bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 107: Mechanism of anticancer activity of BPS-001 (lyophilized leech saliva extract)
Authors: Ammar Amr , Guns Emma , Kucuk Omer , Abdualkader Abdualrahman , Alaama Mohamed , Uddin A.B.M. Helal , Ghawi Abbas , Hassona Mohamed 
Published: July 2017

Abstract
Recent studies, investigating the composition and therapeutic potential of leech saliva have identified many peptides and proteins with multiple therapeutic properties including anti-thrombotic, antimicrobial and anti-metastatic. In vitro anti-cancer effects were shown in breast, prostate and lung cells lines. In vivo anticancer activity of the extract was shown in multiple breast and prostate cancer xenografts studied by our lab. In our previous studies, BPS-001 was non-toxic and demonstrated various activities including pro-apoptotic properties, inhibition of cellular adhesion, angiogenesis and downregulation of AR expression. To investigate the affected pathways, mechanistic studies were carried out using in vivo and in vitro treated samples. Protein expression in samples was determined by Western blotting of in vitro and in vivo samples. AR expression was measured using an eGFP reporter assay in LNCaP cells, with PSA also measured in the media using cobas e 411 analyzer. BPS-001 inhibited Proteinase Activated Receptor 1 (PAR-1) which is responsible for hormone like cellular signals in different cancer cells including those of the breast and prostate. Moreover, in LNCaP cells AR activation and PSA expression were significantly inhibited after treatment with BPS-001. Inhibition of PI3K and PLCG2 were also observed. It has been found that BPS-001 modulates a plethora of pathways which makes it a very promising candidate for treatment of cancer with an important advantage of low toxicity and potential resistance.
Citation Format: Amr Ammar, Emma Guns, Omer Kucuk, Abdualrahman Abdualkader, Mohamed Alaama, A.B.M. Helal Uddin, Abbas Ghawi, Mohamed Hassona. Mechanism of anticancer activity of BPS-001 (lyophilized leech saliva extract) [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 107. doi:10.1158/1538-7445.AM2017-107
Abstract 1084: Combination of eribulin and AURKA inhibitor prevents metastatic colonization and eradicates established metastases in breast cancer
Authors: Pugacheva Elena N. , Kozyreva Varvara , Kiseleva Anna , Ice Ryan , Jones Brandon , Loskutov Yuriy 
Published: July 2017

Abstract
The majority of cancer-related deaths (90%) are happened due to metastasis from the primary tumor site to distant organs. MLN8237 is a small, highly selective molecule inhibitor of Aurora A kinase (AURKA), which results in disruption of the mitotic spindle, chromosome segregation collapse, and inhibition of cell proliferation. Numerous studies have showed that levels of AURKA are elevated in many types of cancer, including breast cancer. Our previous studies indicated that MLN8237 is extremely potent against pulmonary metastasis, but not the primary tumor in orthotropic xenograft model. To further enhance MLN8237 based regiment, its combination with other therapeutic compounds can be used. As a potential partner we chose eribulin - fully synthetic macrocyclic analogue of the marine natural product halichondrin B. Eribulin belong to the class of non-taxane microtubule destabilizing molecules, currently used in clinic to treat taxol resistant metastatic breast cancer. In present study we have investigated the effect of MLN8237 and eribulin against breast cancer in vivo and in vitro. The results showed that combination of drugs possess a synergistic effect on both primary tumor and metastases, through inducing cytotoxic autophagy and apoptosis. This data clearly indicate great potential behind the MLN8237 based therapies and introduce a new hope for the eradication of metastatic breast cancer.
Citation Format: Elena N. Pugacheva, Varvara Kozyreva, Anna Kiseleva, Ryan Ice, Brandon Jones, Yuriy Loskutov. Combination of eribulin and AURKA inhibitor prevents metastatic colonization and eradicates established metastases in 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 1084. doi:10.1158/1538-7445.AM2017-1084
Abstract 1092: PF562271, a Pyk2 inhibitor, reduces glioma tumor growth and invasion in C57Bl6-Gl261 mouse glioma model
Authors: Ortiz-Rivera Jescelica , Rolón-Reyes Kimberleve , Albors Alejandro , Cubano Luis , Kucheryavykh Lilia 
Published: July 2017

