tbuckley/cabot-search huggingface dataset:
Abstract 5246: Disulfiram anticancer metabolite, dithiocarb-copper complex, demonstrates anti-neoplastic activity against hypermutated colorectal cancers
Authors: Daciana Catalina Dumut, Juan B. De Sanctis, Martin Mistrik, Zdenek Skrott, Petr Dzubak, Jiri Bartek, Marian Hajduch, Danuta Radzioch
Journal: Cancer Research (2020)

Abstract Introduction: Colorectal cancer (CRC) is the third leading cause of cancer related deaths in the United States. It was responsible for about 51,000 deaths during 2019. Surgical resection and systemic chemotherapy are standard approaches to treat both localized and metastatic CRC (mCRC). However, the effect of the chemotherapy depends on the characteristics of the individual tumor, for instance CRC subtypes with a microsatellite instability (MSI) tend to have better prognosis and response to both chemotherapy and immune check-point inhibition. Recently, Disulfiram's anti-cancer activity was explored and its metabolite ditiocarb-copper complex (CuET) was found to have high anti-cancer activity. The mechanism of action of CuET was proposed to act through p97 segregase adaptor NPL4 and activation of endoplasmic reticulum stress leading to preferential apoptosis of cancer cells. Since altered protein degradation pathway is targeted by CuET, this compound might display high efficacy in highly mutated colorectal cancers. Methods: To assess CuET anti-cancer activity in vitro, we performed survival curve assays and colony-formation assays in both murine hypermutated colorectal cancer cell line MC-38 as well as in human KRAS mutant and MSI HCT116 cell line. We also evaluated anti-metastatic effect of CuET on both cell lines through migration-invasion assays in Boyden chamber setting. We assessed in vivo efficacy of systemic treatment with CuET alone or in combination with irinotecan, against MC-38 model in immunocompetent C57BL/6 mice. We characterized tumor growth, mice survival and tumor histopathology. Results: Our results demonstrate that CuET displays cytotoxicity in MC-38 and HCT116 cells at very low doses with respective IC50 of 46nM and 88nM. CuET also significantly reduces the ability of both cell lines to grow and form colonies under sustained treatment. Additionally, CuET is effective in significantly reducing cancer cell migration and invasion through porous membrane in vitro. Furthermore, systemic treatment with CuET significantly reduced tumor growth in mice and prolonged survival when compared to controls. Conclusion: CuET demonstrates cytotoxic activity against hypermutated colorectal cancer cells both in vitro and in vivo and should be further investigated in clinical trials. Citation Format: Daciana Catalina Dumut, Juan B. De Sanctis, Martin Mistrik, Zdenek Skrott, Petr Dzubak, Jiri Bartek, Marian Hajduch, Danuta Radzioch. Disulfiram anticancer metabolite, dithiocarb-copper complex, demonstrates anti-neoplastic activity against hypermutated colorectal cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5246.
Abstract 722: Urine for noninvasive liquid biopsy for germline and somatic mutations
Authors: James V. Vowles, Amy K. Kim, James P. Hamilton, Selena Y. Lin, Fwu-Shan Shieh, Harry Luu, Gabrielle Villafana, Chi-Tan Hu, Ying-Hsiu Su
Journal: Cancer Research (2020)

Abstract Circulating tumor DNA (ctDNA) from blood and peripheral blood mononuclear cells (PBMCs) are used to determine comprehensive cancer genetics and germline genomics for precision medicine. To evaluate the use of urine samples as a noninvasive alternative to blood samples, we performed a comprehensive characterization of urine DNA as an alternative to PBMC DNA for germline genomics. Whole genome sequencing (WGS) was performed in PBMC and total urine DNA in six normal subjects to compare the quality and comprehensiveness of the genomic data. There was no significant difference between the sequencing data obtained from PBMC and urine DNA upon comparing the variant calling, percent reads passing Phred score Q30 (p&amp;gt;0.05, paired t-test), and coverage of human genome. Similar to plasma cfDNA, mononucleosomal-sized DNA was the most predominant species present