bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6377: Curcumin analog GO-Y030 diminishes cancer stem cell population by inhibiting interaction of HSP70 with its substrates
Authors: Suzuki Maya , Yamamoto Yohei , Nishijima Aki , Shibata Hiroyuki , Omori Yasufumi 
Published: September 2020

Abstract
It has been established that a cancer tissue contains, in general, a small subpopulation of cancer stem cells (CSCs) having tumor initiation capacity. Because CSCs are resistant to chemoradiotherapy and play important roles in cancer relapse and metastasis, strategies targeting CSCs are crucial for effective anticancer therapies. Curcumin (diferuloylmethane) isolated from the rhizome of the plant turmeric (Curcuma longa) is one of the most widely characterized phytochemicals and well known to suppress cancer cell proliferation, invasion, angiogenesis, and metastasis by regulating multiple cell signaling pathways. However, its bioavailability is limited due to poor absorption. To improve this disadvantage, Ohori et al. (Mol Cancer Ther 2006;5:2563-71.) synthesized a new curcumin analog GO-Y030 (1,5-bis(3,5-bis(methoxymethoxy)phenyl)-1,4-pentadiene-3-one), which has an about 30-fold greater growth-inhibitory effect than curcumin. In the current study, we verified the potency of GO-Y030 to act against CSC population. We first discovered that GO-Y030 could dose-dependently suppress a sphere-forming ability in human HuH7 hepatocellular carcinoma and human PC3 prostatic carcinoma cell lines. Interestingly, the specific inhibitor of the stress-inducible heat shock protein (HSP) 70 (also called HSP72, HSP70-1, or HSPA1A) exhibited effects similar to GO-Y030, i.e., inhibition of CSC sphere formation and upregulation of HSP70 and HSP40 protein expression. As this result suggested that target molecules of GO-Y030 might be HSP70 and its co-chaperones such as HSP40, we next performed in vitro HSP70/HSP40-mediated refolding activity assay and revealed that GO-Y030 efficiently inhibited HSP70/HSP40 chaperone activity. Finally, performing the substrate-binding assay, we have proven that GO-Y030 reduces the substrate-recognition and binding activity of HSP70. HSPs are molecular chaperones that function to prevent denaturation or unfolding of client proteins when they are threatened by stress or high temperature. Since CSCs by nature adapt to oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress by enhancing synthesis of protein-folding chaperones, the function of HSP70/HSP40 is important for the maintenance of CSC population. Our data suggest that GO-Y030 should impair stress tolerance in CSCs by inhibiting the interaction of HSP70 with substrate proteins and disrupting the function of HSP70/HSP40 and thus should finally contribute to reduction of CSC population.
Citation Format: Maya Suzuki, Yohei Yamamoto, Aki Nishijima, Hiroyuki Shibata, Yasufumi Omori. Curcumin analog GO-Y030 diminishes cancer stem cell population by inhibiting interaction of HSP70 with its substrates [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6377.
Abstract 6383: HTBPI inhibits liver tumorigenesis by combined inhibition of Akt
Authors: Yu Haiyang , Liu Hongwei , Chen Qian , Pang Xu , Yin Shuangshuang , Wang Kailong , Wang Rui , Wang Tao , Qiu Yuling 
Published: September 2020

Abstract
Akt, a crucial protein involved in a variety of signaling pathways in cancer, acts as an important regulator of cell survival in hepatocellular carcinoma (HCC), and provides curative option for the related drug development. We have found an active phenanthroindolizidine alkaloid, (13aR,14R)-9,11,12,13,13a,14-hexahydro-3,6,7- trimethoxydibenzo[f,h]pyrrolo[1,2-b]isoquinolin-14-ol (HTBPI), which is a promising Akt inhibitor effective in the suppression of HCC cells proliferation through stimulating apoptotic and autophagic capability in vivo and in vitro. Treatment of HTBPI combined with a classical autophagy-lysosomal inhibitor (bafilomycin A1), could enhance stimulation effects of apoptosis on HCC cell lines. In addition, we confirmed that HTBPI, targeting Akt, occupied the kinase binding domain (Thr 308) of Akt to inactivate its function by CETSA and DARTS assay. Moreover, HTBPI showed a potential therapeutic effect in patient-derived xenograft (PDX) tumors without observed toxicity. Furthermore, high p-Akt (Thr 308) expression was collated with liver tumor formation and poor survival in HCC patients. In conclusions, HTBPI impeded HCC progress through regulation of apoptosis and autophagy machinery via interaction with p-Akt (Thr 308). This may provide potential molecular candidate by inhibiting Akt for the therapy of HCC patients.
Citation Format: Haiyang Yu, Hongwei Liu, Qian Chen, Xu Pang, Shuangshuang Yin, Kailong Wang, Rui Wang, Tao Wang, Yuling Qiu. HTBPI inhibits liver tumorigenesis by combined inhibition of Akt [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6383.
Abstract 6386: Combined PDE4 and VEGFR2 inhibition as a new preclinical rationale in clear cell renal cell carcinoma
Authors: Cao Minghua , Nawalaniec Karol , Luo Yueming , Moench Romana , Hsiao Li-Li , Waaga-Gasser Ana Maria 
Published: September 2020

