tbuckley/cabot-search huggingface dataset:
Specific and Efficient Regression of Cancers Harboring KRAS Mutation by Targeted RNA Replacement
Authors: Sung Jin Kim, Ju Hyun Kim, Bitna Yang, Jin-Sook Jeong, Seong-Wook Lee
Journal: Molecular Therapy (2017)

Mutations in the KRAS gene, which persistently activate RAS function, are most frequently found in many types of human cancers. Here, we proposed and verified a new approach against cancers harboring the KRAS mutation with high cancer selectivity and efficient anti-cancer effects based on targeted RNA replacement. To this end, trans-splicing ribozymes from Tetrahymena group I intron were developed, which can specifically target and reprogram the mutant KRAS G12V transcript to induce therapeutic gene activity in cells. Adenoviral vectors containing the specific ribozymes with downstream suicide gene were constructed and then infection with the adenoviruses specifically downregulated KRAS G12V expression and killed KRAS G12V-harboring cancer cells additively upon pro-drug treatment, but it did not affect the growth of wild-type KRAS-expressing cells. Minimal liver toxicity was noted when the adenoviruses were administered systemically in vivo. Importantly, intratumoral injection of the adenoviruses with pro-drug treatment specifically and significantly impeded the growth of xenografted tumors harboring KRAS G12V through a trans-splicing reaction with the target RNA. In contrast, xenografted tumors harboring wild-type KRAS were not affected by the adenoviruses. Therefore, RNA replacement with a mutant KRAS-targeting trans-splicing ribozyme is a potentially useful therapeutic strategy to combat tumors harboring KRAS mutation. Mutations in the KRAS gene, which persistently activate RAS function, are most frequently found in many types of human cancers. Here, we proposed and verified a new approach against cancers harboring the KRAS mutation with high cancer selectivity and efficient anti-cancer effects based on targeted RNA replacement. To this end, trans-splicing ribozymes from Tetrahymena group I intron were developed, which can specifically target and reprogram the mutant KRAS G12V transcript to induce therapeutic gene activity in cells. Adenoviral vectors containing the specific ribozymes with downstream suicide gene were constructed and then infection with the adenoviruses specifically downregulated KRAS G12V expression and killed KRAS G12V-harboring cancer cells additively upon pro-drug treatment, but it did not affect the growth of wild-type KRAS-expressing cells. Minimal liver toxicity was noted when the adenoviruses were administered systemically in vivo. Importantly, intratumoral injection of the adenoviruses with pro-drug treatment specifically and significantly impeded the growth of xenografted tumors harboring KRAS G12V through a trans-splicing reaction with the target RNA. In contrast, xenografted tumors harboring wild-type KRAS were not affected by the adenoviruses. Therefore, RNA replacement with a mutant KRAS-targeting trans-splicing ribozyme is a potentially useful therapeutic strategy to combat tumors harboring KRAS mutation.
Mechanisms and Activity of PPARγ-Active Triterpenoids CDDO and CDDO-Me in Leukemias.
Authors: Marina Konopleva, Ismael Samudio, Twee Tsao, Steven M. Kornblau, Yue-Xi Shi, Teresa McQueen, Rooha Contractor, Michael B. Sporn, Colin J. Meyer, Warren Huff, Stephen H. Safe, Hagop Kantarjian, Michael Andreeff
Journal: Blood (2005)
Abstract 2105: An EWS-FLI1/MRTF gene regulatory network in Ewing sarcoma
Authors: Anna M. Katschnig, Maximilian Kauer, Raphaela Schwentner, Dave N.T Aryee, Elizabeth Lawlor, Heinrich Kovar
Journal: Cancer Research (2015)

