Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-LB226
Nagarajan Kannan, Syed Mohammed Musheer Aalam, Xiaojia Tang, K. Kalari, P. Kashyap, Jun Chen, Stephen Johnson, A. Sadanandam, M. Sherman
The role of maternal microbiome transmitted at birth in cancer control is poorly understood. We have developed the first germfree B6 mouse model of breast cancer to investigate the role of the maternal microbiome in controlling oncogenic/metastatic frequencies of pro-oncogenic mammary cells. In this model, a DNA barcoded, primitive normal mouse mammary epithelial cell encoding MMTV-PyMT oncogene, was transplanted in large numbers into conventional or germfree B6 mice. Next-gen sequencing analysis of the DNA barcodes in tissues enabled us to clonally track millions of cells and measure the frequency and growth dynamics of clones at the primary site and their systemic distribution in circulation and all vital organs, generating an unprecedented high-definition map of cancer progression. Our results show that in conventional B6 mice with maternal microbial transmission at-birth, a small fraction (~0.01%) of transplanted cells transform de novo and produce slow growing, late-onset benign tumors (mouse median survival of > 1 year). In contrast, in germfree B6 mice, a >10-fold higher frequency of cells transform de novo and generate early-onset, highly aggressive metastatic clones, and are frequently associated with features leading to early euthanasia or endpoint (i.e. sudden death, intracardiac metastasis, paralysis, swollen abdomen, early multiorgan aggressive metastasis) (median survival of ~4 months; p 1 year; p Citation Format: Nagarajan Kannan, Syed Mohammed Musheer Aalam, Xiaojia Tang, Krishna Kalari, Purna Kashyap, Jun Chen, Stephen Johnson, Anguraj Sadanandam, Mark Sherman. Maternal microbiome protects host against clonal de novo transformation, early onset systemic metastasis, and sudden death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB226.
出生时传播的母体微生物组在癌症控制中的作用尚不清楚。我们开发了第一个无菌B6乳腺癌小鼠模型,以研究母体微生物组在控制促癌乳腺细胞的致癌/转移频率中的作用。在该模型中,将编码MMTV-PyMT癌基因的DNA条形码原始正常小鼠乳腺上皮细胞大量移植到常规或无菌B6小鼠中。对组织中DNA条形码的下一代测序分析使我们能够对数百万个细胞进行克隆跟踪,并测量原发部位克隆的频率和生长动态,以及它们在循环系统和所有重要器官中的分布,从而生成前所未有的高清癌症进展图。我们的研究结果表明,在出生时母体微生物传播的常规B6小鼠中,一小部分(~0.01%)的移植细胞会重新转化并产生生长缓慢、晚发性的良性肿瘤(小鼠的中位生存期为100年)。相比之下,在无菌B6小鼠中,细胞新生转化和产生早发、高侵袭性转移克隆的频率高出10倍,并且经常与导致早期安乐死或终点(即猝死、心内转移、瘫痪、腹部肿胀、早期多器官侵袭性转移)的特征相关(中位生存期约4个月;P 1年;p引文格式:Nagarajan Kannan, Syed Mohammed Musheer Aalam, Xiaojia Tang, Krishna Kalari, Purna Kashyap, Jun Chen, Stephen Johnson, Anguraj Sadanandam, Mark Sherman。母体微生物组保护宿主免受克隆新生转化、早发性全身转移和猝死[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):摘要nr LB226。
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Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2559
L. G. Acosta, C. Takita, J. Wright, I. Reis, George R. Yang, Jennifer J. Hu
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Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2547
Balaji Sadhasivam, Camille Catherine Jackson, Katie M Smith, Tristan Coles, Isha Jhingan, Rebekah Stewart, Elizabeth H. Hahn, Sarah E. Johnston, Dan-Yan Zhao, Vengatesh Ganapathy, L. Queimado
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Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-LB223
Xiaotao Zhang, K. Hoffman, Fang-ling Li, E. Irajizad, Gladys J. Browman, K. Basen-Engquist, S. Hanash, P. Scheet, P. Okhuysen, S. Kopetz, J. Petrosino, C. Daniel
