tbuckley/cabot-search huggingface dataset:
Autoantibodies against human insulin
Authors: T. J Wilkin
Journal: BMJ (1984)

Serafrom 680non-diabetic subjects withsuspected autoimmunediseasewere screenedfor13 different antibodies. Ofthe582serafoundtocontain theseantibodies, nineboundinsulin inan IgGspecific enzyme linked immunosorbent assay(microELISA).Fourofthe seraboundhuman,porcine, andbovineinsulins andfive bound exclusively human insulin. Coldhuman, porcine, and bovineinsulins eachdisplaced, ina dose dependent manner,thefourserawhichboundallthree insulins, butonlyhuman insulin displaced theremainingfive, porcine andbovineinsulins havinglittle orno effect inconcentrations up to1000U/1. Theseobservations pointtotheexistence ofautoantibodies specifically against human insulin insome subjects withestablished autoimmunity.
Phase I/II open-label, multiple-dose, dose-escalation study to evaluate the safety and tolerability of SNS01T administered by intravenous infusion in patients with relapsed or refractory multiple myeloma.
Authors: John Anthony Lust, Charles Barranco, Martha Lacy, Angela Dispenzieri, Morie A. Gertz, David Dingli, Stephen J. Russell, Francis Buadi, Steven R. Zeldenrust, Suzanne R. Hayman, S. Vincent Rajkumar, Shaji Kumar, Saad Zafar Usmani, John Thompson, Catherine Taylor, Richard Dondero
Journal: Journal of Clinical Oncology (2012)

TPS8116 Background: Eukaryotic translation initiation Factor 5A (eIF5A) has been implicated in the regulation of apoptosis and is the only known protein to be modified by hypusination. Hypusinated eIF5A is the predominant form of eIF5A in cancer cells. However, in its unhypusinated form, eIF5A is pro-apoptotic. SNS01-T, designed to treat myeloma, consists of two components: a plasmid DNA expressing eIF5A K50R (human eIF5A containing a lysine to arginine substitution at position 50) which remains pro-apoptotic because it cannot be hypusinated, and an siRNA against an untranslated region of native eIF5A mRNA. When these two components are combined with linear polyethyleneimine (PEI), the nucleic acids are condensed into nanoparticles for protection from degradation in the blood and enhanced delivery to tissues. The eIF5A K50R transgene is under the control of the B29 promoter and enhancer, which restricts expression to B cells. The mode of action of SNS01-T is to use an eIF5A-specific siRNA to deplete the pool of hypusinated eIF5A in myeloma cells while simultaneously adding pro-apoptotic eIF5A K50R . In vitro cell studies and in vivo xenograft studies have demonstrated the efficacy of this approach. Methods: Eligible patients are enrolled sequentially into four cohorts of increasingly higher doses. Each cohort will receive SNS01-T by intravenous infusion twice weekly for 6 consecutive weeks and then be observed every 4 weeks during a 24-week follow-up period. Eligible patients must have been diagnosed with multiple myeloma according to IMWG criteria, have measurable disease, have relapsed disease after two or more prior treatment regimens, have a life expectancy of at least 3 months, and not be eligible to receive any other standard therapy known to extend life expectancy. The primary objective is to evaluate the safety and tolerability of multiple escalating doses of SNS01-T. Secondary objectives include pharmacokinetics, immunogenicity studies, proinflammatory cytokine quantitation, and therapeutic efficacy. Two of the planned 15 patients have been enrolled. (Clinical Trials.gov Identifier: NCT01435720.)
Abstract 1052: Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiomyopathy
Authors: Himangshu Sonowal, Pabitra B. Pal, Satish K. Srivastava, Kota V. Ramana
Journal: Cancer Research (2017)