Abstract The pediatric bone cancer Ewing sarcoma (ES) is characterized by the expression of the chimeric transcription factor EWS-FLI1, derived from a chromosomal translocation t(11;22)(q24;q12). The early onset of metastasis in ES leads to poor overall survival and limited treatment options. Remodeling of the actin cytoskeleton is a prerequisite of a tumor cell in order to become metastatic. Previous studies suggest that EWS-FLI1 alters cell morphology and deregulates various cytoskeletal genes. The major point of convergence of extracellular signals influencing cytoskeletal regulation is the Rho pathway. Activation of Rho GTPases promotes polymerization of monomeric G-actin into stress fibers (F-actin) thereby releasing the myocardin-related transcription factor family (MRTF-A, MRTF-B) of transcriptional coactivators. MRTFs translocate to the nucleus and interact with the transcription factor serum response factor (SRF) bound on CArG promoter elements of genes. However, the ternary complex factor (TCF) family, a class of transcriptional coactivators activated downstream of Ras signaling, competes with MRTFs for SRF binding in presence of ets binding sites adjacent to the CArG consensus sequence. The ets-transcription factor EWS-FLI1 has been shown to substitute for TCFs and interact with SRF. We hypothesized that EWS-FLI1 competes with MRTFs for SRF binding and uncouples target gene expression from Rho signaling. In combinatorial knockdown experiments of MRTFA/B and EWS-FLI1 we demonstrate that global changes in gene expression elicited by EWS-FLI1 silencing largely depend on the presence of MRTFs, suggesting that the fusion oncogene prohibits MRTF activity. Using gene expression analysis we identified six different patterns of MRTF/EWS-FLI1 interaction, with predominance of EWS-FLI1 inversely regulating MRTF target genes. Furthermore, we found MRTF transcriptional effects are already present in the absence of serum in A673 ES cells. MRTFB, however, is cytoplasmic under serum starved conditions and translocates to the nucleus only upon serum stimulation unless latrunculin B (LatB), an actin polymerization inhibitor, is added. In contrast, MRTFA is constitutively nuclear even under serum starved conditions or upon LatB treatment indicating that MRTFA might be uncoupled from actin regulation. These findings reveal a previously unknown role of MRTFs and the “CArGome” in EWS-FLI1 driven transcriptional dysregulation. Supported by the Liddy Shriver Sarcoma Initiative. Citation Format: Anna M. Katschnig, Maximilian Kauer, Raphaela Schwentner, Dave N.T Aryee, Elizabeth Lawlor, Heinrich Kovar. An EWS-FLI1/MRTF gene regulatory network in Ewing sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2105. doi:10.1158/1538-7445.AM2015-2105
Dr. Pangloss's Clinic: Prenatal Whole Genome Sequencing and a Return to Reality
Authors: Megan Allyse, James P. Evans, Marsha Michie
Journal: The American Journal of Bioethics (2016)

If there is an overarching theme shared by academic medicine and the social sciences it is this: Context matters. No medical innovation can be effectively imagined, studied, evaluated, or applied o...
Abstract SY27-04: Induction of cancer stemness and drug resistance by EGFR blockade
Authors: David A. Cheresh
Journal: Cancer Research (2015)

Abstract Tumor drug resistance is often accompanied by genetic and biological changes in the tumor cell population reflecting the acquisition of a stem-like state. However, it is not clear whether cancer therapies select for the growth of drug resistance cancer stem cells and/or directly induce the reprograming of tumor cells to a cancer stem-like, drug resistance state. We provide evidence that breast, pancreas and lung carcinomas in the presence of prolonged exposure to EGFR inhibitors undergo an epigenetic reprogramming resulting in a drug resistant stem-like tumor population expressing the cell surface marker CD61 (b3 integrin). In fact, CD61 in the context of KRAS, is necessary and sufficient to account for drug resistance, tumor initiation, self-renewal and expression of the pluripotent genes Oct 4 and Nanog. Once expressed, CD61 in the unligated state recruits KRAS to the plasma membrane leading to the activation of RalB, TBK1 and c-Rel driving both stemness and EGFR inhibitor resistance. Pharmacological targeting this pathway with drugs such as bortezomib or revlimid not only reverses stemness but resensitizes these epithelial tumors to EGFR inhibition. This epigenetic pathway can also be initiated by range of cellular stresses found within the tumor microenvironment such as hypoxia, nutrient deprivation, low pH, and oxidative stress. In normal tissues CD61 is induced during tissue remodeling and repair. For example, CD61 was found to be critical for mammary gland remodeling during pregnancy and as a mediator of pathological neovascularization. Together these findings reveal a stress-induced epigenetic pathway characterized by the upregulation of CD61 that promotes the remodeling of normal tissues but in tumors contributes to EGFR inhibitor resistance and tumor progression. Citation Format: David A. Cheresh. Induction of cancer stemness and drug resistance by EGFR blockade. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY27-04. doi:10.1158/1538-7445.AM2015-SY27-04
Number of Prior Chemotherapy Regimens: Important Prognositic Factor of All-Cause Mortality after Allogeneic Hematopoietic Cell Transplantation.
Authors: Tetsuyuki Kiyokawa, Shoichi Nagakura, Michihiro Hidaka, Naokuni Uike, Motohiro Hamaguchi, Keizo Horibe, Kensaku Sato, Humio Kawano
Journal: Blood (2007)
210. High Expression of Second Generation CD19 CAR with a 4-1BB Costimulatory Domain from a Retroviral Vector Impairs CAR T Cell Expansion by Enhancing Fas-Mediated Apoptosis
Authors: Diogo Silva, Malini Mukherjee, Madhuwanti Srinivasan, Jordan S. Orange, Malcolm K. Brenner, Maksim Mamonkin
Journal: Molecular Therapy (2016)