Background: Dry beans are a prebiotic food source rich in bioactive compounds with anti-inflammatory, anti-lipidemic and chemopreventive properties. The BE GONE trial tested the impact of an increase in dry bean consumption on gut microbiota and blood lipid profiles in high-risk colorectal (CR) patients otherwise consuming their usual diet. Methods: Following initiation of the pilot protocol (July 2016) among patients with a high-risk BMI and/or waist circumference and history of precancerous CR polyps, the crossover trial was expanded to patients with a history of CR cancer (May 2017). Patients were block randomized according to no vs. regular use of chronic disease medications commonly prescribed in the target population. Following a 4-week run-in/equilibration period, participants were randomized to continue the control diet (usual diet, no dry beans) or to begin the intervention diet (usual diet + dry beans). The intervention included a 2-week ramp-up to 1 cup/day navy beans (12 g dietary fiber; 14 g protein; 200 kcal) continued for an additional 6 weeks. Dietary habits, body weight, and other lifestyle parameters were monitored throughout the 20-week study. We characterized the 16Sv4 rDNA microbiome (Illumina MiSeq) and CLIA cholesterol panel in serial stool and fasting blood samples collected at baseline, week 4, and week 8 for each crossover period (n=249). Longitudinal analyses were conducted using generalized linear mixed models with random intercept and slope adjusted for chronic disease medication use examining the post-intervention effect from baseline to 4 weeks and baseline to 8 weeks. Results: Eligible patients were enrolled in the 4-week run-in/equilibration (n=69). Of these, 55 were randomized and 50 completed the 20-week trial in December 2019 with >80% compliance. Primary reasons for withdrawal were work/travel/family obligations. Half (54%) of the participants were male, 74% were CR cancer survivors, 76% were white (non-Hispanic) and 40% were on statins and/or metformin. Pre-study dietary profiles were characterized by low mean intake of legumes ( 80% of patients at baseline, revealed significantly decreased Anaerostipes and Streptococcus at week 4 and increased Faecalibacterium at week 8, along with temporal fluctuations in other known specialized (e.g., pectin) and versatile fiber-fermenting bacteria of the Lachnospiraceae and Ruminococcaceae families. A modest decrease in LDL cholesterol was observed at 8-weeks [-2.64 (-6.91, 1.62)] Conclusions: Early results of the BE GONE trial suggest that an 8-week increase in dry bean intake may be sufficient to balance or enrich the gut microbiome of high-risk CR patients. Continued sample processing and analysis, including stool metagenomics and blood metabolomics should continue to shed light on functional interactions relevant to the human host. Citation Format: Xiaotao Zhang, Kristi L. Hoffman, Fangyu Li, Ehsan Irajizad, Gladys Browman, Karen Basen-Engquist, Samir Hanash, Paul Sch
