bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4780: An antisense-based approach to induce anti-tumorigenic variants of MET receptor
Authors: Rathod Trushar , Cartegni Luca 
Published: August 2019

Abstract
Rational: Aberrant activity of MET receptor, a receptor tyrosine kinase (RTK), is implicated in various forms of cancer. Moreover, functional crosstalk of MET with other RTKs has been reported in tumors and MET has emerged both as a driver and as a primary mechanism of resistance, thus, making MET an attractive target for cancer therapeutics.
Aim: Recently, we have described natural soluble decoy variants for multiple RTKs (sdRKTs), including MET, which can antagonize RTK signaling by ligand sequestration and non-functional dimerization. These isoforms can be generated via intronic polyadenylation (IPA) of RTK’s pre-mRNA in a U1-snRNP dependent manner. Our aim is to activate IPA in MET pre-mRNA using antisense compounds and to increase mRNA variants that express dominant-negative soluble decoy MET (sdMET).
Methods: Identify actionable IPA sites within introns upstream of the transmembrane-coding exon. Express potential sdMET isoforms and characterize their biological properties. For sdMET isoforms with inhibitory functions, anti-sense compounds are utilized to block the upstream U1 binding site, activate IPA sites, and thus increase expression of sdMET variants in MET-dependent cancer cells.
Results: Ectopically expressed sdMET isoforms are secreted into the culture medium. When then added to MET-expressing cells, sdMET variants functioned in a dominant-negative manner over full length MET (FL-MET) and suppressed activation of AKT and MAPK pathways. Moreover, antisense compounds that induce IPA effectively convert oncogenic FL-MET into sdMET variants in multiple cell lines, leading to suppression of downstream pathways and dramatic reduction in cell viability of MET-dependent cells.
Conclusion: Most sdMET isoforms are secreted into extracellular space and have inhibitory function. Our anti-sense approach induces IPA, generates truncated sdMET variants at the expense of FL-MET and efficiently blocks FL-MET’s biological activity.
Citation Format: Trushar Rathod, Luca Cartegni. An antisense-based approach to induce anti-tumorigenic variants of MET receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4780.
Abstract 4784: Combination of sorafenib with liver cancer-targeted gene therapy exerts synergistic efficacy against hepatocellular carcinoma
Authors: Dai Huei-Yue , Li Long-Yuan 
Published: August 2019

Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Sorafenib, a multikinase inhibitor, is the first-line target therapy for patients with advanced HCC, but the response rate is low. Thus, development of more effective therapeutics for HCC is needed. Previously we have established a HCC-targeted BikDD gene therapy vector driven by a liver cancer-specific α-fetoprotein promoter/enhancer and transcriptional amplification module. Systemic administration of liposome-loaded HCC-targeted BikDD gene therapy vector effectively suppressed tumor growth and prolonged survival in multiple orthotopic HCC mouse models with no toxicity. Here, we further investigated whether combination of sorafenib with gene therapy could enhance anti-HCC activity. The results showed that combination of BikDD gene therapy with HCC targeted therapeutic agent sorafenib synergistically killed a panel of liver cancer cells but not normal cells in vitro by WST-1 assays and analysis of combination index according to the Chou and Talalay method. Moreover, a low dose of sorafenib combined with BikDD gene therapy augmented tumor inhibition and better mice survival compared with separate treatment alone in xenograft and syngeneic orthotopic HCC mouse models. These results suggest that sorafenib combined with HCC-targeted gene therapy may improve the therapeutic efficacy and may be a potential alternative therapeutics for HCC.
Citation Format: Huei-Yue Dai, Long-Yuan Li. Combination of sorafenib with liver cancer-targeted gene therapy exerts synergistic efficacy against hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4784.
