Pub Date : 2019-07-01DOI: 10.1158/1538-7445.SABCS18-3621
M. R. Jajja, Lei Zhu, Dazhi Wang, C. Staley, B. El-Rayes, D. Kooby, Lily Yang
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Pub Date : 2019-07-01DOI: 10.1158/1538-7445.AM2019-983
C. Neumann, K. Olivas, K. Wang, A. Waight, David W Meyer, Luke V Loftus, Margo Zaval, Martha E. Anderson, Steven Jin, Julia H Cochran, J. Simmons, Paul G Pittman, Fu Li, Michelle Ulrich, Abbie Wong, Weiping Zeng, R. Lyon, P. Senter
Nicotinamide phosphoribosyltransferase (NAMPT) regulates the biosynthesis of NAD from nicotinamide via a salvage biosynthetic pathway. Inhibition of NAMPT depletes cellular NAD levels leading to disruption of energy metabolism and cell death. Non-targeted small molecule NAMPT inhibitors have demonstrated poor tolerability in clinical trials and in preclinical models, including cardiac and retinal toxicities in rats. In an effort to improve the therapeutic window of this drug class, we pursued a targeted-delivery approach using antibody-drug conjugates. Through a medicinal chemistry effort, we identified novel NAMPT inhibitors that incorporate chemical functionality in the solvent-exposed terminus to allow construction of enzyme-cleavable drug linkers. Additionally, we applied a pyridinium-based linker strategy that allows for traceless linker attachment through a conserved nicotinamide-mimetic moiety of NAMPT inhibitors. Candidate molecules were evaluated for NAMPT binding affinity and cellular cytotoxicity as free drugs, and for cellular cytotoxicity as ADCs with the alternate linker strategies. Comparisons across inhibitors and linker strategies provide insight into optimal design of cleavable drug linkers for this class of drugs. In vitro, the ADCs deplete NAD and lead to downstream ATP depletion in a time-dependent manner. In vivo evaluation using human tumor xenografts shows translation of the pharmacodynamic effect resulting in tumor regression in models of Hodgkin lymphoma, non-Hodgkin lymphoma, and acute myeloid leukemia. Toxicology studies in Sprague Dawley rats demonstrate excellent tolerability at active doses, with no observable cardiac or retinal toxicities at the highest tested doses in single- and multi-dose regimens. These findings detail the development of a novel payload class and optimized linker strategy for use with antibody-drug conjugates, and demonstrate a preclinical efficacy and safety profile to support continued efforts toward clinical therapeutics. Citation Format: Chris Neumann, Kathleen C. Olivas, Kung Pern Wang, Andrew B. Waight, David W. Meyer, Luke V. Loftus, Margo C. Zaval, Martha E. Anderson, Steven Jin, Julia H. Cochran, Jessica K. Simmons, Paul G. Pittman, Fu Li, Michelle L. Ulrich, Abbie Wong, Weiping Zeng, Robert P. Lyon, Peter D. Senter. Antibody-drug conjugates of NAMPT inhibitors: Discovery, optimization, and preclinical characterization [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 983.
烟酰胺磷酸核糖基转移酶(NAMPT)通过补救性生物合成途径调节烟酰胺NAD的生物合成。抑制NAMPT会耗尽细胞NAD水平，导致能量代谢中断和细胞死亡。非靶向小分子NAMPT抑制剂在临床试验和临床前模型中表现出较差的耐受性，包括大鼠的心脏和视网膜毒性。为了改善这类药物的治疗窗口期，我们采用了一种使用抗体-药物偶联物的靶向递送方法。通过药物化学的努力，我们发现了新的NAMPT抑制剂，在溶剂暴露的末端结合化学功能，允许构建酶可切割的药物连接物。此外，我们应用了基于吡啶的连接策略，该策略允许通过NAMPT抑制剂的保守的烟酰胺模拟部分进行无迹连接。候选分子作为游离药物评估了NAMPT结合亲和力和细胞毒性，以及作为adc使用替代连接策略评估了细胞毒性。跨抑制剂和连接策略的比较为这类药物的可切割药物连接的最佳设计提供了见解。在体外，adc以时间依赖性的方式消耗NAD并导致下游ATP消耗。使用人类肿瘤异种移植物的体内评估显示，在霍奇金淋巴瘤、非霍奇金淋巴瘤和急性髓性白血病模型中，药效学效应的翻译导致肿瘤消退。在Sprague Dawley大鼠中进行的毒理学研究表明，在活性剂量下具有良好的耐受性，在单剂量和多剂量方案的最高测试剂量下，没有观察到心脏或视网膜毒性。这些发现详细介绍了一种新的有效载荷类别和优化的抗体-药物偶联物连接策略的发展，并证明了临床前的有效性和安全性，以支持临床治疗的持续努力。引文格式:Chris Neumann, Kathleen C. Olivas, Kung Pern Wang, Andrew B. Waight, David W. Meyer, Luke V. Loftus, Margo C. Zaval, Martha E. Anderson, Steven Jin, Julia H. Cochran, Jessica K. Simmons, Paul G. Pittman，傅莉，Michelle L. Ulrich, Abbie Wong，曾卫平，Robert P. Lyon, Peter D. Senter。NAMPT抑制剂的抗体-药物偶联物:发现、优化和临床前表征[摘要]。摘自:2019年美国癌症研究协会年会论文集;2019年3月29日至4月3日;亚特兰大,乔治亚州。费城(PA): AACR;癌症杂志，2019;79(13增刊):摘要第983期。
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Pub Date : 2019-07-01DOI: 10.1158/1538-7445.AM2019-988
S. Punganuru, H. Madala, Viswanath Arutla, K. Srivenugopal