背景:干豆是一种富含生物活性化合物的益生元食物来源,具有抗炎、抗血脂和化学预防的特性。BE go试验测试了增加干豆摄入量对高危结肠直肠癌(CR)患者肠道微生物群和血脂谱的影响。方法:继试点方案(2016年7月)在具有高危BMI和/或腰围和癌前CR息肉病史的患者中启动后,交叉试验扩展到具有CR癌症病史的患者(2017年5月)。患者根据目标人群中常用的慢性疾病药物的不使用和经常使用进行分组随机化。经过4周的磨合/平衡期后,参与者被随机分配到继续对照组饮食(常规饮食,不含干豆)或开始干预饮食(常规饮食+干豆)。干预包括在两周内增加到每天1杯海军豆(12克膳食纤维;蛋白质14克;200千卡)再持续6周。饮食习惯、体重和其他生活方式参数在整个20周的研究中被监测。我们在每个交叉期的基线、第4周和第8周收集的一系列粪便和空腹血液样本(n=249)中鉴定了16Sv4 rDNA微生物组(Illumina MiSeq)和CLIA胆固醇面板。采用随机截距和斜率调整的广义线性混合模型对慢性疾病药物使用进行纵向分析,检查干预后从基线至4周和基线至8周的效果。结果:符合条件的患者参加了为期4周的磨合/平衡(n=69)。其中,55人被随机分配,50人在2019年12月完成了为期20周的试验,依从性>80%。退出的主要原因是工作/旅行/家庭责任。一半(54%)的参与者为男性,74%为CR癌症幸存者,76%为白人(非西班牙裔),40%服用他汀类药物和/或二甲双胍。研究前的饮食特征是豆类的平均摄入量较低(基线时为80%的患者),在第4周厌氧菌和链球菌显著减少,在第8周粪杆菌增加,以及其他已知的专门(如果胶)和多功能性纤维发酵细菌的时间波动毛螺科和瘤胃球菌科。结论:BE - go试验的早期结果表明,8周增加干豆摄入量可能足以平衡或丰富高危CR患者的肠道微生物群。持续的样本处理和分析,包括粪便宏基因组学和血液代谢组学,应该继续阐明与人类宿主相关的功能相互作用。引文格式:张晓tao, Kristi L. Hoffman,李方雨,Ehsan Irajizad, Gladys Browman, Karen Basen-Engquist, Samir Hanash, Paul Scheet, Pablo C. Okhuysen, Scott Kopetz, Joseph Petrosino, Carrie R. Daniel豆类丰富肠道微生物群vs.肥胖的负面影响:来自BE go在高危结直肠癌患者中的试验的首次结果[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):摘要nr LB223。
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Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-LB220
M. Aslam, S. Mcclintock, M. A. H. Jawad-Makki, K. Knuver, Daniyal M. Nadeem, H. Ahmad, D. Attili, D. Turgeon, J. Varani
Introduction: As part of our effort to understand the role of trace elements in colon polyp chemoprevention, we have conducted both colonoid culture (ex vivo) and human subject (in vivo) studies using Aquamin®— a calcium-, magnesium-, trace elements-rich, multi-mineral product derived from red marine algae as an intervention. Calcium alone was used as a comparator. Methods: Thirty subjects at-risk for colorectal cancer were enrolled and randomized to receive Aquamin® or calcium alone (each providing 800-mg calcium per day) or placebo. Colon biopsies were obtained before and after 90 days of intervention. We employed histologically normal colonic tissue from the same subjects (at baseline), to propagate in colonoid culture. Once established and expanded, we used the same interventions for a period of two weeks and compared the response (at 1.5mM) to the outcome of the studies conducted in human colonic biopsies after 90 days of intervention. Specifically, colonoid tissue and biopsies were subjected to analysis for markers of growth and differentiation by quantitative immunohistochemistry and tandem mass tag mass spectrometry-based proteomics. Results: The normal tissue colonoids demonstrated a high degree of differentiation as indicated by gross and microscopic appearance, and cytokeratin 20 (CK20) expression without either intervention. Only modest increases were seen in the CK20 expression with either calcium alone or Aquamin®. Similarly, CK20 expression was higher in baseline biopsies and there was no increase in the expression with calcium but a 5% increase seen with Aquamin® after 90 days of intervention. On proteomic screen, CK20 expression was increased by 40% in colonoid tissue in response to both interventions at 1.5mM, while CK20 expression increased by 10% and 21% with Calcium and Aquamin® in colon biopsies. When the colonoids were assessed for Ki67 (growth marker) expression, it was decreased by 17.2% and 18.4% with calcium alone and Aquamin® respectively as compared to the control. Analyzing colon biopsies after 90 days of intervention revealed that Aquamin® reduced the level of Ki67 expression by 20%, while no change was seen with calcium alone. Differential proteomic expression of proliferating cell nuclear antigen was decreased by 32% and 39% by calcium and Aquamin® at 1.5mM in colonoid tissue, whereas Ki67 protein was decreased by 4% and 22% with calcium and Aquamin®, respectively in colon biopsies. Conclusion: Colon tissue maintained in colonoid culture, thus, provides a good surrogate for human tissue collected in a clinical trial. It can be used to assess personalized responses or can provide a quick snapshot of the response in a relatively short time. Differential proteomic expression appears to be more sensitive than quantitative immunohistochemistry. A combination of calcium and additional trace elements proved to be more effective than calcium alone in altering differentiation and growth markers in either setting. Citation