Abstract
Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney cancer. Small molecule VEGFR inhibitors are widely used but are not curative and various resistance mechanisms have been described. Previous studies have indicated cross-talk between the cAMP pathway and the MAPK pathway, and the elevation of cAMP levels by inhibition of Phosphodiesterase-4 (PDE4) activities can result in growth arrest and/or cell death. In this study we focused on the effects of PDE4 in ccRCC. We first analyzed the expression of PDE4 in human RCC cell lines and found PDE4D to be dominantly expressed. PDE4D CRISPR Knockout (KO) was then performed on Caki-1 RCC cells and normal renal proximal tubular epithelial cells as control. Cell proliferation, cell cycle cAMP, MAPK plus PI3K/AKT signaling pathways were additionally analyzed to define the effects of PDE4D inhibition. PDE4D KO Caki-1 cells showed decreased cell viability and a higher apoptosis rate compared with wild type controls. Increased intracellular cAMP levels in PDE4D KO resulted in downregulated MAPK but not PI3K/AKT signaling in Caki-1 tumor cells. In addition, PDE4D KO Caki-1 cells demonstrated higher sensitivity to VEGFR inhibitors. To conclude, we provide a new preclinical rationale for dual PDE4/VEGFR2 inhibition in patients with ccRCC. While the MAPK signaling pathway is activated in ccRCC, dual inhibitors may improve the anti-tumor effects in a patient subset with evidence of MAPK involvement. Future work involving in vivo models will be useful to better define efficacy of this dual strategy of anti-tumor activity.
Citation Format: Minghua Cao, Karol Nawalaniec, Yueming Luo, Romana Moench, Li-Li Hsiao, Ana Maria Waaga-Gasser. Combined PDE4 and VEGFR2 inhibition as a new preclinical rationale in clear cell renal cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6386.
Abstract 639: Acute promyelocytic leukemia
Authors: Chale Ravinder Singh , Jimenez Joaquin J. 
Published: September 2020

Abstract
Introduction: Acute Promyelocytic Leukemia (APL) accounts for 10%-15% of all acute myeloid leukemia's. The use of All-Trans Retinoic Acid/ Arsenic trioxide (ATRA/ATO) in the treatment regimens of low to intermediate-risk patients has led to remarkable cure rates (~80%). However, treatment guidelines of high-risk patients (WBC count≥ 10 x 109/L) remain unclear and these patients are at an increased risk of relapse.
Design: Due to ambiguous treatment guidelines for high-risk APL patients as well as limited options for patients with arsenic resistant disease we sought to analyze clinical outcomes in this subset of patients. We conducted a literature search through Pubmed, EBSCO, and JSTOR to identify original articles that evaluated treatment protocols as well as outcomes for high-risk/refractory APL patients. We also evaluated the literature for clinical data involving patients who had arsenic resistant APL. Only relevant articles from 2000 to 2019 were included. Clinical trials where patients did not receive ATRA/ATO treatment were excluded.
High risk patients have an increased mortality and decreased overall survival compared to intermediate and low risk patients. Although early death resulting from bleeding complications remains an important clinical hindrance, cases of arsenic resistant disease are becoming more prevalent. Resistant/refractory APL is a rare occurrence; however, no effective treatment exists to overcome resistance in this subset of patients. Of particular interest is the identification of variant translocations in APL; those that differ from the classical PML-RARA (~95%). 12 non-characteristic rearrangements have so far been described; of these, the ZBTB16-RARA and STAT5b-RARA are the most common variants. Both ZBTB16-RARA & STAT5b-RARA are insensitive to ATRA/ATO combination therapy, leaving these patients with limited options. Clinical outcomes have recently been described in a subset of 13 patients with arsenic resistant disease. Of these 13 patients with arsenic resistant disease, 11 eventually died. Mutations in a particular region of the PML protein have been shown to mediate arsenic resistant disease in both in vitro and in vivo models, suggesting a potential benefit of molecular screening to improve clinical outcomes. Neither ATO nor cytotoxic chemotherapy was successful in inducing remissions in this particular subset of patients.
Conclusion: Well-defined treatment guidelines in high-risk APL and the need for alternative agents in patients resistant to ATO therapy are needed to improve clinical efficacy and outcomes.
1. Zhu, H.H.; Qin, Y.Z.; Huang, X.J. Resistance to arsenic therapy in acute promyelocytic leukemia. N Engl J Med 2014, 370, 1864-1866, doi:10.1056/NEJMc1316382.
Citation Format: Ravinder Singh Chale, Joaquin J. Jimenez. Acute promyelocytic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 639.
Abstract 6393: Targeting the increased endocytosis of Na/K ATPase α1 subunit as a new therapeutic approach to prostate cancer
Authors: Banerjee Moumita , Li Zhichuan , Gao Yingnyu , Huang Minqi , Cai Liquan , Gao Tianyan , Zijian Xie 
Published: September 2020