in urine cfDNA. Samples from three hepatocellular carcinoma (HCC) patients were further analyzed for insert sizes by NGS, which demonstrated predominantly mononucleosomal-sized DNA fragments, with a series of peaks occurring with 10-bp periodicity, in both urine and plasma cfDNA. With shallow WGS, the genome coverage overlap was 53-61%, and by increasing the depth of coverage the overlap increased from 60% to 74%. Interestingly, 8-10% of the genome covered in plasma DNA was not detected in urine DNA, and 4-8% of the genome covered in urine DNA was not covered in plasma DNA. Next, we compared the detectability of three HCC-associated genetic mutations in the matched urine and plasma DNA obtained from 76 HCC patients including mutations at TP53 codon 249 (TP53 249T), CTNNB1 exon 3 regions 32-37 (CTNNB1 32-37), and hTERT promoter region position 124 (hTERT 124). We observed higher levels of the TP53 mutation, similar levels of CTNNB1 mutation, and lower levels of the TERT mutation in urine cfDNA compared to plasma ctDNA. This suggests a potential for urine as a potential noninvasive source for ctDNA analysis, and a combination of both urine and plasma ctDNA may increase the overall sensitivity of ctDNA detection. In conclusion, our data suggest that (1) total urine DNA can replace PBMC DNA for providing comprehensive genomic sequencing data and (2) urine can complement blood for liver cancer liquid biopsy, precision medicine, and potential applications in other cancers. Citation Format: James V. Vowles, Amy K. Kim, James P. Hamilton, Selena Y. Lin, Fwu-Shan Shieh, Harry Luu, Gabrielle Villafana, Chi-Tan Hu, Ying-Hsiu Su. Urine for noninvasive liquid biopsy for germline and somatic mutations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 722.
Abstract 2760: A mouse orthotopic model of pancreatic cancer and response to treatment
Authors: Elizabeth Rainbolt, Madelyn Cecil-Taylor, Andrew Wong, Robin Ball, Patrick Wood, Edgar R. Wood, Paula Miliani de Marval, Susan Yeyeodu
Journal: Cancer Research (2020)

Abstract The mouse pancreatic ductal adenocarcinoma PAN02 was produced in C57BL/6 mice exposed to 3-methyl-cholanthrene. PAN02 is generally resistant to standard cancer therapeutics, thus providing an appropriately rigorous model for the development of clinically effective agents to treat aggressive and intractable pancreatic ductal adenocarcinoma. Subcutaneous implants of syngeneic PAN02 provide the dual advantages of being able to closely monitor changes in tumor growth without compromising the complex pro- and anti-tumor immune responses of the host that collectively determine the outcome of tumor progression. Unfortunately, subcutaneous PAN02 tends to grow slowly and tumor ulcerations are common which may result in tumor regression or loss of animals in a study. Here we report the growth properties and response to therapy of orthotopically implanted PAN02. To establish the orthotopic model, we implanted cells by direct injection into the pancreas through an incision in the abdominal wall at two implant densities, 3 × 105 and 3 × 106 PAN02 cells in 30 μl. Both cell inocula demonstrated progressive growth with median survival of thirty-seven and thirty days post implant respectively. We chose 3 × 106 PAN02 cells to evaluate efficacy of cytotoxic agents gemcitabine and oxaliplatin. Dosing was initiated 7 days after implant; gemcitabine was dosed at 120 mg/kg, by intraperitoneal injection (IP) every third day for four doses and oxaliplatin was dosed at 10 mg/kg IP once a week for 3 weeks. Gemcitabine and oxaliplatin increased life span by 9.0 days and 20.5 days respectively over vehicle control. The morphology of the tumors revealed by histological staining is also presented. The development of this orthotopic pancreatic model provides a more clinically relevant model for evaluation of novel therapies compared to subcutaneous implantation. Citation Format: Elizabeth Rainbolt, Madelyn Cecil-Taylor, Andrew Wong, Robin Ball, Patrick Wood, Edgar R. Wood, Paula Miliani de Marval, Susan Yeyeodu. A mouse orthotopic model of pancreatic cancer and response to treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2760.
