bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5147: Novel warheads for targeted therapies of cancer: The concept and design of proPBDs
Authors: Vlahov Iontcho , Qi Longwu , Hahn Spencer , Wang Kevin , Santhapuram Hari K. , Felten Albert , Kleindl Paul , Vaughn Jeremy , Leamon Christopher P. 
Published: July 2017

Abstract
Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antibiotics, are a class of natural products produced by various actinomycetes bacteria. PBDs are sequence selective DNA-crosslinking alkylating compounds and are considerably more potent than systemic chemotherapeutic agents. Some PBDs have the ability to recognize and bond to specific sequences of DNA. After insertion in the minor groove, a covalent aminal bond is formed through nucleophilic attack of the N-2 of a guanine (G) base on the electrophillic C-11 imine of PBD. The end result is obstruction of tumor cell division without any significant distortion of the DNA’s helix, thus potentially avoiding the common phenomenon of drug resistance.
In recent years, synthetic PBD-dimers have emerged as a promising class of payloads for conjugates in the field of targeted cancer therapies. Unfortunately, many PBD conjugates preserve the strongly alkylating imine moiety within their structural framework, which can react in a deleterious manner while in circulation on their way to their intended targets. As an elegant solution to this inherent problem we designed conjugated prodrugs lacking the imine moiety. Once the prodrug (proPBD) conjugate enters a targeted cell, cleavage of the linker system in the construct triggers the generation of a reactive intermediate possessing an aldehyde and aromatic amine. An intramolecular reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine, and as a result, the diazepine ring.
In our proPBDs, we envision to mask the aldehyde as a hydrolytically sensitive oxazolidine moiety and to exploit its ring system as a part of an arsenal of self-immolative linker systems for conjugation. To prove the range of applications for this new class of latent DNA-alkylators, we designed and prepared a diverse variety of novel warheads, consisting of proPBD dimers, hybrids of proPBD with other powerful alkylating agents, as well as tethers of proPBDs with sequence-selective DNA minor groove binders. The utility of the so prepared novel warheads in the design of small molecule drug conjugates (SMDC) for targeted cancer therapies will be also discussed in the presented poster.
Citation Format: Iontcho Vlahov, Longwu Qi, Spencer Hahn, Kevin Wang, Hari K. Santhapuram, Albert Felten, Paul Kleindl, Jeremy Vaughn, Christopher P. Leamon. Novel warheads for targeted therapies of cancer: The concept and design of proPBDs [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 5147. doi:10.1158/1538-7445.AM2017-5147
Abstract 5152: Cancer stem cell targeted exosomes for the treatment of metastatic breast cancer
Authors: Kibria Golam , Lee Katelyn E. , Ramos Erika K. , Huang Simo , Harding Clifford V. , Lötvall Jan , Liu Huiping 
Published: July 2017

Abstract
Introduction: Therapy resistance and metastasis remain the two biggest challenges of breast cancer that result in a majority of cancer deaths. Cancer stem cells (CSCs) are a subpopulation of cancer cells that can initiate new tumors, remain refractory to conventional therapies, and spread throughout the body. In order to effectively block metastasis, the present study aims to develop novel therapeutics that specifically target breast CSCs and spare normal cells. While nanomedicine represents one of the promising future directions, it is necessary to overcome the shortcomings of synthetic nanoparticles, including bio-instability and off-target toxicity. Here, we aim to bio-engineer the naturally produced cell-secreted small vesicles, exosomes (~100 nm diameter), for a novel therapeutic delivery system.
Methods: Exosomes from the human mesenchymal stem cells (MSCs) were isolated by differential ultracentrifugation, and characterized by multiple approaches including transmission EM, Immunoblotting and immunofluorescence assays to confirm the size, shape and presence of exosomal markers CD63, CD81 and LAMP2B. Exosomes were engineered to express a peptide ligand on its surface to specifically recognize and target CSCs, and the presence of the ligand was confirmed by western blot, flow cytometry (FCM) and a super resolution confocal laser scanning microscopy (CLSM, Leica SP8). The CSC targeting efficiency of the exosomes was evaluated in vitro by FCM and CLSM. Further, the exosomes were loaded with microRNAs (miR-200, miR-30c), as one of the key factors that regulate breast CSC functions, by following a novel transfection technology.
