tbuckley/cabot-search huggingface dataset:
An indirect evaluation of bone saturation with zoledronic acid after long-term Q4 week dosing using plasma and urine pharmacokinetics.
Authors: Gabriel N. Hortobagyi, William Sallas, Ming Zheng, Ramon W. Mohanlal
Journal: Journal of Clinical Oncology (2015)

537 Background: Zoledronic acid (ZA) has a high binding affinity for human bone. This post-hoc analysis from the OPTIMIZE-2 trial evaluated whether there is evidence for bone saturation of ZA following long-term dosing at the standard q 4wk dosing. We hypothesized that if bone saturation of ZA would occur, then 1. Plasma and urinary levels of ZA would increase with prolonged dosing, and 2. Switching to a reduced dosing frequency of q12 weeks would reduce plasma and urinary ZA levels. Methods: OPTIMIZE-2 was a randomized, double-blind, multicenter trial in female pts with bone metastases from breast cancer who previously received long term ZA treatment (1 to 7 yrs) with standard q4 wk (infusion time of 15 min). Pts were randomized (1:1) to receive ZA 4 mg IV q4 wk or q12 wk for 1 year. ZA levels were analyzed in plasma and urine during 0-6h after thefirst dose (week 1) and after the week 36 dose in ZA-pretreated (1-7 yrs) pts with evaluable ZA levels (n=38). Results: Baseline creatinine clearances were comparable between the ZA q4 wk (N=21) and q12 wk (N=17) groups. Pre-infusion urine and plasma concentrations (ng/mL) at either time point (week 1 and 36) were in most cases near or below the lower limit of quantification. The table shows mean (SE) of ZA excreted in urine (in % of dose) and AUC (in h x mg/L) of ZA plasma concentrations, after the first and week 36 dose of ZA in OPTIMIZE-2. The plasma level s in the two dosing frequency groups (q4 wk and q12 wk) and both time points were similar. Urine ZA level s were also similar between the 2 dosing frequencies at both time points. These plasma and urine levels were also similar to levels from newly dosed patients receiving q 4wk ZA dosing for the first time (Chen et al. J Clin Pharmacol 2002;Skerjanec et al. J Clin Pharmacol 2003). Switching ZA dosing frequency from q4 wk to q12 wk did not reduce plasma and urinary ZA levels. Conclusions: Based on plasma and urinary ZA levels with standard and reduced dosing frequencies, our data does not suggest that prolonged treatment with ZA q4 wk results in bone saturation of ZA. Clinical trial information: NCT00320710. First dose; q4 wk Week 36; q4 wk First dose; q12 wk Week 36; q 12wk Plasma AUC 0-6h 0.37 (0.03) 0.43 (0.06) 0.40 (0.02) 0.43 (0.05) Urine 0-6h 26.0 (4.4) 36.6 (6.6) 23.7 (5.6) 30.8 (4.7)
Abstract 2769: Project Survival: Prospective clinical study utilizing multiomics and artificial intelligence to discover novel molecular markers for detection, stratification, and outcome in pancreatic cancer
Authors: Rangaprasad Sarangarajan, John Crowley, Amy Stoll-D'Astice, Valerie Bussberg, Cindy Nguyen, Leonardo O. Rodrigues, Emily Chen, Eric Michael Grund, Vivek K. Vishnudas, Michael Kiebish, Viatcheslav R. Akmaev, Manuel Hidalgo, Niven R. Narain, A. James Moser
Journal: Cancer Research (2017)