Abstract
Glioblastoma is an extraordinarily aggressive type of brain cancer due to its invasive and proliferative nature. The tumor microenvironment, with microglia as a critical player, has an important role in tumor progression. Microglia infiltrate majority of gliomas and release factors, which favor tumor growth and invasion. Previously we demonstrated that microglia residing within the tumor stimulate glioma cell invasion through the proline rich tyrosine kinase 2 (Pyk2) signaling cascade. We hypothesize that the use of pharmacological inhibitors of Pyk2 together with currently applied chemotherapy can significantly reduce invasiveness of glioblastoma tumor and improve the outcome of the treatment. Using C57Bl/6-Gl261 mouse glioma implantation model we investigated the effect of the combined treatment for glioblastoma with temozolomide (TMZ, 50 mg/kg, once/day, orally) together with a Pyk2 inhibitor PF562271 (twice/daily, 25 mg/kg, orally) vs. TMZ monotherapy. Treatment was provided during 14 days, beginning the 5th day after glioma implantation. For the assessment of the effectiveness of treatment animals’ survival, tumor size, and invasion area were evaluated. Western blot were used for the evaluation of the level of Pyk2 phosphorylation in tumor cells. For the purification of glioma cells from total tumor tissue Percol gradients were used. The study revealed that treatment with PF562271 reduced invasion of glioma cells at the tumor edge, while TMZ reduced the tumor growth. Combined treatment showed significantly more prominent effect on reduction of tumors growth compared to TMZ monotherapy and additionally reduced invasiveness of tumors similar to PF562271 monotherapy. In both PF562271 monotherapy and combined treatments the downregulation of Pyk2 phosphorylation in glioma cells has been recorded. Survival analysis demonstrated a significance increase of survival of animals received combined treatment compare to TMZ monotherapy. In conclusion, we can state that combined treatment with TMZ together with PF562271 reduced Pyk2-related tumor growth and invasiveness and increased animal survival. This research was made possible by NIH grant numbers: 1SC2GM102040, G12MD007583, R25GM110513, Puerto Rico Science, Technology, and Research Trust grant number 2016-00157, and US Department of Education Grant number P031S130068.
Citation Format: Jescelica Ortiz-Rivera, Kimberleve Rolón-Reyes, Alejandro Albors, Luis Cubano, Lilia Kucheryavykh. PF562271, a Pyk2 inhibitor, reduces glioma tumor growth and invasion in C57Bl6-Gl261 mouse glioma model [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 1092. doi:10.1158/1538-7445.AM2017-1092
Abstract 1094: Combining the pan-FGFR inhibitor AZD4547 with radiation in lung and head and neck squamous cell carcinoma
Authors: Baschnagel Andrew M. , Li Chunrong , Morgan Alecia M. , Brennan Sean R. , Russo Kalley A. , Harari Paul M. 
Published: July 2017