Results: The bio-engineered exosomes specifically target and internalize into the CSCs compared to normal cells with absent expression of the ligand-binding protein. The developed exosomes can effectively deliver candidate miRNAs into the recipient cells and knock down the genes important for functional CSCs. The in vivo targeting of CSCs and therapeutic applications of the exosomes using patient-derived human-in-mouse breast tumor xenograft models are underway.
Conclusion: It is expected that exosome-based miRNA therapeutics will have high biocompatibility, low toxicity, high specificity, and promising efficiency in preclinical and clinical applications to reduce breast cancer metastasis and improve patient survival.
Citation Format: Golam Kibria, Katelyn E. Lee, Erika K. Ramos, Simo Huang, Clifford V. Harding, Jan Lötvall, Huiping Liu. Cancer stem cell targeted exosomes for the treatment of metastatic breast 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 5152. doi:10.1158/1538-7445.AM2017-5152
Abstract 5154: Enhancing tumor blood perfusion using orally active heparin to increase the distribution of anticancer therapeutics inside the tumor tissue
Authors: Choi Jeong Uk , Al-Hilal Taslim A. , Chung Seung Woo , Yun Jisuk , Nam Hwajung , Lee Myungyun , Hwang Jinha , Kim Kyungjin , Byun Youngro , Cho Youngseok , Lee Seong Wook 
Published: July 2017

Abstract
Here, we suggest in the first time that the cancer associated thrombosis(CAT) might be one of the major factor which limit the tumor blood perfusion and drug distribution inside the tumor tissue by reducing the effective radius of blood vessels. In order to prevent CAT and achieve enhanced drug distribution, we developed orally active heparin to be combined with other anti-cancer therapies. We injected dye conjugated fibrinogen and chitosan nanoparticles to mice which were bearing highly thrombotic tumor to visualize CAT and nanoparticle distribution inside the tumor tissue. When CAT is prevented by heparin, we found that nanoparticle distribution and accumulation were significantly enhanced compared to the group not treated with heparin. This results signify that the CAT can limit the tumor perfusion and prevention of CAT can enhance the drug accumulation and distribution. We used highly thrombotic cancer models such as melanoma and pancreatic cancer to evaluate the therapeutic efficacy of the doxorubicin containing nanoparticle and the combination of oxaliplatin and gemcitabine when they are combined with heparin. We have found that when heparin is combined with each therapy, their tumor inhibition efficacy increased about 25% and also confirmed that this synergistic effect comes from enhanced drug distribution inside the tumor tissue by preventing the CAT using anticoagulant. These results were also supported by histological analysis.
We have validated our hypothesis by showing that CAT can limit the tumor perfusion, which in turn brings reduced drug distribution inside the tumor tissue. We also confirmed that our oral heparin could enhance the tumor perfusion and the efficacy of anti-cancer therapeutics by preventing the CAT in the tumor tissue.
Citation Format: Jeong Uk Choi, Taslim A. Al-Hilal, Seung Woo Chung, Jisuk Yun, Hwajung Nam, Myungyun Lee, Jinha Hwang, Kyungjin Kim, Youngro Byun, Youngseok Cho, Seong Wook Lee. Enhancing tumor blood perfusion using orally active heparin to increase the distribution of anticancer therapeutics inside the tumor tissue [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 5154. doi:10.1158/1538-7445.AM2017-5154
Abstract 516: High-throughput functional evaluation of variants of unknown significance in EGFR
Authors: Kohsaka Shinji , Nagano Masaaki , Ueno Toshihide , Suehara Yoshiyuki , Hayashi Takuo , Shimada Naoko , Takahashi Kazuhisa , Suzuki Kenji , Takamochi Kazuya , Takahashi Fumiyuki , Mano Hiroyuki 
Published: July 2017

Abstract
Since transforming mutations in epidermal growth factor receptor gene (EGFR) were first identified in non-small-cell lung carcinoma (NSCLC), advancement of diagnostics for such mutations, and evolution of targeted therapeutics against EGFR has driven unprecedented improvements in the management as well as outcome of patients with this lethal disease. However, next-generation sequencer (NGS)-driven extensive analyses on NSCLC have revealed a large number of variants of uncertain significance (VUS) in EGFR and other regions in the cancer genome that await further investigation. Here we present a mixed all nominated mutants in one (MANO) method to evaluate the transforming potential and drug sensitivity of VUS of oncogenes, and applied this method to 101 non-synonymous EGFR mutants in a high-throughput manner. The sensitivity of individual mutants to tyrosine kinase inhibitors (TKIs) against EGFR was shown diverged, ranging from relatively insensitive mutations such as missense mutations within exon 19 to a highly resistant mutation within exon 21. Our data thus support the importance of examining uncommon mutations within EGFR, and also of functional evaluation of such mutations. Our MANO method may become a novel foundation for in vitro and in vivo assessments of variants of cancer-related genes to deliver precision medicine to individual cancer patients.