作为我们努力了解微量元素在结肠息肉化学预防中的作用的一部分,我们进行了结肠体培养(离体)和人体受试者(体内)研究,使用Aquamin®-一种富含钙,镁,微量元素的多矿物质产品,源自红色海洋藻类作为干预。单独使用钙作为比较物。方法:招募了30名有结直肠癌风险的受试者,随机接受Aquamin®或单独钙治疗(每人每天提供800毫克钙)或安慰剂。在干预前后90天分别进行结肠活检。我们使用来自同一受试者的组织学上正常的结肠组织(基线),在结肠体培养中繁殖。一旦建立和扩大,我们使用相同的干预措施为期两周,并将反应(1.5mM)与干预90天后进行的人类结肠活检研究的结果进行比较。具体来说,通过定量免疫组织化学和基于串联质量标签质谱的蛋白质组学分析结肠镜组织和活检组织的生长和分化标志物。结果:在没有任何干预的情况下,正常组织结肠体的肉眼和显微镜外观以及细胞角蛋白20 (CK20)的表达均显示出高度分化。单独使用钙或Aquamin®时,CK20的表达仅略有增加。同样,CK20的表达在基线活检中较高,钙组的表达没有增加,但在干预90天后,Aquamin®组的表达增加了5%。在蛋白质组学筛选中,两种干预措施在1.5mM时,CK20在结肠组织中的表达增加了40%,而在结肠活检中,钙和Aquamin®的CK20表达分别增加了10%和21%。当对结肠体进行Ki67(生长标志物)表达评估时,与对照组相比,单独钙和Aquamin®分别降低了17.2%和18.4%。干预90天后的结肠活检分析显示,Aquamin®使Ki67的表达水平降低了20%,而单独使用钙则没有变化。在结肠样组织中,1.5mM处,钙和Aquamin®可使增殖细胞核抗原的差异蛋白组学表达降低32%和39%,而在结肠活检中,钙和Aquamin®可使Ki67蛋白分别降低4%和22%。结论:结肠镜培养维持的结肠组织为临床试验中收集的人体组织提供了良好的替代品。它可以用来评估个性化的响应,或者在相对较短的时间内提供响应的快速快照。差异蛋白质组学表达似乎比定量免疫组织化学更敏感。事实证明,钙和其他微量元素的组合在改变分化和生长标志物方面比单独钙更有效。引文格式:Muhammad N. Aslam, Shannon McClintock, Mohamed Ali H Jawad-Makki, Karsten Knuver, Daniyal M. Nadeem, Haris Ahmad, Durga Attili, Danielle (Kim) Turgeon, James Varani。人类结肠上皮细胞分化和生长控制:比较临床试验结果与人类结肠样细胞培养反应[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):摘要nr LB220。
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Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2537
Asim Siddiqui, J. Blume, Margaret K. R. Donovan, Marwin Ko, Ryan W. Benz, Theodore L. Platt, J. Cuevas, S. Batzoglou, O. Farokhzad
{"title":"Abstract 2537: Application of the proteograph to the identification of differential protein isoform plasma abundance in early lung cancer vs. healthy controls","authors":"Asim Siddiqui, J. Blume, Margaret K. R. Donovan, Marwin Ko, Ryan W. Benz, Theodore L. Platt, J. Cuevas, S. Batzoglou, O. Farokhzad","doi":"10.1158/1538-7445.AM2021-2537","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2537","url":null,"abstract":"","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":"117 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88067527","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 : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2581
C. Torres, Georgina Mancinelli, Emily Chen, J. Cordoba-Chacon, D. Pins, R. McKinney, Sara Saeed, Karla J. Castellanos, G. Orsi, M. Singhal, S. Grimaldo, Poorna Chandra Rao Yalagala, P. Subbaiah, Cecilia Leal, P. Grippo
Pancreatic cancer (PC) is one of the few cancers for which incidence and mortality continue to rise despite increasing knowledge of its etiology and risk factors. Amongst the latter, dietary patterns are significantly associated with PC risk. Due to its relatively slow progression, preventive strategies represent a simple means to improve outcomes. We are interested in understanding the influence of diet on PC prevention and have studied the effects of polyunsaturated fatty acids (PUFAs) in the progression of the disease both in vitro (via PC cell lines) and in vivo (via EL-KrasG12D and p48Cre/LSL-KrasG12D