Abstract
The fibroblast growth factor receptors (FGFR1, FGR2, FRG3, FGR4) are frequently altered or overexpressed in both lung and head and neck squamous cell carcinomas (SCC). Amplification of FGFR1 has been reported to be as high as 22% in lung SCC and 17% in head and neck SCC (HNSCC). FGFRs have been identified as a potential therapeutic target in lung and head and neck cancers. In addition, FGFRs activate multiple pathways involved in the radiation response including RAS/RAF/MAPK, PI3K/AKT and STAT. AZD4547 is a potent and selective tyrosine kinase inhibitor of the FGFR family and is currently being investigated in clinical trials. Since a substantial portion of lung cancer and HNSCC patients are treated with radiotherapy, we examined the anti-tumor effects of AZD4547 in combination with radiation in both lung and head and neck cancer model systems. FGFR protein and RNA expression and cell proliferation with AZD4547 were evaluated in 8 lung and 8 head and neck cancer cell lines. Clonogenic survival assays were performed on 4 lung and 4 head and neck cancer cell lines and xenograft experiments were performed on one HNSCC cell line. These cell lines demonstrated varying levels of FGFR1, 2 and 3 protein and RNA expression. The half maximal inhibitory concentration (IC50) of AZD4547 in these cell lines ranged from 0.05 to 128 uM. Sensitivity to AZD4547 did not correlate directly with protein or RNA expression. In vitro clonogenic survival assays showed limited effects of combining AZD4547 with radiation. However, significant tumor growth delay was observed with the combination of radiation and AZD4547 compared to radiation or drug alone in the SCC1483 FGFR2 expressing HNSCC xenograft model. These findings suggest that AZD4547 can augment the response of radiation in an in vivo model system. Further studies are underway to test these findings in additional cell lines including FGFR dependent amplified cancer cell lines.
Citation Format: Andrew M. Baschnagel, Chunrong Li, Alecia M. Morgan, Sean R. Brennan, Kalley A. Russo, Paul M. Harari. Combining the pan-FGFR inhibitor AZD4547 with radiation in lung and head and neck squamous cell carcinoma [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 1094. doi:10.1158/1538-7445.AM2017-1094
Abstract 1097: Enhancing the efficacy of Temozolomide with Biochanin A: Mechanistic and metabolic effects
Authors: Desai Vilas , Jain Aditi , Perepelyuk Maryna , Chhun Annie , Farrell Christopher , Lai James C. K. , Bhushan Alok 
Published: July 2017

Abstract
Enhancing the efficacy of Temozolomide with Biochanin A: Mechanistic and Metabolic effects
Glioblastoma multiforme (GBM) is the most frequent, primary malignant brain tumor prevalent in humans. GBM is characterized by aggressive cell proliferation and rapid invasion of normal brain tissue resulting in poor patient prognosis. Furthermore, the current standard therapy of surgical resection followed by radiotherapy and chemotherapy with Temozolomide is not very effective. The inefficacy of the currently available chemotherapeutic agents for GBM can be attributed to the challenges of drug delivery to the tumor. Our laboratory has previously reported the anticancer potential of isoflavones like Biochanin A against oral, pancreatic, breast and brain cancers. In this study, we tested our hypothesis that, Biochanin A sensitizes the GBM cells to Temozolomide, thereby increasing its efficacy in combination treatment. We used the MTT assay to determine the effects of Biochanin A alone and in combination with Temozolomide on survival of U-87 MG cells. Furthermore, two different nanoformulations of Single Walled Carbon Nanotubes (SWCNTs) functionalized with Biochanin A and Atorvastatin and SWCNTs functionalized with Temozolomide were synthesized and their effects on cell viability of U-87 MG glioblastoma cells tested. The cell viability results indicate a decrease in cell proliferation with the combination treatment as compared to the individual drug treatment. Similarly, the flow cytometry analysis showed an increased induction of apoptosis with combination treatment as compared to the drugs alone. Western-blot analysis and Immunofluorescence imaging methods were used to elucidate some of the cell survival/proliferation mechanisms involving EGFR, p-AKT, MMP-2, MT-MMP1. The effects of the drugs on U-87 MG cell metabolism (parameters like ECAR & OCR) studied using Seahorse XFp analyser, suggest an increase in the mitochondrial respiration. Our results provide support for our hypothesis and the data shows that it may have implications in increasing the efficacy of the conventional treatments for GBM. These results will potentially aid in designing new therapies that can improve the outcome of GBM.
Citation Format: Vilas Desai, Aditi Jain, Maryna Perepelyuk, Annie Chhun, Christopher Farrell, James C. K. Lai, Alok Bhushan. Enhancing the efficacy of Temozolomide with Biochanin A: Mechanistic and metabolic effects [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 1097. doi:10.1158/1538-7445.AM2017-1097
Abstract 11: The oncolytic peptide LTX-315 enhances T cell clonality and induces synergy with chemotherapy
Authors: Camilio Ketil André , Wang Meng Yu , Nestvold Janne , Mælandsmo Gunhild , Sveinbjørnsson Baldur , Rekdal Øystein 
Published: July 2017