Doxorubicin (DOX) an anthracycline is a leading anticancer drug with a broad spectrum of activity against numerous solid and hematologic malignancies. However, its clinical application is limited by lower efficacy, severe cardiotoxicity and occurrence of secondary malignancies. There is an urgent need for eliminating the Dox adverse effects while retaining its anticancer efficacy. One of the major goals of cancer therapy is the selective targeting of malignancies over normal tissues. One way to avoid these severe adverse reactions is to develop tumor-targeted prodrugs that are converted to active antitumor drugs at tumor sites in the presence of enzymes that are overexpressed human cancers. Among these, the histone deacetylases (HDACs) and cathepsin L (CTSL) are highly expressed in cancer cells and are considered as potential cancer-specific targets. HDACs are critical enzymes involved in the regulation of histone and non-histone proteins and elevated HDACs in tumor cells are known to be closely associated with tumor initiation, progression, and metastasis. Similarly, the lysosomal cysteine protease CTSL plays key roles at multiple stages of tumor progression and metastasis. In the present study, we developed a new prodrug by coupling an acetylated lysine group to doxorubicin (Lys(Ac)-Dox), a masked cytotoxic agent, which is consecutively activated by HDACs and a CTSL to liberate doxorubicin. We first verified whether Lys(Ac)-Dox could be specifically cleaved by HDACs and CTSL in vitro. The results showed that after incubating with HDACs and CTSL at 37 °C for 20 h, the hydrolysis of Lys(Ac)-Dox reached 99%, suggesting that Lys(Ac)-Dox could be successfully cleaved by the target enzymes. To prove that the Lys(Ac)-Dox would have a much improved growth-inhibitory effect against cancer cells, the cytotoxicity of free DOX and Lys(Ac)-Dox against lung cancer cell lines normal human lung epithelial cell line was determined. The dose-response curves obtained from the cell lines tested indicated that Dox was equally cytotoxic against both cancer and normal cells. In contrast, Lys(Ac)-Dox highly cytotoxic against cancer cells and non-toxic to the normal counterparts. To measure the in vivo anticancer efficacy of Lys(Ac)-Dox vis-vis Dox, we developed subcutaneous xenografts by injecting human lung cancer A549 and H460 cells in nude mice. Lys (Ac)-Dox and Dox were administered daily i.p. at 5 mg/kg. The prodrug showed a significantly higher (>2-fold) tumor regression than Dox. A diminished circulating reticulocyte counts from whole blood after Dox treatment is known to reflect the hematological toxicity caused by the drug. Only Dox caused significant reticulocyte ablation while the prodrug did not, validating our drug design. Biochemical tests involving topo II inhibition and ROS production by the prodrug are in progress (supported by CPRIT grant RP 170207 to KSS). Note: This abstract was not presented at the meeting. Citation Format: Surendra R. Punganuru,
多柔比星(DOX)是一种蒽环类药物，是一种领先的抗癌药物，对许多实体和血液恶性肿瘤具有广泛的活性。但其疗效低、心脏毒性大、易发生继发性恶性肿瘤，限制了其临床应用。目前迫切需要在保持其抗癌作用的同时消除其不良反应。癌症治疗的主要目标之一是选择性地靶向恶性肿瘤而不是正常组织。避免这些严重不良反应的一种方法是开发靶向肿瘤的前药，这些前药在肿瘤部位转化为活性抗肿瘤药物，存在过度表达的人类癌症酶。其中，组蛋白去乙酰化酶(hdac)和组织蛋白酶L (CTSL)在癌细胞中高度表达，被认为是潜在的癌症特异性靶点。hdac是参与组蛋白和非组蛋白调控的关键酶，已知肿瘤细胞中hdac的升高与肿瘤的发生、进展和转移密切相关。同样，溶酶体半胱氨酸蛋白酶CTSL在肿瘤进展和转移的多个阶段起着关键作用。在本研究中，我们开发了一种新的前药，将乙酰化赖氨酸基团偶联到阿霉素上(Lys(Ac)-Dox)，这是一种被hdac和CTSL连续激活的细胞毒性药物，释放阿霉素。我们首先在体外验证了hdac和CTSL是否能特异性切割Lys(Ac)-Dox。结果表明，与hdac和CTSL在37℃下孵育20 h后，Lys(Ac)-Dox的水解率达到99%，表明目标酶可以成功裂解Lys(Ac)-Dox。为了证明Lys(Ac)-Dox对癌细胞具有较强的生长抑制作用，我们测定了游离DOX和Lys(Ac)-Dox对肺癌细胞系正常人肺上皮细胞系的细胞毒性。从细胞系测试得到的剂量-反应曲线表明，Dox对癌细胞和正常细胞具有相同的细胞毒性。相比之下，Lys(Ac)-Dox对癌细胞具有高度的细胞毒性，对正常细胞无毒。为了检测Lys(Ac)-Dox对Dox的体内抗癌作用，我们在裸鼠身上皮下注射人肺癌细胞A549和H460，建立了异种移植物。Lys (Ac)-Dox和Dox以5 mg/kg的剂量每日ig给药。前药的肿瘤消退明显高于Dox(>2倍)。阿霉素治疗后全血循环网状细胞计数减少反映了药物引起的血液学毒性。只有阿霉素引起明显的网状细胞消融，而前药没有，验证了我们的药物设计。包括topo II抑制和前药ROS产生的生化测试正在进行中(由CPRIT授予KSS RP 170207支持)。注:本摘要未在会议上提交。引文格式:Surendra R. Punganuru, Hanumantha Rao Madala, Viswanath Arutla, Kalkunte S. Srivenugopal。组蛋白去乙酰化酶和组织蛋白酶L激活双刺激反应性阿霉素前药的合成及临床前评价[摘要]。摘自:2019年美国癌症研究协会年会论文集;2019年3月29日至4月3日;亚特兰大,乔治亚州。费城(PA): AACR;癌症杂志，2019;79(13增刊):摘要第988期。
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Pub Date : 2019-07-01DOI: 10.1158/1538-7445.AM2019-1861
Peiying Yang, Tara Conway, P. Rhea, Dongmei Chen, Bo Wei, Jibin Ding, H. Lentzen, J. McQuade