Abstract
Prostate cancer (PCa) is the second leading cause of cancer-related death in males and there is no effective therapeutics to treat aggressive metastatic PCa (~70% mortality rate). We previously reported that the α1 Na/K-ATPase (α1 NKA), the product of ATP1A1 gene, is a tumor suppressor protein whose expression was significantly reduced in primary tumor and further reduced in the bone metastatic lesions (≤10% of normal tissue). Here we show that loss of cell surface expression of ATP1A1 induces Epithelial Mesenchymal Transition (EMT), and promotes metastatic potential and tumor growth of PCa by decreasing E-cadherin expression and upregulating c-Myc expression via Src-dependent signaling. The progressive loss of α1 NKA in PCa is because of increased endocytosis by activating the α1 NKA/Src receptor complex. Using a unique α1 NKA screening platform, we have discovered MB5, an inverse agonist of receptor α1 NKA that can block ouabain, an agonist-induced signaling and endocytosis of α1 NKA. Functionally, MB5 treatment increased the expression of α1 NKA and E cadherin-which reversed EMT and decreased the invasion and growth of tumor xenografts. Thus, we have revealed a hitherto unrecognized mechanism that regulates the EMT and invasiveness, and identified α1 NKA inverse agonists such as MB5 as a potential drug candidate for the treatment of aggressive PCa.
Citation Format: Moumita Banerjee, Zhichuan Li, Yingnyu Gao, Minqi Huang, Liquan Cai, Tianyan Gao, Xie Zijian. Targeting the increased endocytosis of Na/K ATPase α1 subunit as a new therapeutic approach to prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6393.
Abstract 6394: Combined FLT3 and PARP inhibition induces synthetic lethality in non-small cell lung cancer cells
Authors: Ryu Hwani , Kim Hyo Jeong , Song Jie-Young , Hwang Sang-Gu , Ahn Jiyeon 
Published: September 2020

Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Fms-like receptor tyrosine kinase 3 (FLT3), a member of class III receptor tyrosine kinase, targeted inhibitors have not been well studied in lung cancer including NSCLC. Since recent studies have been reported that FLT3 inhibitors can suppress DNA repair activities, we investigated the antitumor activities of quizartinib, an FLT3 inhibitor, in NSCLC cells to expand the use of FLT3 inhibitors. Quizartinib inhibited the growth of NSCLC cells in a concentration-dependent manner, and induced DNA damage and reactive oxygen species (ROS) generation in A549 and H1299 cells. We found that quizartinib suppressed DNA damage repair genes through the downregulation of STAT5, resulting in the ‘BRCAness' or ‘DNA-PKness' phenotype in A549 and H1299 cells. As quizartinib-induced ‘BRCAness/DNA-PKness' and poly(ADP-ribose) polymerase inhibitors (PARP) inhibition can induce synthetic lethality, combined treatment with quizartinib and olaparib, a PARP inhibitor, showed synergistic inhibitory proliferation and apoptotic cell death in A549 and H1299 cells compared with either drug alone. Taken together, our findings suggest that quizartinib may be a synthetic lethal partner of PARP inhibitors to enhance therapeutic efficacy in NSCLC cells.
Citation Format: Hwani Ryu, Hyo Jeong Kim, Jie-Young Song, Sang-Gu Hwang, Jiyeon Ahn. Combined FLT3 and PARP inhibition induces synthetic lethality in non-small cell lung cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6394.
Abstract 6395: VHL deficiency sensitizes CC-RCC to inhibition of small GTPases by statins
Authors: Razorenova Olga V. , Thompson Jordan M. , Alvarez Alejandro , Singha Monika K. , MW Matthew W. Pavesic , Nguyen Quy H. , Nelson Luke J. , Fruman David A. 
Published: September 2020