Abstract
LTX-315, a novel oncolytic peptide is effective against both drug-resistant and drug-sensitive cancer cells with lower toxicity towards normal cells. Intratumoral treatment with LTX-315 results in growth inhibition, complete regression and long lasting tumor-specific immune responses.
The oncolytic effect of LTX-315 involves perturbation of the plasma membrane and distortion of intracellular organelles including the mitochondria with subsequent release of Damage-Associated Molecular Pattern molecules (DAMPs) such as ATP, cytochrome c and HMGB1. LTX-315 effectively induces necrosis within the tumor followed by the release of tumor antigens as demonstrated by a greater increase in tumor infiltrating CD8+ T cells, expansion of T cell clonality, and number of clones within the tumor microenvironment.
LTX-315`s ability to modify the tumor microenvironment makes it ideal as a combination partner for other cancer therapies, including chemotherapy and immune checkpoint inhibitors.
In preclinical tumor models, combination of LTX-315 and chemotherapeutic agents such as cyclophosphamide and doxorubicin demonstrates significant synergy.
Citation Format: Ketil André Camilio, Meng Yu Wang, Janne Nestvold, Gunhild Mælandsmo, Baldur Sveinbjørnsson, Øystein Rekdal. The oncolytic peptide LTX-315 enhances T cell clonality and induces synergy with chemotherapy [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 11. doi:10.1158/1538-7445.AM2017-11
Abstract 110: Quantitative high throughput screening as a tool to identify novel therapies in bladder cancer
Authors: Railkar Reema , Sanford Thomas , Krane L. Spencer , Agarwal Piyush K. 
Published: July 2017

Abstract
Introduction: Bladder cancer (CaB) is the 4th most common cancer among men in the US. It is the most expensive malignancies to treat from diagnosis to death. No new pharmacological agents have been approved for treatment of bladder cancer since the approval of BCG in 1990. Thus, there is an urgent need for development of new treatment therapies. Quantitative high throughput screening (qHTS) of representative cancer lines with oncology drugs may identify new treatments or re-purpose already existing therapies for different disease. We utilized this technique to identify new therapies in two primary bladder lines (T24 and UMUC3) and their metastatic lines (T24T, SLT3 and FL3 of T24 and LUL-2 for UMUC3).
Methods: We screened 7 bladder cancer cell lines against 1,912 oncology drugs using a 48 hour cell proliferation assay with an ATP−based readout (CellTiterGlo) to determine activity and potency of compounds in a dose response manner. One of the candidate drugs inhibitory in all cell lines tested is flavopiridol, a pan CDK inhibitor. We further characterized the mechanism of action and in vivo effects of flavopiridol using various cell based assays and mouse xenograft studies.
Results: The initial screen identified 95 compounds active in 7 cell lines. The top 50 compounds were further analyzed for molecular size of &gt;200 g/mol and TPSA&lt;90. This identified mitomycin C and 8 novel compounds. Further testing revealed Flavopiridol to be most consistent with qHTS data having IC50 of 100-300nM in all the cell lines tested. Flavopiridol induces G2/M arrest; however, very little apoptosis was seen suggesting cytostatic rather than cytotoxic mechanism of flavopiridol action. Flavopiridol showed dose dependent inhibition of migration, invasion and colony formation in CaB cell lines tested. Xenograft studies in rapidly growing UMUC-3 cells showed slowing of tumor growth but not complete reduction indicating cytostatic mechanism of flavopiridol. However, in slow growing cells, 5637, 5/8 treated mice showed complete tumor reduction.
Conclusions: qHTS can identify novel compounds. Flavopiridol seems to be a very effective inhibitor both in vitro and in vivo. Physical properties of Flavopiridol are most suited for intravesical use which may lead to it being an effective inhibitor of CaB in the bladder at higher doses without any/few systemic toxicities. Studies are underway to elucidate the use of flavopiridol as a single intravesical agent.
Citation Format: Reema Railkar, Thomas Sanford, L. Spencer Krane, Piyush K. Agarwal. Quantitative high throughput screening as a tool to identify novel therapies in bladder 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 110. doi:10.1158/1538-7445.AM2017-110
Abstract 1102: Anti-tumor effects of imipridone ONC201 in combination with anti-angiogenic agents significantly impact on colorectal cancer growth in vivo
Authors: Wagner Jessica , El-Deiry Wafik 
Published: July 2017