Aviscumine, a recombinant mistletoe lectin I, is produced in E. coli and has been evaluated for its antitumor activities in various experimental in-vitro and in-vivo tumor models as well as in clinical trials. A phase II trial demonstrated the safety and efficacy of Aviscumine in pretreated patients with metastatic melanoma (stage IV). However, the mechanism(s) underlying the effect of Aviscumine in melanoma is inconclusive. Here, the antitumor activities and relevant mode of actions of Aviscumine were investigated in human melanoma A375, mouse melanoma Yummer and B16 cells as well as their relevant xenograft animal models. Cells were treated with Aviscumine (0-20 ng/mL) for 48 and 72 hrs, and cell proliferation was measured by MTT assay. Alteration of cell growth regulatory proteins and cell signaling proteins were determined by Reverse Phase Proteomic Array (RPPA) and validated with western blotting. Aviscumine exerted much stronger anti-proliferative activity in both A375 and Yummer cells with IC50 of 0.18 ± 0.03 ng/ml and 0.41 ± 0.06 ng/ml, respectively than that of B16 cells (IC50 15.93 ± 3.48 ng/ml). In A375 cells, Aviscumine significantly increased subG0/G1 population suggesting Aviscumine treatment led to apoptotic and necrotic cell death. Additionally, downregulation of various proteins associated with apoptotic cell death (pCDK1, pRB, MCl-1) was also observed by RPPA. Furthermore, Aviscumine significantly decreased c-Myc protein expression in a concentration-dependent manner measured by both RPPA and western blot. Interestingly, baseline c-Myc protein expression was much higher in the Aviscumine-sensitive A375 and Yummer cells than that in the Aviscumine-resistant B16 cells. Finally, the effects of Aviscumine on tumor growth were tested via subcutaneous injection (30 ng/kg, twice per week for three weeks) in mice bearing A375 or B16 melanoma. At 3 weeks, A375 tumors were markedly smaller in Aviscumune treated mice (383.8 ± 102.2 mg) than in the control-treated group (922.4 ± 296.1 mg). c-Myc protein expression was also significantly reduced (62% vs. control) in Aviscumine treated A375 tumors, as were levels of multiple downstream metabolites (pyruvate, malate, and glutamate) (p Citation Format: Peiying Yang, Tara Conway, Patrea Rhea, Dongmei Chen, Bo Wei, Jibin Ding, Hans Lentzen, Jennifer McQuade. Aviscumine (ME-503) suppresses the growth of melanoma by potentially targeting c-Myc pathway [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 1861.
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Pub Date : 2019-07-01DOI: 10.1158/1538-7445.AM2019-1864
A. Salvi, Julia R. Austin, D. Lantvit, J. Burdette
High grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy affecting women worldwide and the fifth most common cause of cancer related deaths among U.S. women. New targeted therapies are needed to prevent HGSOC progression and metastasis related lethality from the disease. The goal of this study was to test the novel natural compound, Verticillin A, for its anticancer properties and mode of action in HGSOC cells. Verticillin A is an epipolythiodioxopiperazine (ETP) alkaloid that is isolated from several terrestrial and marine filamentous fungi and has been shown to be cytotoxic in several cancer cell lines including OVCAR8, OVCAR4 and Kuramochi. Our data indicated that Verticillin A treatment caused cytotoxicity in HGSOC cell lines in a dose-dependent manner. Furthermore, treatment with Verticillin A in HGSOC cell line OVCAR8 and OVCAR4 enhanced apoptosis, which was demonstrated by PARP cleavage and Annexin V/ Propidium iodide staining. To determine whether Verticillin A caused in vivo tumor growth inhibition, OVCAR8-RFP cells were xenografted in mice to form tumors and the mice were treated with Verticillin A. Encapsulated nanoparticles of Verticillin A decreased tumor growth in vivo and had low cytotoxicity compared to the naked drug. RNA-Seq analysis was performed with OVCAR8 cells treated with Verticillin A and the data found an upregulation of apoptosis signaling pathway and oxidative stress response and downregulation of cancer stemness signaling pathways. A proteomic histone profiling performed in OVCAR8 cells indicated that Verticillin A caused epigenetic modifications with global changes in histone methylation and acetylation marks. Thus, our study identifies Verticillin A as a novel epigenetic modifier in ovarian cancer cells and indicates therapeutic potential for treatment of HGSOC. Note: This abstract was not presented at the meeting. Citation Format: Amrita Salvi, Julia Austin, Daniel Lantvit, Joanna Burdette. Verticillin A causes DNA damage and apoptosis in high grade serous ovarian cancer [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 1864.
