tbuckley/cabot-search huggingface dataset:
Genomic copy number predicts esophageal cancer years before transformation
Authors: Sarah Killcoyne, Eleanor Gregson, David C. Wedge, Dan J. Woodcock, Matthew D. Eldridge, Rachel de la Rue, Ahmad Miremadi, Sujath Abbas, Adrienn Blasko, Cassandra Kosmidou, Wladyslaw Januszewicz, Aikaterini Varanou Jenkins, Moritz Gerstung, Rebecca C. Fitzgerald
Journal: Nature Medicine (2020)
Abstract 5255: The SAGE Direct TestTM: A reliable way of functional profiling to predict the most effective treatment for cancer patients
Authors: Dhruva Mishra, Jennifer Moy, Chris Apfel
Journal: Cancer Research (2020)

Abstract Cancer is a genetic disease with increasing heterogeneity during disease progression. However, despite the widespread use of genomic testing, a recent publication estimated that only 5% of cancer patients in the US benefit from genome-driven targeted therapies, largely because “actionable mutations” are rare.[1] Thus, SageMedic has developed the SAGE Direct Test™, leading the next generation of functional precision medicine to accurately predict the most effective treatment for virtually all cancer patients without limitations of genomic sequencing or having to identify a specific pathway. Our SAGE Direct Test™ consists of four critical steps, i.e., tissue processing, creation of 3D microtumors, live/dead cell imaging, and metabolic profiling. Using our proprietary technology, we can create hundreds of 3D microtumors from a core needle biopsy sample that recapitulate the in vivo tumor heterogeneity and microenvironment of the tumor biopsy. After these microtumors have been treated with a panel of drugs, we quantify the number of live and dead cells in those microtumors using our proprietary technology and scalable automatic stage confocal imaging (Molecular Devices). The advantage of our SAGE Direct Platform™ is the ability to multiplex our image-based results with the metabolic profile of our 3D microtumors, which cross validates our image-based readout. Our SAGE Direct Test™ has been optimized with ATCC cell lines and further validated with patient-derived tumor cells from lung, ovarian, and colon cancer tumor samples. Validation of high-quality confocal imaging samples followed by quantitative metabolic analysis suggests accurate quantification of viable cells, as reflected in a positive correlation between imaging quantitation and metabolic analysis (correlation coefficient r=0.84, p&amp;lt;0.01). In summary, SageMedic has developed the SAGE Direct Test™, a simple, highly sensitive, robust, and straightforward functional profiling assay with significant clinical relevance, as it can model the natural physiological conditions of tumors. [1] Marquart et al. Estimation of the Percentage of US Patients With Cancer Who Benefit From Genome-Driven Oncology. JAMA Oncology 2018 Aug 1;4(8):1093-1098 Citation Format: Dhruva Mishra, Jennifer Moy, Chris Apfel. The SAGE Direct TestTM: A reliable way of functional profiling to predict the most effective treatment for cancer patients [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 5255.
Abstract 3432: Zinc metallochaperones for mutant p53 reactivation in cancer therapeutics
Authors: Xin Yu, Bing Na, Saif Zaman, Tracy Withers, John Gilleran, Alan J. Blayney, Anthony F. Bencivenga, Adam R. Blanden, Yue Liu, David A. Boothman, Stewart N. Loh, S. David Kimball, Shridar Ganesan, Darren R. Carpizo
Journal: Cancer Research (2020)