Abstract Chemotherapy is one of the most common option for colorectal cancer (CRC), specifically at the advanced stages and after surgical resection of the tumor. Anthracycline drugs such as doxorubicin, daunorubicin are the most commonly used for the therapy of leukemia, lymphoma and breast cancer. However, doxorubicin is not a very effective drug to kill CRC cells since a high amount of doxorubicin is required for colon cancer therapy, which leads to unwanted side effects like cardiac toxicity and cardiomyopathy. Therefore, better adjuvant therapies are required to increase sensitivity of CRC to doxorubicin as well as to decrease the associated cardiomyopathy. Our recent studies indicate that aldose reductase (AR; AKR1B1) inhibitors such as fidarestat prevent CRC growth as well as metastasis in nude mice xenograft models. We now examined our hypothesis that AR inhibition increases the sensitivity of CRC to doxorubicin and decreases its cardiotoxicity by modulating oxidative stress-mediated signaling pathways. We have investigated the effect of co-administration of doxorubicin along with AR inhibitor fidarestat in in vitro and in vivo CRC cells growth and toxicity. Our results suggest that treatment of CRC cells with fidarestat increases the efficacy of doxorubicin-induced death of HT-29 and SW-480 colon cancer cells. Flow cytometric analysis indicates that in fidarestat + doxorubicin -treated CRC cells, the intracellular accumulation of doxorubicin is increased as compared to doxorubicin alone-treated cells. Further, AR inhibition prevents doxorubicin-induced increase in the expression of drug transporter proteins such as MRP-1 and ABCG-2 in CRC cells. In addition, combination of fidarestat with doxorubicin significantly prevented the growth of CRC cells in nude mice xenografts as compared to doxorubicin alone. Fidarestat also prevented the doxorubicin-induced cardiac toxicity as measured by serum troponin-I levels and inflammatory cytokines and chemokines in the serum and heart of doxorubicin-treated mice in combination with fidarestat. Most importantly, fidarestat protects the cardiac damage and dysfunction in doxorubicin-treated mice. Thus, our results suggest that fidarestat could be used as a novel adjuvant therapy in enhancing doxorubicin sensitivity of CRC cells and to reduce the doxorubicin-associated cardiotoxicity. Citation Format: Himangshu Sonowal, Pabitra B. Pal, Satish K. Srivastava, Kota V. Ramana. Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiomyopathy [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 1052. doi:10.1158/1538-7445.AM2017-1052
Abstract CT082: Impact of tumor mutation burden on the efficacy of first-line nivolumab in stage iv or recurrent non-small cell lung cancer: An exploratory analysis of CheckMate 026
Authors: Solange Peters, Benjamin Creelan, Matthew D. Hellmann, Mark A. Socinski, Martin Reck, Prabhu Bhagavatheeswaran, Han Chang, William J. Geese, Luis Paz-Ares, David P. Carbone
Journal: Cancer Research (2017)

Abstract Background: CheckMate 026 is a randomized trial of nivolumab monotherapy versus platinum doublet chemotherapy in patients with untreated stage IV or recurrent non-small cell lung cancer (NSCLC) and ≥1% programmed death-1 ligand 1 (PD-L1) tumor expression. Nivolumab was not associated with improved progression-free survival (PFS) versus chemotherapy in patients with ≥5% PD-L1 expression, however, nivolumab had a favorable safety profile compared with chemotherapy and overall survival (OS) was similar between treatment arms. In an exploratory analysis, we assessed whether patients with high tumor mutation burden (TMB) may derive enhanced benefit from nivolumab compared with platinum doublet chemotherapy. Methods: TMB scores for missense, somatic mutations were determined in patients with sufficient samples for whole exome sequencing of tumor and matched whole blood DNA. For the initial analyses, patients were equally divided into groups based on TMB tertile distribution. Patients in the low, medium, and high TMB tertiles had 0-99, 100-242, and ≥243 mutations, respectively. Results: Of 541 randomized patients, 312 (57.7%) had evaluable data to determine TMB. The percentage of patients with high TMB was lower in the nivolumab arm than in the chemotherapy arm (29.7% vs 39.0%). Baseline characteristics, PFS, and OS in patients evaluable for TMB were similar to all randomized patients. In patients with high TMB, PFS was improved (median PFS of 9.7 vs. 5.8 months; HR, 0.62; 95% CI, 0.38 to 1.00) and objective response rate was higher with nivolumab versus chemotherapy (46.8% vs 28.3%). OS in patients with high TMB was similar between the 2 treatment arms, which may be attributable in part to a 65% crossover rate to nivolumab in the chemotherapy arm for this subgroup. Conclusions: This is the first pivotal randomized phase 3 trial to incorporate an analysis evaluating TMB and clinical benefit with programmed death-1 inhibitor therapy. The findings of this exploratory retrospective analysis suggest that nivolumab improves ORR and PFS compared with platinum doublet chemotherapy in patients with high TMB. Citation Format: Solange Peters, Benjamin Creelan, Matthew D. Hellmann, Mark A. Socinski, Martin Reck, Prabhu Bhagavatheeswaran, Han Chang, William J. Geese, Luis Paz-Ares, David P. Carbone. Impact of tumor mutation burden on the efficacy of first-line nivolumab in stage iv or recurrent non-small cell lung cancer: An exploratory analysis of CheckMate 026 [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 CT082. doi:10.1158/1538-7445.AM2017-CT082
Abstract 5610: Quantitative cell-based bioassays to advance individual or combination immune checkpoint immunotherapy
Authors: Jamison Grailer, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng
Journal: Cancer Research (2017)