高级别浆液性卵巢癌(HGSOC)是影响全球女性的最致命的妇科恶性肿瘤，也是美国女性癌症相关死亡的第五大常见原因。需要新的靶向治疗来防止HGSOC的进展和转移相关的致死率。本研究的目的是测试新的天然化合物Verticillin A在HGSOC细胞中的抗癌特性和作用方式。Verticillin A是一种表聚硫代二氧哌嗪(ETP)生物碱，从几种陆地和海洋丝状真菌中分离出来，已被证明对几种癌细胞系(包括OVCAR8、OVCAR4和Kuramochi)具有细胞毒性。我们的数据表明，Verticillin A以剂量依赖的方式引起HGSOC细胞系的细胞毒性。此外，经PARP切割和膜联蛋白V/碘化丙啶染色证实，Verticillin A可促进HGSOC细胞株OVCAR8和OVCAR4的凋亡。为了确定Verticillin A是否在体内抑制肿瘤生长，我们将OVCAR8-RFP细胞移植到小鼠体内形成肿瘤，并给小鼠注射Verticillin A。与裸药相比，Verticillin A包封的纳米颗粒在体内抑制肿瘤生长，具有较低的细胞毒性。对Verticillin A处理的OVCAR8细胞进行RNA-Seq分析，数据发现凋亡信号通路和氧化应激反应上调，癌症干细胞信号通路下调。在OVCAR8细胞中进行的蛋白质组学组蛋白分析表明，Verticillin A引起表观遗传修饰，组蛋白甲基化和乙酰化标记发生全局变化。因此，我们的研究确定了Verticillin A是卵巢癌细胞中一种新的表观遗传修饰因子，并表明了治疗HGSOC的治疗潜力。注:本摘要未在会议上提交。引文格式:Amrita Salvi, Julia Austin, Daniel Lantvit, Joanna Burdette。Verticillin A在高级别浆液性卵巢癌中引起DNA损伤和细胞凋亡[摘要]。摘自:2019年美国癌症研究协会年会论文集;2019年3月29日至4月3日;亚特兰大,乔治亚州。费城(PA): AACR;癌症杂志，2019;79(13增刊):摘要第1864期。
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Pub Date : 2019-07-01DOI: 10.1158/1538-7445.AM2019-2749
V. Prabhu, A. Kawakibi, Neel S. Madhukar, L. Anantharaman, Sean W. Deacon, N. Charter, M. Garnett, U. McDermott, C. Benes, W. Oster, O. Elemento, M. Stogniew, J. Allen
G protein-coupled receptors (GPCRs) represent the most widely exploited superfamily of drug targets for FDA-approved therapies for many diseases, however, these receptors are underexploited for oncology. ONC201 is a selective antagonist of GPCRs dopamine receptor D2 (DRD2) and DRD3 that has been shown to induce tumor regressions with a benign safety profile in high grade glioma patients. ONC201 (benzyl-2-methylbenzyl-imipridone) is the founding member of the imipridone class of small molecules that share a unique tri-heterocyclic core chemical structure. Imipridones share several chemical and biological properties that are desirable drug-like characteristics: oral administration, wide therapeutic window, chemical stability and blood brain barrier penetrance. In this study, we profiled a series of imipridones for GPCR engagement and anti-cancer efficacy. Several imipridones were screened against a large panel of human GPCRs using a β-arrestin recruitment assay. The imipridones tested resulted in GPCR agonist/antagonist activity (threshold set at >20% activity) that was heterogenous, but exclusive among Class A GPCRs that represent the largest class. Minor chemical modifications to the ONC201 chemical structure caused large shifts in agonist versus antagonist activity and selectivity for GPCRs. Specifically, switching the ONC201 imipridone core from an angular to a linear isomer resulted in loss of DRD2 antagonist activity and impaired inhibition of cancer cell viability, indicating the imipridone core structure is critical for GPCR engagement and anti-cancer effects. The addition of electron withdrawing groups (e.g. di- or tri-halogen substitution) to the methyl benzyl ring improved potency for GPCR engagement and anti-cancer effects, but not for the benzyl ring. Loss of the benzyl ring impaired anti-cancer effects. Among all of the GPCR hits identified, maximal variance in imipridone GPCR engagement was identified for DRD2/DRD3 antagonism and GPR132 agonism that were prioritized considering their known biological relevance in oncology. ONC206 (benzyl-2,4-difluoromethylbenzyl-imipridone) emerged as the most selective and potent antagonist for D2-like dopamine receptors that are overexpressed and critical for survival in several cancers. ONC212 (benzyl-4-trifluoromethylbenzyl-imipridone) was the most selective and potent agonist for tumor suppressor GPR132. Both compounds were tested in the GDSC panel of >1000 cancer cell lines and demonstrated broad spectrum nanomolar inhibition of cancer cell viability and a wide therapeutic window. GPCR target expression correlated with anti-cancer efficacy in the GDSC panel for both compounds, providing potential biomarkers of response. Thus, chemical derivatization of ONC201 has generated a class of novel GPCR-targeting agents with promising preclinical efficacy and safety profiles in oncology. Citation Format: Varun V. Prabhu, Abed Rahman Kawakibi, Neel S. Madhukar, Lakshmi Anantharaman, Sean Deacon, Neil S.