Abstract The p53 transcription factor functions as one of cancer's most potent tumor suppressors and is the most frequently mutated gene in human cancer. Restoration of wild type structure and function (so-called reactivation) of the high levels of the deficient mutant p53 protein with a small molecule is a highly sought after goal in anti-cancer drug development. We discovered a new class of small molecule zinc chelators named zinc metallochaperones (ZMCs) that reactivate zinc deficient mutant p53 through a novel mechanism by refolding p53 protein and inducing a p53 mediated apoptotic program. We identified the role of cellular zinc homeostasis as the OFF switch in ZMC pharmacodynamics indicating that a brief period of p53 mutant reactivation is sufficient for on-target efficacy. We conducted pre-clinical pharmacokinetic (PK), pharmacodymanic (PD) and efficacy studies in the murine pancreatic cancer (KPC) and BRCA1-deficient breast cancer models and found that ZMC1 and its new formulation of the drug in complex with zinc improved survival and inhibited tumor growth specifically for the zinc deficient allele. Using the BRCA1-deficient breast cancer model, we observed a highly synergistic effect of ZMC1 and the PARP inhibitor olaparib. Olaparib is now approved for the treatment of advanced BRCA1/2 mutant ovarian cancers, and recent clinical data also support its efficacy in BRCA1/2 mutant breast cancers. However acquired resistance to PARP inhibitors is inevitable in most advanced cancers. We investigated the ZMC therapeutic efficacy and found that the cell lines derived from olaparib resistant tumors are still sensitive to ZMC1 treatment. We are currently investigating the mechanism and testing the combination in vivo. In addition, we explored synergistic combinations of ZMC1 and other chemotherapy drugs based on its mechanism of action including ZMC1 with MDM2 antagonists and BCL2 antagonists. Overall, our findings indicate that the mutant p53 reactivational activity of ZMCs is governed by a unique ON/OFF switch mechanism that allows the compounds to be effective with a brief exposure to avoid the off target toxicities. The targeted and synergistic combinatorial treatments represent a significant departure from the traditional paradigm for developing a targeted molecular therapeutic in cancer. Citation Format: Xin Yu, Bing Na, Saif Zaman, Tracy Withers, John Gilleran, Alan J. Blayney, Anthony F. Bencivenga, Adam R. Blanden, Yue Liu, David A. Boothman, Stewart N. Loh, S. David Kimball, Shridar Ganesan, Darren R. Carpizo. Zinc metallochaperones for mutant p53 reactivation in cancer therapeutics [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 3432.
Abstract 1230: Critical role of cav1 in high-throughput identification of gallic acid as a novel late-stage autophagy suppresser against invasive breast cancer
Authors: Neng Wang, Fengxue Zhang, Zhiyu Wang, Yifeng Zheng, Shengqi Wang, Bowen Yang
Journal: Cancer Research (2020)

Abstract Purpose: Development of autophagy inhibitors has important clinical significance in cancer therapies. We and others demonstrated that over-expression of Caveolin-1 (Cav1), which was the major scaffolding protein of caveolae, was associated with higher tumor stage, metastasis and worse prognosis in various carcinomas, particularly in breast cancer. Furthermore, we identified critical role of Cav1 in breast cancer metastasis via modulation of lysosomal function and autophagy. Based on the above, we screened a series of 2, 645 kinds of small-molecule drugs to find out certain cav1 inhibitors which could suppress autophagy and breast cancer metastasis. Experimental Design: We conducted the 1st high-throughput screening based on surface plasmon resonance (SPR) analysis of cav-1 interaction with 2, 645 kinds of small-molecule drugs. Secondly, we launched the 2nd high-throughput screening based on CCK8 analysis to validate the anti-cancer potential of the selected compounds. We also carried out the final high-throughput screening to investigate their autophagic effects with high content image cytometry assay. The anti-cancer and anti-metastasis effects of the final drug candidate was investigated using invasive breast cancer cells MDA-MB-231 and BT-549, and its role on autophagy was further investigated by transfection of mRFP-GFP-LC3 adenoviral vector and western blot analysis of autophagic proteins. Results: 2, 645 kinds of small-molecule drugs were screened based on a series of high-throughput screening. The compound gallic acid was identified as the candidate drug owing to its strong interaction and competitive inhibition with cav1, its potent anti-proliferation potential on both invasive breast cancer cells MDA-MB-231 and BT-549, as well as its potent autophagic inhibition compared with the other 2, 644 drugs. Further experimental validation revealed that gallic acid was a potent late-stage autophagy inhibitor via inhibiting autophagosome-lysosome fusion. Conclusions: Collectively, these results demonstrated that the cav1 inhibitor gallic acid was a novel late-stage autophagy suppressor with potential clinical application for invasive breast cancer therapy. Citation Format: Neng Wang, Fengxue Zhang, Zhiyu Wang, Yifeng Zheng, Shengqi Wang, Bowen Yang. Critical role of cav1 in high-throughput identification of gallic acid as a novel late-stage autophagy suppresser against invasive breast 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 1230.
Abstract 3029: Population pharmacokinetics and dose regimen evaluation of monalizumab, a monoclonal antibody targeting NKG2a, in patients with advanced solid tumors
Authors: Xuyang Song
Journal: Cancer Research (2020)

