bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5114: Design, synthesis, and biological evaluation of tricyclic thieno[2,3- d]pyrimidines as microtubule targeting antitumor agents
Authors: Islam Farhana , Gangjee Aleem , Zhang Xin , Zhou Xilin , Mooberry Susan L. 
Published: July 2017

Abstract
Microtubules are dynamic structures that, together with actin microfilaments and intermediate filaments, constitute the cellular cytoskeleton. Besides their well-known roles in cell division, their functions involve maintenance of cell shape and morphology, cellular motility, and trafficking of organelles and vesicles. Recently, we reported a compound AG 370 as a microtubule targeting agent, that circumvented the Pgp and βIII-tubulin mediated drug resistance mechanisms that limit the efficacy of paclitaxel, docetaxel, and the vinca alkaloids. Molecular modeling and docking studies of the parent compound (AG 370) in the colchicine binding site (PDB: 402B) suggest that the C-5 and C-6 of parent compound are oriented towards the hydrophobic pockets with the side chain of Ala316, Val315, Leu255 and Met259. However, this binding pocket in tubulin is relatively large. To further explore the hydrophobic pocket, an additional cyclohexene ring was introduced at C-5 and C-6 of AG370. In the molecular modeling study, the resulting tricyclic scaffold showed hydrophobic interactions with the amino acids of the colchicine binding site. The 2-Me substituent of the tricyclic scaffold was replaced with a 2-H and a 2-NH2 group and 4-position of the scaffold was replaced with appropriate anilines. The 2-amino- N4-methoxyphenyl moiety (AG61) was found to be the most potent analog in the tricyclic series in both antiproliferative assay in human melanoma cancer cell line (MDA-MB-435 cell line, IC50 = 9.0 ± 0.2 nM) and in microtubule depolymerization assay in A-10 cells (EC50= 19 nM). Thus, we identified tricyclic thieno[2,3-d]pyrimidines as a novel structural scaffold with potent antiproliferative activity as well as microtubule depolymerizing activity. These analogs are selected for preclinical development.
Citation Format: Farhana Islam, Aleem Gangjee, Xin Zhang, Xilin Zhou, Susan L. Mooberry. Design, synthesis, and biological evaluation of tricyclic thieno[2,3- d]pyrimidines as microtubule targeting antitumor agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5114. doi:10.1158/1538-7445.AM2017-5114
Abstract 5125: Muscadine grape extract inhibits breast cancer brain metastatic cells by multiple mechanisms
Authors: Chen Wenhong , Gallagher Patricia , Tallant Ann , Metheny-Barlow Linda J. 
Published: July 2017

Abstract
Tumor metastasis to the brain is a common complication of cancer, affecting 500,000 patients each year. Due to poor penetration of most chemotherapeutics into the brain, brain metastasis may occur even while systemic disease in under control. Despite aggressive treatments including radiation therapy, survival at 12 months following diagnosis is only 20%, underscoring the need for better means to prevent and/or treat brain metastases.
Natural products have historically been a very successful source of new drugs. We are investigating the anti-cancer potential of a proprietary muscadine grape extract (MGE; from Piedmont Research & Development Corp.) on breast cancer cell lines that are metastatic to the brain. In a colony formation assay, MGE (10 μg/mL) decreased clonogenic survival of 4T1.luc2.Br5 cells by 50% (n=3, p&lt;0.0001). The Eo771.luc.Br5 cells were more sensitive to MGE, showing 33% inhibition at 5 μg/mL (n=3, p&lt;0.001) and 91% inhibition at 7.5 μg/mL (n=3, p&lt;0.0001). We also assessed response to the combined treatment of MGE and ionizing radiation (IR). While MGE did not sensitize cells to IR, combined administration of MGE and IR resulted in decreased clonogenic survival compared to either modality alone for both cell lines (n=3-4 experiments, p&lt;0.01), suggesting an additive effect.
