tbuckley/cabot-search huggingface dataset:
Abstract 4114: Blocking Ezrin can inhibit HGF/Met signaling-induced metastasis
Authors: Yanlin Yu, Liping Huang, Glenn Merlino
Journal: Cancer Research (2016)

Abstract Hepatocyte Growth Factor (HGF) binds its receptor Met and induces autophosphorylation of MET, which in turn activate appropriate signaling pathways. Aberrant HGF/Met signaling promotes tumor progression by facilitating cell proliferation, migration, invasion, and metastasis. Previously, we found that constitutive HGF/Met signaling promotes melanoma metastasis through a nonautocrine mechanism in engineered mouse models (Cancer Res, 2002); however, the molecular mechanisms by downstream of HGF/Met signaling that induce metastasis are not known. We recently identified the cytoskeletal organizer Ezrin as a key metastatic regulator using an HGF transgenic mouse model (Nature Medicine, 2004), implicating Ezrin is in HGF/Met signaling-induced metastasis. We hypothesize that HGF/Met signaling promotes metastasis by regulating expression of Ezrin. To test hypothesis, we are: 1) evaluating the relationship between ezrin expression and HGF/Met signaling; 2) validating the role of Ezrin in HGF/Met signaling -induced metastasis; 3) elaborating mechanisms underlying this HGF/Met signaling-mediated regulation of Ezrin expression; 4) evaluating the clinical therapeutic utility of blockage of Ezrin function in preclinical mouse models. We found that HGF is able to stimulate the expression of Ezrin. Moreover, analysis of the established model systems with HGF and Met alone or HGF with Met demonstrated that Ezrin expression correlated with activated HGF/Met signaling, suggesting that HGF/Met signaling regulates the expression of Ezrin. Interestingly, we showed that HGF/Met signaling could activate transcription factor Sp1 through the MAPK pathway. We further found that activated Sp1 could directly bind to the promoter of the Ezrin gene and regulate the transcription of Ezrin. Notably, knockdown of Ezrin expression by shRNAs inhibited the metastasis induced by both HGF/Met autocrine and notautocrine signaling in syngeneic host and HGF GEM hosts. We also used small molecule drugs in preclinical mouse models to confirm that Ezrin is at least one of downstream molecules mediating HGF/Met signaling-induced metastasis in melanoma. We conclude that Ezrin is a key downstream substrate involved in the regulation of HGF/Met signaling-induced metastasis. We demonstrate a link between Ezrin and HGF/Met/MAPK/Sp1 activation in the metastatic process. Our data indicate that Ezrin represents a promising therapeutic target for patients with activated HGF/Met signaling. Citation Format: Yanlin Yu, Liping Huang, Glenn Merlino. Blocking Ezrin can inhibit HGF/Met signaling-induced metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4114.
Abstract 5129: Delineating immune networks in colorectal cancers to predict effects of immune checkpoint inhibitors using CANScript platform technology preserving tumor immune microenvironment
Authors: Pradip K. Majumder, Nilesh Brijwani, Nikita N. Karandikar, Vinod D. Radhakrishna, Muthusamy Oliyarasi, Dency D. Pinto, Babu Balakrishnan, Vasathakumar Sekar, Manoj Rajappa, Debapriya G. Mehrotra, Priyanka Chevur, Priyanka Chevur, Arkasubhra Ghosh, Saravanan Thyiagarajan, Padhma Radhakrishnan, Biswanath Majumder
Journal: Cancer Research (2016)

Abstract Colorectal cancer (CRC) is one of the leading causes of cancer related mortality. Recent findings from clinical studies showed that immune checkpoint inhibitors are making good progress towards clinical practise. However, existing biomarkers and 3D platforms are not equipped to offer reliable prediction of response of these drugs. We recently engineered a personalized ex vivo systems biology based platform using patient tumors called CANScriptTM (Majumder B et al Nat. Commun. 2015, Goldman A et al Nat. Commun. 