tbuckley/cabot-search huggingface dataset:
Abstract 4642: RNA interference reveals tumor promoting roles of integrin alpha 6 (ITGA6) in hepatocellular carcinoma
Authors: Guixi Zheng, Carla Zeballos, Hakim Bouamar, Matyas Cserhati, Francisco G Cigarroa, Lu-zhe Sun
Journal: Cancer Research (2019)

Abstract Introduction: Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the third leading cause of cancer related mortality. The incidence and mortality rates of HCC are two times higher in Latinos than in the general population in the US and are the highest in Latinos from the South Texas region. The genetic and epigenetic events associated with the increased incidence of HCC in this population are still unclear. Increasing evidence suggests that integrins are one of the most important receptors for cell metastasis including integrin α6β1 and α6β4. However, few studies have focused on the function of integrin alpha 6 (ITGA6) in the tumorigenesis and progression of HCC. We aim to investigate the expression and potential roles of ITGA6 in HCC. Materials and Methods: Paired HCC tissues and adjacent non-tumor tissues were collected for RNA sequencing. ITGA6 RNA and protein expression levels were evaluated by RNA sequencing, RT-qPCR, Western blot and immunohistochemistry. HCC cell lines (SNU398 and Huh7) were transiently transfected with two ITGA6siRNAs and stably transfected with an ITGA6 shRNA lentivector. These cell lines were used for assays testing the effects of ITGA6 knockdown on HCC cell proliferation, migration and anchorage independent growth. Results: Analysis of RNA sequencing data indicated that the expression of ITGA6 increased 4-fold in HCC tumor tissues compared to adjacent non-tumor tissues, which was validated by RT-qPCR. Western blotting also confirmed increased expression of ITGA6 in the tumor tissues. The knockdown of ITGA6 by siRNAs and shRNA was confirmed with Western blot and qRT-PCR. ITGA6 knockdown significantly decreased proliferation, migration and anchorage independent growth of HCC cell lines. Conclusions: ITGA6 is upregulated in HCC tumors in Latinos patients. ITGA6 may play a malignant-promoting role in HCC cells. Our studies provided new insights into the molecular mechanisms that drive HCC progression and potential therapeutic targets for treating patients with HCC including South Texas Latino patients. Citation Format: Guixi Zheng, Carla Zeballos, Hakim Bouamar, Matyas Cserhati, Francisco G Cigarroa, Lu-zhe Sun. RNA interference reveals tumor promoting roles of integrin alpha 6 (ITGA6) in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4642.
A First Step toward a New Approach to Treating Membranous Nephropathy
Authors: Piero Ruggenenti, Giuseppe Remuzzi
Journal: New England Journal of Medicine (2019)

Membranous nephropathy, the leading cause of nephrotic syndrome in adults (approximate incidence among white adults without diabetes, 8 to 10 cases per million population per year), is the result of IgG deposition in the subepithelial space of glomerular capillaries.1,2 Strategies for treating patients with membranous nephropathy have engendered major controversy in nephrology for several decades. A few trials, most of which have been underpowered, have shown that glucocorticoids do not affect outcomes. Other studies indicate that alkylating agents are useful in patients with membranous nephropathy who have nephrotic syndrome but serum creatinine levels below 1.1 mg per deciliter (100 μmol . . .
Abstract 1217: Exploiting host pre-existing immunity for melanoma cancer immunotherapy
Authors: Priscilla S. Briquez, Sylvie Hauert, Grégoire Repond, Melody A. Swartz, Jeffrey A. Hubbell
Journal: Cancer Research (2019)

