Nagarajan Kannan, Syed Mohammed Musheer Aalam, Xiaojia Tang, K. Kalari, P. Kashyap, Jun Chen, Stephen Johnson, A. Sadanandam, M. Sherman
{"title":"Abstract LB226: Maternal microbiome protects host against clonal de novo transformation, early onset systemic metastasis, and sudden death","authors":"Nagarajan Kannan, Syed Mohammed Musheer Aalam, Xiaojia Tang, K. Kalari, P. Kashyap, Jun Chen, Stephen Johnson, A. Sadanandam, M. Sherman","doi":"10.1158/1538-7445.AM2021-LB226","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB226","url":null,"abstract":"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.","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72704937","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}
L. G. Acosta, C. Takita, J. Wright, I. Reis, George R. Yang, Jennifer J. Hu
{"title":"Abstract 2559: An analysis of patient-reported outcomes of radiation dermatitis in a multiracial/ethnic breast cancer population","authors":"L. G. Acosta, C. Takita, J. Wright, I. Reis, George R. Yang, Jennifer J. Hu","doi":"10.1158/1538-7445.AM2021-2559","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2559","url":null,"abstract":"","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85639852","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}
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
{"title":"Abstract 2547: DNA damage level correlates with grade of cervical dysplasia: a potential biomarker to assess cervical cancer risk","authors":"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","doi":"10.1158/1538-7445.AM2021-2547","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2547","url":null,"abstract":"","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76855551","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}
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
{"title":"Abstract LB223: Beans to Enrich the Gut microbiome vs. Obesity's Negative Effects: First results from the BE GONE Trial in high-risk colorectal patients","authors":"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","doi":"10.1158/1538-7445.AM2021-LB223","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB223","url":null,"abstract":"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","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85816915","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}
M. Aslam, S. Mcclintock, M. A. H. Jawad-Makki, K. Knuver, Daniyal M. Nadeem, H. Ahmad, D. Attili, D. Turgeon, J. Varani
{"title":"Abstract LB220: Cellular Differentiation and Growth Control in the Human Colonic epithelium: Comparing Clinical Trial Outcomes to Responses in Human Colonoid Culture","authors":"M. Aslam, S. Mcclintock, M. A. H. Jawad-Makki, K. Knuver, Daniyal M. Nadeem, H. Ahmad, D. Attili, D. Turgeon, J. Varani","doi":"10.1158/1538-7445.AM2021-LB220","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB220","url":null,"abstract":"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 ","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82243381","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}
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":null,"pages":null},"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}
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
{"title":"Abstract 2581: Dietary fat influences pancreatic cancer progression by altering cell membrane lipid content to impact the PI3K/AKT pathway","authors":"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","doi":"10.1158/1538-7445.AM2021-2581","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2581","url":null,"abstract":"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 [","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89458472","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}
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
{"title":"Abstract 2605: A natural history study of men with high-risk genetics for prostate cancer (PCa) using multiparametric MRI (mpMRI)","authors":"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","doi":"10.1158/1538-7445.AM2021-2605","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2605","url":null,"abstract":"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.","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78028173","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}
R. A. Deabel, Joyce Zhang, Anand Puaar, Avinash Kumar, A. S. Levenson
{"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":null,"pages":null},"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}
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":null,"pages":null},"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}