2015) and a companion in vivo patient derived immune reconstituted xenograft model (Mi-HTX) preserving multiple critical phenotypic profiles orchestrating tumor-immune cross talk and dysfunction. We further performed baseline characterization of immune markers (CD4, CD8, CD68, CXCR4 and CD45-RO). Intratumor heterogeneity of both M1 and M2 phenotypes were observed irrespective of clinico-pathological features. Baseline CD68 enrichment status was found to be correlated with therapy failure for some patients where clinical outcome (PERCIST) was available. Flow cytometry and microarray analysis showed preservation of diverse sets of functional CD4, CD8 and NK phenotypes along with degranulation markers (CD107a), IFN-γ and FoxP3 in both in vivo and ex vivo tumors reconstituted with ex vivo primed PBMC. The comparative response profiling of these models following treatment with immune checkpoint inhibitors suggested enhanced antitumor effects (as measured by multiple functional parameters like viability, proliferation, morphology and apoptosis). Together, these findings highlight the strengths of immune-competent functional testing tools to stratify patients for precision immunotherapy where direct response prediction biomarkers are still elusive. 1. Majumder B et al. Nat. Commun.6:6169 (2015). 2. Goldman A et al. Nat. Commun. 6:6139 (2015). Citation Format: Pradip K. Majumder, Nilesh Brijwani, Nikita N. Karandikar, Vinod D. Radhakrishna, Muthusamy Oliyarasi, Dency D. Pinto, Babu Balakrishnan, Vasathakumar Sekar, Manoj Rajappa, Debapriya G. Mehrotra, Priyanka Chevur, Priyanka Chevur, Arkasubhra Ghosh, Saravanan Thyiagarajan, Padhma Radhakrishnan, Biswanath Majumder. Delineating immune networks in colorectal cancers to predict effects of immune checkpoint inhibitors using CANScript platform technology preserving tumor immune microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5129.
Abstract 1723: Novel drug candidates CEP1430 and CEP1507 against cancer stem cells and circulating tumor cells in advanced stage pancreatic cancer
Authors: Cristian Sharma, Padmini Narayanan, Michael Sharma, Robert Rodriguez, Miriam Navel, Donna Stanton, Natalee Amezcua, Shaleekha Sharma, Mandana Amiri, Jitesh Jani, Sherven Sharma, Jay P. Sharma
Journal: Cancer Research (2016)

Abstract Despite improvements in treatment modalities, pancreatic cancer remains the fourth leading cause of cancer mortality in the US. The 5-year survival rate is less than 6% because of the extent of metastases at the time of diagnosis. The treatment of pancreatic cancer remains challenging however there is much optimism with targeted strategies and trial designs. The interrogation of pathway centric targets that regulate the regenerative and metastatic activities in the tumor, adequate molecular-hypothesis driven trial designs with robust prognostic and predictive markers of response are necessary for the development of effective therapeutic strategies for long term anti-tumor benefit. Here, we examined the efficacy of CEP1430 and CEP1507 to target cancer stem cells (CSC) and circulating tumor cells (CTC) in human pancreatic cancer. The pancreatic CSCs expressed the following markers(CD133,CD44,CXCR4,SSEA3/4,Oct4,ALDH,Telomerase,&amp; Nestin). In vitro CEP1430 inhibited the growth of CSCs whereas CEP1507 inhibited CTCs that expressed the following markers [CK19, CEA, CA19-9,CK8 /18,h-TERT,C-MET,CK20,EpCAM, Vimentin, E- Cadherin, MUC1, CEA CAM5,CD45 neg]. Gemcitabine on the other hand suppressed the viability of non-CSCs (differentiated tumor Cells) by 70%. In accord, in vivo studies showed that CEP1507 when combined with gemcitabine eliminated the engraftment of human pancreatic cancer CTCs by 85% (n = 20,p&amp;lt;0.001). In contrast, CEP1430 in combination with gemcitabine selectively inhibited CSCs by 80% (n = 20,p&amp;lt;0.001) and was more effective than the individual agents. This data demonstrates that CEP1430 and CEP1507 that target CSCs and CTCs respectively may change the treatment paradigm and enhance the efficacy of gemcitabine in advanced pancreatic cancer. Further studies will evaluate the full potential of this approach to target the CSCs - and metastasis-initiating cells (CTCs) as combination therapy against locally advanced and metastatic pancreatic cancer. Citation Format: Cristian Sharma, Padmini Narayanan, Michael Sharma, Robert Rodriguez, Miriam Navel, Donna Stanton, Natalee Amezcua, Shaleekha Sharma, Mandana Amiri, Jitesh Jani, Sherven Sharma, Jay P. Sharma. Novel drug candidates CEP1430 and CEP1507 against cancer stem cells and circulating tumor cells in advanced stage pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1723.