Citation Format: Shinji Kohsaka, Masaaki Nagano, Toshihide Ueno, Yoshiyuki Suehara, Takuo Hayashi, Naoko Shimada, Kazuhisa Takahashi, Kenji Suzuki, Kazuya Takamochi, Fumiyuki Takahashi, Hiroyuki Mano. High-throughput functional evaluation of variants of unknown significance in EGFR [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 516. doi:10.1158/1538-7445.AM2017-516
Abstract 5160: Development of REDX05358, a novel highly selective and potent pan RAF inhibitor and a potential therapeutic for BRAF and RAS mutant tumors
Authors: Mason Helen , Scrace Simon , Testar Richard , Rainard Julie , Talab Fatima , Poonawala Ryaka , Smith Philippa , Brooke Harriet , Frith Sarah , Ahmet Jonathan , Hall Jonathan , Sorrell David , Moore Jon , Phillips Caroline , France Dennis , Bingham Matilda , Armer Richard 
Published: July 2017

Abstract
REDX05358 has been identified as a novel, highly selective and potent next generation pan RAF inhibitor with improved therapeutic potential and predicted safety profile. Aberrant signalling via the MAPK pathway is commonly seen in cancer. RAF inhibitors such as Dabrafenib and Vemurafenib have been approved for the treatment of unresectable and metastatic BRAF mutant melanoma, but these agents lack efficacy in BRAF mutant colorectal cancer (CRC), partly because of EGFR-mediated feedback reactivation of the MAPK pathway via CRAF. Furthermore, RAF inhibitor treatment of RAS-mutant, BRAF wildtype melanomas has been associated with other skin cancers, such as cutaneous squamous cell carcinoma due to MAPK pathway paradoxical activation mediated by CRAF. There is therefore a clinical need for novel agents targeting the MAPK pathway that do not have these undesirable properties. Here we present, REDX05358 that demonstrates subnanomolar binding affinity for BRAF and CRAF with high selectivity profile against a panel of 468 kinases that exhibits negligible paradoxical activation due to inhibition of both RAF monomers and dimers. As a result, REDX05358 not only inhibits MAPK signalling in BRAF V600E mutant tumor cells, but also in those harbouring NRAS and KRAS mutations. Furthermore, REDX05358 does not induce feedback reactivation of the pathway through its ability to sustain inhibition of MAPK signalling in CRC cell lines. Correspondingly, profiling of REDX05358 in a panel of CRC, melanoma and NSCLC cell lines shows it has potent anti-proliferative activity in cell lines harbouring BRAF or RAS mutations. REDX05358 is an orally bioavailable, well tolerated small molecule that has demonstrated in vivo efficacy in BRAF V600E CRC xenograft model. In contrast, first generation inhibitors such as Vemarafenib and Dabrafanib have been reported to be ineffective in this genetic background in CRC cell lines and patients. Thus, we have developed a pan RAF inhibitor with unique pharmacological properties enabling it to have utility in treating BRAF and RAS mutant cancers
Citation Format: Helen Mason, Simon Scrace, Richard Testar, Julie Rainard, Fatima Talab, Ryaka Poonawala, Philippa Smith, Harriet Brooke, Sarah Frith, Jonathan Ahmet, Jonathan Hall, David Sorrell, Jon Moore, Caroline Phillips, Dennis France, Matilda Bingham, Richard Armer. Development of REDX05358, a novel highly selective and potent pan RAF inhibitor and a potential therapeutic for BRAF and RAS mutant 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 5160. doi:10.1158/1538-7445.AM2017-5160
Abstract 5163: Characterization of NMS-E194, a selective and potent PERK inhibitor with efficacy in the KMS-11 multiple myeloma
Authors: Perrera Claudia , Pulici Maurizio , Carenzi Davide , Motto Ilaria , Fasolini Marina , Casale Elena , Depaolini Stefania Re , Rizzi Simona , Asa Daniela , Roletto Fulvia , Bindi Simona , Casero Daniele , Banfi Patrizia , Ardini Elena , Amboldi Nadia , Ballinari Dario , Gasparri Fabio , Cribioli Sabrina , Mancini Laura , Ciomei Marina , Donati Daniele , Felder Eduard , Galvani Arturo , Isacchi Antonella , Valsasina Barbara 
Published: July 2017

Abstract
