tbuckley/cabot-search huggingface dataset:
Abstract 832: Construction and optimization of gene expression signatures for prediction of survival in two-arm clinical trials
Authors: Joachim Theilhaber, Marielle Chiron, Jennifer Dreymann, Donald Bergstrom, Jack Pollard
Journal: Cancer Research (2020)

Abstract Gene expression signatures for the prediction of differential survival of patients undergoing anti-cancer therapies are of great interest because they can be used to prospectively stratify patients entering new clinical trials, or to determine optimal treatment for patients in more routine clinical settings. Unlike prognostic signatures however, predictive signatures require training set data from clinical studies with at least two treatment arms, and the methodology for constructing and optimizing predictive signatures has been less prominently explored. Focusing on the “use case” of a two-arm clinical trial for metastatic colorectal cancer (CRC) patients treated with the anti-angiogenic molecule aflibercept, we present tools for the construction of signatures predictive of progression-free survival based on cross-validated multivariate Cox models. The work is organized around a specific approach called subtype correlation, which leverages a priori knowledge of molecular subtypes of tumors for a given indication. The tools and concepts presented here include the so-called differential log-hazard ratio, the survival scatter plot, the hazard ratio receiver operating characteristic, the area between curves and the patient selection matrix. In the CRC use case, the resulting signature stratifies the patient population into “sensitive” and “relatively-resistant” groups achieving a more than two-fold difference in the aflibercept-to-control hazard ratios across signature-defined patient groups. Through cross-validation and resampling the probability of generalization of the signature to similar CRC data sets is predicted to be high. The tools presented here should be of general use for building and using predictive multivariate signatures in oncology and in other therapeutic areas. Citation Format: Joachim Theilhaber, Marielle Chiron, Jennifer Dreymann, Donald Bergstrom, Jack Pollard. Construction and optimization of gene expression signatures for prediction of survival in two-arm clinical trials [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 832.
Teaching Old Dogs New Tricks? The Plasticity of Lung Alveolar Macrophage Subsets
Authors: Justina Kulikauskaite, Andreas Wack
Journal: Trends in Immunology (2020)

HighlightsIn mice at steady state, embryonically derived tissue-resident alveolar macrophages (AMs) self-sustain over a lifetime and fulfill their homeostatic function of surfactant removal. Following various lung insults, including influenza A virus infection and bleomycin-induced lung fibrosis, these cells show only minimal transcriptional and functional changes, suggesting that resident AMs are terminally differentiated, highly specialized, and not very plastic.In naïve mice, the contribution of monocyte-derived cells to AMs is negligible, but they become major components of the AM population post-lung insult. The functionality of recruited AMs can determine increased antibacterial protection, reduced asthma, and elevated lung fibrosis, depending on the specific initial insult studied.When the newly recruited population of monocyte-derived AMs persist in the mouse lung, they start to resemble tissue-resident AMs, suggesting that the lung environment sends cues to shape their relatively non-inflammatory, immunosedated phenotype.The high reactivity of recently recruited AMs might be best explained as a transcriptional and epigenetic legacy from their prior monocyte identity. Alternatively, training, acting through epigenetic and transcriptional reprogramming on hematopoietic stem cells or monocytes in the blood or in the lung, may imprint the high reactivity of recruited AMs.AbstractAlveolar macrophages (AMs) are highly abundant lung cells with important roles in homeostasis and immunity. Their function influences the outcome of lung infections, lung cancer, and chronic inflammatory disease. Recent findings reveal functional heterogeneity of AMs. Following lung insult, resident AMs can either remain unchanged, acquire new functionality, or be replaced by monocyte-derived AMs. Evidence from mouse models correlates AM function with their embryonic or monocyte origin. We hypothesize that resident AMs are terminally differentiated cells with low responsiveness and limited plasticity, while recruited, monocyte-derived AMs are initially highly immunoreactive but more plastic, able to change their function in response to environmental cues. Understanding cell-intrinsic and -extrinsic mechanisms determining AM function may provide opportunities for intervention in lung disease.
Abstract 1655: Hyperspectral metabolic imaging with a camera
Authors: Per Niklas Hedde, Enrico Gratton
Journal: Cancer Research (2020)