G蛋白偶联受体(gpcr)代表了fda批准的许多疾病治疗中最广泛利用的药物靶点超家族，然而，这些受体在肿瘤治疗中的利用不足。ONC201是GPCRs多巴胺受体D2 (DRD2)和DRD3的选择性拮抗剂，已被证明在高级别胶质瘤患者中可诱导肿瘤消退并具有良性安全性。ONC201 (benzyl-2-methylbenzyl-imipridone)是具有独特的三杂环核心化学结构的小分子丙米普利酮类的创始成员。吡普利酮具有几种理想的药物样特性的化学和生物学特性:口服给药、宽治疗窗口、化学稳定性和血脑屏障穿透性。在这项研究中，我们分析了一系列吡普利酮的GPCR参与和抗癌功效。几种吡普利酮通过β-抑制蛋白招募试验对大量人类gpcr进行筛选。测试的吡普利酮导致GPCR激动剂/拮抗剂活性(阈值设置为>20%的活性)是异质性的，但在代表最大类别的A类GPCR中是排他性的。对ONC201化学结构的微小化学修饰导致gpcr的激动剂与拮抗剂活性和选择性的巨大变化。具体来说，将ONC201吡喃酮核心从一个角度转换为一个线性异构体导致DRD2拮抗剂活性的丧失和对癌细胞活力的抑制受损，这表明吡喃酮核心结构对GPCR参与和抗癌作用至关重要。在甲基苄环上加入吸电子基团(如二卤素或三卤素取代)可以提高与GPCR结合的效力和抗癌作用，但对苄基环没有作用。苯环的缺失削弱了抗癌作用。在所有确定的GPCR命中中，最大的差异被确定为DRD2/DRD3拮抗剂和GPR132拮抗剂，考虑到它们在肿瘤学中的已知生物学相关性，优先考虑它们。ONC206(苄基-2,4-二氟甲基苄基-丙米普利酮)成为d2样多巴胺受体的最具选择性和最有效的拮抗剂，d2样多巴胺受体在几种癌症中过度表达，对生存至关重要。ONC212(苄基-4-三氟甲基苄基-丙米普利酮)是肿瘤抑制因子GPR132的最具选择性和最有效的激动剂。这两种化合物在超过1000个癌细胞系的GDSC面板中进行了测试，显示出广谱的纳米摩尔抑制癌细胞活力和宽的治疗窗口。GPCR靶表达与两种化合物的GDSC面板的抗癌功效相关，为反应提供了潜在的生物标志物。因此，ONC201的化学衍生化产生了一类新的gpcr靶向药物，在肿瘤学中具有良好的临床前疗效和安全性。引文格式:Varun V. Prabhu, Abed Rahman Kawakibi, Neel S. Madhukar, Lakshmi Anantharaman, Sean Deacon, Neil S. Charter, Mathew J. Garnett, Ultan McDermott, Cyril H. Benes, Wolfgang Oster, Olivier Elemento, Martin Stogniew, Joshua E. Allen确定吡咪酮小分子与GPCR结合及抗癌功效的构效关系[摘要]。摘自:2019年美国癌症研究协会年会论文集;2019年3月29日至4月3日;亚特兰大,乔治亚州。费城(PA): AACR;癌症杂志，2019;79(13增刊):2749。
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Pub Date : 2019-07-01DOI: 10.1158/1538-7445.AM2019-1867
J. O. Olugbami, R. Damoiseaux, J. Gimzewski, O. Odunola
Background: The aggressive and asymptomatic nature of liver cancer etiology in blacks is well documented. Furthermore, in Egypt, bladder cancer accounts for as many as 31% of all cancer cases, while in the US, the incidence in whites is higher than in blacks. There has been an increased search for phytochemicals, such as capsaicin (a bioactive component of hot peppers), which are easily available, and possess chemopreventive and chemotherapeutic activities. We therefore investigated the potential scientific relevance of aqueous leaf extract of Terminalia glaucescens (ALET) in cancer management. Terminalia glaucescens has been ethnomedicinally associated with various biological and therapeutic properties. Methods: Total flavonoid and phenolic contents of ALET were assessed spectrophotometrically using gallic acid and quercetin as standards, in addition to its free-radical-scavenging activity involving 2,2-diphenyl-1-picrylhydrazyl assay with butylated hydroxytoluene and vitamin C as reference compounds. The hydroxyl-radical-scavenging and reducing-power activities were correspondingly assessed. In addition, antiproliferative activities of ALET in comparison with capsaicin on normal and cancer cell lines of human liver (THLE-3 and HepG2) and urinary bladder (HUC-PC and MC-T11) were evaluated using fluorometry. Luminometry was used to determine ATP concentrations, caspase 3/7 activities, glutathione status, and mitochondrial functions. Results: Quantitative phytochemical assessments indicate the predominance of phenolic compounds (599.61 ± 6.14 µg gallic acid equivalents per mg of ALET) as compared with flavonoids (144.27 ± 3.44 µg quercetin equivalents per mg of ALET). ALET possesses comparable free-radical-scavenging, antioxidant and reducing-power activities in comparison to the standards. Treatment of the four cell lines with ALET for three days results in the following percent total cells: THLE-3 (30.13% at 24 h; 5.65% at 48 h; 5.43% at 72 h), HepG2 (31.09% at 24 h; 4.75% at 48 h; 1.41% at 72 h), HUC-PC (7.33% at 24 h; 2.35% at 48 h; 1.74% at 72 h), and MC-T11 (19.79% at 24 h; 9.20% at 48 h; 0.29% at 72 h). Assessment of the ATP levels after 24 h treatment with ALET resulted in a concentration-dependent depletion with a remarkable effect on HUC-PC and MC-T11 urinary bladder cells. ALET specifically caused a concentration-dependent decrease in caspase 3/7 activities and glutathione levels in HepG2 cells. ALET seems more toxic to the mitochondria at higher concentrations as compared with capsaicin. Conclusions: ALET could be a natural source of mitocans for the treatment of cancers. Citation Format: Jeremiah Olorunjuwon Olugbami, Robert Damoiseaux, James Kazemier Gimzewski, Oyeronke Adunni Odunola. Liver and urinary bladder cancers: The modifying role of aqueous leaf extract of Terminalia glaucescens Planch. ex Benth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Ph
背景:黑人肝癌病因的侵袭性和无症状性已被充分证实。此外，在埃及，膀胱癌占所有癌症病例的31%，而在美国，白人的发病率高于黑人。人们越来越多地寻找植物化学物质，如辣椒素(辣椒的一种生物活性成分)，它们很容易获得，并具有化学预防和化学治疗活性。因此，我们研究了黄连叶水提取物(ALET)在癌症治疗中的潜在科学相关性。在民族医药学上，菖蒲具有多种生物学和治疗特性。方法:以没食子酸和槲皮素为标准品，分光光度法测定ALET的总黄酮和酚类含量;以丁基羟基甲苯和维生素C为参比物，采用2,2-二苯基-1-苦酰肼法测定ALET的自由基清除活性。对其羟基自由基清除能力和还原能力进行了评价。此外，用荧光法比较ALET与辣椒素对人肝脏(THLE-3和HepG2)和膀胱(HUC-PC和MC-T11)正常细胞和癌细胞的抗增殖活性。用光度法测定ATP浓度、caspase 3/7活性、谷胱甘肽状态和线粒体功能。结果:定量植物化学评估表明，与黄酮类化合物(144.27±3.44µg槲皮素当量/ mg ALET)相比，酚类化合物(599.61±6.14µg没食子酸当量/ mg ALET)优势。与标准相比，ALET具有相当的自由基清除，抗氧化和还原能力。四种细胞系经ALET处理3天后，细胞总数百分比如下:THLE-3 (24 h时30.13%;48 h 5.65%;72 h 5.43%)， HepG2 24 h 31.09%;4.75% 48 h;72 h时为1.41%)，24 h时为7.33%;48 h 2.35%;72 h时1.74%)，24 h时MC-T11为19.79%;48小时9.20%;ALET处理24小时后的ATP水平评估导致浓度依赖性耗尽，对HUC-PC和MC-T11膀胱细胞有显著影响。ALET特异性地引起HepG2细胞中caspase 3/7活性和谷胱甘肽水平的浓度依赖性降低。与辣椒素相比，高浓度的ALET似乎对线粒体的毒性更大。结论:ALET可能是治疗癌症的线粒体的天然来源。引文格式:Jeremiah Olorunjuwon Olugbami, Robert Damoiseaux, James Kazemier Gimzewski, Oyeronke Adunni Odunola。黄连叶水提物对肝癌和膀胱癌的调节作用。ex Benth[摘要]。摘自:2019年美国癌症研究协会年会论文集;2019年3月29日至4月3日;亚特兰大,乔治亚州。费城(PA): AACR;癌症杂志，2019;79(13增刊):摘要第1867期。