Abstract 4072: Analysis of clinical <i>BRCA1/2</i> reversions identifies hotspot mutations and predicted neoantigens associated with therapy resistance
Authors: Stephen Pettitt, Jessica Frankum, Marco Punta, Stefano Lise, John Alexander, Yi Chen, Syed Haider, Andrew N. Tutt, Christopher J. Lord
Journal: Cancer Research (2020)

Abstract Although PARP inhibitors and platinum salts form part of the standard-of-care for cancers with homologous recombination (HR) defects, drug resistance does emerge and is often caused by reversion mutations in BRCA1 or BRCA2. Reversion mutations are secondary mutations that restore functional protein or compensate for frameshift mutations. To better understand the nature and aetiology of these mutations, we collated, codified and analysed over 200 reversion mutations from 24 published studies. Most reversions have been reported as case reports or small clinical series - we have collected all published reports into a single freely-accessible database to which further cases can be submitted. The majority of reported reversion mutations are from BRCA1/2 mutant serous ovarian cancer, reflecting the longer use of platinum and PARP inhibitors in this disease. Our analysis identified reversion “hotspots” and “deserts” in the N- and C-terminal coding regions (respectively) of BRCA2, suggesting that pathogenic mutations in these domains may be at higher or lower chance of reversion, an effect not seen for BRCA1. Missense and splice-site pathogenic mutations in BRCA1/2 also appeared less likely to revert than frameshift-causing mutations. Unexpectedly, whilst most reversions were &amp;lt;100 bp “second site” deletions, microhomology use was not universal, especially in BRCA1-mutant cancers, suggesting that multiple DNA repair processes cause reversion and these vary in BRCA1 vs. BRCA2 mutant tumours. Reversions in BRCA1 mutant tumours were less likely to be mediated by deletions. Many reversions contain novel protein sequence not found in the wild type protein, for example where a stretch of out-of-frame protein sequence is retained between the pathogenic and reversion mutations. We modelled MHC binding affinities for these sequences and found that many reversions were predicted to encode potentially immunogenic neopeptides, suggesting a route to the treatment of reverted disease. These observations have implications for how drug resistance might be managed in BRCA-mutant cancers. Citation Format: Stephen Pettitt, Jessica Frankum, Marco Punta, Stefano Lise, John Alexander, Yi Chen, Syed Haider, Andrew N. Tutt, Christopher J. Lord. Analysis of clinical BRCA1/2 reversions identifies hotspot mutations and predicted neoantigens associated with therapy resistance [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4072.
Abstract 5957: Roles for the cancer stem cell marker Aldh1A1 in Merlin null nervous system tumors
Authors: Lily Hillson, Liyam Laraba, Aditya G. Shivane, Philip Edwards, Ganesha Bantukallu, Anton Simeonov, Natalia J. Martinez, Shyh-Ming Yang, David B. Parkinson
Journal: Cancer Research (2020)

Abstract Our lab is interested in the development and growth of schwannoma and meningioma tumors of the nervous system. Approximately 70% of these tumors arise due to loss of the tumor suppressor Merlin. In a mouse model of schwannoma (P0-CRE NF2fl/fl), we observed increased mRNA levels of the cancer stem cell marker Aldehyde dehydrogenase 1A1 (Aldh1A1) in Merlin-null Schwann cells. Immunostaining showed elevated levels of Aldh1A1 protein in this mouse model and in another mouse model (Postn-CRE NF2fl/fl), in which schwannoma tumors arise spontaneously within the vestibulocochlear nerve and dorsal root ganglia of the nervous system. Similarly, staining of human schwannoma samples also showed a strong elevation of Aldh1A1 protein in all tumor cells. Parallel analysis of meningioma tumor samples, in which Merlin loss also occurs, also showed a strong increase of Aldh1A1 protein levels. Western blotting enabled identification of the mechanism by which Merlin loss regulates Aldh1A1. Merlin/TAZ double knockout, but not Merlin/YAP double knockout, sciatic nerves show reduced Aldh1A1 expression. This implicates Hippo signalling through the TAZ effector as the mechanism of Aldh1A1 upregulation both in vitro and in vivo in both tumor types. Chemical inhibition with Aldh1a1-specific inhibitor (NCT-505) or shRNA knockdown of Aldh1A1 in Merlin-null schwannoma and meningioma cells in culture attenuated tumor cell growth, proving Aldh1A1 has a role in tumor cell proliferation; studies using Aldh1A1 null mice to test this in vivo are ongoing. A major target of Aldh1A1 signalling is the regulation of retinoic acid (RA) signalling. We are examining expression and activation of components of RA signalling in both schwannoma and meningioma tumor cells to identify whether this may be of therapeutic use in the future for these two tumor types. In conclusion, the TAZ-dependent upregulation of Aldh1A1 in Merlin-null schwannoma and meningioma tumor cells has a functional role in driving cell proliferation in these two clinically important tumor types. Further work will seek to identify the mechanism by which Aldh1A1 activity contributes to tumor growth. Citation Format: Lily Hillson, Liyam Laraba, Aditya G. Shivane, Philip Edwards, Ganesha Bantukallu, Anton Simeonov, Natalia J. Martinez, Shyh-Ming Yang, David B. Parkinson. Roles for the cancer stem cell marker Aldh1A1 in Merlin null nervous system tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5957.