Abstract 4805: Cannabinoid WIN 55,212-2 induces endoplasmic reticulum stress in prostate cancer cells through CB1and CB2receptors
Authors: Roberto Domenica , Klotz Laurence H. , Venkateswaran Vasundara 
Published: August 2019

Abstract
Cannabinoids have demonstrated anticarcinogenic properties in a variety of malignancies, including prostate cancer. WIN 55,212-2 (WIN) is a highly potent synthetic cannabinoid that binds to cannabinoid receptors (CB1 and CB2). We have previously demonstrated that WIN significantly reduces prostate cancer cell proliferation, migration, invasion, induces apoptosis, and arrests cells in the G0/G1 phase through a cannabinoid receptor 2 dependent manner. We also determined that these effects were mediated though a pathway involving cell cycle regulators p27, Cdk4, and pRb. The current study aims to examine the role of endoplasmic reticulum (ER) stress in apoptosis and investigates whether this effect is modulated by WIN and the cannabinoid receptors.
In this study, we evaluated the effect of WIN and CB receptors on ER stress induced apoptosis in established prostate cancer cells (DU145, PC3). Cells were treated with WIN, cannabinoid receptor 1 antagonist (AM251), and cannabinoid receptor 2 antagonist (AM630). Cell proliferation was determined using MTS assays. Quantitative PCR was used to examine changes in expression of ER stress related genes, including CHOP, TRIB3, and ATF4. Western blotting will be completed to determine changes in the expression of apoptotic markers after treatment with WIN and cannabinoid antagonists. Further studies are ongoing looking at the use of the ER stress inhibitor, Salubrinal, to determine whether ER stress is vital for WIN-induced apoptosis.
Our results reveal that treatment with 20μM WIN resulted in a significant reduction in the proliferation of DU145 and PC3 cells after 24 h compared to control (p&lt;0.05). In contrast, treatment with 5μM of either AM251 or AM630 did not result in any significant changes in cell proliferation. Quantitative PCR studies revealed significant upregulation of ER stress genes CHOP, TRIB3 and ATF4 in WIN treated cells (p&lt;0.05). Expression of ER stress genes were significantly downregulated after blocking CB1 and CB2 receptors (p&lt;0.05).
Interim results suggest that WIN has significant antitumoral activity and modulates ER stress-induced apoptosis in prostate cancer cells, thus, may offer a novel therapeutic strategy in the treatment of prostate cancer.
Citation Format: Domenica Roberto, Laurence H. Klotz, Vasundara Venkateswaran. Cannabinoid WIN 55,212-2 induces endoplasmic reticulum stress in prostate cancer cells through CB1and CB2receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4805.
Abstract 4807: Pimavanserin suppresses pancreatic tumor growth and resistance to gemcitabine by inhibiting Akt/Gli1 signaling
Authors: Ramachandran Sharavan , Srivastava Sanjay K. 
Published: August 2019

Abstract
Despite major advances in cancer treatment, pancreatic cancer is still incurable and the treatment outcomes are limited. In the current study, we evaluated the anti-cancer effects of pimavanserin tartrate (PVT), a drug used for the treatment of Parkinson’s disease psychosis. Our observations indicated that, PVT significantly suppressed the proliferation of pancreatic cancer cells by inducing apoptosis without exerting any cytotoxic effects in normal human pancreatic ductal epithelial (HPDE-6) cells. The colony forming ability of pancreatic cancer cells was significantly inhibited with PVT treatment. Anti-proliferative and apoptosis inducing effects of PVT were mediated by the inhibition of pAkt (Ser473), Akt, Gli1, Oct-4, SOX-2, NANOG and c-Myc. Akt and Oct-4 inhibition by PVT treatment was further validated by immunofluorescence analysis. Moreover, PVT inhibited the formation of tumorspheres in PANC1 pancreatic cancer cells. Pharmacologically inhibiting or genetically knocking out Akt or Gli1 enhanced the growth suppressive effects of PVT in pancreatic cancer cells. Subsequently, we evaluated the effects of PVT in gemcitabine resistant cells. Our results demonstrated that, PVT reduced the survival of MIAPaCa2 gemcitabine resistant cells in a concentration and time-dependent manner. Further mechanistic analysis indicated that, PVT suppressed the phosphorylation of Akt at Ser 473 and inhibited the expression of Gli1, Oct-4 and c-Myc in MIAPaCa2 gemcitabine resistant cells. Moreover, PVT increased the cleavage of caspase-3 and PARP as an indicator of apoptosis. Oral administration of PVT suppressed BxPC3 tumor xenografts by 50% in athymic nude mice. In another in vivo experiment, PVT treatment inhibited the growth of orthotopically implanted PANC1 tumors by 75%. Chronic administration of PVT did not exhibit any general signs of toxicity or behavioral side effects in mice. Taken together, our results indicate that pancreatic tumor growth suppression by PVT is orchestrated by inhibition of Akt/Gli-1 signaling. Since PVT is already available in the clinic with an established safety profile, our results will accelerate its clinical development for the treatment of patients with pancreatic cancer.