Abstract 3070: Potent and selective inhibition of CDK7 by novel covalent inhibitors
Authors: Leena Khare Satyam, Ramulu Poddutoori, Subhendu Mukherjee, Sivapriya Marappan, Sreevalsam Gopinath, Raghuveer Ramachandra, Manoj Kumar Pothuganti, Shilpa S. Nayak, Nandish C, Chandranath Naik, Ravindra MV, Madhu B. Dabbeeru, Nagaraju A, Mahankali B, Thomas Antony, Chetan Pandit, Shekar Chelur, Girish Daginakatte, Susanta Samajdar, Murali Ramachandra
Journal: Cancer Research (2016)

Abstract Background: Phosphorylation of the RNA polymerase II (RNAPII) in C-terminal domain (CTD) by Cyclin-dependent kinase 7 (CDK7) is an important step in cellular transcription process. Hence pharmacological modulation of CDK7 kinase activity is considered as an interesting approach to treat cancers that critically dependent on transcription to maintain their oncogenic state. Experimental procedures: Multiple series of novel covalent CDK7 inhibitors were identified by SBDD approach based on the binding mode of known CDK7 inhibitors to find early hits. Iterative medicinal chemistry efforts were performed to identify several lead compounds by optimizing the initial hits to achieve good physicochemical properties, high potency, good selectivity and desirable pharmacokinetic profile. Summary: Highly potent ATP competitive covalent inhibitors of CDK7 from two distinct chemical series were identified. They show time-dependent inhibition of CDK7 enzyme activity as a proof of covalent binding and exhibit potent anti-proliferative activity in cell lines derived from various tumor types. CDK7 modulation by these compounds was also confirmed by monitoring cellular pS5RNAPII levels. Representative compounds from each series showed very good selectivity profile in broad kinase (332) panel. Lead molecules were identified based on excellent drug-like properties (solubility, permeability and good oral bioavailability). Tolerability and efficacy studies in rodent xenograft models are ongoing with selected leads to test their impact on tumor growth inhibition and to determine therapeutic window by oral administration. Conclusion: We have identified novel and selective CDK7 covalent inhibitors from two distinct chemical series with optimized drug-like properties including oral bioavailability. These compounds are being evaluated for anti-tumor activity in mouse xenograft models. Citation Format: Leena Khare Satyam, Ramulu Poddutoori, Subhendu Mukherjee, Sivapriya Marappan, Sreevalsam Gopinath, Raghuveer Ramachandra, Manoj Kumar Pothuganti, Shilpa S. Nayak, Nandish C, Chandranath Naik, Ravindra MV, Madhu B. Dabbeeru, Nagaraju A, Mahankali B, Thomas Antony, Chetan Pandit, Shekar Chelur, Girish Daginakatte, Susanta Samajdar, Murali Ramachandra. Potent and selective inhibition of CDK7 by novel covalent inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3070.
Prognostic value of neutrophil-to-lymphocyte ratio (NLR) in pts with metastatic castration-resistant prostate cancer (mCRPC) receiving a new agent (NA)- based third-line treatment: Final results from a multicenter Italian study.
Authors: Orazio Caffo, Emilio Bria, Ugo De Giorgi, Marcello Tucci, Luca Galli, Lucia Fratino, Sabrina Rossetti, Roberto Iacovelli, Giovanni Lo Re, Claudia Mosillo, Donatello Gasparro, Pamela Guglielmini, Azzurra Damiani, Giuseppe Procopio, Delia De Lisi, Cinzia Ortega, Sarah Scagliarini, Maddalena Donini, Isabella Sperduti, Umberto Basso
Journal: Journal of Clinical Oncology (2017)

230 Background: High NLR has been reported to be a poor prognostic indicator in both first and second mCRPC lines, while no information is available concerning this issue in pts treated in third line therapy. The present study is aimed to assess the possible relationship between third line clinical outcomes and NLR in a series of mCRPC pts treated with a NA [abiraterone acetate (AA), cabazitaxel (CABA), or enzalutamide (ENZ)] after the failure of docetaxel (DOC) and another NA. Methods: We collected data of pts who received sequentially two NAs after DOC in 38 Italian hospitals. For each pt we recorded the clinical outcome of all treatments received after DOC. Cox regression analysis was used to assess the independent prognostic value of a series of pretreatment covariates, in terms of overall survival (OS), comprising NLR. Results: A consecutive series of 476 mCRPC pts with bone (86%), nodal (56%) or visceral (15%) mets, was collected. All pts received a NA-based third line: 135 received AA, 221 CABA and 120 ENZ. Data on NLR were available for 398 pts (84%). In the univariate analyses, the NLR as a discrete variable dichotomized according to the Maximally Selected Log-Rank statistics (optimal cut-off: 3.66), was significantly associated with both OS and progression free survival (PFS), calculated from the third line start (p &lt; 0.0001). At the multivariate analysis, NLR, performance status, pain, hemoglobin, alkaline phosphatase, treatment with AA and with CABA were independent prognostic factors for PFS, while NLR, performance status, hemoglobin, PSA, and lactate dehydrogenase were independent prognostic factors for OS . In Kaplan-Meier analysis, the median OS from the start of third-line was higher (14.2 vs 9.3 mos) in pts with NLR ≤ 3.1 compared to those with NLR &gt; 3.1 (log-rank; P &lt; 0.0001). Similarly, the median PFS was 5.5 and 3.8 (log-rank; P &lt; 0.0001) in pts with NLR ≤ 3.66 and &gt; 3.66, respectively. Conclusions: Our results, observed in the largest cohort of mCRCP pts treated with NA-based third line after DOC and another NA, confirms that NLR is an independent factor for PFS and OS also in this population.