Abstract Immune checkpoint receptors play a critical role in maintaining immune homeostasis and are genetically and functionally associated with autoimmune disease, cancer and persistent viral infections. Blockade of immune checkpoints (e.g., PD-1 and CTLA-4) has emerged as a promising new approach to enhance anti-tumor immune responses. While immunotherapies directed against PD-1 and CTLA-4 are showing unprecedented efficacy in the treatment of cancer, many patients and tumor types remain refractory to these therapies. This has resulted in a broadening of immunotherapy research and development to include additional immune checkpoint receptors (e.g., LAG-3, TIGIT, CD112R) targeted individually or in combination with other immunotherapy strategies. A major challenge in the development of biologics that target immune checkpoints is access to quantitative and reproducible functional bioassays. Existing methods rely on primary cells and measurement of complex functional endpoints. These assays are cumbersome, highly variable, and fail to yield the quality of data that is required for drug development in a quality-controlled environment. To address this need, we have developed a suite of immune cell line-based bioluminescent reporter bioassays for individual and combination immune checkpoint immunotherapy targets including PD-1 (PD-L1 or PD-L2), CTLA-4, LAG-3, TIGIT, PD-1+TIGIT and more. These assays consist of stable cell lines that express luciferase reporters driven by specific response elements under the precise control of intracellular signals mediated by the T cell receptor and immune checkpoint target(s). These mechanism of action-based bioassays are available in “thaw-and-use” format and demonstrate high specificity, sensitivity and reproducibility. The bioassays are pre-qualified according to ICH guidelines and demonstrate the performance required for use in antibody screening, potency testing and stability studies. Citation Format: Jamison Grailer, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng. Quantitative cell-based bioassays to advance individual or combination immune checkpoint immunotherapy [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 5610. doi:10.1158/1538-7445.AM2017-5610
Abstract 2183: Targeted delivery of hyaluronic acid-labeled chitosan nanoparticles against CD44 overexpressed endothelial cell for tumor angiogenesis therapy
Authors: Gahee Kim, Heedong Han
Journal: Cancer Research (2017)

Abstract Objective: RNA interference (RNAi)-based approaches hold great potential for cancer therapy. Here, we developed siRNA-incorporated chitosan nanoparticles coated with hyaluronic acid (HA-CH-NP/siRNA) to target CD44 receptor on the surface of tumor endothelial cells Methods: Size and zeta potential of HA-CH-NP were measured by light scattering with a particle size analyzer and Zeta Plus. Morphology of HA-CH-NP was observed by atomic force microscopy (AFM). HA-based selective binding of HA-CH-NP on the CD44 positive cells was assessed by flow cytometry and immunohistochemistry (IHC) analysis. Therapeutic efficacy was examined in orthotopic mouse models of ovarian carcinoma. PLXDC1 mRNA was quantified using real-time reverse transcription-polymerase chain reaction (RT-PCR). Additionally, biological effect on angiogenesis (MCD), cell proliferation (Ki67), and apoptosis (TUNEL) in the tumor tissue were examined by IHC analysis. Results: HA-CH-NP/siRNA was 185 ± 10 nm in size and zeta potential was 26.4 mV, respectively. The loading efficiency of siRNA into HA-CH-NP/siRNA was up to 60%. We confirmed selective binding efficiency of HA-CH-NP/siRNA with CD44+ tumor endothelial cells was increased 2.1-fold compared to CH-NP/siRNA. PLXDC1 silencing using HA-CH-NP/siRNA significantly inhibited tumor growth in A2780 tumor growth in A2780 tumor-bearing mice compared to control (p &amp;lt; 0.0001), and mRNA expression of PLXDC1 was significantly decreased in HA-CH-NP/siRNA treated group. In addition, treatment with HA-CH-NP/siRNA resulted in significant inhibition of cell proliferation (p &amp;lt; 0.05), microvessel density ( p &amp;lt; 0.05), and increased cell apoptosis (p &amp;lt; 0.05). Conclusion: This study demonstrated that HA-CH-NP/siRNA was a novel and highly selective delivery system for siRNA with potential for broad applications for tumor angiogenesis therapy. Citation Format: Gahee Kim, Heedong Han. Targeted delivery of hyaluronic acid-labeled chitosan nanoparticles against CD44 overexpressed endothelial cell for tumor angiogenesis therapy [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 2183. doi:10.1158/1538-7445.AM2017-2183
Comparative effectiveness of everolimus (EVE) and axitinib (AXI) for 2<sup>nd</sup> targeted therapy (TT) of metastatic renal cell carcinoma (mRCC) in the US: A retrospective chart review.
Authors: James E. Signorovitch, Sumanta Kumar Pal, William M Reichmann, Nanxin Li, Zhimei Liu, Jose Ricardo Perez, Nicholas J. Vogelzang, Eric Jonasch
Journal: Journal of Clinical Oncology (2015)