Abstract Pancreatic adenocarcinoma is the third leading cause of cancer death and has an extremely poor response to first line therapies. There is a critical unmet need to discover and implement effective diagnostic panels to stratify this disease and personalize treatment. Project Survival is a prospective study designed to discover biomarkers for patient diagnosis, stratification, and prognostics for pancreatic cancer. The multisite study is in year 2 of enrolling subjects within 6 categories: healthy volunteers with a relative with pancreatic cancer (N=50), pancreatitis (N=50), pancreatic cystic neoplasm (N=50), suspicious pancreatic masses with pathology other than pancreatic cancer (N=50), early stage (N=200) and metastatic pancreatic cancer (N=200). The study analyzes matched subject sera, plasma, buffy coat, saliva, urine, and tumor/adjacent normal tissues and integrates them with full clinical annotation. Multiple time points per subject per year are taken longitudinally over the course of the six year timeline enabling dynamic modeling. Samples are analyzed by Mass Spectrometry for the proteome, signaling lipidome, structural lipidome, and metabolome. The BERG Interrogative Biology® platform utilizes Artificial Intelligence to integrate multiomic profiles with medical annotation and clinical endpoints. Utilizing the power of the Bayesian Network learner, bAIcis™ (BERG Artificial Intelligence Clinical Information System), multiomic profiles were aligned to the longitudinal clinical information and subjected to the AI-algorithms that inferred probabilistic cause-and-effect relationships among molecular and clinical variables inferring markers of pancreatic cancer status and defining the interconnectivity of molecular features with clinical phenotype. Network features linking clinical endpoints and key network pressure points will be identified as molecular drivers. The drivers of clinical endpoints will be analyzed to rank potential biomarkers. Citation Format: Rangaprasad Sarangarajan, John Crowley, Amy Stoll-D'Astice, Valerie Bussberg, Cindy Nguyen, Leonardo O. Rodrigues, Emily Chen, Eric Michael Grund, Vivek K. Vishnudas, Michael Kiebish, Viatcheslav R. Akmaev, Manuel Hidalgo, Niven R. Narain, A. James Moser. Project Survival: Prospective clinical study utilizing multiomics and artificial intelligence to discover novel molecular markers for detection, stratification, and outcome in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2769. doi:10.1158/1538-7445.AM2017-2769
Abstract 1026: Identify BRD4 as a facilitator of replication stress response signaling
Authors: Jingwen Zhang, Brandon Willis, Maureen Hattersley, Alan Lau, Corinne Reimer, Michael Zinda, Stephen Fawell, Gordon Mills, Austin Dulak, Huawei Chen
Journal: Cancer Research (2017)

Abstract BRD4 is a member of the BET (bromodomain and extraterminal domain) family of chromatin readers that recognize acetylated-lysines on histones and nuclear proteins. Previous reports have demonstrated that select cancers depend on BRD4 to regulate oncogenic gene transcriptional programs. However, whether BRD4 contributes to cancer malignancy through other mechanisms has not been extensively evaluated. Here, we show that BRD4 is important for maintaining an intact DNA replication checkpoint in cancers. Displacement of BRD4 by BET bromodomain inhibitor AZD5153 in cell lines under intrinsic or exogenous replication stress led to a time-dependent reduction in phospho-Chk1 first detected within 30 minutes, and reaching maximum phospho-Chk1 inhibition (~85%) at an hour after AZD5153 treatment in U2OS cells. The decrease in Chk1 phosphorylation was observed without a concomitant decrease in total Chk1, and this was not replicated by treatment with pan-transcriptional inhibitors, suggesting a non-transcriptional mechanism linked to BRD4. Furthermore, BRD4 interacts with the DNA pre-replication complex and inhibition of BRD4 leads to hyperactivation of the pre-replication complex and aberrant DNA replication re-initiation under replication stress conditions. Consistent with a role in S-phase signaling, BETi treatment sensitizes replicating cells to replication stress-inducing agents. Finally, we observed that ovarian cancer cell lines are highly-sensitive to the combined inhibition of BRD4 and ATR. Coadministration of AZD5153 and AZD6738 (ATR inhibitor) significantly inhibited tumor growth in OVCAR3 ovarian xenograft model (TGI after 21 day dosing: AZD5153, 52%; AZD6738, 46%; Combo, 84%). Sustained tumor growth delay was observed after combination treatment cessation. Together, our study uncovered a novel function for BRD4 in regulating DNA replication stress response, and provide mechanistic rational for combining BETi with DNA damage-targeted agents for cancer therapies. Citation Format: Jingwen Zhang, Brandon Willis, Maureen Hattersley, Alan Lau, Corinne Reimer, Michael Zinda, Stephen Fawell, Gordon Mills, Austin Dulak, Huawei Chen. Identify BRD4 as a facilitator of replication stress response signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1026. doi:10.1158/1538-7445.AM2017-1026
Abstract 3173: AKT1low quiescent cancer cells persist after neoadjuvant chemotherapy in triple-negative breast cancer patients
Authors: Sheheryar Kabraji, Xavier Sole, Ying Huang, Clyde Bango, Michaela Bowden, Aditya Bardia, Dennis Sgroi, Massimo Loda, Sridhar Ramaswamy
Journal: Cancer Research (2017)