Abstract Vaccines are considered one of greatest successes of modern medicine; indeed, prophylactic vaccinations allow tight control of disease spreading and even eradication of some diseases. Vaccines immunize patients against known antigens derived from infectious agents, so that the immune system can efficiently block pathogen entry and mount a faster and better immune reaction in case of infection. In the context of cancer, finding good antigens for immunization against tumor cells can be challenging since tumor cells are derived from the self, and thus are not always efficiently recognized as malignant by the immune system. Here, we seek to develop a cancer immunotherapy that delivers a pre-encountered antigen to tumor cells to redirect the host pre-existing immunity against cancer. As a vaccine model, we used ovalbumin (OVA) antigen adjuvanted with CpG-B oligodeoxynucleotides to pre-immunize C57BL/6 mice, developing both T cell and B cell immunity against OVA. At least one month later, mice were challenged with B16-OVA melanoma cells. We observed that tumor growth in pre-immunized mice was slightly delayed compared to growth in naïve mice, but this effect was modest, leading to an overall 1-day increased survival. We reasoned that this effect could be improved by modifying the cellular localization of OVA antigen; indeed, OVA is expressed intracellularly in B16-OVA cells, thus excluding potential antibody-mediated anti-tumoral immune response. Therefore, we created a B16 melanoma cell line that overexpresses a membrane-bound OVA (B16memOVA), using similar design as published elsewhere (DiLillo et al., J. Immunol. 2010). In vitro, B16memOVA cells behaved similarly to the parental B16 cell line, and the growth of B16memOVA tumors in OVA-expressing mice (which are tolerant to OVA) was similar to the growth of B16 tumors, thus validating our B16memOVA tumor model. When implanted in naïve mice, B16memOVA tumors were able to grow, despite the onset of a neo-immune reaction against OVA, which slows tumor growth. In contrast, mice pre-immunized against OVA totally rejected B16memOVA tumors. Our efforts are now focusing on the development of an antigen-delivery method to trigger the expression of membrane-bound OVA in B16 tumors after implantation, to apply this approach in a therapeutic setup. Citation Format: Priscilla S. Briquez, Sylvie Hauert, Grégoire Repond, Melody A. Swartz, Jeffrey A. Hubbell. Exploiting host pre-existing immunity for melanoma cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1217.
Abstract 4821: Development of a potent Trop-2 antibody-drug conjugate, BAT8003, for the treatment of Trop-2 positive gastric tumors
Authors: Weijia Tang, Xingxing Mei, Ziqiang Ou, Jirong Gan, Shengfeng Li, Jin-Chen Yu
Journal: Cancer Research (2019)

Abstract Trophoblast cell surface antigen 2 (Trop-2) is overexpressed on many epithelial carcinomas while having low levels of expression on normal tissue. Overexpression of Trop-2 has been correlated with poor prognosis in several solid tumors. Trop-2 is overexpressed in ~60% of gastric cancer, which causes more than 500,000 mortalities every year in China. We have developed a Trop-2 antibody-drug conjugate (ADC), BAT8003, that utilizes an anti-Trop-2 IgG1 antibody, engineered for site-specific conjugation, a novel uncleavable linker, and a potent maytansine derivative as the payload. Site-specific conjugation allows for a more controllable drug-antibody ratio (DAR), resulting in a more homogenous product. BAT8003 also incorporates increased ADCC effects through afucosylation to further enhance potency. Here we show that BAT8003 is internalized in Trop-2 positive cells. It inhibits proliferation of a number of different Trop2-overexpressed tumor cells with IC50s of ~1 nM. In a gastric cancer (NCI-N87) mouse xenograft model, BAT8003 demonstrates strong inhibition activity on tumor growth at doses of 5 mg/kg and 15 mg/kg. A multiple dose toxicity study in monkey reveals that the highest non-severely toxic dose (HNSTD) of BAT8003 is 20 mg/kg when dose once every 3 weeks. The preclinical profile of BAT8003 warrants further clinical development for the treatment of gastric cancer as well as other Trop-2 over-expressing cancers. Citation Format: Weijia Tang, Xingxing Mei, Ziqiang Ou, Jirong Gan, Shengfeng Li, Jin-Chen Yu. Development of a potent Trop-2 antibody-drug conjugate, BAT8003, for the treatment of Trop-2 positive gastric tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4821.
Safety and tolerability of BION-1301 in adults with relapsed or refractory multiple myeloma.
Authors: William Bensinger, Anastasios Raptis, James R. Berenson, Alexander I. Spira, Ajay K. Nooka, Maria Chaudhry, Peter van Zandvoort, Nitya Nair, Jeannette Lo, Jeroen Elassaiss-Schaap, Jackie Walling, Parameswaran Hari
Journal: Journal of Clinical Oncology (2019)