Recent clinical trials in patients with B cell malignancies demonstrated that CD19 CAR T cells could expand in vivo and eliminate target cells. Two main variants of the CD19 CAR have been successful - a retroviral construct with CD28 and CD3 zeta signaling domains (28. zeta) and a lentivirus with 4-1BB. zeta. While infused CD28. zeta CAR T cells rapidly expanded and produced immediate anti-tumor activity, 4-1BB. zeta CAR T cells persisted longer and had sustained anti-tumor activity. Although these differences may represent differences in the costimulation provided by each CAR, the choice of viral vector may also contribute to differences in performance. We compared the in vitro expansion and anti-tumor activity of T cells transduced with either 28. zeta or 4-1BB. zeta CD19 CAR using a standard retroviral vector SFG. We demonstrate that retroviral transduction of T cells with a 4-1BB. zeta CD19 CAR reduced T cell expansion 18 fold after 2 weeks of culture and impaired anti-tumor activity compared to cells transduced with a similar vector encoding CD28. zeta CD19 CAR. High expression of the 4-1BB. zeta CD19 CAR led to upregulation of Fas and relocation of intracellular FasL to the cell surface, resulting in co-localization of both proteins on the plasma membrane. Consistent with this finding, we observed a 5-fold increase in apoptosis of 4-1BB. zeta CAR T cells which was completely reversed by chemical blockade of caspase-8, a key initiator caspase activated by Fas signaling. We also observed a gradual downregulation of 4-1BB. zeta CD19 CAR levels on surviving T cells suggesting that high CAR expression is toxic for T cells. In fact, reducing the level of 4-1BB. zeta CD19 CAR expression by inserting an IRES sequence upstream of the CAR normalized Fas levels on T cells and restored T cell expansion and anti-tumor activity. Similarly, transducing T cells with a self-inactivating lentiviral vector resulted in reduced levels of 4-1BB. zeta CD19 CAR expression allowed excellent expansion, similar to that of T cells with 28. zeta CD19 CAR. We also observed improved cytotoxicity of T cells with lower expression of 4-1BB. zeta CAR in co-culture assays with CD19+ cell lines Daudi (5-fold reduction in remaining tumor cells with lenti-CAR and 22-fold for IRES-CAR) and Raji (18-fold reduction for both lenti- and IRES-CAR constructs) and sustained performance in sequential killing assays. These studies reveal a mechanism that limits expansion and function of T cells expressing high levels of 4-1BB. zeta CD19 CAR and provide a basis for rational choice of expression systems and design of chimeric molecules that incorporate the 4-1BB signaling domain.
Abstract 1707: PACE4-dependent cellular uptake and retention of the Multi-Leucine peptide inhibitor into cancer cells
Authors: Frédéric Couture, Kevin Ly, Christine Levesque, Anna Kwiatkowska, Roxane Desjardins, Brigitte Guérin, Robert Day
Journal: Cancer Research (2015)