Individualized Molecular Analyses Guide Efforts (IMAGE): A Prospective Study of Molecular Profiling of Tissue and Blood in Metastatic Triple-Negative Breast Cancer
Authors: Heather A. Parsons, Julia A. Beaver, Ashley Cimino-Mathews, Siraj M. Ali, Jennifer Axilbund, David Chu, Roisin M. Connolly, Rory L. Cochran, Sarah Croessmann, Travis A. Clark, Christopher D. Gocke, Stacie C. Jeter, Mark R. Kennedy, Josh Lauring, Justin Lee, Doron Lipson, Vincent A. Miller, Geoff A. Otto, Gary L. Rosner, Jeffrey S. Ross, Shannon Slater, Philip J. Stephens, Dustin A. VanDenBerg, Antonio C. Wolff, Lauren E. Young, Daniel J. Zabransky, Zhe Zhang, Jane Zorzi, Vered Stearns, Ben H. Park
Journal: Clinical Cancer Research (2016)

Abstract Purpose: The clinical utility of next-generation sequencing (NGS) in breast cancer has not been demonstrated. We hypothesized that we could perform NGS of a new biopsy from patients with metastatic triple-negative breast cancer (TNBC) in a clinically actionable timeframe. Experimental Design: We planned to enroll 40 patients onto a prospective study, Individualized Molecular Analyses Guide Efforts (IMAGE), to evaluate the feasibility of obtaining a new biopsy of a metastatic site, perform NGS (FoundationOne), and convene a molecular tumor board to formulate treatment recommendations within 28 days. We collected blood at baseline and at time of restaging to assess cell-free circulating plasma tumor DNA (ptDNA). Results: We enrolled 26 women with metastatic TNBC who had received ≥1 line of prior chemotherapy, and 20 (77%) underwent NGS of a metastatic site biopsy. Twelve (60%) evaluable patients received treatment recommendations within 28 days of consent. The study closed after 20 patients underwent NGS, based on protocol-specified interim futility analysis. Three patients went on to receive genomically directed therapies. Twenty-four of 26 patients had genetic alterations successfully detected in ptDNA. Among 5 patients, 4 mutations found in tumor tissues were not identified in blood, and 4 mutations found in blood were not found in corresponding tumors. In 9 patients, NGS of follow-up blood samples showed 100% concordance with baseline blood samples. Conclusions: This study demonstrates challenges of performing NGS on prospective tissue biopsies in patients with metastatic TNBC within 28 days, while also highlighting the potential use of blood as a more time-efficient and less invasive method of mutational assessment. Clin Cancer Res; 23(2); 379–86. ©2016 AACR.