Abstract New methods to quantify metabolism in cells, organoids, and tissues are highly demanded for cancer diagnosis and treatment. We developed a light sheet-based volumetric imaging platform to rapidly quantify metabolism via fluorescence spectral signatures of intrinsically fluorescent biomolecules. The ability to quantify metabolism in live cells and tissues can be very powerful as the metabolic activity in rapidly proliferating cells, such as cancer cells, is fundamentally different from non-proliferating cells. Most cancer cells rely on aerobic glycolysis to ferment glucose into lactate independent of the presence of oxygen whereas healthy, differentiated cells primarily rely on oxidative phosphorylation. The rapid generation of cytosolic adenosine triphosphate (ATP) during proliferation results in elevated ratios of the reduced form of nicotinamide adenine dinucleotide (NADH) to NAD+ in cancerous cells that can be detected with fluorescence microscopy of intrinsically (auto)fluorescent molecules such as NADH and flavin adenine dinucleotide (FAD) and its variants. This opens a window to quantify ongoing redox reactions as well as important enzymatic reactions via changes of their fluorescence spectral signatures reporting on the metabolic activity of cells. We developed a light sheet-based hyperspectral imaging platform leveraging custom designed sine/cosine filters and spectral phasor data analysis to directly obtain spectral information with a regular camera. The approach was verified by spectrally resolving 3D reconstructions of fluorescence images of fragments of mouse intestinal crypts. The acquisition speed of light sheet-based hyperspectral imaging is on the order of seconds for one 3D stack allowing for sequential, repeated imaging of several samples over the course of hours to days. In summary, the overall goal of this project is to develop a modular imaging platform to overcome the limitations of current, laser scanning-based spectral imaging and to make quantification of metabolism viable in live three-dimensional cell, organoid and tissue samples, that can then be used to, for example, to study the effects of cancer chemotherapy reagents on the metabolism of patient-derived organoids. Citation Format: Per Niklas Hedde, Enrico Gratton. Hyperspectral metabolic imaging with a camera [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 1655.
Abstract 1092: A systematic analysis of BRAF mutations and their sensitivity to different BRAF inhibitors
Authors: Zohar Barbash, Dikla Haham, Liat Hafzadi, Ron Zipor, Shaul Barth, Arie Aizenman, Lior Zimmerman, Gabi Tarcic
Journal: Cancer Research (2020)