Citation Format: Sharavan Ramachandran, Sanjay K. Srivastava. Pimavanserin suppresses pancreatic tumor growth and resistance to gemcitabine by inhibiting Akt/Gli1 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4807.
Abstract 481: Distinct and overlapping patterns of B-cell growth pathway mutations in CD5-negative B-cell lymphoproliferative disorders
Authors: Shaddy Sophia , Zhao Weiqiang , Tu Huolin , Sisson Brianna , Ren Rongqin , Caruthers Sean , Long Susan , Ru Peng , Epperla Narendranath , Abruzzo Lynne , Maddocks Kami , Jones Dan 
Published: August 2019

Abstract
Low-grade CD5-negative B-cell lymphoproliferative disorders (CD5- LG B-LPD) encompass several entities that often show mutations in different growth regulatory pathways. These include MYD88 (TLR signaling), CD79A/B (BCR complex), CARD11 (CBM signalosome), CXCR4 (chemokine receptor), and NOTCH1/2 and are complemented by KLF2 mutations and BCL6 and MALT1 overexpression. Using targeted, next-generation sequencing (NGS) for 50 B-cell associated growth regulators and epigenetic modifiers (&gt;1000X depth) and cytogenetic/FISH data, we sought to delineate the complementary mutation and gene amplification patterns in 45 consecutive cases of CD5- LG B-LPD. In mutation-negative cases, a 572-gene NGS panel was used to interrogate these pathways more completely. WHO diagnostic criteria were used, without reliance on molecular data, emphasizing morphology features, paraprotein level and type to distinguish lymphoplasmacytic lymphoma (LPL) from marginal zone lymphoma (MZL). As expected, MYD88 L265P mutations were seen in the majority of LPL (11/17, 65%), but also in CD5- chronic lymphocytic leukemia (CLL) (3/9, 33%) and splenic (S) MZL (1/6, 17%) but not in nodal MZL. In 4 LPL cases lacking MYD88 L265P, extra copies of chromosome 3 (BCL6), 6 (IRF4), 12 and/or 18 (MALT1) were seen, with CARD11 mutations in the other 2. NOTCH1/2 mutations were mostly associated with SLL/CLL (3/9, 33%). Mutations in epigenetic regulators (see Table) were seen in the majority of nodal MZL (8/13, 62%) but only few LPL (2/17, 12%) and SMZL (1/6, 17%). CXCR4 inactivating mutations were seen with MYD88 and CD79B mutations and +3/BCL6 alteration. CARD11 mutations were seen with KLF2, MYD88 and NOTCH1/2 mutations. Less common mutations targets included PTPRC and PLCG2 (pre-ibrutinib treatment). The higher rate of mutation in epigenetic regulators (along with loss of KLF2-mediated BCR signaling) supports a distinct pathogenesis for nodal MZL in contrast to other CD5- B-LPD.
Calls per gene in MYD88 negative cases; *TP53, TET2, ASXL1, DNMT3A, BCORCD79BCARD11NOTCH1/2CXCR4KLF2Epigenetic gene set*LPL023000010000000010CD5- CLL000002001001001000001000000001sMZL011010010000000001nMZL000002000022000001010011000101000001000001000001012010000200
Citation Format: Sophia Shaddy, Weiqiang Zhao, Huolin Tu, Brianna Sisson, Rongqin Ren, Sean Caruthers, Susan Long, Peng Ru, Narendranath Epperla, Lynne Abruzzo, Kami Maddocks, Dan Jones. Distinct and overlapping patterns of B-cell growth pathway mutations in CD5-negative B-cell lymphoproliferative disorders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 481.