e15612 Background: EVE and AXI are approved as 2nd TTs for mRCC. This study compares OS and PFS among mRCC patients (pts) treated with EVE and AXI following 1st TKI. The extent to which duration of 1st TKI treatment modifies comparative effectiveness of 2nd TT is also assessed. Methods: Retrospective reviews of medical records were conducted by medical oncologists or hematologists/oncologists recruited from a nationwide panel. Pt eligibility criteria included: 1) aged ≥ 18 years; 2) initiated and discontinued 1st TKI (sunitinib [SUN], sorafenib [SOR], or pazopanib [PAZ]) for medical reasons; 3) initiated 2nd TT between 2/2012 and 1/2013. OS was defined as time from initiation of 2nd TT to death. PFS was defined as time from initiation of 2nd TT to physician-assessed progression or death, whichever occurred first. Multivariable Cox proportional hazards models were used to estimate the comparative hazard ratios (HRs) for OS and PFS between EVE and AXI, adjusting for age, gender, type and duration of 1st TKI, response to 1st TKI, duration of mRCC at 2nd TT, metastatic disease at initial diagnosis, clear cell RCC, prior nephrectomy, performance status, metastatic sites, comorbidity, and years of physician practice. Comparative effectiveness was also analyzed by type and duration ( < 6, 6-12, ≥ 12 months) of 1st TKI. Results: 325 and 127 pts received 2nd TT with EVE and AXI. After adjusting for baseline characteristics, there was no statistically significant difference between EVE and AXI for OS [HR (95% CI): 1.16 (0.73-1.82)] or PFS [HR (95% CI): 1.16 (0.85-1.59)]. When stratified by type and duration of 1st TKI, there was no statistically significant difference in OS between EVE and AXI in all subgroups, except for pts with < 6 months on SUN or SOR as 1st TT [HR (95% CI): 2.98 (1.10, 8.12)]. No statistically significant difference in PFS was observed in any subgroup. Conclusions: In this large, retrospective chart review, there was no significant difference in OS or PFS between EVE and AXI in the overall population. Longer durations of 1st TKI were not associated with better comparative effectiveness for subsequent treatment with AXI vs. EVE.
Abstract 2663: Characterization of the pharmacodynamic immune response to a novel immunotherapeutic agent, ALKS 4230, in mice and non-human primates
Authors: Jared E. Lopes, Heather C. Losey, Reginald L. Dean, Heather L. Flick, Michael R. Huff, Rosemarie A. Moroso, Lei Sun, Juan C. Alvarez
Journal: Cancer Research (2017)

Abstract ALKS 4230 is a selective agonist of the intermediate-affinity IL-2 receptor (IL-2R). A phase 1 study is ongoing to evaluate the safety and tolerability of ALKS 4230 in the treatment of patients with refractory solid tumors. The selectivity of ALKS 4230 is achieved through the stable fusion of circularly permuted IL-2 to the extracellular portion of the IL-2Rα chain, CD25. The resulting fusion protein is sterically prevented from binding to the high-affinity IL-2R complex, comprised of IL-2Rα, IL-2Rβ, and common gamma chain, expressed preferentially on CD4+ FOXP3+ regulatory T cells (CD4+ Tregs) yet retains full ability to signal through the intermediate-affinity IL-2R complex, comprised of IL-2Rβ and common gamma chain, expressed on memory CD8+ T cells and NK cells. Repeated dosing of ALKS 4230 drives the significant expansion of various CD8+ T cell and NK cell populations without activation and minimal expansion of CD4+ Tregs in mice and non-human primates (NHP). The kinetics of the immunological responses in mice and NHP demonstrate that the pharmacodynamic effects persist beyond systemic exposure of ALKS 4230. Data demonstrating the effects of ALKS 4230 on tumor-infiltrating lymphocyte populations in syngeneic tumor models will also be presented. Citation Format: Jared E. Lopes, Heather C. Losey, Reginald L. Dean, Heather L. Flick, Michael R. Huff, Rosemarie A. Moroso, Lei Sun, Juan C. Alvarez. Characterization of the pharmacodynamic immune response to a novel immunotherapeutic agent, ALKS 4230, in mice and non-human primates [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 2663. doi:10.1158/1538-7445.AM2017-2663
Abstract 1209: FGFR inhibition re-sensitizes BRAF/MEK dual resistant cells to the BRAF/MEK inhibitor combination
Authors: Victoria E. Wang, Jeffrey Settleman, Frank McCormic
Journal: Cancer Research (2017)