Abstract The MAPK-ERK signaling cascade is among the most frequently mutated pathways in human cancer, with the BRAF V600 mutation being the most common alteration. FDA-approved BRAF inhibitors as well as combination therapies of BRAF and MEK inhibitors are available and provide survival benefits to patients with a BRAF V600 mutation in several indications. Yet non-V600 BRAF mutations are found in many cancers and are even more prevalent than V600 mutations in certain tumor types. As the use of NGS profiling in precision oncology is becoming more common, novel alterations in BRAF are being uncovered. This has led to the classification of BRAF mutations, which is dependent on its biochemical properties and affects it sensitivity to inhibitors. Therefore, annotation of these novel variants is crucial for assigning correct treatment. Using a high throughput method for functional annotation of MAPK activity, we profiled 151 different BRAF mutations identified in the AACR Project GENIE dataset, and their response to 4 different BRAF inhibitors- vemurafenib and 3 different exploratory 2nd generation inhibitors. The system is based on rapid synthesis of the mutations and expression of the mutated protein together with fluorescently labeled reporters in a cell-based assay. Our results show that from the 151 different BRAF mutations, ~25% were found to activate the MAPK pathway. All of the class 1 and 2 mutations tested were found to be active, providing positive validation for the method. Additionally, many novel activating mutations were identified, some outside of the known domains. When testing the response of the active mutations to different classes of BRAF inhibitors, we show that while vemurafenib efficiently inhibited V600 mutations, other types of mutations and specifically BRAF fusions were not inhibited by this drug. Alternatively, the second-generation experimental inhibitors were effective against both V600 as well as non-V600 mutations. Using this large-scale approach to characterize BRAF mutations, we were able to functionally annotate the largest number of BRAF mutations to date. Our results show that the number of activating variants is large and that they possess differential sensitivity to different types of direct inhibitors. This data can serve as a basis for rational drug design as well as more accurate treatment options for patients. Citation Format: Zohar Barbash, Dikla Haham, Liat Hafzadi, Ron Zipor, Shaul Barth, Arie Aizenman, Lior Zimmerman, Gabi Tarcic. A systematic analysis of BRAF mutations and their sensitivity to different BRAF 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 1092.
Making sense of big data in health research : towards an EU action plan (vol 8, pg 71, 2016)
Authors: C. Auffray, R. Balling, I. Barroso, L. Bencze, M. Benson, J. Bergeron, E. Bernal-Delgado, N. Blomberg, C. Bock, A. Conesa, S. del Signore, C. Delogne, P. Devilee, A. di Meglio, M. Eijkemans, P. Flicek, N. Graf, V. Grimm, H.J. Guchelaar, Y.K. Guo, I.G. Gut, A. Hanbury, S. Hanif, R.D. Hilgers, A. Honrado, D.R. Hose, J. Houwing-Duistermaat, T. Hubbard, S.H. Janacek, H. Karanikas, T. Kievits, M. Kohler, A. Kremer, J. Lanfear, T. Lengauer, E. Maes, T. Meert, W. Muller, D. Nickel, P. Oledzki, B. Pedersen, M. Petkovic, K. Pliakos, M. Rattray, J.R.I. Mas, R. Schneider, T. Sengstag, X. Serra-Picamal, W. Spek, L.A.I. Vaas, O. van Batenburg, M. Vandelaer, P. Varnai, P. Villoslada, J.A. Vizcaino, J.P.M. Wubbe, G. Zanetti
Journal: Genome Medicine (2016)
Pomalidomide, bortezomib, and dexamethasone for multiple myeloma previously treated with lenalidomide (OPTIMISMM): outcomes by prior treatment at first relapse
Authors: Meletios Dimopoulos, Katja Weisel, Philippe Moreau, Larry D. Anderson, Darrell White, Jesus San-Miguel, Pieter Sonneveld, Monika Engelhardt, Matthew Jenner, Alessandro Corso, Jan Dürig, Michel Pavic, Morten Salomo, Eva Casal, Shankar Srinivasan, Xin Yu, Tuong Vi Nguyen, Tsvetan Biyukov, Teresa Peluso, Paul Richardson
Journal: Leukemia (2020)

Abstract In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated superior efficacy vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma previously treated with lenalidomide, including those refractory to lenalidomide. This analysis evaluated outcomes in patients at first relapse ( N = 226) by lenalidomide-refractory status, prior bortezomib exposure, and prior stem cell transplant (SCT). Second-line PVd significantly improved PFS vs Vd in lenalidomide-refractory (17.8 vs 9.5 months; P = 0.0276) and lenalidomide-nonrefractory patients (22.0 vs 12.0 months; P = 0.0491), patients with prior bortezomib (17.8 vs 12.0 months; P = 0.0068), and patients with (22.0 vs 13.8 months; P = 0.0241) or without (16.5 vs 9.5 months; P = 0.0454) prior SCT. In patients without prior bortezomib, median PFS was 20.7 vs 9.5 months ( P = 0.1055). Significant improvement in overall response rate was also observed with PVd vs Vd in lenalidomide-refractory (85.9% vs 50.8%; P &lt; 0.001) and lenalidomide-nonrefractory (95.7% vs 60.0%; P &lt; 0.001) patients, with similar results regardless of prior bortezomib or SCT. No new safety signals were observed. These data demonstrate the benefit of PVd at first relapse, including immediately after upfront lenalidomide treatment failure and other common first-line treatments.
Abstract 1884: The activation of YES1 leads to the acquired resistance to neratinib in <i>HER2</i>-amplified breast and lung cancers
Authors: Hiromasa Yamamoto, Tatsuaki Takeda, Ken Suzawa, Shuta Tomida, Shunsaku Miyauchi, Kota Araki, Kentaro Nakata, Akihiro Miura, Tadahiko Shien, Yoshihisa Kitamura, Toshiaki Sendo, Shinichi Toyooka
Journal: Cancer Research (2020)