mouse models that recapitulate IPMN- and PanIN-like lesions, respectively). Our data demonstrate that dietary PUFAs are incorporated into plasma membrane phospholipids (PL) affecting signal transduction, particularly PI3K/AKT signaling, supporting the emergence of membrane-targeted therapies. We evaluated the effects of diets supplemented with omega-3 (ω-3) or omega-6 (ω-6) PUFAs on neoplastic lesion development. This work supports that ω-3 reduces while ω-6 accelerates lesion penetrance, tumor formation and proliferation associated with changes in pAKT. These results were also recapitulated in vitro to confirm that reduced activity of the PI3K/AKT pathway when incubated with Docosahexaenoic Acid (DHA), the primary component of the ω-3 enriched diet. This effect was abrogated by over-activation of the pathway when dosed with the main component of the ω-6 enriched diet, Linoleic Acid (LA). Since PI3K depends on its binding to PIP2 in the membrane for its activity, we next aimed to study if PUFAs were altering PL composition. By using IF and stably-transfected PC cells with a fluorescent translocation biosensor to monitor PIP2 and PIP3 lipids in the membrane, we discovered an effect of exogenous fatty acids expressed as a ratio of PIP2 to PIP3 in the plasma membrane. Enriched areas of membrane GFP staining (or PIP3) were observed in LA-treated Panc-1 cells. DHA treatment prevented PIP3 localization in the membrane of tumor cells, keeping the GFP signal diffuse in the cytoplasm. Using the PIP2 biosensor we sought to study the affinity of PI3K for PIP2 depending on the incorporation of DHA or LA in PIP2. DHA treatment reduced PI3K interaction (not total PI3K) with PIP2 resulting in lower levels of PIP3 in the membrane and reduced pAKT activation. Our results are encouraging because these PUFAs impinge on AKT, a downstream target of Kras which serves as a logical alternative to the elusive therapies for Kras and often toxic effects of PI3K/AKT pathway inhibition. Citation Format: Carolina Torres, Georgina Mancinelli, Emily Chen, Jose Cordoba-Chacon, Danielle Pins, Ronald McKinney, Sara Saeed, Karla Castellanos, Giulia Orsi, Megha Singhal, Sam Grimaldo, Poorna Chandra Rao Yalagala, Papasani Subbaiah, Cecilia Leal, Paul Grippo. Dietary fat influences pancreatic cancer progression by altering cell membrane lipid content to impact the PI3K/AKT pathway [
胰腺癌(PC)是少数几种发病率和死亡率持续上升的癌症之一,尽管人们对其病因和危险因素的了解不断增加。在后者中,饮食模式与PC风险显著相关。由于其进展相对缓慢,预防性战略是改善结果的一种简单手段。我们有兴趣了解饮食对PC预防的影响,并在体外(通过PC细胞系)和体内(分别通过EL-KrasG12D和p48Cre/LSL-KrasG12D小鼠模型,分别概括IPMN和panin样病变)研究了多不饱和脂肪酸(PUFAs)在疾病进展中的作用。我们的数据表明,膳食PUFAs被纳入质膜磷脂(PL),影响信号转导,特别是PI3K/AKT信号传导,支持膜靶向治疗的出现。我们评估了补充omega-3 (ω-3)或omega-6 (ω-6) PUFAs的饮食对肿瘤病变发展的影响。本研究支持ω-3降低而ω-6加速与pAKT变化相关的病变外显率、肿瘤形成和增殖。这些结果也在体外重现,以证实当与ω-3富含饮食的主要成分二十二碳六烯酸(DHA)孵育时,PI3K/AKT通路的活性降低。当ω-6富集饮食的主要成分亚油酸(LA)被过量激活时,这种效应被消除了。由于PI3K的活性依赖于其与膜上PIP2的结合,我们下一步的目标是研究PUFAs是否改变了PL的组成。通过使用IF和稳定转染的PC细胞,并使用荧光易位生物传感器监测膜中的PIP2和PIP3脂质,我们发现外源脂肪酸在质膜中以PIP2与PIP3的比例表达的影响。在la处理的Panc-1细胞中观察到膜GFP染色(或PIP3)富集区。DHA处理可阻止PIP3在肿瘤细胞膜中的定位,使GFP信号在细胞质中保持弥漫性。使用PIP2生物传感器,我们试图研究PI3K对PIP2的亲和力,这取决于DHA或LA在PIP2中的掺入。DHA处理降低了PI3K与PIP2的相互作用(不是总PI3K),导致膜中PIP3水平降低,pAKT激活降低。我们的研究结果令人鼓舞,因为这些PUFAs影响Kras的下游靶点AKT,这是Kras难以捉摸的治疗方法和PI3K/AKT通路抑制的毒性作用的合理替代方案。引文格式:Carolina Torres, Georgina Mancinelli, Emily Chen, Jose Cordoba-Chacon, Danielle Pins, Ronald McKinney, Sara Saeed, Karla Castellanos, Giulia Orsi, Megha Singhal, Sam Grimaldo, Poorna Chandra Rao Yalagala, Papasani Subbaiah, Cecilia Leal, Paul Grippo。膳食脂肪通过改变细胞膜脂质含量影响PI3K/AKT通路影响胰腺癌进展[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):2581。