Abstract 4826: Enhancement of PTEN activity via peptidomimetics
Authors: Palumbo Emily , Teng Peng , Malaney Prerna , Wilson Jacob , Kearns Fiona , Kemp Michael T. , Tian Zhi , Uversky Vladimir , Allen-Gipson Diane , Chen Yu , Woodcock H. Lee , Cai Jianfeng , Dave Vrushank 
Published: August 2019

Abstract
Compromised PTEN function is associated with multiple cancers. As per the continuum model, variable degree of PTEN inactivation drives distinct cancer phenotypes. Loss of PTEN activity, via genomic/non-genomic mechanisms, leads to enhanced oncogenic PI3K signaling. While kinase inhibitors have proved effective in the clinic, they are increasingly met with off-target effects and therapy-resistance due to compensatory feedback mechanisms. Although PTEN restoration therapy has proved promising in experimental models; implementation of these therapies in the clinic remains challenging. To fill this therapy gap, we have targeted endogenous PTEN for activation via peptidomimetics, mitigating PI3K signaling. Our selected peptidomimetics reduced cell proliferation, migration and cell cycle activity after treatment of non-small cell lung cancer cells expressing endogenous PTEN. Computational studies utilizing PTEN crystal structures revealed a binding site at the interface of the Phosphatase Domain (PD) and C2 Domain (C2D). Induced fit docking indicated that a unique functional group is responsible for peptidomimetic-mediated enhancement of PTEN activity. Molecular dynamics analysis revealed energetically favorable binding of our lead peptidomimetic at the PD/C2D interface, which allosterically modulated the conformation of the active site. Binding of our peptidomimetic altered the active site orientation of PIP3, increasing its binding affinity. In summary, we have developed the first-known direct PTEN activators and analyzed their effects in suppressing oncogenic activities in lung cancer. Refinement of our peptidomimetics, complemented with in vivo studies, will provide a novel clinical rationale to reduce doses of standard therapy and their associated toxicities, decreasing morbidity and mortality observed in the clinic.
Citation Format: Emily Palumbo, Peng Teng, Prerna Malaney, Jacob Wilson, Fiona Kearns, Michael T. Kemp, Zhi Tian, Vladimir Uversky, Diane Allen-Gipson, Yu Chen, H. Lee Woodcock, Jianfeng Cai, Vrushank Dave. Enhancement of PTEN activity via peptidomimetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4826.
Abstract 4832: Preclinical evaluation of neratinib plus T-DM1 in orthotopic PDX models of HER2-positive breast cancer brain metastases
Authors: Ni Jing , Wang Yanzhi , Diala Irmina , Kabraji Sheheryar , Freedman Rachel , Lin Nancy , Zhao Jean 
Published: August 2019

Abstract
Up to half of patients with metastatic HER2-positive breast cancer will develop brain metastases. Breast cancer brain metastases (BCBM) are a major cause of morbidity and mortality, despite multimodal management including surgery, radiotherapy, and systemic therapies. Therefore, there is an urgent need to develop novel, efficacious therapies. Neratinib is an orally bioavailable, irreversible pan-HER tyrosine kinase inhibitor that is FDA-approved in the extended adjuvant treatment setting for HER2-positive, early breast cancer. Neratinib has only modest activity as a single agent in clinical trials of patients with HER2-positive brain metastases. Though the combination of neratinib and capecitabine results in CNS responses in up to half of patients, patients eventually develop drug resistance, and toxicities have been a concern-thus exploration of alternative neratinib combinations is of significant clinical interest. Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate with reported single-agent activity against HER2-positive BCBM. Here, we used HER2-positive orthotopic patient derived xenograft (PDX) models of BCBM to test if combining neratinib with T-DM1 could improve tumor response. PDX cells are labelled with luciferase to allow tumor growth measurement in vivo. We found that neratinib is able to reduce phosphorylated HER2 in an orthotopic PDX tumor derived from HER2-positive BCBM, indicating that neratinib can cross the BBB and inhibit HER2 activation in BCBM PDX tissues. However, in the HER2-positive DF-BM354 PDX model, single agent neratinib did not block orthotopic tumor growth compared to vehicle control as monitored by bioluminescence measurements. In contrast, combined treatment of neratinib with T-DM1 significantly reduced tumor growth compared to single agent treatment of neratinib or T-DM1 alone at earlier time points. At later time points, the combined treatment is comparable to T-DM1 alone. These data warrant further testing of neratinib alone or in combination with T-DM1 in additional BCBM PDX models to better understand drivers of resistance and susceptibility to HER2-inhibitors in HER2-positive BCBMs. Furthermore, they support the launch of a prospective clinical trial (NCT01494662) to test the efficacy and tolerability of T-DM1 in combination with neratinib in patients with progressive HER2-positive BCBM.