Abstract The mechanisms that allow triple negative breast cancer tumors to survive neoadjuvant chemotherapy are incompletely understood. Evidence suggests that proliferative heterogeneity may contribute to primary chemotherapy resistance in patients with triple negative breast cancer. AKT1low quiescent cancer cells (QCCs) are a quiescent, epigenetically plastic, and chemotherapy resistant subpopulation initially identified in experimental cancer models. Here, we identify QCCs in primary and metastatic human breast tumors using automated, quantitative, immunofluorescence microscopy coupled with computational and statistical analysis. We show that QCCs exist as non-random and heterogeneously distributed clusters within primary tumors. In addition, these QCC clusters persist after treatment with multi-agent, multi-cycle, neoadjuvant chemotherapy in both residual primary tumors as well as nodal and distant metastases in patients with triple negative breast cancer. Together, these data qualify QCCs as a non-genetic mechanism of chemotherapy resistance in triple negative breast cancer patients that warrants further study. Citation Format: Sheheryar Kabraji, Xavier Sole, Ying Huang, Clyde Bango, Michaela Bowden, Aditya Bardia, Dennis Sgroi, Massimo Loda, Sridhar Ramaswamy. AKT1low quiescent cancer cells persist after neoadjuvant chemotherapy in triple-negative breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3173. doi:10.1158/1538-7445.AM2017-3173
Abstract 811: Histological heterogeneity contributes to sunitinib resistance in clear cell renal cell carcinoma
Authors: Zsuzsanna Lichner, Rola Saleeb, Henriett Butz, Roy Nofech-Mozes, Sara Riad, Mina Farag, Andras Kapus, George Yousef
Journal: Cancer Research (2017)

Abstract Introduction: The receptor tyrosine kinase (RTK) inhibitor sunitinib is the first line treatment for advanced clear cell renal cell carcinoma (ccRCC). Sunitinib inhibits angiogenesis via blocking signaling through VEGFR. About 80% of patients develop resistance after a drug-sensitive period. Molecular changes early in treatment may impact drug resistance, but are poorly understood. Experimental Procedures: ACHN, 786-O and Renca cell lines were treated with 1 µM sunitinib. NSG mice were s.c. xenografted with the model cell lines and were treated with sunitinib at 40 mg/kg/day dose. mRNA expression was screened using Illumina HT-12 bead chip array and miRNA expression was assessed by Nanostring nCounter assay. R statistical packages were used for data processing. Reactome and miRPath softwares were used for downstream analysis. Results: Sunitinib treatment of ccRCC xenografts led to several early changes in tumor histology, such as the emergence of live tumor areas within the necrotic spaces. These areas showed membranous staining for E-cadherin, and β-catenin, while the rest of the tumor and vehicle-treated tumors were negative. In vitro model cell lines developed cancer spheroids when treated with sunitinib. Cancer spheroids were highly tumorigenic and metastatic, and expressed several established cancer stem cell markers. ccRCC cancer spheres, but not the 2D adherent cells, showed membranous staining for E-cadherin and β-catenin; similarly to the live tumor areas observed in in vivo sunitinib treatment. In vitro inhibition of E-cadherin by EGTA or by siRNA, interfered with viability of sunitinib treated ccRCC cell lines. Conclusions: Sunitinib treatment causes early phenotypic changes of the tumor in vivo and in vitro. The formation of highly metastatic and tumorigenic cancer spheres in model cell lines is the most prominent effect in vitro. We provide preliminary evidence that sunitinib induced in vitro cancer spheres and the live tumor areas that survive within necrotic patches of the sunitinib-treated xenografts, are related. Finally, membranous expression of E-cadherin enhances the survival of ccRCC cell lines under sunitinib treatment. Citation Format: Zsuzsanna Lichner, Rola Saleeb, Henriett Butz, Roy Nofech-Mozes, Sara Riad, Mina Farag, Andras Kapus, George Yousef. Histological heterogeneity contributes to sunitinib resistance in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 811. doi:10.1158/1538-7445.AM2017-811
Abstract 1642: Evaluation of ENMD-2076 in combination with anti-PD1 in syngeneic cancer models
Authors: Graham C. Fletcher, Reza Kiarash, Mark R. Bray, Amanda S. Hu, Ken K. Ren
Journal: Cancer Research (2017)