8012 Background: BION-1301 (BION) is first in class humanized monoclonal antibody directed against a proliferation-inducing ligand (APRIL) for treatment of relapsed/refractory (R/R) multiple myeloma (MM). APRIL secreted by cells in the bone marrow (BM) niche binds to BCMA (B-Cell maturation antigen) and TACI (transmembrane activator and CAML interactor) expressed on human MM cells to drive their proliferation and survival. In patients (pts) with MM, serum APRIL levels are elevated and are correlated with promotion of malignancy, chemo- and immune-resistance. This study evaluated tolerability and clinical activity of BION monotherapy in R/R MM pts. Methods: Adults with MM, progression after ≥3 systemic therapies, and ECOG 0-1 were enrolled in this phase 1/2, open-label study. The phase 1 study is evaluating 6 cohorts with increasing BION doses of 50, 150, 450, 1350, and 2700 mg administered Q2W intravenously (cohort 6 - 1350 mg dose given QW and Q2W). Response was assessed by investigators Q4W. Serum was analyzed for BION, anti-drug antibodies (ADA), and soluble unbound “free APRIL” (fAPRIL) and evaluated by PK-PD modeling. Results: As of 7Dec2018, 15 pts were enrolled in 4 cohorts at doses between 50-1350 mg given Q2W. 5/15 (33%) had ECOG 0 and pts received median of 6 prior systemic therapies (range: 4-17). Related treatment emergent adverse events (TEAE) were reported in 8/15 (36%); most common related TEAE included anemia (n=3), arthralgia (n=2), and dysgeusia (n=2). 1 subject receiving 4 th dose of BION experienced grade 3 wheezing considered infusion-related and serious. No dose-limiting toxicities were observed. Of 14/15 evaluable for response, no objective response was observed and 5/14 (36%) had stable disease. Median time on treatment was 2 months (range: 0.9-4.9+) and median of 3 doses of BION (range: 2-11) were administered. BION exposure increased dose proportionally from 50-1350 mg, and half-life (T 1/2 ) and clearance (CL) did not differ significantly (median T 1/2 = 9.0 days [range: 3.9-20], median CL = 0.52 L/day [range: 0.32-0.72]). Levels of fAPRIL in serum and BM decreased with increasing BION doses. By 450 mg, 95% target engagement (TG) was achieved around peak exposure levels. Non-neutralizing ADA was detected in 1/15 pts. Conclusions: BION, at doses 50-1350 mg given Q2W, was well-tolerated and dose-dependently reduces serum levels of fAPRIL. To date, objective responses have not been observed. The study is ongoing with pts exposed to higher and/or more frequent doses with the objective of achieving accelerated and sustained APRIL TG. Clinical trial information: NCT03340883.
Abstract 4381: Investigating the reversible MDH1 catalytic reaction in squamous non-small cell lung cancer
Authors: Joi L. Weeks, Grace Wells, Sati Alexander, Christian Metallo, Christal D. Sohl
Journal: Cancer Research (2019)

Abstract Non-small-cell lung cancer (NSCLC) is a leading cause of death in men and women worldwide. NSCLC relies on glycolysis to support cell proliferation and to synthesize proteins, nucleic acids and lipids. Malate dehydrogenase (MDH) is an enzyme critical for replenishing intermediates in the tricarboxylic acid (TCA) cycle and for helping to drive glycolysis through its reversible coenzyme system NAD+/NADH by interconverting oxaloacetate and malate. The cytosolic form of MDH (MDH1) has been reported to be amplified in squamous cell NSCLC, which has high glycolytic activity. Elucidation of the role of MDH1 in altering cellular metabolism to drive tumorigenic progression has yet to be determined. Thus, our interest lies in identifying the chemical and cellular characteristics required to drive the reversible MDH1 catalytic reaction in squamous cell NSCLC. Previously, we have shown that metabolic dehydrogenases are regulated by microenvironmental changes in pH and oxidation levels, and we are currently extending this work to MDH1. We are also evaluating various cell lines to gain a better understanding of how the MDH1 reaction can be altered to decrease the tumorigenic capacity of squamous cell NSCLC. Experimental knowledge obtained has the potential to increase our understanding of the MDH1 reaction and educate the design of future anti-tumor therapeutics. Citation Format: Joi L. Weeks, Grace Wells, Sati Alexander, Christian Metallo, Christal D. Sohl. Investigating the reversible MDH1 catalytic reaction in squamous non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4381.
Abstract 3093: Prognostic value of novel immune basal subtypes in muscle invasive bladder cancer
Authors: Woonyoung Choi, Debasish Sundi, I-ling Lee, Arlene Siefker-Radtke, Colin Dinney, Bogdan Czerniak, Seungchan Kim, David McConkey
Journal: Cancer Research (2019)