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Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2605
F. Karzai, A. Couvillon, Y. McKinney, Katherine Lee-Wisdom, P. Choyke, V. Giri, T. Morgan, Heather H. Cheng, M. Merino, P. Pinto, B. Turkbey, W. Dahut
Introduction: The understanding of molecular genetics in PCa provides insight into disease progression and treatment. Less is known about PCa development in men with known high-risk germline pathogenic/likely pathogenic variants in PCa related genes, particularly DNA damage repair (DDR). mpMRI can localize and detect PCa lesions in this population. We are conducting a multicenter natural history study of male participants (prts) with documented germline variant(s) in BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, HOXB13, ATM, NBN, TP53, CHEK2, PALB2, RAD51D, BRIP1, or FANCA who do not have a PCa diagnosis using mpMRI (NCT03805919). Methods: Up to 500 men, 30-75 years old (y/o) will undergo mpMRI evaluation at baseline and every 2 years (yrs). Prts are followed at 12-mo intervals to determine PSA, PCa diagnosis, and/or disease/survival status until death. Indication for prostate biopsy includes PSA >2.0 for 30 - 49 y/o; >2.5 ng/mL for 50 - 75 y/o and/or PIRADS 3+ MRI lesion or clinical discretion. Tissue obtained will undergo full transcriptome analysis. Results: 100 prts have enrolled. Median age is 47 y/o. Median on-study PSA is 0.87 (0.16-10.05 ng/mL). Median PSA density is 0.029. Gene mutations are BRCA2 (40%), BRCA1 (33%), MSH2 (9%), and CHEK2 (4%). Mutations in ATM, HOXB13, MLH1, MSH6, PMS2, and EPCAM are ≤3%. No significant AEs have been observed. Of 96 prts, 25 (26%), had indication for biopsy [PIRADS 4 lesion: 16 (64%), PIRADS 3 lesion: 4 (16%), elevated PSA: 6 (24%), or clinical indication 1: (4%)]. 22 prostate biopsies were performed and 6 prts were diagnosed with PCa. One prt was upstaged on radical prostatectomy (RP). Conclusions: We found mpMRI-based PCa screening in men with high-risk gene mutations, especially DDR genes, is feasible and can be used to identify clinically significant PCa and monitor for disease progression. Future guidelines should consider age, mutation specificity and mpMRI. Accrual and correlative studies (biomarkers, PBMCs) are on-going. Citation Format: Fatima Karzai, Anna Couvillon, Yolanda McKinney, Katherine Lee-Wisdom, Peter L. Choyke, Veda N. Giri, Todd M. Morgan, Heather H. Cheng, Maria J. Merino, Peter A. Pinto, Baris Turkbey, William L. Dahut. A natural history study of men with high-risk genetics for prostate cancer (PCa) using multiparametric MRI (mpMRI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2605.
简介:了解分子遗传学在前列腺癌提供洞察疾病进展和治疗。对于PCa相关基因,特别是DNA损伤修复(DDR)中存在高危种系致病/可能致病变异的男性,PCa的发展情况知之甚少。mpMRI可以定位和检测该人群的前列腺癌病变。我们正在对男性参与者(prts)进行一项多中心自然史研究,这些参与者记录了BRCA1、BRCA2、MLH1、MSH2、MSH6、PMS2、EPCAM、HOXB13、ATM、NBN、TP53、CHEK2、PALB2、RAD51D、BRIP1或FANCA的种系变异,但没有使用mpMRI (NCT03805919)进行PCa诊断。方法:多达500名30-75岁(y/o)的男性将在基线和每2年(年)进行mpMRI评估。每隔12个月随访一次,以确定PSA、PCa诊断和/或疾病/生存状态,直至死亡。前列腺活检指征:30 - 49岁,PSA >2.0;50 - 75岁和/或PIRADS 3+ MRI病变>2.5 ng/mL或临床判断。获得的组织将进行完整的转录组分析。结果:100例患者入组。平均年龄为47岁。研究中PSA中位数为0.87 (0.16-10.05 ng/mL)。中位PSA密度为0.029。基因突变为BRCA2(40%)、BRCA1(33%)、MSH2(9%)和CHEK2(4%)。ATM、HOXB13、MLH1、MSH6、PMS2和EPCAM的突变≤3%。