Abstract The proprotein convertase PACE4 is strongly overexpressed in prostate cancer and plays an important role in tumor progression by promoting cell proliferation and tumor angiogenesis. Because the high expression levels and the necessity of this enzyme for cancer progression, we have developed a peptide-based inhibitor known as the Multi-Leucine (ML) peptide, which is a PACE4-specific inhibitor. Just like PACE4-downregulation through stable shRNA transfections, this compound displays anti-proliferative properties when applied on cancer cells. We showed its target-specific uptake into prostate cancer xenografts by positron emission tomography, which allowed clear tumor visualization. The ML-peptide has potent effects to block the further progression of prostate cancer cells, however, the uptake mechanism of this peptide is not clear and whether it is PACE4-dependent. We therefore tested the uptake and efflux rates of the ML-peptide peptide in prostate cancer cells and correlated these with PACE4 expression levels in wild type and stable PACE4-knockdown cell lines. In addition to prostate cancer cell lines LNCaP, DU145 and PC3, we tested HepG2, Huh7 and HT1080 cells, which also express PACE4. To measure peptide uptake, the ML peptide was modified through the addition a 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) moiety to strongly chelate radiometal such as 64Cu. Our study shows that uptake of the ML-peptide is correlated with expression levels, but more importantly can be blocked in PACE4-knockdown cell lines, demonstrating a PACE4-dependant uptake mechanism. We also correlated uptake with the anti-proliferative effects of the ML-peptide and showed that entry into these cell lines predicted the effects of the ML-peptide on the growth of these cells. These results confirm the notion that ML-peptide entry within cell is an important requirement to exert growth inhibition properties, and further provide a mechanism for that entry. This study demonstrates further support for the use of the ML-peptide or its analogs as potential drugs in prostate cancer, as well as any other PACE4-dependent tumors. These indications of peptide uptake within tumor could allows PACE4-status to be determined by positron emission tomography and may be of great theranostics uses in the context of pharmacological intervention with PACE4 inhibitors. Citation Format: Frédéric Couture, Kevin Ly, Christine Levesque, Anna Kwiatkowska, Roxane Desjardins, Brigitte Guérin, Robert Day. PACE4-dependent cellular uptake and retention of the Multi-Leucine peptide inhibitor into cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1707. doi:10.1158/1538-7445.AM2015-1707
PP-009 Significant increase in the incidence of hepatocellular carcinoma in wales
Authors: R J Aspinall, C White, T Crosby
Journal: Gut (2010)

<h3>Introduction</h3> Increasing mortality rates for some types of primary liver cancer have been documented in several countries in recent years. The figures published for England and Wales have described a marked increase in cases of intrahepatic cholangiocarcinoma with a static or declining rate of mortality from hepatocellular carcinoma (HCC).1 However, over the last decade, the prevalence of several risk factors for HCC (chronic viral hepatitis, alcoholic liver disease and obesity/NASH) have all dramatically increased in Wales. We therefore hypothesised that, due to the significant difference in population size between these two regions, a dilutional effect may have masked the true incidence of HCC within Wales. <h3>Methods</h3> The database of the Welsh Cancer Intelligence and Surveillance Unit was examined for all liver tumour types affecting Welsh residents regardless of treatment location across the years 1999–2008 inclusive. The incidence was recorded as the European Age Standardised Rate (EASR) per 100 000 population. Subcategory analysis was made for hepatocellular carcinoma, fibrolamellar HCC, combined HCC and cholangiocarcinoma and all liver malignant neoplasms. Patients were stratified according to age and sex and an additional 3 years moving-average EASR calculated across the whole study period. <h3>Results</h3> There was a significant and progressive increase in the incidence of HCC in Wales from 1999 to 2008. The absolute numbers of HCC cases, the EASR and the proportion of malignant liver neoplasms have all risen. In men, the EASR increased by 100% in just 8 years from 1.9 to 3.8 per 100 000. In addition, the EASR increased in women by 83% from 0.6 to 1.1 per 100 000. The rolling 3-year average rates closely followed these trends throughout the 10-year study period. Notably, in both sexes there has been a substantial rise in the number of HCC cases in patients under the age of 70 years. <h3>Conclusion</h3> In contrast to the previously published trends, we found the incidence of hepatocellular carcinoma has consistently increased over the last decade in Wales. This rise may reflect regional changes in HCC risk factors and may have been obscured by combining figures with the much larger population of England. Further research will be necessary to determine the underlying causes of this increase and to direct resources toward the prevention and early detection of HCC in Wales.
Cutaneous T-cell lymphoma (CTCL) responses to a TLR9 agonist CPG immunomodulator (CPG 7909), a phase I study
Authors: Y. Kim, M. Girardi, S. McAuley, T. Schmalbach
Journal: Journal of Clinical Oncology (2004)