{"title":"Abstract 1867: Liver and urinary bladder cancers: The modifying role of aqueous leaf extract ofTerminalia glaucescensPlanch. ex Benth","authors":"J. O. Olugbami, R. Damoiseaux, J. Gimzewski, O. Odunola","doi":"10.1158/1538-7445.AM2019-1867","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2019-1867","url":null,"abstract":"Background: The aggressive and asymptomatic nature of liver cancer etiology in blacks is well documented. Furthermore, in Egypt, bladder cancer accounts for as many as 31% of all cancer cases, while in the US, the incidence in whites is higher than in blacks. There has been an increased search for phytochemicals, such as capsaicin (a bioactive component of hot peppers), which are easily available, and possess chemopreventive and chemotherapeutic activities. We therefore investigated the potential scientific relevance of aqueous leaf extract of Terminalia glaucescens (ALET) in cancer management. Terminalia glaucescens has been ethnomedicinally associated with various biological and therapeutic properties. Methods: Total flavonoid and phenolic contents of ALET were assessed spectrophotometrically using gallic acid and quercetin as standards, in addition to its free-radical-scavenging activity involving 2,2-diphenyl-1-picrylhydrazyl assay with butylated hydroxytoluene and vitamin C as reference compounds. The hydroxyl-radical-scavenging and reducing-power activities were correspondingly assessed. In addition, antiproliferative activities of ALET in comparison with capsaicin on normal and cancer cell lines of human liver (THLE-3 and HepG2) and urinary bladder (HUC-PC and MC-T11) were evaluated using fluorometry. Luminometry was used to determine ATP concentrations, caspase 3/7 activities, glutathione status, and mitochondrial functions. Results: Quantitative phytochemical assessments indicate the predominance of phenolic compounds (599.61 ± 6.14 µg gallic acid equivalents per mg of ALET) as compared with flavonoids (144.27 ± 3.44 µg quercetin equivalents per mg of ALET). ALET possesses comparable free-radical-scavenging, antioxidant and reducing-power activities in comparison to the standards. Treatment of the four cell lines with ALET for three days results in the following percent total cells: THLE-3 (30.13% at 24 h; 5.65% at 48 h; 5.43% at 72 h), HepG2 (31.09% at 24 h; 4.75% at 48 h; 1.41% at 72 h), HUC-PC (7.33% at 24 h; 2.35% at 48 h; 1.74% at 72 h), and MC-T11 (19.79% at 24 h; 9.20% at 48 h; 0.29% at 72 h). Assessment of the ATP levels after 24 h treatment with ALET resulted in a concentration-dependent depletion with a remarkable effect on HUC-PC and MC-T11 urinary bladder cells. ALET specifically caused a concentration-dependent decrease in caspase 3/7 activities and glutathione levels in HepG2 cells. ALET seems more toxic to the mitochondria at higher concentrations as compared with capsaicin. Conclusions: ALET could be a natural source of mitocans for the treatment of cancers. Citation Format: Jeremiah Olorunjuwon Olugbami, Robert Damoiseaux, James Kazemier Gimzewski, Oyeronke Adunni Odunola. Liver and urinary bladder cancers: The modifying role of aqueous leaf extract of Terminalia glaucescens Planch. ex Benth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Ph","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"75 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83817385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-07-01DOI: 10.1158/1538-7445.AM2019-4543
A. Majumder, Guolin Zhang, Emma Adhikari, B. Fang, E. Welsh, J. Koomen, E. Haura