Abstract Background: Monalizumab (IPH2201) is a humanized IgG4 monoclonal antibody that targets NKG2a, resulting in suppression of inhibitory signaling by tumors on NK cells. We aimed to develop a population pharmacokinetics (PK) model of monalizumab and to identify and quantitate the impact of patient/disease characteristics on PK variability, and to compare body weight-based and fixed dosing regimens of monalizumab. Methods: Data were pooled from two clinical studies: NCT02671435 (Phase 1/2; monalizumab + durvalumab in all comers) and NCT02643550 (Phase 2; monalizumab + cetuximab in SCCHN). 95 patients provided monalizumab PK data following 0.4−10 mg/kg every 2 weeks (Q2W), 22.5 mg−750 mg Q2W, or 750 mg every 4 weeks (Q4W). Population PK modeling was performed using a non-linear mixed effects modeling approach in NONMEM software (v. 7.2). Impact of demographics, clinical indices, and biomarkers on PK was explored. The appropriateness of the final model was tested using diagnostics including visual predictive check (VPC). Results: Monalizumab PK profiles were best described using a linear 2-compartment model. The clearances (CL) and central volume of distribution (V1) were 0.27 L/day and 3.6 L with a modest between-subject variability of 40% and 30% for CL and V1, respectively. Body weight on CL and volume of distribution resulted in ~30% impact; other evaluated covariates showed no impact on PK parameters, indicating no need for dose adjustment. VPC results demonstrated good predictability of the final population PK model. Simulations indicated that similar overall PK exposures are expected following either the fixed 750 mg Q2W or the body-weight based 10 mg/kg Q2W regimens. Both regimens are projected to result in maintenance of trough exposures &amp;gt;2 µg/mL in ≥95% of patients where nonlinear clearance is expected to be fully saturated. Conclusions: A population PK model of monalizumab was developed and validated. No dose adjustments were needed based on patient or disease characteristics. Similar PK is expected following both body weight-based and fixed dosing regimens. These results support further evaluation of 750 mg Q2W or equivalent dose in future Phase 2/3 clinical studies. Citation Format: Xuyang Song. Population pharmacokinetics and dose regimen evaluation of monalizumab, a monoclonal antibody targeting NKG2a, in patients with advanced solid 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 3029.
Abstract 4755: Chemoprevention and pharmacokinetics study using Gasdermin D knock out induced colon cancer model mouse treated with FAS inhibitors
Authors: Hajime Orita, Hyeoncheol Lee, Toshiyuki Kobayashi, Tetsu Fukunaga
Journal: Cancer Research (2020)

Abstract (Introduction) It is well known that cancer cell harness different metabolic pathway from normal cells more efficiently. Recent studies indicate disorder of lipid metabolism has happen even in the benign cell, and that cause to be malignancy. Our research group focus attention on irregular accumulation of fatty acid in cancer cells. This time, we analysis several studies using Gasdermin D knock out induced colon cancer model mouse treated with FAS inhibitors. 1) metabolism analysis for mouse colon cancer. 2) Colon cancer treatment and chemoprevention by FAS inhibitor 3)Pharmacokinetics status of FAS inhibitor (colon cancer model mouse) Gasdermin D (GSDM D), pylotosis key factor, knockout mouse treat with AOM and DSS. 3month after all mouse has several big tumors (patent in Japan 2016-69775) (Result) 1) There are Many famous long chain fatty acids in cancer tissue. And also Very Long Chain Fatty Acid (:VLCFA) can detected by this analysis. 2) C75 and Kampo (include Berberine) can decrease tumor number and size. And they has chemoprevention effects, too. 3) Almost 40% FAS activity can reduce by everyday FAS inhibitor treatment. (Conclusion) AS metabolic disorders seem to induce colon cancer carcinogenesis, this target therapy can work for that prevention and treatment. Citation Format: Hajime Orita, Hyeoncheol Lee, Toshiyuki Kobayashi, Tetsu Fukunaga. Chemoprevention and pharmacokinetics study using Gasdermin D knock out induced colon cancer model mouse treated with FAS inhibitors [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 4755.
Abstract 2548: Pentose phosphate pathway inhibition potentiates metformin cytotoxic effects on HNSCC cells
Authors: Marcela Solange Villaverde, Jorge Silvio Gutkind
Journal: Cancer Research (2020)