Abstract ENMD-2076 is a clinical stage compound with potent activity towards Aurora A and angiogenic kinases. ENMD-2076 has shown promising activity in multiple Phase 1 clinical trials, as well as in a Phase 2 trial in advanced ovarian cancer. ENMD-2076 is currently the subject of several ongoing Phase 2 clinical trials including fibrolamellar carcinoma, triple-negative breast cancer (TNBC), advanced/metastatic soft tissue sarcoma (STS), and advanced ovarian clear cell carcinomas (OCCC). ENMD-2076 has been developed to date as a single agent, however ENMD-2076 inhibits a spectrum of targets including Aurora A, FAK, CSF1R, c-Kit, and KDR, that are potentially involved in immune evasion mechanisms. These kinases have been shown in published studies, when inhibited, to enhance or augment the activity of immune checkpoint inhibitors such as anti-PD1. A study was thereby conducted in syngeneic models to determine the utility of ENMD-2076 combined with immune checkpoint inhibition as a rational strategy for cancer therapy. The study evaluated the efficacy of ENMD-2076 administered daily by oral gavage in the MC38 and CT26 colon cancer models, alone and in combination with an anti-PD1 antibody. Xenografts were established in the appropriate mouse strain (C57BL/6 and BALBc, respectively) by the subcutaneous inoculation of MC38 or CT26 cells into the right flank of female mice. Treatment was initiated 7 days following inoculation when tumor volumes had reached a mean volume of approximately 85 mm3. All treatments were well tolerated, with no significant body weight loss seen during either study. While CT26 tumors were relatively refractory to single agent ENMD-2076, tumor regression was observed in several MC38-bearing animals suggesting an immune activating mechanism. In both models a trend was observed for an augmentation of anti-tumor response in combination relative to single agent ENMD-2076 and anti-PD1 alone. Further studies to evaluate mechanism and an assessment of re-challenge experiments in animals exhibiting complete regression of tumors will be discussed. These studies support the further evaluation of ENMD-2076 in combination with immune checkpoint inhibition as a strategy for cancer therapy. Citation Format: Graham C. Fletcher, Reza Kiarash, Mark R. Bray, Amanda S. Hu, Ken K. Ren. Evaluation of ENMD-2076 in combination with anti-PD1 in syngeneic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1642. doi:10.1158/1538-7445.AM2017-1642
Abstract 981: The design and characterization of a selective TRIM24 degrader
Authors: Lara N. Gechijian, Dennis Buckley, Matthew Lawlor, Thomas Scott, Joshiawa Paulk, Jaime Reyes, Georg Winter, Michael Erb, Chris Ott, Sirano Dhe-Paganon, James Bradner
Journal: Cancer Research (2017)

Abstract A fundamental biological understanding of the individual contributions of functional domains within multidomain proteins is critical to inform therapeutic approaches to targeting mechanisms driving human disease. TRIM24 is a multi-domain protein that has been broadly characterized as a co-regulator of transcription. It is therapeutically relevant as it is implicated as a dependency in many human cancers, however, the potent and selective inhibitors of the TRIM24 bromodomain do not have well-characterized phenotypic consequences. Where inhibition of one activity of a protein does not appear to be efficacious, chemical knockdown tools allow for the acute depletion of the entire protein, therefore eliminating all protein activities. In this study, we have used chemical degradation as one strategy to target the entire TRIM24 protein, where we have shown that a bifunctional degrader molecule hijacks the ubiquitin ligase machinery for targeted TRIM24 degradation. We have shown that TRIM24 degradation is required to perturb the oncogenic state in leukemia. In this context, TRIM24 degradation rather than bromodomain inhibition alone is required to displace TRIM24 from chromatin. Using this probe, a further understanding of the contribution of TRIM24 domains to its transcriptional activation function will provide mechanistic insight as to how TRIM24 promotes a gene expression program permissive of the oncogenic state, as well as inform a therapeutic approach to target multidomain proteins, such as TRIM24, that are tightly linked to disease. Citation Format: Lara N. Gechijian, Dennis Buckley, Matthew Lawlor, Thomas Scott, Joshiawa Paulk, Jaime Reyes, Georg Winter, Michael Erb, Chris Ott, Sirano Dhe-Paganon, James Bradner. The design and characterization of a selective TRIM24 degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 981. doi:10.1158/1538-7445.AM2017-981
Abstract 1077: Extra-virgin olive oil Met inhibitor oleocanthal-lapatinib: a novel synergistic combination for HER2-dependent breast malignancies
Authors: Abu Bakar Siddique, Hassan Y. Ebrahim, Mohamed R. Akl, Mohamed M. Mohyeldin, Khalid A. El Sayed
Journal: Cancer Research (2017)