AXL is an attractive drug target because of its role in EMT-mediated resistance to EGFR tyrosine kinase inhibitor (TKI) in lung cancer (LC). Lack of genetic alterations and the role of stroma-mediated AXL activation in cancer cells, underscore the need to better characterize AXL TKIs, understand their effects on signaling and phenotype of cells, and develop assays to visualize active AXL signaling complexes. For this, 25 LC cells were analyzed for total (t) and phosphorylated (p) AXL expression. AXL TKIs, RXDX106, R428 and Cabozantinib, were profiled using western blotting (WB), viability assay and activity-based protein profiling (ABPP). Phosphoproteins (pSTY) altered by RXDX106 were identified using mass spectrometry. Effects of RXDX106 on signaling, viability and migration of LC cells were also evaluated. Cell line models of EMT-mediated acquired drug resistance, treated with a combination of AXL and EGFR TKIs, were analyzed for changes in signaling, cell viability and EMT. Immunoprecipitation (IP) identified adaptors of AXL signaling, and Proximity Ligation Assays (PLA) were developed to detect these active complexes in situ. H1299 cells, expressing highest levels of p and t AXL among the LC lines screened, was used in this study. RXDX106 and Cabozantinib potently inhibited pAXL in H1299 cells, but did not affect cell viability at these doses. R428 reduced cell viability at doses that did not efficiently inhibit pAXL, suggesting AXL independent phenotypic effects. Our ABPP data shows that apart from AXL, these TKIs target other overlapping and distinct subsets of proteins. R428 has the highest number of off targets and its unique ability to inhibit the FoxO pathway may explain the AXL independent phenotypic effects of R428. The pSTY data shows that RXDX106 deregulates phosphorylation of proteins involved in PI3K signaling, receptor endocytosis and cell migration pathways in H1299 cells. WB and phenotypic assays support these results by showing that RXDX106 inhibits pAXL, downstream pAKT but not pERK, and migration/invasion in these cells. In EGFR TKI resistant cells, EGFR and AXL TKI combination fails to alter downstream signaling, cell viability or EMT. Consistent with the WB and pSTY analyses, IP identifies PI3KR1 as an AXL interactor. PLAs to detect active AXL:PI3KR1 and AXL:pY100 signaling complexes show high basal PLA foci in H1299 and Calu1 cells that are abrogated by AXL TKI. HCC827 cells, which lack ligand independent pAXL, do not show significant labeling by either PLA. Overall, we demonstrate that different AXL TKIs have distinct target profiles and that inhibition of AXL suppresses downstream PI3K/AKT signaling and migration/ invasion of LC cells. We also show that AXL TKI fails to suppress downstream signaling, cell viability or EMT in EGFR TKI resistant cell lines. We have also established a PLA to annotate AXL adaptor foci that could be developed as a tool to measure drug-targetable active AXL complexes in patient tissues. Citat
AXL是一个有吸引力的药物靶点，因为它在肺癌(LC)中emt介导的对EGFR酪氨酸激酶抑制剂(TKI)的耐药性中起作用。缺乏遗传改变和基质介导的AXL在癌细胞中激活的作用，强调需要更好地表征AXL TKIs，了解它们对细胞信号传导和表型的影响，并开发检测活性AXL信号复合物的方法。为此，分析了25个LC细胞的总(t)和磷酸化(p) AXL表达。AXL TKIs, RXDX106, R428和Cabozantinib，采用western blotting (WB)，活力测定和基于活性的蛋白分析(ABPP)进行分析。质谱法鉴定了RXDX106改变的磷酸化蛋白(pSTY)。研究了RXDX106对LC细胞信号转导、活力和迁移的影响。用AXL和EGFR TKIs联合治疗EMT介导的获得性耐药细胞系模型，分析信号传导、细胞活力和EMT的变化。免疫沉淀(IP)鉴定了AXL信号转导的接头，并开发了邻近结扎法(PLA)来原位检测这些活性复合物。在筛选的LC细胞系中，p和t AXL表达水平最高的是H1299细胞。RXDX106和Cabozantinib在H1299细胞中有效抑制pAXL，但在这些剂量下不影响细胞活力。R428在没有有效抑制pAXL的剂量下降低了细胞活力，提示AXL独立的表型效应。我们的ABPP数据显示，除了AXL，这些tki靶向其他重叠和不同的蛋白质亚群。R428脱靶数量最多，其独特的抑制FoxO通路的能力可能解释了R428不依赖AXL的表型效应。pSTY数据显示，RXDX106解除了H1299细胞中PI3K信号通路、受体内吞作用和细胞迁移途径相关蛋白的磷酸化调控。WB和表型分析支持这些结果，显示RXDX106抑制pAXL，下游pAKT，但不抑制pERK，以及这些细胞的迁移/侵袭。在EGFR TKI耐药细胞中，EGFR和AXL TKI联合不能改变下游信号、细胞活力或EMT。与WB和pSTY分析一致，IP将PI3KR1识别为AXL交互子。检测活跃的AXL:PI3KR1和AXL:pY100信号复合物的PLA在H1299和Calu1细胞中显示出高的基础PLA灶，而AXL TKI则消除了这些灶。HCC827细胞缺乏与配体无关的pAXL，两种PLA均未显示出显著的标记。总之，我们证明了不同的AXL TKIs具有不同的靶标谱，并且抑制AXL可抑制下游PI3K/AKT信号传导和LC细胞的迁移/侵袭。我们还发现AXL TKI不能抑制EGFR TKI耐药细胞系的下游信号、细胞活力或EMT。我们还建立了一个PLA来注释AXL适配器焦点，可以开发作为测量患者组织中药物靶向活性AXL复合物的工具。引用格式:Anurima Majumder，张国林，Emma Adhikari，方斌，Eric A. Welsh, John M. Koomen, Eric B. Haura。AXL激酶抑制剂的蛋白质组学特征和信号通路[摘要]。摘自:2019年美国癌症研究协会年会论文集;2019年3月29日至4月3日;亚特兰大,乔治亚州。费城(PA): AACR;癌症杂志，2019;79(13增刊):4543。
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Pub Date : 2019-07-01DOI: 10.1158/1538-7445.SABCS18-4541
A. Busso-Lopes, C. Rivera, B. Mello, L. Villa, W. González-Arriagada, A. Leme
{"title":"Abstract 4541: Malignant and non-malignant cells from primary tumor and lymph node metastasis ecosystems show different behavior for patient-associated protein signatures in head and neck cancer","authors":"A. Busso-Lopes, C. Rivera, B. Mello, L. Villa, W. González-Arriagada, A. Leme","doi":"10.1158/1538-7445.SABCS18-4541","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-4541","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73902408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-07-01DOI: 10.1158/1538-7445.SABCS18-4456
A. Endo, Dae-Shik Kim, Kuan-Chun Huang, M. Hao, S. Mathieu, Hyeong-Wook Choi, U. Majumder, Xiaojie Zhu, Yongchun Shen, Kristen Sanders, Thomas Noland, D. Chandra, Yu Chen, Karen Tendyke, K. Loiacono, D. Kolber-Simonds, Rongrong Jiang, Vaishali Dixit, J. Hutz, John Y. Wang, Xingfeng Bao, F. Fang, N. Sarwar