Mechanistically, acute exposure (24 h) to 10 μg/mL MGE induced apoptosis in 4T1.luc2.Br5 cells as evidenced by PARP cleavage and detection of activated cleaved caspase 3. Further, ERK1/2 activation was decreased 68% at this time point (n=3, p&lt;0.05). In contrast, although Eo771.luc.Br5 cells are more sensitive to clonogenic inhibition, no PARP cleavage, caspase 3 cleavage, or ERK1/2 inhibition was observed. Analysis of cyclin D1, a major regulator of cell cycle progression, identified &gt;80% decrease following MGE treatment (24 h, 10 μg/mL) in both cell lines. Together these data suggest that MGE inhibits breast cancer brain metastatic cell proliferation by multiple mechanisms, including inhibition of clonogenic growth through induction of apoptosis and/or decreased cell cycle progression, suggesting that MGE may have utility in the treatment of breast cancer brain metastasis.
Citation Format: Wenhong Chen, Patricia Gallagher, Ann Tallant, Linda J. Metheny-Barlow. Muscadine grape extract inhibits breast cancer brain metastatic cells by multiple mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5125. doi:10.1158/1538-7445.AM2017-5125
Abstract 5129: Cell-penetrating doxorubicin released from Elastin-like polypeptide kills doxorubicin-resistant cancer cells
Authors: Ryu Jung Su , Raucher Drazen 
Published: July 2017

Abstract
A drug-releasing system facilitated by external stimuli could be used to deliver cytotoxic chemotherapy agents to tumor sites selectively and safely. Among many suggested strategies, elastin-like polypeptide (ELP) exploits its characteristic of phase transitioning in response to changes in ambient temperature. This unique property permits selective targeting of the polymer to hyperthermic tumors by aggregating as it transitions. ELP therefore can be used as a thermosensitive vector for the delivery of chemotherapy agents and therapeutic peptides, resulting in a rise in drug concentration exclusively in tumors. This novel strategy introduces unprecedented options for treating cancer, with fewer concerns about indiscriminate side effects from the chemotherapy.
In this study, the ELP-drug conjugate was further modified with incorporation of an enzyme-specific cleavable linker in order to trigger drug release within tumors. The suggested system is composed of ELP, a matrix metalloproteinase (MMP) substrate, a cell penetrating peptide (CPP), and 6-maleimidocaproyl amide derivative of doxorubicin (Dox). Rationale for this design is that this construct may be initially targeted to the tumor site by local application of mild heat. When the construct reaches tumor site, it is cleaved by MMP, releasing CPP conjugated Dox, which is able to more efficiently infiltrate tumor tissues and penetrate cancer cell membranes. This strategy shows up to 4-fold increase in cell penetration up to four times and results more cell death in breast cancer cells than the ELP-doxorubicin complex. Even in doxorubicin-resistant cancer cells (NCI/ADR and MES/ADR), ELP-released, cell-penetrating doxorubicin demonstrated better membrane penetration (two fold), leading to at least twice killing of the resistant cancer cells than ELP-Dox and free Dox.
Citation Format: Jung Su Ryu, Drazen Raucher. Cell-penetrating doxorubicin released from Elastin-like polypeptide kills doxorubicin-resistant cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5129. doi:10.1158/1538-7445.AM2017-5129
Abstract 5141: Optimizing peptide-drug conjugate delivery as an alternative to antibody-drug conjugates for solid tumors
Authors: Sottero Theo L. , Girard Emily J. , Myers Carrie H. , Olson James M. 
Published: July 2017

Abstract
Antibody-drug conjugates (ADCs) have been FDA approved for targeted delivery of chemotherapy to a small subset of cancers. However, there are significant limitations in their clinical utility in the majority of cancers: despite hundreds of clinical trials, there are only two FDA approved drugs currently on the market. ADCs are further limited by their poor penetration into solid tumors and an inability to cross the blood-brain-barrier (BBB). Our lab has over a decade of experience with peptide-dye conjugates such as chlorotoxin-Cy5.5, which demonstrates tumor-specific accumulation in a wide range of cancers including solid tumors and tumors protected by the BBB. However, chlorotoxin-Cy5.5 accumulates in mouse liver – a potential liability if a chlorotoxin-drug conjugate exhibited similar biodistribution. Tumor Paint/BLZ-100 is a derivative of this molecule optimized for tumor accumulation that is currently in clinical trials to aid in cancer surgery. We sought to expand upon the utility of Tumor Paint and optimize a novel peptide that is capable of delivering both imaging agents and chemotherapeutics specifically to tumor cells in vitro and in vivo.