PERK (PKR-like endoplasmic reticulum kinase) is a serine-threonine kinase associated to endoplasmic reticulum membrane. Together with ATF6 and IRE1, PERK is a key effector of the Unfolded Protein Response (UPR), a network of signaling pathways that ensures protein homeostasis in the endoplasmic reticulum. Multiple Myeloma (MM) and other protein-secreting tumors are highly dependent on UPR for survival, and inhibition of PERK may be an effective strategy to inhibit growth of these tumors. Here we describe the in vitro and in vivo properties of NMS-E194, a novel potent and selective ATP-competitive PERK inhibitor belonging to the arylsulfonamide chemical class. NMS-E194 inhibits PERK kinase with a Ki of ca 1.5 nM in biochemical assay and possesses high selectivity towards a panel of 54 kinases. When tested in cell proliferation assays, NMS-E194 is preferentially active on multiple myeloma (MM) and diffuse large B cell lymphoma cell lines. In mechanism of action studies, NMS-E194 shows a bi-phasic behaviour: at low nanomolar doses it activates PERK, causing ATF4 accumulation, while at &gt;200 nM it inhibits PERK and downstream pathway, inducing apoptosis. NMS-E194 possesses a favourable in vitro ADME profile and has promising PK properties in the mouse. NMS-E194 demonstrated strong anti-tumor activity following oral administration at 25 mg/kg daily to mice harbouring luciferized KMS-11 cells in a disseminated growth model of MM, with no overt toxicity. Overall, the data available so far warrant further development of NMS-E194 and support PERK inhibition as a novel therapeutic approach in MM and other PERK-dependent tumors.
Citation Format: Claudia Perrera, Maurizio Pulici, Davide Carenzi, Ilaria Motto, Marina Fasolini, Elena Casale, Stefania Re Depaolini, Simona Rizzi, Daniela Asa, Fulvia Roletto, Simona Bindi, Daniele Casero, Patrizia Banfi, Elena Ardini, Nadia Amboldi, Dario Ballinari, Fabio Gasparri, Sabrina Cribioli, Laura Mancini, Marina Ciomei, Daniele Donati, Eduard Felder, Arturo Galvani, Antonella Isacchi, Barbara Valsasina. Characterization of NMS-E194, a selective and potent PERK inhibitor with efficacy in the KMS-11 multiple myeloma [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 5163. doi:10.1158/1538-7445.AM2017-5163
Abstract 5170: HDAC inhibitors and the mechanism of resistance in colorectal cancer: RAS and MYC - the partners in crime
Authors: Ispasanie Sylvia S. , Boehme Lena , Eilers Martin , Brummer Tilman , Klotz-Noack Kathleen , Kuhn Natalia , Gastl Bastian , Sers Christine 
Published: July 2017

Abstract
Although histone deacetylase inhibitors (HDACi) are considered a promising novel therapeutic approach in the light of their potent tumour-selective effects, the use of these inhibitors for treatment of colorectal cancer (CRC) have thus far demonstrated limited success as a monotherapy. What this eventually boils down to is our incomplete understanding of the molecular mechanisms, the impact of oncogenes, and thus the key pathways through which HDACi affect tumour cell growth. To shed further light on this, the involvement of oncogenic RAS - a key driver of CRC, in determining the responsiveness to HDACi has been explored. By using cell line model systems harbouring conditional oncogenic NRAS, KRAS and HRAS, we uncovered an oncogenic RAS-dependent “safeguard” mechanism imposed in order to evade the cytotoxic effect of HDACi and therefore apoptosis. Characteristically, cells harbouring oncogenic RAS were observed to undergo a reversible senescence-like growth arrest in G2, allowing for re-entry into cell cycle following the withdrawal of HDACi. This mechanism is implemented as a consequence of the direct targeting of RAS by HDAC inhibition, which resulted in a further amplified GTP-binding activity and subsequent signalling through the MAPK pathway. The observed outcome was an increase in the priming of MYC for ubiquitin-mediated proteasomal degradation, thereby enabling the cells to exit the cell cycle and enter the protective state of G2 arrest. This process was functionally reversed with a conditional non-degradable MYC (T58A/S62A), which in turn rendered the cells more susceptible to undergo apoptosis. Conclusively, in the context of a constitutively activating RAS mutation, the prospect of HDACi treatment was effectively improved using current MAPK-targeted therapy by preventing the observed pro-oncogenic effect of the HDACi treatment alone.
