activity in a range of tumors, the durable benefit of these agents appears to be limited to a subset of patients. One hypothesis is that activity in these patients is limited by a lack of immune priming or by additional immunosuppressive pathways. Combination with molecular targeted therapies offers the potential to explore additional treatment strategies for patients. However, in order to select the best combination partners, a greater understanding is needed as to how each therapy affects the immune system both directly, through effects on
leukocytes, and indirectly, through effects on tumor immunogenicity and the microenvironment. Selumetinib is a potent inhibitor of the mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2), involved in the activation of signaling pathways which regulates cellular growth, proliferation and survival. Given that these pathways are often found aberrantly activated in human tumors, and also play key roles in the regulation of immunological processes, it is difficult to predict the combinatorial effect of MEK1/2 inhibition and IMT in cancer treatment. To assess the effect of selumetinib in a tumor model with an intact immune system, we have characterized the impact of dosing selumetinib with or without anti-CTLA-4 mAb on the immune system in the CT26 syngeneic tumor model. Flow cytometric analysis showed that this combination reduced T-cell proliferation and memory T-cell generation, but increased the frequency of splenic T cells. Selumetinib treatment decreased PD-L1 expression and increased MHC class II expression on the tumor cells, whilst decreasing myeloid-derived suppressor cell (MDSC)-like cells in the tumor. Despite the apparent ability of selumetinib to have both positive and negative effects on immune responses in vivo, the combination of selumetinib and anti-CTLA4 mAb was found to show anti-tumor activity in the CT26 colorectal tumor mouse model. These studies highlight the potential for enhancing anti-tumor immune response through combinations of molecular targeted therapies and IMT-Cs.
Citation Format: Stefanie R. Mullins, Edmund Poon, Amanda Watkins, Paul D. Smith, Andrew Leishman, Ross Stewart, Robert Wilkinson. Preclinical assessment of combination therapy with selumetinib and CTLA-4 for 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 270. doi:10.1158/1538-7445.AM2015-270
Abstract 2707: Downregulation of cyclin D1 sensitizes cancer cells to MDM2 antagonist Nutlin-3
Authors: Ou Wenbin , Chen Weicai , Zhu Jiaqing , Eilers Grant , Li Xuhui , Yang Peipei , Li Hailong , Meng Fanguo , Fletcher Jonathan 
Published: August 2015

Abstract
The MDM2-p53 pathway plays a prominent role in various cancer pathogenesis. Nutlin-3, a small-molecule antagonist of MDM2, inhibits proliferation in cancer cells with wild-type p53 by blocking the interaction of MDM2 and p53. However, different cancer cells differ greatly sensitivity of Nutlin-3 because of MDM2 amplification and/or p53 mutation status. Herein, we evaluate the sensitivity of Nutlin-3 in different cancer cell lines including four mesothelioma cell lines, one breast cancer line, and one leiomyosarcoma cell line with nonmutant p53 expression, two liposarcoma cell lines harboring MDM2 amplification and wild-type p53, and one control mesothelioma cell line JMN1B harboring p53 point mutation. Unexpectedly, Nutlin-3 treatment induced cyclin D1 expression accompanied with inhibition of MDM2-p53 interaction in nonmutant cancer cell lines. Additive effects were obtained through a coordinated attack on MDM2-p53 interaction and cyclin D1, as demonstrated by immunoblots, cell viability and cell cycle analyses, showing that lentiviral mediated cyclin D1 knockdown or drug inhibition, and block of MDM2-p53 interaction, in cancer cell lines containing wild-type p53, induced greater anti-proliferative effects, compared to either intervention alone. Further results demonstrated that upregulation of cyclin D1 after Nutlin-3 treatment to some extent was dependent on expression and ubiquitin E3-ligase activity of MDM2. These compelling anti-proliferative responses indicate that combination inhibition of cyclin D1 and MDM2-p53 interaction warrants clinical evaluation as a novel therapeutic strategy in cancer cells harboring wild-type p53.
Citation Format: Wenbin Ou, Weicai Chen, Jiaqing Zhu, Grant Eilers, Xuhui Li, Peipei Yang, Hailong Li, Fanguo Meng, Jonathan Fletcher. Downregulation of cyclin D1 sensitizes cancer cells to MDM2 antagonist Nutlin-3. [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 2707. doi:10.1158/1538-7445.AM2015-2707
Abstract 2730: Additional mutations in genes relevant to the Ras signaling pathway promote the malignant characteristics of NF1-associated malignant peripheral nerve sheath tumor (NF1-MPNST) cells
Authors: Arima Yoshimi , Kosaki Kenjiro , Hirose Chikako , Saya Hideyuki 
Published: August 2015

Abstract
Malignant peripheral nerve sheath tumors (MPNST) are soft tissue sarcomas surrounding the peripheral nerve and occur sporadically or more often in association with neurofibromatosis type 1 (NF1, von Recklinghausen disease), which is an inherited disease caused by NF1 gene germline mutations. The NF1 tumor suppressor gene encodes neurofibromin and is a functional Ras GTPase-activating protein (RasGAP) that regulates the Ras signal negatively by accelerating the conversion of activated Ras-GTP to inactive Ras-GDP.
We hypothesized that additional genetic alterations promote malignancy of NF1-associated tumors. Hence, we inoculated a GFP-labeled human NF1-MPNST cell line, sNF96.2-GFP, which has a frame-shift mutation (c.3683delC, p.Asn1229MetfsTer11) in the NF1 gene, into the renal sub-capsules of immunodeficient mice. A subclonal cell line, the A-1 cell, was established from the developed tumor. We found that A-1 cells show much higher tumorigenic activity and Akt activation than parental sNF96.2-GFP cells.
We analyzed the genomic DNA of both the sNF96.2 and the A-1 cells by using the next-generation sequencing and the medical exome panel including 4813 genes, which are known to be responsible for most human genetic disorders. We identified 18 heterozygous variants in 17 genes that were present in the A-1 cells, but not in the original sNF96.2 cells. Two of these genes are associated with the regulation of the Ras signaling pathway.
Our data suggests that the additional gene mutations that regulate Ras pathways do in fact promote the malignant characteristics of NF1-associated tumors through the Akt activation.
Citation Format: Yoshimi Arima, Kenjiro Kosaki, Chikako Hirose, Hideyuki Saya. Additional mutations in genes relevant to the Ras signaling pathway promote the malignant characteristics of NF1-associated malignant peripheral nerve sheath tumor (NF1-MPNST) 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 2730. doi:10.1158/1538-7445.AM2015-2730