We have identified a novel Optide (OPtimized knottin pepTIDE) able to accumulate in a range of cancers (lymphoma, sarcoma, colon cancer, and pediatric medulloblastoma). To test whether an Optide could be created with a greater tumor specificity, we looked to both natural homologs as well as specific charged residue modifications. We have identified two next-generation Optides with enhanced uptake in mouse models of sarcoma. We have used these peptides to deliver a microtubule inhibitor to sarcoma and lymphoma in vitro and in vivo. Using in vitro flow cytometry, we have also identified multiple FDA approved drugs that upregulate or downregulate uptake of our family of peptide drug-conjugates. In understanding the pathways regulating the uptake of these peptides, we hope to both be able to identify tumors best suited for treatment with peptide-drug conjugates (PDCs) based on our Optide scaffold.
Citation Format: Theo L. Sottero, Emily J. Girard, Carrie H. Myers, James M. Olson. Optimizing peptide-drug conjugate delivery as an alternative to antibody-drug conjugates for solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5141. doi:10.1158/1538-7445.AM2017-5141
Abstract 5143: Fusogenic targeted liposomes: novel nanotherapy for specific treatment of prostate cancer
Authors: Mriouah Jihane , Nesbitt Rae Lynn , Richter Susan , Wuest Melinda , Pink Desmond , Sosnowski Deborah , Duncan Roy , Wuest Frank , Zijlstra Andries , Lewis John 
Published: July 2017

Abstract
Metastatic or castrate-resistant prostate cancer is the second-leading cause of cancer mortality in males. In the past 3 years, chemotherapies have extended survival, but efficacy is limited by dose-limiting toxicities due to suboptimal biodistribution. Here, we have addressed the lack of specificity and accumulation in Castrate Resistant Prostate Cancer (CRPC) by developing a unique nano-carrier for drug delivery: molecular targeted fusogenic liposomes. Previously, we have developed a platform whereby lipid nanoparticles are formulated with fusion associated small transmembrane (FAST) protein p14. The p14 protein catalyzes mixing of the nanoparticle lipids with target plasma membrane to deliver the cargo directly into the cytoplasm. In this study, we have engineered the p14 protein to incorporate the prostate cancer targeting ligand bombesin, which binds specifically to the Gastrin-releasing Peptide (GRPR) that is overexpressed in prostate cancer. We hypothesized that this novel targeted fusogenic liposome formulation would significantly improve the biodistribution and efficacy of chemotherapy. A clinical liposomal doxorubicin formulation (DOXIL) was modified to incorporate targeted fusogenic p14 protein, and the efficacy and biodistribution of these new formulations was evaluated using in vitro and in vivo models of CRPC. In PC3 cells, compared to conventional liposomes, intracellular levels of doxorubicin are increased by 15 and 25 times when p14 or p14-bombesin liposomes are used. Additionally, the IC50 is reduced from 85mM to 2mM. In mice bearing PC3 tumors treated with targeted fusogenic liposomal doxorubicin, we observed improved tumor growth inhibition by 57% (vs control) and 1.5 fold increased accumulation in tumors within 24h after administration. These proof of concept experiments indicate that molecular targeted fusogenic nanomedicines can improve both the intracellular delivery and tumor accumulation of chemotherapy, improving outcomes in this preclinical model. This highlights the potential for improved outcomes in patients with CRPC through the enhancement of approved drugs.
Note: This abstract was not presented at the meeting.