6600 Background: Available systemic therapies for CTCL produce significant response rates and may relieve skin symptoms or complications, but there is a lack of well-tolerated systemic therapies with reliable and durable responses in patients with recurrent or advanced disease. A new class of chemically defined CpG immunomodulators target dendritic cell TLR9 receptors with induction of IL-12, IFN-gamma, and NK cell function. In several early trials, CPG 7909 has been well tolerated by weekly s.c. dosing and has clinical anti-tumor activity. Methods: Cohorts of 3 patients with recurrent/refractory CTCL were enrolled to receive weekly s.c. doses of 0.08, 0.16, 0.24, or 0.28 mg/kg of CPG 7909. Clinical response was monitored using the Composite Assessment of Index Lesion Disease Severity Index (CA) and the Physician's Global Assessment of Clinical Condition (PGA). Results: Of 12 patients treated to date (8 females, 10 Caucasians, 1 Hispanic and 1 African-American), 2 at the lowest dose had progressive disease (PD), 5 have stable disease, and 3 have had partial or total clearing of disease (see table below). Stable disease and response was maintained for up to 6 months of treatment. Doses were generally well tolerated; dose related injection site reactions (erythema, induration, redness and pain) and mild or moderate flu-like symptoms were common. Conclusions: CPG 7909 has significant antitumor activity in CTCL. Responses will be correlated with immunomodulator biologic responses and PK. Enrollment is ongoing with additional dose escalations to optimize response at tolerable doses. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Coley Pharmaceutical Group Coley Pharmaceutical Group Coley Pharmaceutical Group
OC-029 Expression of heat shock protein 27 and caspase-3 in hepatitis C virus-related hepatocellular carcinoma: relation to tumour progression
Authors: H A El Aggan, A M Ibrahim, N F El Deeb, A E Zeid
Journal: Gut (2010)

<h3>Introduction</h3> Hepatitis C virus (HCV) is a major risk factor for development of hepatocellular carcinoma (HCC), however, the mechanism of hepatocarcinogenesis in HCV infection is still undefined. Heat shock protein (HSP) 27 is a ubiquitous chaperone molecule induced in cells exposed to different stress conditions, including carcinogenesis. It also has potent anti-apoptotic properties through inhibition of caspase-3 activation. Therefore, the aim of the present work was to study the expression of HSP27 and caspase-3 in HCV-related HCCs in relation to tumour progression. <h3>Methods</h3> Twenty cirrhotic patients with HCV-related HCC were enrolled in the study. The severity of liver disease was assessed according to the Model for End Stage Liver Disease (MELD) score. Serum levels of α-fetoprotein (AFP) were measured by enzyme immunoassay kit. The tumour stage was classified using the scoring system proposed by the Cancer of the Liver Italian Program (CLIP). Histological grading of tumour s was performed according to the Edmondson and Steiner9s criteria and the surrounding liver tissue was examined for the presence of cirrhosis and steatosis. Expression of HSP27 and caspase-3 was studied in HCC and adjacent non-neoplastic liver tissues by immunohistochemistry and the staining intensity of the tumour was designated as “negative/low expression” or “high expression” if &lt;25% and &gt;25% of cells were positively-stained, respectively. <h3>Results</h3> HCV-related HCCs showed a significant increase in HSP27 expression and a significant decrease in caspase-3 expression as compared with adjacent non-neoplastic liver tissues (p=0.029 and p=0.040, respectively). The expression of HSP27 showed an inverse correlation with caspase-3 expression in HCC tissues (r=−0.691, p=0.001). High HSP27 expression and negative/low caspase-3 expression in HCCs were associated with significant increases in serum levels of aminotransferases, HCV RNA and AFP, MELD score, tumour size, tumour stage, histological tumour grade, body mass index and the presence of steatosis in the surrounding liver tissue (P&lt;0.05). No relationship was found between expression of HSP27 and caspase-3 in HCCs and age, gender, apparent duration of HCV infection, and tumour encapsulation, multiplicity, location and lymphocyte infiltration (P&gt;0.05). <h3>Conclusion</h3> HSP27 plays an important role in the pathogenesis and progression of HCC in HCV infection through inhibition of caspase-3 mediated cell apoptosis and may serve as a potentially useful therapeutic target.