Abstract The pentose phosphate pathway (PPP) enables cancer cells to adapt to anabolic demands that require rapid DNA, RNA, and lipid synthesis and to oxidative cellular stress. Metformin can efficiently inhibit the malignant progression of oral premalignant lesions by indirectly inhibiting the mammalian target of rapamycin (mTORC1). Frequently activated in cancer cells, mTORC1 may upregulate the oxidative branch of the pentose phosphate pathway (PPP) through the sterol regulatory element binding protein (SREBP1). Our previous results showed that the combination of metformin and 6-AN (a PPP inhibitor) strongly potentiates their individual cytotoxic effects on melanoma, glioblastoma, mammary and colon carcinoma cell lines. However, the mechanism of this synergism remains unclear. In this context, the aim of this project was to determine the cell signaling events underlying the therapeutic potential of this combinatory approach, against HNSCC cell lines. Then, we study the effect of metformin alone or in combination with 6-AN on AMPK/mTOR/S6K/S6 and SREBP1 pathway. We found that the inhibition of PPP strongly potentiated metformin cytotoxic effect on 2D and 3D cultures of CAL33 and HN12, both HNSCC cell lines. Furthermore, the combination synergized to increase the activation of AMPK, concomitant with decreased phosphorylation of mTOR, decreased phosphorylation of S6K and decreased phosphorylation of S6. Interestingly, activation of SREBP1 was also synergistically decreased by this combinatory approach. We conclude that the inhibition of PPP and metformin converges to inhibit mTOR pathway. This interaction deserves to be further investigated as a potential strategy to potentiate metformin therapy. Citation Format: Marcela Solange Villaverde, Jorge Silvio Gutkind. Pentose phosphate pathway inhibition potentiates metformin cytotoxic effects on HNSCC cells [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 2548.
Abstract 1349: Improved human exome sequencing workflow with the most complete coverage
Authors: Manqing Hong, Bosun Min, Nicole Roseman, Ekaterina Star, Timothy Rusch, Krishnalekha Datta, Steve Groenewold, Longhui Ren, Jinglie Zhou, Kevin Lai, Xiaohui Wang, Nick Downey, Kristina Giorda, Alexandra Wang, Yu Wang, Lynette A. Lewis, Patrick J. Lau, Steven Henck
Journal: Cancer Research (2020)

Abstract Consisting of only ~2% of the human genome, the exome accounts for ~85% of genetic disorders. Efficient sequencing of the human exome with complete and high coverage depth at low cost is invaluable for furthering research in clinical applications. IDT's xGen Exome Panel has proven to be a high performing option. Here, we present the updated xGen Exome Research Panel v2.0 in direct comparison with two other leading commercial human exome panels, using workflows per manufacturer's specifications. NA12878 genomic DNA libraries were pooled together for 8-plex captures for all three platforms and sequenced on the Illumina NextSeq 500. Equivalent number of reads per sample were analyzed against a universal human exome target space to compare across the different exome panels. IDT's Exome NGS solution provided significantly highest on-target percentage at &amp;gt;90% as well as the greatest depth of coverage at &amp;gt;96% bases covered at &amp;gt;20X and &amp;gt;98% bases covered at &amp;gt;10X. Importantly, IDT's platform also reported the most complete gene-level coverage, demonstrated by minimal exon drop-outs in difficult-to-target genes. While 8-plex is the upper limit supported by other suppliers, IDT's platform supports 12-plex workflow. The higher multiplex in combination with high coverage and on-target performance enables IDT to present the lowest total sequencing cost per sample. Since IDT hybridization capture baits are individually synthesized and qualified with the same high standards as standalone oligonucleotide products, lot-to-lot variability is negligible. This presents researchers with an option they can rely on for long-term use and places the focus on the true variabilities of the sample. In conclusion, this study demonstrates xGen Exome Research Panel v2.0, when combined with IDT's DNA Library Prep Kit, provides researchers with a complete Exome NGS solution that is competitive both in performance and sequencing cost. Citation Format: Manqing Hong, Bosun Min, Nicole Roseman, Ekaterina Star, Timothy Rusch, Krishnalekha Datta, Steve Groenewold, Longhui Ren, Jinglie Zhou, Kevin Lai, Xiaohui Wang, Nick Downey, Kristina Giorda, Alexandra Wang, Yu Wang, Lynette A. Lewis, Patrick J. Lau, Steven Henck. Improved human exome sequencing workflow with the most complete coverage [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 1349.
Abstract 2322: A polygenic risk score-based genetic stratification for endometrial cancer
Authors: Cemsel Bafligil, Deborah J. Thompson, Artitaya Lophatananon, Miriam J. Smith, Joe Dennis, Gareth D. Evans, Emma J. Crosbie
Journal: Cancer Research (2020)