Abstract
Small molecule imipridone ONC201 is an investigational anti-tumor agent with a wide therapeutic index and broad-spectrum efficacy in vivo. ONC201 upregulates intratumoral TRAIL expression and the integrated stress response pathway. A Phase I clinical trial using ONC201 as therapy in advanced cancer patients has been completed and the drug has progressed into several Phase II trials in multiple cancer types. Colorectal cancer (CRC) remains one of the leading causes of cancer worldwide and metastatic disease continues to have a poor prognosis. Clinical trials in CRC and other tumor types have demonstrated that therapeutics targeting the vascular endothelial growth factor (VEGF) pathway, such as bevacizumab, are effective in combination with certain chemotherapeutic agents. Bevacizumab is a humanized monoclonal antibody that targets VEGF and is an FDA-approved treatment for advanced CRC patients, in addition to other tumor types. We are investigating the potential combination of VEGF inhibitors such as bevacizumab and ONC201 in both CRC xenograft and patient-derived xenograft (PDX) studies. Our results demonstrate significant tumor regression and occasional tumor ablation in human xenografts with the combination of ONC201 with bevacizumab, and in syngeneic MC-38 colorectal cancer xenografts using a murine VEGF-A inhibitor. Non-invasive angiogenesis imaging demonstrated the impact of this combination on decreasing tumor growth and tumor metastasis. With the use of both a murine VEGF inhibitor in syngeneic models, and bevacuzimab in human cell line-derived xenografts, we have demonstrated that combining anti-angiogenic therapies with ONC201 could enhance antitumor efficacy. Thus, ONC201 in combination with anti-angiogenic therapies such as bevacizumab represents a promising combinatorial approach that may be exploited in the clinic for the treatment of CRC.
Citation Format: Jessica Wagner, Wafik El-Deiry. Anti-tumor effects of imipridone ONC201 in combination with anti-angiogenic agents significantly impact on colorectal cancer growth in vivo [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 1102. doi:10.1158/1538-7445.AM2017-1102
Abstract 1113: Inhibition of DNA repair by NR1D1 enhances chemosensitivity of breast cancer cells
Authors: Ka Na-Lee , Na Tae-Young , Na Hyelin , Lee Mi-Ock 
Published: July 2017

Abstract
Most chemotherapeutic agents exert cytotoxic effects by inducing excessive DNA lesions in cancer cells. Therefore, regulating DNA repair networks is a critical factor that determines sensitivity of cancer cells to chemotherapeutic drugs. In this study, we identified the role of nuclear receptor NR1D1 in DNA repair, which enhanced chemosensitivity in breast cancer cells. NR1D1 inhibited recruitment of the DNA repair complex to damaged DNA sites, thereby impaired proper DNA repair upon doxorubicin treatment in breast cancer cells. Interaction with Poly(ADP-ribose) polymerase-1 and subsequent PARylation were critical steps that allow NR1D1 to translocate to DNA double-strand breaks. In agreement, depletion of NR1D1 in MCF-7 cells resulted in resistance to a chemotherapeutic drug, doxorubicin, in both in vitro and in vivo experiments. Further, NR1D1 expression level was correlated positively with clinical outcomes in breast cancer patients who received chemotherapy. Thus, NR1D1 and its ligands may provide better therapeutic options that could enhance the outcomes of adjuvant chemotherapy in breast cancer patients.
Citation Format: Na-Lee Ka, Tae-Young Na, Hyelin Na, Mi-Ock Lee. Inhibition of DNA repair by NR1D1 enhances chemosensitivity of breast 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 1113. doi:10.1158/1538-7445.AM2017-1113