Note: This abstract was not presented at the meeting.
Citation Format: Sylvia S. Ispasanie, Lena Boehme, Martin Eilers, Tilman Brummer, Kathleen Klotz-Noack, Natalia Kuhn, Bastian Gastl, Christine Sers. HDAC inhibitors and the mechanism of resistance in colorectal cancer: RAS and MYC - the partners in crime [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 5170. doi:10.1158/1538-7445.AM2017-5170
Abstract 5173: Discovery of a series of benzimidazoles as potent Wnt/β-catenin signaling inhibitors in colorectal cancer cells
Authors: Li Yonghe , Oliver Patsy G. , Lu Wenyan , Pathak Vibha , Augelli-Szafran Corinne E. , Buchsbaum Donald J. , Suto Mark J. 
Published: July 2017

Abstract
Aberrant activation of Wnt/β-catenin signaling is a necessary initiating event in the genesis of most colorectal cancers. Loss-of-function mutations in the tumor suppressor gene adenomatous polyposis coli (APC) are present in about 80% of all colorectal cancers, and gain-of-function mutations in the oncogene CTNNB1 (β-catenin encoding gene) exist in approximately 10% of colorectal cancers. Both APC and CTNNB1 mutations lead to cytosolic accumulation and nuclear translocation of β-catenin, and therefore constitutive activation of β-catenin/TCF4-mediated gene transcription. As such, the Wnt/β-catenin pathway has emerged as one of the most promising targets for colorectal cancer treatment. Despite tremendous efforts in the past decade, there are no small molecule Wnt inhibitors approved by the FDA for cancer treatment. Recent work in our laboratories has identified a series of benzimidazoles as potent Wnt/β-catenin inhibitors. Here, we show that several benzimidazoles displayed strong activities against Wnt/β-catenin signaling in colorectal cancer cells harboring mutations in CTNNB1 or APC. In particular, SRI36324, the lead compound in this series, inhibited Wnt/β-catenin signaling in colorectal cancer HCT116 and DLD-1 cells with IC50 values of 4.1 and 3.7 nM, respectively. Moreover, the benzimidazole compounds exhibited potent activities against colorectal cancer cell proliferation under both standard cell culture conditions (adherent cells in complete medium containing 10% FBS) and conditions designed to enrich for cancer initiating cells. In addition, the benzimidazole compounds had no off-target effects on other pathways (e.g., STAT3 and mTORC1 signaling) in colorectal cancer cells, and were less antiproliferative to non-cancerous cells. Together, our findings indicate that the benzimidazole compounds are promising candidates for development as novel therapeutic agents for colorectal cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Yonghe Li, Patsy G. Oliver, Wenyan Lu, Vibha Pathak, Corinne E. Augelli-Szafran, Donald J. Buchsbaum, Mark J. Suto. Discovery of a series of benzimidazoles as potent Wnt/β-catenin signaling inhibitors in colorectal 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 5173. doi:10.1158/1538-7445.AM2017-5173