Abstract Background: Molecular-targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan-HER tyrosine-kinase inhibitor, and was approved by the FDA as an effective drug for HER2-positive breast cancer. However, acquired resistance of various cancers to molecular-targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. Methods: We established various types of neratinib-resistant cell lines from HER2-amplified breast and lung cancer cell lines using various drug exposure conditions. Then we analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Results: YES1, which is a member of the SRC family, was amplified in two neratinib-resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1-amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. Moreover, this combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Conclusion: YES1 plays an important role in the emergence of resistance to HER2-targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome. Citation Format: Hiromasa Yamamoto, Tatsuaki Takeda, Ken Suzawa, Shuta Tomida, Shunsaku Miyauchi, Kota Araki, Kentaro Nakata, Akihiro Miura, Tadahiko Shien, Yoshihisa Kitamura, Toshiaki Sendo, Shinichi Toyooka. The activation of YES1 leads to the acquired resistance to neratinib in HER2-amplified breast and lung 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 1884.
Abstract 3020: Tumor pharmacokinetics of the metastatic cancer inhibitor MBQ-167 in mice
Authors: Maria Del Mar Maldonado, Ailed M. Cruz-Collazo, Luis D. Borrero-García, Gabriela T. Rosado-González, Jean F. Ruiz-Calderon, Jorge Duconge, Suranganie Dharmawardhane
Journal: Cancer Research (2020)

Abstract The Rho GTPases Rac and Cdc42 are potential targets against metastatic disease. Our group characterized the small molecule MBQ-167 as an effective dual Rac/Cdc42 inhibitor that reduces HER2 positive and triple negative tumor growth and metastasis in mice by ~90%. To continue validating this drug for FDA approval, we recently elucidated the plasma pharmacokinetics and the tissue distribution of MBQ-167 in mice (Maldonado et al., 2019). However, further studies are needed to characterize the tumor pharmacokinetics of MBQ-167 to determine drug exposure, time-to-peak, and the length of time that MBQ-167 remains in tumors after administration. The purpose of this study was to determine the tumor pharmacokinetics of MBQ-167 in a single dose input scheme (10 mg/kg BW) following intraperitoneal (IP) administration. Thirty-five female BALB/c mice (5 mice/group) were injected with 2.5 × 105 4T1 murine metastatic breast cancer cells at the mammary fat pad. After tumor establishment, a single dose of MBQ-167 (10 mg/kg BW) was administered via IP. Tumors were collected at 0.5, 1, 3, 6, 9,12, and 24 hours following drug administration. We used a validated bioanalytical method using supercritical fluid chromatography coupled with tandem mass spectrometry (SFC-MS/MS) to quantify MBQ-167 in tumors. Pharmacokinetic parameters were obtained by non-compartmental analysis using WinNolin® software. Pharmacokinetic analysis revealed that MBQ-167 has an elimination half-life (t1/2) of 8.64 hours in tumors, which is much longer than its half-life in plasma (2.17 hours), indicating preferential absorption and retention of this lipophilic small molecule in tumor tissues. The area under the curve (AUC0-t) was 4.39 %ID⋅hr/g with a maximum concentration (Cmax) of 1268.9 ng/g in tumors. Moreover, the time-to-peak concentration in tumors was 0.5 hours. Hence, this study supports the continued development of MBQ-167 as a potential anti-cancer therapeutic. Citation Format: Maria Del Mar Maldonado, Ailed M. Cruz-Collazo, Luis D. Borrero-García, Gabriela T. Rosado-González, Jean F. Ruiz-Calderon, Jorge Duconge, Suranganie Dharmawardhane. Tumor pharmacokinetics of the metastatic cancer inhibitor MBQ-167 in mice [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 3020.
Abstract 1449: The molecular dissection of pro-tumorigenic activity of mesothelin in pancreatic cancer
Authors: Sarah Mary Joseph, Leela Rani Avula, Xianyu Zhang, Christine Campo Alewine
Journal: Cancer Research (2020)