Biochemical and structural analysis of the interaction between β-amyloid and fibrinogen
Authors: Daria Zamolodchikov, Hanna E. Berk-Rauch, Deena A. Oren, Daniel S. Stor, Pradeep K. Singh, Masanori Kawasaki, Kazuyoshi Aso, Sidney Strickland, Hyung Jin Ahn
Journal: Blood (2016)
Abstract 987: A novel cell cycle-associated lncRNA, HOXA11-AS, is transcribed from 5-prime end of HOXA transcript and a biomarker of progression in glioma
Authors: Qixue Wang, Junxia Zhang, Yanwei Liu, Junhju Zhou, Chunsheng Kang, Lei Han
Journal: Cancer Research (2016)

Abstract The comprehensive lncRNA expression signature in glioma remains fully unknown. We performed a high throughput microarray to detect ncRNA expression profile in 225 human glioma tissues. One novel lncRNA, HOXA11-AS with unknown function, is the antisense transcript of HOX11 gene. The results showed that HOXA11-AS was closely associated with glioma grade and poor prognosis. Multivariate cox regression analysis revealed that HOXA11-AS was an independent prognostic factor in glioblastoma multiforme patients and its expression was correlated with glioma molecular subtype of the Cancer Genome Atlas. Gene set enrichment analysis indicated that gene sets most correlated with HOXA11-AS expression involved in cell cycle progression. Overexpression of HOXA11-AS transcript promoted cell proliferation in vitro while knockdown of HOXA11-AS expression manifested a repressive function during these cellular processes via regulating cell cycle progress. The growth promoting and inhibiting effect of HOXA11-AS was also demonstrated in a xenograft mouse model. For the first time, our data confirms that HOXA11-AS is an important long non-coding RNA that primarily serves as a prognostic factor for glioma patient survival, a biomarker for identifying glioma molecular subtypes, and therapeutic target for glioma patient. Citation Format: Qixue Wang, Junxia Zhang, Yanwei Liu, Junhju Zhou, Chunsheng Kang, Lei Han. A novel cell cycle-associated lncRNA, HOXA11-AS, is transcribed from 5-prime end of HOXA transcript and a biomarker of progression in glioma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 987.
Randomized head-to-head prospective study of pharmacokinetic and pharmacodynamic properties of leuprolide acetate formulations: 7.5 mg single depot subcutaneous vs 7.5 mg intramuscular microsphere.
Authors: Daniel R. Saltzstein, Judd W. Moul, Stephan de la Motte, John A. McLane, David W. Osborne, Alex Yang, Raoul S. Concepcion
Journal: Journal of Clinical Oncology (2015)

e16048 Background: Leuprolide acetate (LA), a LHRH agonist, is the standard of care and used to suppress serum testosterone (T) to castrate level. Currently 2 LA formulations are available: a viscous liquid that forms a solid, controlled release implant (ATRIGEL) injected subcutaneously (SQ) or a microsphere intramuscular (IM) injection. The objective was to compare head-to-head the pharmacokinetics (PK) and pharmacodynamics (PD) of SQ-LA to IM-LA. Methods: In this open label, randomized, single dose, head to head study, healthy, male subjects (ages 18-55) received 7.5 mg LA in either IM formulation or solid depot SQ formulation. Blood samples were taken at 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 h post-dose, every other day until day 7, and once a week until day 56. LA concentration in serum was analyzed with HPLC. PK parameters AUC, Cmax, Tmax (time to Cmax), t1/2 and concentration-time data were evaluated and descriptive statistics determined LA concentration over time. Concentration-time curves showed PD of T from radioimmunoassay detection. Results: The study was conducted in 32 healthy males, randomized equally to SQ-LA (N = 16) and IM-LA (N = 16) groups. Following administration, mean Cmax was 19 ± 8 ng/mL with a mean Tmax of 2.1 ± 0.8 h for SQ-LA, compared to Cmax of 27 ± 4.9 ng/mL and Tmax 1 ± 0.4 h for IM-LA. AUC for SQ-LA and IM-LA products were 479 ± 133 and 248 ± 65 ng*h/mL, respectively. As a result of significantly higher AUC, SQ-LA suppressed median serum T longer than IM-LA (14-49 vs 14-35 days, respectively). Conclusions: The AUC of SQ-LA was approximately twice that of IM-LA, indicating a larger delivery of drug over time for SQ-LA. The lower Cmax and delayed Tmax of SQ-LA further suggest a more consistent and continuous PK profile. The improved PK and longer duration of action of SQ-LA may allow greater testosterone suppression and fewer breakthroughs. Further studies are needed to understand if these results will improve patient outcomes. SQ-LA has twice the AUC of IM-LA and 70% longer duration of T suppression. SQ-LA N = 16 IM-LA N = 16 Ratio SQ-LA/IM-LA AUClast (ng*h/mL) 479 ± 133 248 ± 65 1.9 T suppression (Days) 14-49 14-35 1.7