Abstract
Clear cell renal cell carcinoma (CC-RCC) type of kidney cancer has limited therapeutic options available for advanced stages. The objective of this study was to investigate statins as potential therapeutics for CC-RCC. Importantly, treatment with statins was found to be synthetically lethal with the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in 90% of CC-RCC driving the disease. Treatment with statins causes a profound cytostatic effect at nanomolar concentrations and becomes cytotoxic at low micromolar concentrations in VHL-deficient CC-RCC. The synthetic lethal effect can be fully rescued by both mevalonate and geranylgeranylpyrophosphate, but not by squalene, indicating that the effect is due to disruption of small GTPase isoprenylation and not the inhibition of cholesterol synthesis. Rho and Rho kinase (ROCK) inhibition by siRNAs, as well as C3-toxin (for Rho) and Y27637 (for ROCK) mimic the statin-mediated synthetic lethality effect, suggesting the involvement of Rho/ROCK pathway in the mechanism. Overactivation of hypoxia-inducible factor signaling resulting from VHL loss is required for statin-mediated toxicity. Since both VHL and ROCK were previously reported to control mitosis fidelity, we show that mitotic catastrophe is one of the mechanisms of action of compounds targeting the Rho/ROCK pathway in VHL-deficient CC-RCC. Finally, statin treatment is able to inhibit both tumor initiation and progression of subcutaneous 786-OT1-based CC-RCC tumors in mice. Thus, statins represent potential therapeutics for the treatment of VHL-deficient CC-RCC.
Citation Format: Olga V. Razorenova, Jordan M. Thompson, Alejandro Alvarez, Monika K. Singha, Matthew W. Pavesic MW, Quy H. Nguyen, Luke J. Nelson, David A. Fruman. VHL deficiency sensitizes CC-RCC to inhibition of small GTPases by statins [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6395.
Abstract 6396: Sarcoma treatment using HSP90 inhibitors in combinatorial synergy with doxorubicin
Authors: Kirkham Matt , Luelling Sarah , Fatema Kaniz , Barrott Jared 
Published: September 2020

Abstract
Synovial sarcoma, a rare muscle cancer, has few targeted therapies, and is most commonly treated using doxorubicin (DOX). Even as a primary treatment agent, successful treatment and remission rates are low, and the significant cardiotoxicity of DOX limits dosage options. Synovial sarcoma, and other sarcomas, have a high expression of HSP90, a protein that acts as a chaperone molecule to stabilize and help fold other proteins within the cellular matrix. Under high stress situations, HSP90 is upregulated and acts to stabilize other more thermally labile proteins, including many oncogenes. Using FDA approved drug panels, it was determined that HSP90 is a suitable target for treatment. We look to use a novel HSP90 inhibitor (HS10) compound, to target the high expression of HSP90 within synovial sarcoma and osteosarcoma in combination with the chemotherapy standard DOX to determine if a synergistic effect is observed. This synergistic effect would allow for an overall decreased dose to induce effective cancer cell targeting, reducing overall systemic toxicity within patients. Our results indicate such synergism does occur between DOX and HS10, at a dosage of 5-25 nM DOX and 1000 nM HS10, reducing cell survival to 37-68%, dependent on cell line. DOX dosage alone reduced cell survival to 74% in the most effective case, with no reduction in the least effective case, at a dose of 100 nM. This dose is four times stronger than the highest DOX synergistic dose. It can be concluded, then, that synergistic combination does exist between DOX and HS10, and dosage of DOX can be reduced with more effective targeting for synovial and osteosarcoma cell lines. Protein expression was evaluated using immunoblotting to isolate protein fractions within the cytoplasm and cell membrane, showing high expression within the cytoplasm. Isolated blood plasma from mice with and without tumors was analyzed through ELISA, showing elevated HSP90 presence in mice with tumors (236.4±190pg) vs mice without tumors (6.5±3.5pg). This confirmation of elevated HSP90 expression within sarcoma patients suggests targeting using HS10 to induce synergy to be a viable approach for advanced sarcoma treatment.
Citation Format: Matt Kirkham, Sarah Luelling, Kaniz Fatema, Jared Barrott. Sarcoma treatment using HSP90 inhibitors in combinatorial synergy with doxorubicin [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6396.
Abstract 6407: A live cell method to assess E3 ligase and target protein occupancy for PROTACs
Authors: Vasta James , Corona Cesear , Wilkinson Jennifer , Ingold Morgan R. , Zimprich Chad , Schwinn Marie , Machleidt Thomas , Hartnett Jim , Cong Mei , Fan Frank , Somberg Richard L. , Robers Matthew 
Published: September 2020