Citation Format: Jihane Mriouah, Rae Lynn Nesbitt, Susan Richter, Melinda Wuest, Desmond Pink, Deborah Sosnowski, Roy Duncan, Frank Wuest, Andries Zijlstra, John Lewis. Fusogenic targeted liposomes: novel nanotherapy for specific treatment of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5143. doi:10.1158/1538-7445.AM2017-5143
Abstract 5146: Increasing penetration of anticancer drugs through sortilin receptor-mediated cancer therapy: A new targeted and personalized Approach in the treatment of ovarian cancer
Authors: Demeule Michel , Curie Jean-Christophe , Larocque Alain , Charfi Cyndia , Béliveau Richard , Vezeau Claude , Annabi Borhane 
Published: July 2017

Abstract
The development of personalized therapies against ovarian cancer remains highly challenging in current modern oncology. One way to achieve greater selectivity and better anticancer drug delivery into cancer cells is to conjugate cytotoxic agents to specific peptide ligands that will selectively target receptors abundantly and/or exclusively expressed on these cells. Increased expression of Sortilin, a scavenging receptor, has been clinically observed in several human cancers including breast, prostate, colon, pancreas, skin, and pituitary. In particular, Sortilin has also been reported to be overexpressed in ovarian cancers as compared to non-malignant ovarian tissue. In light of this, we developed a peptide conjugation platform using a new Sortilin receptor-mediated vectorization strategy to increase cell targeting selectivity and cell delivery efficacy of anticancer agents. As a proof-of-concept, Doxorubicin was conjugated to peptide sequences, termed Katana peptides (KA). In vitro, significantly increased Sortilin mediated intracellular delivery of the Doxorubicin-Katana peptide conjugate (DoxKA) was observed in SKOV3 and ES-2 ovarian cancer cell line models, with conserved efficient Doxorubicin cytotoxic mechanism. Uptake of DoxKA in ES-2 ovarian cancer cells was reduced when Sortilin expression was specifically silenced by using siRNA or upon competition with the Sortilin ligands neurotensin and progranulin. In addition, DoxKA was found to bypass the P-glycoprotein (P-gp) efflux pump since, in contrast to Doxorubicin uptake in MDCK-MDR1 cells overexpressing the P-gp efflux pump, the uptake of DoxKA was unaffected by the P-gp inhibitor Cyclosporin A. In vivo, DoxKA was better tolerated and caused a more potent inhibition of human ovarian tumor xenografts growth than did Doxorubicin alone. These results provide strong evidence for the potential of this drug development platform in the generation of novel personalized therapeutics with specific targeting of SORT1-positive cancer cells.
Citation Format: Michel Demeule, Jean-Christophe Curie, Alain Larocque, Cyndia Charfi, Richard Béliveau, Claude Vezeau, Borhane Annabi. Increasing penetration of anticancer drugs through sortilin receptor-mediated cancer therapy: A new targeted and personalized Approach in the treatment of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5146. doi:10.1158/1538-7445.AM2017-5146
Abstract 5156: A synthesized RNA aptamer targeting and inhibiting non-small cell lung cancer
Authors: Wang Hanlu , Qin Meng , Ren Zhihua , Chen Irvin S.Y. , Jiang Yongping 
Published: July 2017

Abstract
A specific RNA aptamer (RA16) targeting non-small cell lung cancer (NCI-H460 cells) was previously reported by in vivo SELEX. The aptamer RA16 was identified specifically targeting and inhibiting human NCI-H460 cell proliferation in vitro, as well as xenograft tumor tissues in vivo. In this study, we synthesized RNA aptamer (syn-RA16) and make comparison studies with transcribed RNA aptamer (trans-RA16) in vitro in respect of the specific targeting and direct inhibitory activity towards NCI-H460 cells.To characterize the targeting specificity in vitro, biotin-labeled syn-RA16 and trans-RA16 were incubated with NCI-H460 cells, other tumor cell lines or normal control cells. Specific fluorescent binding was observed only for NCI-H460 cells, but not for HEK293T, Hela, and Jurkat cells or buffer control. Moreover, binding affinity of Kd values to the NCI-H460 cells for syn-RA16 and trans-RA16 were determined at 24.75±2.28 nM and 12.14±1.46 nM(n=3), respectively, by flow cytometry using streptavidin-PE labelling, indicating that the specific targeting binding affinity for syn-RA16 was highly retained, as trans-RA16. On the other hand, syn-RA16 aptamer, like trans-RA16 aptamer, was also capable of inhibiting non-small cell lung cancer cell (H460) proliferation in a dose-dependent manner. At 300 nM, syn-RA16 aptamer suppressed cell proliferation by 84.5%, comparing by 86.8% with trans-RA16. The IC50 for syn-RA16 was determined at 118.4±1.1 nM, while trans-RA16 was at 105.7±1.2 nM (n=4). Intestinally, both syn-RA16 and trans-RA16 exhibited no any inhibitory effect on HeLa and Jurkat cell lines even at concentration of 600 nM. In conclusion, a specific entire RA16 RNA aptamer was synthesized. The synthesized RA16, like transcribed RA16 aptamer, demonstrated the specific targeting ability and inhibitory activity to human NCI-H460 cells. The syn-RA16 could be potential to develop a diagnostic kit or treatment for NCI-H460 cell-related non-small cell lung cancer in the clinic.