未观察到明显的ae。96例患者中,25例(26%)有活检指征[PIRADS 4级病变:16例(64%),PIRADS 3级病变:4例(16%),PSA升高:6例(24%),或临床指征1例(4%)]。22例行前列腺活检,6例诊断为前列腺癌。一名患者在根治性前列腺切除术(RP)中被抢镜。结论:我们发现基于mpmri的前列腺癌筛查在高危基因突变的男性,特别是DDR基因,是可行的,可用于识别临床显著的前列腺癌和监测疾病进展。未来的指南应考虑年龄、突变特异性和mpMRI。应计性和相关研究(生物标志物、PBMCs)正在进行中。引文格式:Fatima Karzai, Anna Couvillon, Yolanda McKinney, Katherine Lee-Wisdom, Peter L. Choyke, Veda N. Giri, Todd M. Morgan, Heather H. Cheng, Maria J. Merino, Peter A. Pinto, Baris Turkbey, William L. Dahut。使用多参数磁共振成像(mpMRI)对前列腺癌(PCa)高危遗传男性的自然史研究[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):2605。
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Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2582
R. A. Deabel, Joyce Zhang, Anand Puaar, Avinash Kumar, A. S. Levenson
The activation of androgen receptor (AR) is a key process in the development and progression of prostate cancer (PCa). After significant clinical response to androgen-deprivation therapy, patients with advanced PCa regularly relapse with more aggressive castrate-resistant PCa, in which AR and its oncogenic variants are reactivated. Therefore, there is an urgent necessity to develop therapeutic strategies that effectively suppress the tumor promoting signals associated with AR action in castrate-resistant PCa. Dietary stilbenes found in grapes and various berries are promising anticancer agents with multiple cellular targets, including AR. Particularly, we previously demonstrated that resveratrol (Res) and its naturally occurring analogs, pterostilbene and piceatannol, can decrease expression of AR in LNCaP and 22Rv1 cells, therefore presenting an attractive potential for stilbenes as promising pharmacologically safe agents in managing PCa. Gnetin C, a Res-dimer found abundantly in melinjo (Gnetum gnemon) plant, which possesses potent biological properties compared to Res and analogs due to its improved pharmacokinetics, is shown to be safe in healthy volunteers. Here, for the first time, we examine the efficacy of Gnetin C in targeting both full-length and ligand-independent AR splice variant (AR-V7) expressed in the castrate-resistant 22Rv1 cells. First, we found that Gnetin C shows significantly more potent cytotoxic effect in 22Rv1 cells compared to Res and Pter. Immunoblot analysis demonstrated that Gnetin C inhibited expression of both full-length (100 kDA) and truncated (80 kDA) AR-V7 in a dose-dependent manner and, importantly, with significantly higher efficacy than Res and Pter when treated with the same dose (50 μM). In addition, Gnetin C used in twice lesser dose (25 μM), showed substantially more inhibitory effect compared to flutamide and enzalutamide (50 μM), two known AR antagonists used in clinic. Moreover, since neuroendocrine trans-differentiation (NED) is associated with AR-dependent mechanisms and enzalutamide resistance in PCa, we evaluated the effects of Gnetin C on SYP and CHGA. Ongoing in vivo studies using transgenic mice with activated AR signaling treated with Gnetin C are in progress. Taken together, we propose that Gnetin C is a lead compound among stilbenes for effectively blocking AR reactivation in PCa and may potentially have noteworthy therapeutic implications against advanced PCa. Citation Format: Rabab M. Al Deabel, Joyce Zhang, Anand Puaar, Avinash Kumar, Anait S. Levenson. Gnetin C inhibits reactivated AR signaling in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2582.