Abstract Mesothelin (MSLN) is a cancer-specific antigen that is differentially expressed in many human cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. The MSLN gene encodes a 71 kD precursor protein, that is reportedly cleaved by the intracellular protease furin to produce a 31 kD N-terminal fragment called megakaryocyte potentiating factor (MPF) and mature 40 kD MSLN C-terminal fragment. Mature MSLN is localized to the cell surface by a GPI-linkage. We synthesized a series of mutant MSLN constructs containing sequence modifications predicted to disrupt the canonical signaling sequences for furin cleavage and GPI-linkage. These constructs were then expressed in a MSLN knock-out pancreatic cancer cell line. We used flow cytometry to detect cell surface MSLN expression and immunoblotting for MSLN proteins to assess the effect of mutation. We expected that a 23aa C-terminal truncation that removed a predicted hydrophobic signaling sequence for GPI-linkage would eliminate plasma membrane insertion of MSLN. However, this truncation did not suppress cell surface expression. A deeper 31aa truncation which eliminated two potential anchoring sites at Ser599 and Ser606 was required to successfully eliminate surface expression. We are currently evaluating the growth of this pancreatic cancer cell line expressing GPI-truncated soluble MSLN in vitro and in vivo. Our results suggest that MSLN may have an alternate means for membrane insertion besides GPI-linkage. For the panel of furin site mutants, non-conservative mutations were made to disrupt the reported consensus recognition motif for furin 290-RPRFRR-295 (R290H, R292Q, RR294-5GG) or the entire motif region was deleted (289_315del). Mutants were also made to disrupt the putative furin cleavage site (R286A) and neighboring basic residues that were potential protease cleavage sites (R282A, K306Q, K307Q). These furin site mutants were expected to eliminate cleavage of the 71 kD precursor protein to 40 kD mature MSLN. We found that all mutants did increase levels of precursor but did not ablate formation of mature MSLN. Similarly, expression of WT full-length MSLN into the LoVo cell line, which lacks furin activity, still resulted in formation of 40 kD mature MSLN predominately. In conclusion, we found that precursor processing to mature MSLN still took place despite extensive mutation of the putative furin cleavage site and in the absence of active furin. These results suggest that additional proteases besides furin can perform MSLN precursor cleavage. Citation Format: Sarah Mary Joseph, Leela Rani Avula, Xianyu Zhang, Christine Campo Alewine. The molecular dissection of pro-tumorigenic activity of mesothelin in pancreatic 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 1449.
Abstract 4070: Development of MAEGI as a new class of immune gene therapy for cancer treatment
Authors: Sidi Chen
Journal: Cancer Research (2020)

Abstract Current major types of immunotherapy include checkpoint blockade, adoptive cell transfer, human recombinant cytokines, and cancer vaccines. However, immunotherapy has met challenges in immunologically cold tumors. These challenges urge for new types of immunotherapies that are more potent and potentially less toxic. Recently, we have developed CRISPRa-mediated Multiplexed Activation of Endogenous Genes as an Immunotherapy (MAEGI) (Wang et al. 2019 Nature Immunology, in press). The CRISPR activation (CRISPRa) system uses a catalytically inactive Cas9 (dCas9), enabling simple and flexible gene expression regulation through dCas9-transcriptional activators paired with single guide RNAs (sgRNAs). This enables precise targeting of large gene pools of endogenous genes in a flexible manner. We demonstrate that MAEGI has therapeutic efficacy across three tumor types. Mechanistically, our preliminary work showed that MAEGI treatment elicits anti-tumor immune responses by recruiting effector T cells and remodeling the tumor microenvironment. We will perform advanced development, characterization and optimization of MAEGI, as a novel immune-gene therapy approach to elicit a potent and specific immune response to tumors based on their unique genetic composition. Citation Format: Sidi Chen. Development of MAEGI as a new class of immune gene therapy for cancer 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 4070.