Abstract Endometrial cancer (EC) is the most common of gynecological cancers in the UK. There is evidence for genetic predisposition to EC, however, single nucleotide polymorphisms have not been considered in risk prediction models so far. We hypothesized that a polygenic risk score (PRS) based on a panel of robust SNPs may be useful to predict women at high risk of developing EC. We conducted a systematic review to identify the most robust SNPs which may be associated with EC risk. The resulting panel of SNPs was validated in an independent cohort comprising EC cases, and control women with intact uterus. In the present study, we used 560 cases and 1202 controls of broad-European origin to construct a PRS. Our systematic review suggested twenty four SNPs, nineteen of which were reported to reach genome-wide significance in large GWAS. Preliminary results using 560 cases and 1202 controls produced effect sizes, directions and dosages similar to published data. The mean PRS for EC cases was 0.64 (SD=0.43, 95%CI 0.60-0.68) while mean PRS for controls was 0.48 (SD=0.42, 95% CI 0.46-0.51). The AUC of the PRS achieved was 0.61. Women in the highest tertile of the PRS score had a 2.4 times increased risk of developing EC compared to women in the lowest tertile (OR=2.40, 95%CI 1.85-3.09, p = 1.47E-11). Women in the mid tertile also had a modestly increased risk of EC compared to the lowest tertile (OR=1.40, 95%CI 1.06-1.84, p = 0.017). There was a clear trend of increasing risk with category (p = 6.25E-12). There is mounting evidence for polygenic input from common variants in EC susceptibility. Our results, for the first time, validate the potential use of a PRS for risk stratification of women at high risk of EC. When considered alongside epidemiological risk factors, the PRS could provide a good discrimination for early detection and prevention of EC in a clinical setting. Citation Format: Cemsel Bafligil, Deborah J. Thompson, Artitaya Lophatananon, Miriam J. Smith, Joe Dennis, Gareth D. Evans, Emma J. Crosbie. A polygenic risk score-based genetic stratification for endometrial 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 2322.
Elotuzumab, lenalidomide, and dexamethasone in RRMM: final overall survival results from the phase 3 randomized ELOQUENT-2 study
Authors: Meletios A. Dimopoulos, Sagar Lonial, Darrell White, Philippe Moreau, Katja Weisel, Jesus San-Miguel, Ofer Shpilberg, Sebastian Grosicki, Ivan Špička, Adam Walter-Croneck, Hila Magen, Maria-Victoria Mateos, Andrew Belch, Donna Reece, Meral Beksac, Andrew Spencer, Heather Oakervee, Robert Z. Orlowski, Masafumi Taniwaki, Christoph Röllig, Hermann Einsele, Morio Matsumoto, Ka Lung Wu, Kenneth C. Anderson, Ying-Ming Jou, Alex Ganetsky, Anil K. Singhal, Paul G. Richardson
Journal: Blood Cancer Journal (2020)

Prolonging overall survival (OS) remains an unmet need in relapsed or refractory multiple myeloma (RRMM). In ELOQUENT-2 (NCT01239797), elotuzumab plus lenalidomide/dexamethasone (ERd) significantly improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd) in patients with RRMM and 1-3 prior lines of therapy (LoTs). We report results from the pre-planned final OS analysis after a minimum follow-up of 70.6 months, the longest reported for an antibody-based triplet in RRMM. Overall, 646 patients with RRMM and 1-3 prior LoTs were randomized 1:1 to ERd or Rd. PFS and overall response rate were co-primary endpoints. OS was a key secondary endpoint, with the final analysis planned after 427 deaths. ERd demonstrated a statistically significant 8.7-month improvement in OS versus Rd (median, 48.3 vs 39.6 months; hazard ratio, 0.82 [95.4% Cl, 0.68-1.00]; P = 0.0408 [less than allotted α of 0.046]), which was consistently observed across key predefined subgroups. No additional safety signals with ERd at extended follow-up were reported. ERd is the first antibody-based triplet regimen shown to significantly prolong OS in patients with RRMM and 1-3 prior LoTs. The magnitude of OS benefit was greatest among patients with adverse prognostic factors, including older age, ISS stage III, IMWG high-risk disease, and 2-3 prior LoTs.