Abstract Using gene expression profiling we previously reported the existence of 3 molecular subtypes (basal, p53-like and luminal) characterized by distinct gene expression patterns and clinical outcomes in muscle-invasive bladder cancer (MIBC). Among the subtypes, basal tumors were associated with advanced stage at presentation and shorter survival in the absence of neoadjuvant chemotherapy (NAC). Our recent analysis identified two novel immune subtypes within the basal tumors (basal immune signature enriched - “BIE” and basal immune signature suppressed - “BIS”) using immune infiltration markers that are known to have prognostic value in multiple solid tumors. The analysis revealed that BIE had significantly improved survival outcomes while BIS was associated with the worst survival outcomes among all subtypes in TCGA MIBC data (n=408). Survival outcomes in BIE tumors were validated in an independent cohort (GSE48075, p &amp;lt;0.05). The characterization of the immune landscape in our novel subtypes using TCGA’s recent pan-cancer immunogenomics data showed that the BIE subtype was significantly enriched with ‘INF -γ dominant’ immune subtype out of the 6 TCGA immune subtypes (wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet and TGF-β dominant, p &amp;lt; 0.05). Since immune activation has been associated with response to chemotherapy in other tumor types, we explored the potential significance of the novel immune subtypes using public data consisting of patients who received NAC followed by radical cystectomy (GSE52219 and GSE69795). In these cohorts, chemotherapy was active as measured by pathological downstaging rates (≤ pT1 at cystectomy). Based on pathological downstaging, BIE was the most responsive to chemotherapy while BIS and p53-like tumors were resistant to chemotherapy (p &amp;lt; 0.05). We also used the recently developed CIBERSORT tool to estimate stromal cell infiltration in the NAC cohort. The results predicted that the BIE subtype was highly enriched with CD8+ T cells and NK cells (p &amp;lt;0.001). Taken together, our results reveal the existence of novel immune subtypes within basal tumors with distinct molecular features and survival outcomes in MIBC. The clinical implications of these subtypes will be further evaluated. Citation Format: Woonyoung Choi, Debasish Sundi, I-ling Lee, Arlene Siefker-Radtke, Colin Dinney, Bogdan Czerniak, Seungchan Kim, David McConkey. Prognostic value of novel immune basal subtypes in muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3093.
Abstract 4025: STEAP4 ISH and IHC diagnostics for Tarloxotinib activation in EGFR/HER2 mutant cancers
Authors: Hui Yu, Shevan Silva, Adriana Estrada-Bernal, Chris Rivard, Fred Hirsch, Maria Abbatista, Jeff Smaill, Robert C. Doebele, Adam Patterson, Avanish Vellanki, Vijaya G. Tirunagaru
Journal: Cancer Research (2019)