Citation Format: Jing Ni, Yanzhi Wang, Irmina Diala, Sheheryar Kabraji, Rachel Freedman, Nancy Lin, Jean Zhao. Preclinical evaluation of neratinib plus T-DM1 in orthotopic PDX models of HER2-positive breast cancer brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4832.
Abstract 4834: Effective treatment of squamous cell carcinoma of the head and neck (HNSCC) using a combined regimen of tipifarnib and cetuximab
Authors: Shu Lihua , Wang Dongsheng , Nannapaneni Sreenivas , Shin Dong M. , Saba Nabil F. , Chen Georgia Z. 
Published: August 2019

Abstract
Background: H-RAS driven carcinogenesis has been reported in many types of cancer including squamous cell carcinoma of the head and neck (HNSCC). The mutation rate of H-RAS in HNSCC is 4 - 8%. Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FT). It is known that H-RAS, but not K-RAS and N-RAS, is delocalized into cytoplasm and inactivated by farnesyltransferase inhibitors (FTI), such as tipifarnib. Tipifarnib has demonstrated proof of concept activity in H-RAS mutant HNSCC in an ongoing clinical trial (NCT02383927). In this study, we examined H-RAS associated signaling pathway in HNSCC cell lines and PDX models to see if inhibition of wild-type HRAS signaling could re-sensitize cetuximab resistant cells and tumors to inhibition by cetuximab. UMSCC47 and SCC1-C are both H-RAS wild-type HNSCC cell lines, and SCC1-C is resistant to EGFR targeted therapy.
Methods: In vitro cell growth with and without tipifarnib and/or cetuximab treatments were examined by Sulforhodamine B (SRB) and colony formation assay. Patient derived xenograft (PDX) models were then used to study the efficacy of the tipifarnib treatment as a single agent or in combination with cetuximab. Western blot analyses were performed to verify the effect of these treatments on EGFR/ERK/AKT signaling pathways.
Results: Our results showed that tipifarnib could inhibit HNSCC growth, both in vitro and in the PDX model in a dose-dependent manner (control vs the low dose of tipifarnib, p = 0.02; control vs the high dose of tipifarnib, p = 0.001). However, the combined treatment with cetuximab significantly enhanced tipifarnib efficacy in the H-RAS wild type setting, particularly in the PDX model (control vs tipifarnib, p = 0.123; control vs cetuximab, p = 0.022; control vs the combination, p = 0.010). Western blot analyses showed that neither ERK nor AKT phosphorylation was effectively reduced after a prolonged treatment (48 hours) with tipifarnib alone. However, the addition of cetuximab reduced pERK.
Conclusions: Our study demonstrates that cetuximab enhances the anti-tumor effect of tipifarnib in the H-RAS wild type setting through ERK inhibition. This study supports the rationale for combining tipifarnib with EGFR inhibitors as a possible effective therapeutic approach in HNSCC.
Citation Format: Lihua Shu, Dongsheng Wang, Sreenivas Nannapaneni, Dong M. Shin, Nabil F. Saba, Georgia Z. Chen. Effective treatment of squamous cell carcinoma of the head and neck (HNSCC) using a combined regimen of tipifarnib and cetuximab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4834.