Abstract 4223: Combination therapy of BCR-ABL-positive B cell acute lymphoblastic leukemia by tyrosine kinase inhibitor dasatinib and c-Jun N-terminal kinase inhibition
Authors: Xinhua Xiao, Bo Jiao, Ruibao Ren
Journal: Cancer Research (2020)

Abstract The Philadelphia chromosome (Ph), which leads to creation and expression of the fusion gene product BCR-ABL, underlines the pathogenesis of chronic myelogenous leukemia (CML) and a fraction of adult and pediatric acute B-lymphoblastic leukemia (B-ALL). The BCR-ABL tyrosine kinase inhibitors (TKIs) has shown a remarkable clinical activity in patients with CML, but their efficacy in treating Ph+ B-ALL is limited. Identifying additional therapeutic targets is important for the effective treatment of Ph+ B-ALL. In this study, we found that the c-Jun N-terminal kinase (JNK) signaling pathway is abnormally activated in both human and mouse BCR-ABL+ B-ALL cells, but the BCR-ABL TKI does not inhibit JNK activation in these cells. Inhibition of JNK, either by RNAi-mediated downregulation or by JNK inhibitors, could significantly reduce viability of Ph+ B-ALL cells. JNK inhibition by RNAi-mediated downregulation or JNK inhibitors also showed a synergistic effect with the BCR-ABL TKI, dasatinib, in killing Ph+ B-ALL cells in vitro. Furthermore, a potent JNK inhibitor, JNK-IN-8, in combination with dasatinib markedly improved the survival of mice with BCR-ABL induced B-ALL, as compared to the treatment with dasatinib alone. Our findings indicate that simultaneously targeting both BCR-ABL and JNK kinase might serve as a promising therapeutic strategy for Ph+ B-ALL. Citation Format: Xinhua Xiao, Bo Jiao, Ruibao Ren. Combination therapy of BCR-ABL-positive B cell acute lymphoblastic leukemia by tyrosine kinase inhibitor dasatinib and c-Jun N-terminal kinase inhibition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4223.
Abstract 5915: HPV oncogenes regulated the aberrant expression of microRNAs in cervical cancer
Authors: Yan Deng, Yi Song, Tao Tang, Chi Chiu Wang
Journal: Cancer Research (2020)

Abstract The high risk human papillomavirus (HPV) is the single most important etiological agent in cervical cancer. The E5, E6 and E7 genes in the early region of HPV genome are proved to have a significant impact on progression of cervical cancer. MicroRNA (miRNA) is a kind of short non-coding RNA which has been proven to play a role in tumor development. Previously, we have identified several differentially expressed miRNAs in cervical cell lines and clinical specimens, including 9 down-regulated and 2 up-regulated. Here we further investigate the direct relationship between the oncogenes (E5, E6 and E7) and the above miRNAs by overexpressing the oncogenes and silencing each single one separately. The result of the relative expression level of miRNAs showed some consistency that HPV E5, E6 and E7 could down-regulate the expression of miR-145, miR-195 and miR-142-3p. However, there were also discrepancy. For instance, E6 from HPV 16 and HPV 52 showed a significant down-regulation in the expression of miR-195, while E6 of other subtypes (HPV18, 31, 52) had no effect on the miR-195 expression level. Meanwhile, the oncogenetic effect of miR-142-3p has been examined by measuring cell proliferation. Further mechanism study of HPV/miR-142-3p pathway in the cervical cancer would also be investigated. The work could provide new insight in understanding the development of cervical cancer and potentially help to develop novel therapeutic approaches and bio-markers for cervical cancer. Citation Format: Yan Deng, Yi Song, Tao Tang, Chi Chiu Wang. HPV oncogenes regulated the aberrant expression of microRNAs in cervical cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5915.