Introduction STING (stimulator of interferon genes) is an emerging target for cancer immunotherapy. 2’,39-cGAMP, a natural cyclic dinucleotide (CDN) STING agonist, and its phosphorothioate analogs, have drawn broad attention as lead molecules for STING targeted drug discovery. These CDNs, however, lack efficacy in some common STING genotypes disproportionally represented in non-Caucasians. Moreover, such CDNs have not fully addressed liability in chemical/metabolic stability. Here we report our chemistry approach to control STING agonist conformation to enhance binding affinity across all common STING genotypes and broaden the therapeutic potential of such compounds. Methods Our SBDD approach started with analysis of the binding pocket and key protein-ligand interactions to prioritize a focused set of analogs for chemical synthesis. Systematic SAR was built upon in vitro assays for STING binding affinity and activation of STING genotypes. X-ray single crystal structures were established for STING and diverse analogs, in free and bound states, to provide structural insight for rational analog design. Results Structural modeling was refined to evaluate different binding modes and dynamic conformational changes in the STING-ligand interface. We observed that STING-bound CDNs had the two ancillary nucleobases specifically oriented in close proximity with parallel pi-pi stacking and discovered that covalently linking the nucleobases advantageously pre-organize the bioactive constrained conformation for enhanced STING affinity. Our discovery established a novel class of macrocycle-bridged STING agonists (MBSAs). E7766, a representative of Eisai MBSA platform, shows superior in vitro activity against all the major human STING genotypes over reference CDNs, most distinctly in STINGREF. E7766 co-crystal structures with STINGWT and STINGREF provide structural basis for the added benefit of the topological novelty. The macrocyclic linker bridging the top of nucleobases perturbs the STING lid loop conformation and create new and specific interactions with both genotypes. In twelve subcutaneous tumor models in immune competent mice, single intra-tumoral injections achieved either complete regression or significant tumor growth delay with no serious adverse effect. E7766 also shows excellent chemical and metabolic stability, presumably conferred by conformational rigidity of the unique macrocycle bridge. More biological characterization of E7766 can be found in abstract #. Conclusion Eisai successfully discovered E7766, a representative of a novel class of macrocycle-bridged STING agonist topologically distinct from conventional STING agonists. E7766 demonstrated pan-genotypic STING activation, potent anti-cancer activities and excellent chemical and metabolic stability for further development. Citation Format: Atsushi ENDO, Dae-Shik Kim, Kuan-Chun Huang, Ming-Hong Hao, Steven Mathieu, Hyeong-wook Choi, Utpal Majumder, Xiaojie Zhu, Yongchun Shen, Kristen Sande
干扰素基因刺激因子(STING)是肿瘤免疫治疗的新兴靶点。2 '，39-cGAMP是一种天然的环二核苷酸(CDN) STING激动剂，其硫代类似物作为STING靶向药物的先导分子受到了广泛关注。然而，这些cdn在非白种人中不成比例地代表的一些常见STING基因型中缺乏效力。此外，这些cdn并没有完全解决化学/代谢稳定性的责任。在这里，我们报告了我们的化学方法来控制STING激动剂的构象，以增强所有常见的STING基因型的结合亲和力，并扩大这些化合物的治疗潜力。我们的SBDD方法从分析结合袋和关键蛋白质与配体的相互作用开始，优先考虑化学合成的一组重点类似物。系统SAR建立在体外检测STING结合亲和力和STING基因型激活的基础上。在自由态和束缚态下建立了STING和多种类似物的x射线单晶结构，为合理的类似物设计提供了结构见解。结果改进了结构模型，以评估sting -配体界面的不同结合模式和动态构象变化。我们观察到，与STING结合的cdn具有两个辅助核碱基，它们通过平行的pi-pi堆叠特异性地靠近定向，并发现共价连接核碱基有利于预先组织生物活性受限构象，以增强STING亲和力。我们的发现建立了一类新的大环桥接STING激动剂(MBSAs)。E7766是卫材MBSA平台的代表，对所有主要的人STING基因型的体外活性都优于参考cdn，其中在STING ref中表现得最为明显。与STINGWT和STINGREF的E7766共晶结构为该拓扑新颖性的附加效益提供了结构基础。桥接在核碱基顶部的大环连接物扰乱了STING盖环构象，并与两种基因型产生新的特异性相互作用。在免疫正常小鼠的12个皮下肿瘤模型中，单次肿瘤内注射实现了肿瘤完全消退或明显的肿瘤生长延迟，没有严重的不良反应。E7766还表现出优异的化学和代谢稳定性，这可能是由于其独特的大环桥的构象刚性。更多E7766的生物学特性可以在摘要#中找到。结论卫材成功发现了一种具有不同于传统STING激动剂拓扑结构的新型大环桥接STING激动剂E7766。E7766显示出泛基因型STING激活、强抗癌活性和良好的化学和代谢稳定性，值得进一步开发。引用格式:Atsushi ENDO, Dae-Shik Kim, Kuan-Chun Huang, Ming-Hong Hao, Steven Mathieu, hung -wook Choi, Utpal Majumder, Xiaojie Zhu, Yongchun Shen, Kristen Sanders, Thomas Noland, Dinesh Chandra, Yu Chen, Karen TenDyke, Kara Loiacono, Donna Kolber-Simonds, rongong Jiang, Vaishali Dixit, Janna Hutz, John Wang, Xingfeng Bao, Francis Fang, Nadeem SarwarE7766的发现:一类具有卓越效力和泛基因型活性的新型大环桥接STING激动剂(mbsa)的代表[摘要]。摘自:2019年美国癌症研究协会年会论文集;2019年3月29日至4月3日;亚特兰大,乔治亚州。费城(PA): AACR;癌症杂志，2019;79(13增刊):摘要nr 4456。
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