雄激素受体(AR)的激活是前列腺癌(PCa)发生发展的关键过程。在对雄激素剥夺治疗有显著的临床反应后,晚期PCa患者经常复发为更具侵袭性的去势抵抗性PCa,其中AR及其致癌变异被重新激活。因此,迫切需要开发有效抑制去势抵抗性前列腺癌中与AR作用相关的肿瘤促进信号的治疗策略。在葡萄和各种浆果中发现的膳食二苯乙烯是有希望的抗癌药物,具有多种细胞靶点,包括AR。特别是,我们之前证明了白藜芦醇(Res)及其天然类似物,紫檀二苯乙烯和picetanol,可以降低LNCaP和22Rv1细胞中AR的表达,因此,二苯乙烯作为治疗PCa的有希望的药理学安全药物具有吸引力。木糖素C是一种富含木糖素二聚体的植物,由于其改善的药代动力学,与木糖素和类似物相比,具有强大的生物学特性,在健康志愿者中是安全的。在这里,我们首次研究了Gnetin C靶向在抗去势22Rv1细胞中表达的全长和配体无关的AR剪接变体(AR- v7)的功效。首先,我们发现与Res和Pter相比,Gnetin C在22Rv1细胞中表现出更强的细胞毒作用。免疫印迹分析显示,Gnetin C抑制全长(100 kDA)和截断(80 kDA) AR-V7的表达呈剂量依赖性,重要的是,在相同剂量(50 μM)下,其效果明显高于Res和Pter。此外,与氟他胺和恩杂鲁胺(50 μM)这两种临床已知的AR拮抗剂相比,25 μM剂量的木糖素C的抑制作用要小2倍。此外,由于神经内分泌反分化(NED)与ar依赖机制和恩杂鲁胺耐药有关,我们评估了木质素C对SYP和CHGA的影响。目前正在进行的体内研究中,使用的是经过凝集素C处理的具有激活AR信号的转基因小鼠。综上所述,我们认为木质素C是二苯乙烯类化合物中的先导化合物,可有效阻断前列腺癌的AR再激活,可能对晚期前列腺癌具有显著的治疗意义。引文格式:Rabab M. Al Deabel, Joyce Zhang, Anand Puaar, Avinash Kumar, anit S. Levenson。木质素C抑制晚期前列腺癌中再激活的AR信号传导[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):2582。
{"title":"Abstract 2582: Gnetin C inhibits reactivated AR signaling in advanced prostate cancer","authors":"R. A. Deabel, Joyce Zhang, Anand Puaar, Avinash Kumar, A. S. Levenson","doi":"10.1158/1538-7445.AM2021-2582","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2582","url":null,"abstract":"The activation of androgen receptor (AR) is a key process in the development and progression of prostate cancer (PCa). After significant clinical response to androgen-deprivation therapy, patients with advanced PCa regularly relapse with more aggressive castrate-resistant PCa, in which AR and its oncogenic variants are reactivated. Therefore, there is an urgent necessity to develop therapeutic strategies that effectively suppress the tumor promoting signals associated with AR action in castrate-resistant PCa. Dietary stilbenes found in grapes and various berries are promising anticancer agents with multiple cellular targets, including AR. Particularly, we previously demonstrated that resveratrol (Res) and its naturally occurring analogs, pterostilbene and piceatannol, can decrease expression of AR in LNCaP and 22Rv1 cells, therefore presenting an attractive potential for stilbenes as promising pharmacologically safe agents in managing PCa. Gnetin C, a Res-dimer found abundantly in melinjo (Gnetum gnemon) plant, which possesses potent biological properties compared to Res and analogs due to its improved pharmacokinetics, is shown to be safe in healthy volunteers. Here, for the first time, we examine the efficacy of Gnetin C in targeting both full-length and ligand-independent AR splice variant (AR-V7) expressed in the castrate-resistant 22Rv1 cells. First, we found that Gnetin C shows significantly more potent cytotoxic effect in 22Rv1 cells compared to Res and Pter. Immunoblot analysis demonstrated that Gnetin C inhibited expression of both full-length (100 kDA) and truncated (80 kDA) AR-V7 in a dose-dependent manner and, importantly, with significantly higher efficacy than Res and Pter when treated with the same dose (50 μM). In addition, Gnetin C used in twice lesser dose (25 μM), showed substantially more inhibitory effect compared to flutamide and enzalutamide (50 μM), two known AR antagonists used in clinic. Moreover, since neuroendocrine trans-differentiation (NED) is associated with AR-dependent mechanisms and enzalutamide resistance in PCa, we evaluated the effects of Gnetin C on SYP and CHGA. Ongoing in vivo studies using transgenic mice with activated AR signaling treated with Gnetin C are in progress. Taken together, we propose that Gnetin C is a lead compound among stilbenes for effectively blocking AR reactivation in PCa and may potentially have noteworthy therapeutic implications against advanced PCa. Citation Format: Rabab M. Al Deabel, Joyce Zhang, Anand Puaar, Avinash Kumar, Anait S. Levenson. Gnetin C inhibits reactivated AR signaling in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2582.","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78150432","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 : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2535
Nam H. K. Nguyen, Huiyun Wu, Junmin Peng, J. Rubnitz, S. Pounds, J. Lamba
{"title":"Abstract 2535: Leukemic Cell Proteomic Profiling in Pediatric AML","authors":"Nam H. K. Nguyen, Huiyun Wu, Junmin Peng, J. Rubnitz, S. Pounds, J. Lamba","doi":"10.1158/1538-7445.AM2021-2535","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2535","url":null,"abstract":"","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79663669","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}