Abstract Background: Tarloxotinib is a clinical-stage prodrug that releases a potent, irreversible EGFR/HER2 inhibitor (Tarloxotinib-E) selectively in severely hypoxic regions of tumors. One-electron reduction leads to loss of the trigger moiety under oxygen-deficient conditions, releasing the neutral, diffusible ‘warhead’ Tarloxotinib-E. CRISPR/cas9-mediated disruption of the metalloreductase STEAP4 has demonstrated its role as the dominant plasma membrane reductase that facilitates one-electron reduction of Tarloxotinib. Methods: Cancer cell lines, PDX and resected tumor tissues processed in Formalin Fixed Paraffin Embedded (FFPE) blocks were evaluated. RNAScope technology was used to develop a method to assess STEAP4 mRNA expression by in situ hybridization using specific probes for human STEAP4. mRNA ISH technology for STEAP4 was optimized on a Leica Bond RX autostainer for detection of STEAP4 in FFPE specimens. STEAP4 antibodies were evaluated for Immunohistochemistry (IHC) analysis. STEAP4 IHC was employed as cross-reference, using an anti-STEAP4 antibody validated against STEAP4 knockout and over-expressing cell line and tumor models. Staining data was compared to quantitative PCR results for mRNA ISH and Western blot analysis for IHC. STEAP4 mRNA expression was assessed in FFPE sections of various EGFR/HER2 mutant tumor xenografts and EGFR/HER2 mutant patient tumor specimens. Results: The STEAP4 mRNA ISH assay was optimized and validated using FFPE sections from cell lines and STEAP4 overexpressing tumor blocks and compared to wild type tumors with minimal expression. High level of STEAP4 mRNA was observed in STEAP4 overexpressing tumors. STEAP4 mRNA ISH analysis revealed variable levels of expression in EGFR/HER2 mutant xenograft tumors. STEAP4 mRNA and protein expression level correlated with Tarloxotinib conversion to Tarloxotinib-E. STEAP4 mRNA expression in EGFR/HER2 mutant patient tumor specimens will be presented. Conclusion: STEAP4 reduces Tarloxotinib and leads to the conversion to the active drug, Tarloxotinib-E, in hypoxic tumors. Assessment of STEAP4 expression in individual patients is important to guide patient stratification in Tarloxotinib clinical trials and represents an attractive biomarker to enroll tarloxotinib-responsive patients in clinical trials. Citation Format: Hui Yu, Shevan Silva, Adriana Estrada-Bernal, Chris Rivard, Fred Hirsch, Maria Abbatista, Jeff Smaill, Robert C. Doebele, Adam Patterson, Avanish Vellanki, Vijaya G. Tirunagaru. STEAP4 ISH and IHC diagnostics for Tarloxotinib activation in EGFR/HER2 mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4025.
Comparative analyses between younger and older patients with pancreatic adenocarcinoma: differences in clinicopathological features, treatment patterns, and outcomes
Authors: M. Salem, K. Kadakia, S. Trufan, J. Hwang, R. Nazemzadeh, M. Jagosky, W. Worrilow, H. Coley, M. Al Hallak, N. Gower, P. Philip, E. O’Reilly
Journal: Annals of Oncology (2019)
Abstract 2174: A solution for simultaneous DNA &amp; RNA extraction from single tissue without lysate splitting
Authors: Han Wei
Journal: Cancer Research (2019)

Abstract Extraction of intact and high quality gDNA or RNA is one of the most common procedures in molecular biology labs. With the advance of NGS, scientists can analyze both genomic and transcriptomic information from the same sample. Techniques that offer the ability to isolate both DNA and RNA from a single biological sample are crucial for this application. There is still great need for improved protocols in this area especially for precious and low-yield samples. Currently, most researchers use TRIzol® to isolate RNA and DNA from the same tube by extracting DNA from the organic phase and RNA from the aqueous phase. Although this method can extract high-quality RNA, the DNA yield is often low. With many biological samples in short supply, it is crucial to maximize yields. We report here using Beckman Coulter reagents, a protocol to isolate both DNA and RNA from the same fresh/frozen sample. The method utilizes size selection to separate DNA and RNA. We tested this method on 4 different frozen mouse tissues and report consistent extraction performance across all 4 tissue types. There are two advantages for this method: (1) There is no need to split a lysate for separate preparation of DNA/RNA; thus, researchers will not lose any portion of DNA or RNA. (2) Due to the different size distributions between DNA and RNA, this method offers quick and efficient extraction. Citation Format: Han Wei. A solution for simultaneous DNA &amp; RNA extraction from single tissue without lysate splitting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2174.