Abstract Breast cancer (BC) is the most commonly diagnosed cancer in women, claiming the lives of hundreds of thousands of women each year. The Mediterranean diet is known to reduce BC and colon cancer incidence. Extra-virgin olive oil (EVOO) represents a main ingredient in this diet. The EVOO-derived (-)-oleocanthal was shown to target the Receptor tyrosine kinases (RTK) c-Met. Oleocanthal exerted potent in-vivo efficacy in an orthotopic athymic nude mouse breast cancer xenograft model much greater than its modest in-vitro potency. Dysregulation of RTKs, specifically EGFR/HER-2 pathways, correlates with poor prognosis and more aggressive breast cancer phenotypes. Dysregulation of hepatocyte growth factor (HGF) and its receptor c Met correlates with aggressive proliferation, invasive character, and pathological motility. c-Met amplification correlates with escape from the anticancer effects of EGFR/HER2 inhibitors and cetuximab. (-)-Oleocanthal (OC) is a naturally occurring phenolic secoiridoid from EVOO showed significant in vivo activity against invasive breast cancers through targeting HGF/Met axis. The Dual EGFR/HER-2 inhibitor lapatinib (LP) has already been in clinical practice for HER2-amplified breast cancer, which occasionally develops resistance through c-Met upregulation. Lapatinib’s therapeutic dose induced significant hepatotoxicity. The combined use of OC and LP was hypothesized not only for therapeutic synergy but also to notably reduce LP’s effective doses and therefore minimize its hepatotoxicity. Combined treatment of subeffective doses of lapatinib and OC caused significant in vitro and in vivo synergistic antiproliferative effects against the HER-2-dependent BT-474 and SKBR-3 BC cells. Interestingly, OC induced 4-fold lapatinib dose reduction index with improved potency. Protein microarray and Western blot analyses of OC-LP combination treatments synergistically reduced EGFR, HER-2, FAK, JAK1, MEK, and c-Met activation. These results propose OC use as dietary supplement to synergize the chemotherapeutic effects of LP, reduce its therapeutic dose to ¼ and therefore can minimize its morbidity. Combinatorial inhibition of c-Met-HER-2-EGFR is an effective strategy for the control of HER-2 positive breast cancer. This study was supported by NIH/NCI project 1R15CA167475-01. Citation Format: Abu Bakar Siddique, Hassan Y. Ebrahim, Mohamed R. Akl, Mohamed M. Mohyeldin, Khalid A. El Sayed. Extra-virgin olive oil Met inhibitor oleocanthal-lapatinib: a novel synergistic combination for HER2-dependent breast malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1077. doi:10.1158/1538-7445.AM2017-1077
Abstract 1855: Developed operation method for patient-drived orthotopic xenograft model of hepatocellular carcinoma
Authors: Hye Rim Byeon, YunSung Seo, Sun-Young Kong, Seung Duk Lee
Journal: Cancer Research (2017)

Abstract Patient-drived xenograft(PDX) model is a biological organized platform and a patient substitute. Recent studies use the ectopic model for hepatocellular carcinoma(HCC) but this model don’t reflect likewise the tumor state of patient. For exact prognosis, it is need to establish patient-derived orthotopic xenograft(PDOX) mouse model of hepatocellular carcinoma using direct injection technique. Additionally, secretion of growth factor from bone marrow stem cells is promoted after partial hepatectomy. This mechanism is helpful to not only general liver regeneration but also tumorigenesis. Based on former PDX research, we develop the new protocol using direct injection technique. From January 2015 to June 2016, consent about getting tumor pieces to the patient of hepatocellular carcinoma. The pieces is stored in RPMI1640 and moved from operation room to research room immediately. For PDOX and PDX to subcutaneous model, 8~10weeks old NOD SCID and NSG male mouse is used. The tumor pieces cutted to the cube size 1mm. For stop the bleeding, inferior vena cava is blocked using Bulldog Clamp and the cube is directly injected median lobe to 3 places randomly. After clear the Bulldog Clamp, a left lobe is removed using tie and weighted. After 3 months, the PDOX mouse is checked for cancer growth using MRI or PET-CT. Successful PDOX or PDX to subcutaneous model is sacrificed and succeeded a generation to another Balb/C-nude male mouse 8~10weeks old. The rate of success of PDOX model and PDX to subcutaneous model is about 10% respectively. Formed tumor is verified by H&amp;E staining. Based on protocol established, further study plan is required for improving on the rate of success to establish PDOX model and clinical application. Note: This abstract was not presented at the meeting. Citation Format: Hye Rim Byeon, YunSung Seo, Sun-Young Kong, Seung Duk Lee. Developed operation method for patient-drived orthotopic xenograft model of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1855. doi:10.1158/1538-7445.AM2017-1855