Citation Format: Hanlu Wang, Meng Qin, Zhihua Ren, Irvin S.Y. Chen, Yongping Jiang. A synthesized RNA aptamer targeting and inhibiting non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5156. doi:10.1158/1538-7445.AM2017-5156
Abstract 5157: Preparation of curcumin analog nanoparticles and determination of their anticancer activity in prostate cancer
Authors: Juan-Rivera Maylein C. , Sánchez-Vázquez Maria M. , Maldonado Gamalier , Ruíz Geovanny , Vázquez Noralejandra , Vélez Christian , Zayas Beatriz , Cabrera Carlos , Martínez-Ferrer Magaly , Sanabria-Ríos David 
Published: July 2017

Abstract
Prostate cancer is the most frequently diagnosed cancer and the second cause of cancer-related deaths in American men. Bioavailability of therapeutic agents is important for the treatment effectiveness. Previous studies have shown that the development of nanoparticles (NPs) drug delivery vehicles offers an opportunity for targeted drug delivery to tumor cells. Natural compounds such as curcumin have shown decreased bioavailability and stability when used as anticancer agents. Therefore, the purpose of this study is to synthesize the curcumin analog m-nitrochalcone (3bNchalc) encapsulated into poly (lactic-co-glycolic acid) (PLGA) NPs and determine the anticancer activity against prostate cancer cell lines. In our approach, 3bNChalc were encapsulated into PLGA NPs in the presence of PVA using the single emulsion-solvent evaporation method. 3bNChalc loading, encapsulation efficiency, and drug release was determined by spectrophotometric techniques. Physico-chemical properties such as zeta potential, particle size, polydispersity index (PDI), and morphology was measured using a combination of Dynamic Light Scattering (DLS) and Scanning Electron Microscopy (SEM). Cell viability and proliferation of PC3 and 22RV1 prostate cancer cell lines treated with 3bNchalc NPs and control were assessed using the MTS assay. 3bNchalc PLGA NPs were found to have a particle size of 250 nm and smooth spherical shape. In addition, zeta potential and mobility values revealed that 3bNChalc PLGA NPs are negatively charged and they tend to repel each other avoiding the tendency to flocculate. Moreover, 22RV1 cells treated with 3bNchalc PLGA NPs showed decreased in viability and proliferation when compared to control. We demonstrated that 3bNChalc was successfully encapsulated into PLGA NPs. In addition, our results showed that 3bNchalc PLGA NPs decreased the viability of 22RV1 prostate cancer cells when compared to control, suggesting that PLGA improves the delivery of 3bNChalc inside the cell. Results of our study will impact broadly the field by developing more effective and less toxic PLGA NPs based therapies.
Citation Format: Maylein C. Juan-Rivera, Maria M. Sánchez-Vázquez, Gamalier Maldonado, Geovanny Ruíz, Noralejandra Vázquez, Christian Vélez, Beatriz Zayas, Carlos Cabrera, Magaly Martínez-Ferrer, David Sanabria-Ríos. Preparation of curcumin analog nanoparticles and determination of their anticancer activity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5157. doi:10.1158/1538-7445.AM2017-5157