Abstract 3905: Human liver organoids for disease modeling of fibrolamellar hepatocellular carcinoma
Authors: Nicole J. Croteau, David Requena, Gadi Lalazar, Denise Ng, Solomon Levin, Bassem Shebl, Ruisi Wang, William J. Hammond, James A. Saltsman, Helmuth Gehart, Hans Clevers, Michael P. LaQuaglia, Sanford Simon
Journal: Cancer Research (2020)

Abstract Fibrolamellar Hepatocellular Carcinoma (FLC) is a usually lethal liver cancer affecting adolescents and young adults without previous liver disease. FLC is characterized by a ~400kb nucleotide deletion resulting in a fusion of a heatshock protein cofactor, DNAJB1, with the catalytic subunit of protein kinase A (PRKACA). One limitation to the study of this disease is the lack of in vitro models. Organoids have shown utility as a model system for studying many diseases, including cancer. This study describes the development and characterization of FLC tumor organoids. With IRB approval, normal liver and FLC tumor tissue was obtained from patients undergoing surgical resection. Liver cells were isolated from the tissue samples and placed into a 3D basement membrane matrix and the media supplemented with growth factors specific to promote liver organoid expansion. Normal and tumor organoids were analyzed by microscopy for morphology, by PCR for presence of the DNAJB1-PRKACA chimeric transcript, by Western blot for chimeric protein expression, and by RNA sequencing for transcriptomic changes. Eight organoid lines have been developed from normal liver and eight from FLC tumor tissue, including multiple independent organoids developed from different metastases from the same patient. A distinct morphological difference between normal liver organoids and FLC tumor organoids can be seen with either brightfield microscopy or with H&amp;E. The DNAJB1-PRKACA chimeric transcript was detected in all of the tumor tissue and tumor organoids by RT-PCR and not detected in any of the normal tissue or organoids. The presence of the DNAJB1-PRKACA fusion protein was verified by Western blot in tumor organoids and tissue but not detectable in the normal tissue. The RNA sequencing analysis shows clustering of tumor organoids with tumor tissue. Tumor organoids injected subcutaneously in mice grew as tumors. Now that the normal and tumor organoids have been developed and validated, they are being used for screening for potential therapeutics. Citation Format: Nicole J. Croteau, David Requena, Gadi Lalazar, Denise Ng, Solomon Levin, Bassem Shebl, Ruisi Wang, William J. Hammond, James A. Saltsman, Helmuth Gehart, Hans Clevers, Michael P. LaQuaglia, Sanford Simon. Human liver organoids for disease modeling of fibrolamellar hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3905.
AB0209 Long term analysis and evaluation of side effects related to cyclosporine treatment of 59 patients with rheumatic diseases
Authors: MM Martinez-Losa, HC Macias, EM Camargo, AR De la Serna, CD López, JM Llobet, CG Ferrer
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Cyclosporine has been used in the area of rheumatology, and various published articles describe evidence of side effects in short and long term, which have lead to withdrawal of the treatment. <h3>Objectives</h3> Evaluate the presence of side effects in 59 patients that received cyclosporine treatment in dosis of 2.5–3 mg/Kg/day. <h3>Methods</h3> This is a prospective study which carried out 59 patients that received cyclosporine treatment: 45 females with an average age of 57 years (range 23–80) and 15 males with an average age of 50.6 years (range 31–72) with the follow disease: 41 Rheumatoid Arthritis, 6 Psoriatic Arthritis and tha remainder included sufferers of Systemic Lupus Erythematosus, Scleroderma, Ankylosing Spondylitis and Cryoglobulinemia. Female patients suffering from the illness for an average of 19.95 years, were treated for a total period of 22.11 months. Male patients suffering from the illness for an average of 8.7 years, were treated for a total period of 19.4 months. <h3>Results</h3> Reasosn for treatment withdrawal were: a) increase in levels of creatinine in 27 out of 59 patients causing treatment suspension for 3 patients; b) nausea and vomiting in 8 cases; c) 6 out of 8 patients presenteds hypertension; d) 11 patients suffered from headache and treatment was withdrawn in 4 cases; e) 13 patients showed increase of levels of alkaline phosphatse, 3 of them were under combined methotrexate treatment; f) other causes: diarrhoea (4), dermatitis (1), trombocytopenia (1) and metrorrhagias (1). <h3>Conclusion</h3> Cyclosporine is an effective treatment for the rheumatic diseases, neverthless, the side effects have forced us to withdraw treatment for half of patients under the study. <h3>Reference</h3> Lynch AR. 2000;43:5344