Abstract
Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that hijack ubiquitin E3 ligases and induce degradation of intracellular proteins through a tightly regulated proteosomal mechanism. Although several successful PROTACs have been developed against key intracellular target classes including bromodomains, kinases, and nuclear hormone receptors, these bivalent molecules often suffer from poor cell permeability due to high molecular weight. To enable a high-throughput, quantitative readout for PROTAC permeability and E3 ligase occupancy in living cells, we have developed a panel of target engagement (TE) assays for key E3 ligase including CRBN, VHL, XIAP, cIAP, and MDM2. These intracellular assays are the first biophysical method to enable the quantitative determination of compound occupancy, potency, and residence time for specific target proteins inside living cells. The assays provide a direct measure of compound binding or occupancy to a target under physiological conditions using bioluminescent resonance energy transfer (BRET).
Citation Format: James Vasta, Cesear Corona, Jennifer Wilkinson, Morgan R. Ingold, Chad Zimprich, Marie Schwinn, Thomas Machleidt, Jim Hartnett, Mei Cong, Frank Fan, Richard L. Somberg, Matthew Robers. A live cell method to assess E3 ligase and target protein occupancy for PROTACs [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6407.
Abstract 6408: E3scan™ ligand binding assay platform for targeted protein degradation and PROTAC discovery
Authors: Katsenelson Ksenya Cohen , Gonzalez Luis , Pallares Gabriel , King Alastair J. , Treiber Daniel K. 
Published: September 2020

Abstract
E3 ligases have emerged as pivotal targets for a next generation protein degradation-based drug discovery paradigm. This new paradigm includes both ligand binding-directed “reprogramming” of E3 substrate specificity approaches and a more directed approach, using small molecule proteolysis-targeting chimeras (PROTACs), to selectively degrade disease-driving proteins. As there are hundreds of diverse putative E3 ligases with differentiated tissue expression, this new paradigm may well define a next dimension of precision medicine defined by an axis of tissue-specific activity. While there have been some early successes, the E3 drug discovery field has a significant unmet need for a standardized biochemical ligand binding assay platform. A platform is required that: 1) Can measure ligand binding across the E3 family using a standardized method enabling “apples to apples” comparisons; 2), Is highly scalable and rapid; 3) Has an exquisite dynamic range for the measurement of accurate KD values as low as digit picomolar (pM). Eurofins DiscoverX herein presents its novel E3scan™ technology that addresses each of these unmet needs. E3scan, based upon well-established KINOMEscan® technology, has been successfully applied to diverse E3 ligases, including CRBN, VHL, MDM2, MDMX, cIAP1, cIAP2, and XIAP, with many other E3 assays in progress. We shall present assay validation data for these targets, including data for ligands with KD values in the low to mid pM range. In conclusion, we present Eurofins DiscoverX's novel E3scan platform that shall enable accelerated screening and SAR analysis in the E3 drug discovery field, with rapid turnaround times for discovery library screens (20 business day TAT) and weekly SAR (5 business day TAT) and the largest assay panel available on a single technology platform.
Citation Format: Ksenya Cohen Katsenelson, Luis Gonzalez, Gabriel Pallares, Alastair J. King, Daniel K. Treiber. E3scan™ ligand binding assay platform for targeted protein degradation and PROTAC discovery [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6408.