Abstract The BRAF-MEK pathway is frequently mutated in human melanoma. Inhibitors of these kinases have proven to prolong survival in melanoma patients. However, clinical benefit is relatively short-lived due to acquired drug resistance. To explore mechanisms of resistance in melanoma cells treated with dual BRAF and MEK inhibitors, A375, a cell line harboring the BRAF V600E mutation, was treated with escalating doses of vemurafenib and cobimetinib to generate a cellular population resistant to combination therapy. These cells display a reversible resistance phenotype. Upon initial treatment of the drug combination, upregulation of pSTAT3 is observed but the cells lose dependency on the pSTAT3 pathway upon prolonged drug treatment. A pharmacological synthetic lethal screen was performed and the FGFR inhibitor class re-sensitizes the cells to BRAF and MEK inhibition through inhibitions of pERK. The dual resistant cells also displayed hyperactivation of the PI3K-AKT pathway. Interrogation of patient samples confirmed these findings. These findings provides a biological rationale for a polytherapy strategy using a FGFR inhibitor in patients with resistance to dual BRAF and MEK inhibition. &amp;lt;!–EndFragment–&amp;gt; Citation Format: Victoria E. Wang, Jeffrey Settleman, Frank McCormic. FGFR inhibition re-sensitizes BRAF/MEK dual resistant cells to the BRAF/MEK inhibitor combination [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 1209. doi:10.1158/1538-7445.AM2017-1209
Abstract 3127: Roles of ERKs-RSK2 signaling in human cancers
Authors: Yong Yeon Cho
Journal: Cancer Research (2017)

Abstract RSK2 is a member of p90RSK superfamily consisted with RSK1-4 and MSK1-2, and has suggested involving in many cellular processes including cell proliferation, differentiation, transformation and cancer development. Accumulating data obtained by our 16-year researches strongly demonstrated that RSK2 is a key player in cell transformation and cancer metastasis. We found that ectopic expression of RSK2 induced anchorage-independent cell transformation. Notably, knockdown of RSK2 strongly suppressed constitutive active-Ras (CA-Ras)-induced foci-formation, EGF-induced cell transformation and cancer cell growth in anchorage-independent condition. The results obtained from human skin cancer tissue array demonstrated that total protein levels and RSK2 activity were higher in cancer tissues than that of normal tissues. Molecular targeting of RSK2 or ERK1 and 2 with natural compounds demonstrated that ERKs-RSK2 signaling pathway plays a key role in cell transformation and cancer development. Moreover, inhibition of ERKs-RSK2 signaling suppressed NF-κB activity in JB6Cl41 cells. The EGF-induced NF-κB activity was abrogated up-regulation of COX-2 mRNA expression and COX-2 protein levels by inhibition of ERKs-RSK2 signaling pathway. Interestingly, magnolin, a specific inhibitor of ERK1 and ERK2, suppressed ERK-mediated MMP-2 and NF-κB-mediated MMP-9 expression. In addition, we found that the protein expression of N-cadherin involved in metastasis was markedly attenuated by inhibition of ERKs-RSK2 signaling pathway. Notably, magnolin suppressed the migration and invasion of lung cancer cells in a dose-dependent manner. Taken together, these results demonstrated that targeting of ERKs-RSK2 signaling is beneficial for the chemoprevention, and anti-invasion and -migration in cancer metastasis. Key words: MAPK pathway, Transformation, Metastasis, Molecular targets Citation Format: Yong Yeon Cho. Roles of ERKs-RSK2 signaling in human cancers [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 3127. doi:10.1158/1538-7445.AM2017-3127