tbuckley/cabot-search huggingface dataset:
Abstract 6674: Multi-dimensional time-series analysis to reveal pharmacodynamic changes induced by immunotherapy
Authors: Jingjing Wang, Panpan Wang, Wenli Zhang, Qiyao Zhang, Qingyang Gu, Qunsheng Ji
Journal: Cancer Research (2020)

Abstract Background: Immune checkpoint inhibitors currently represent the most promising cancer therapeutics to produce durable responses. Many studies have highlighted checkpoint inhibitors' targets for future monotherapies or combination therapies. However, due to the complexity of tumor microenvironment, different types of cells exhibit different reaction time and order. To understand the MoA of immune checkpoint inhibitors in cell or animal models, time-series analysis will help select proper PD sampling time, as well as administration time &amp; order in combination therapy. However, such analysis has limited application in syngeneic tumor models in the early stage of drug treatment due to the small tumor volumes. Methods and Results: In this study, we combined NanoString technology and flow cytometry in an in-vivo efficacy study to explore the therapeutic response mechanism in mouse breast cancer EMT-6 model by the combinational treatment with anti-PD1 and an undisclosed compound A. Through time-course sampling of tumor tissues of EMT-6 xenograft tumors in the early stage of treatment, we found that anti-PD1 could enhance antigen-presentation and T cell priming as a single agent, and this effect could be enhanced by combination with compound A. In addition, we found the change of antigen-presentation induced by anti-PD1 occurs at RNA level, but not at protein level by flow cytometry analysis, which might imply to employ different time points to combine with RNA-targeted or protein-targeted drugs on T cell priming. Summary: We have developed a time-series analysis combining in vivo efficacy study and NanoString technology with flow cytometry, to evaluate the dynamic changes of TME after immune checkpoint blocker treatment. This can be a powerful method to reveal time-dependent drug-induced pharmacodynamic changes, and help us to select the best time course for combination therapy. Citation Format: Jingjing Wang, Panpan Wang, Wenli Zhang, Qiyao Zhang, Qingyang Gu, Qunsheng Ji. Multi-dimensional time-series analysis to reveal pharmacodynamic changes induced by immunotherapy [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 6674.
Abstract 2878: Granzyme B functionalized nanocarriers targeting membrane-bound Hsp70 for multimodal cancer therapies
Authors: Maxim Shevtsov, Susanne Kaesler, Stefan Stangl, Luidmila Yakovleva, Ruslana Tagaeva, Yaroslav Marchenko, Boris Nikolaev, William Khachatryan, Oleg Galibin, Emil Pitkin, Gabriele Multhoff
Journal: Cancer Research (2020)

Abstract Functionalized superparamagnetic iron oxide nanoparticles (SPIONs) have emerged as potential clinical tools for cancer theranostics. Membrane-bound 70 kDa heat shock protein (mHsp70) is ubiquitously expressed on the cell membrane of various tumor types but not on normal cells and therefore provides a tumor-specific target. The serine protease granzyme B (GrB) that is produced as an effector molecule by activated T and NK cells has been shown to specifically target mHsp70 on tumor cells. Following binding to Hsp70, GrB is rapidly internalized into tumor cells inducing the process of cellular apoptosis. Decoration of the nanoparticles surface with GrB increased the targeting properties of the nanocarriers as was shown by confocal and electron microscopies. In series of in vivo studies it was demonstrated that GrB functionalized SPIONs act simultaneously as a contrast enhancement agent when being intravenously administered for magnetic resonance imaging and induce specific tumor cell apoptosis (human U87 glioblastoma in NMRI nu/nu mice, rat C6 glioma in Wistar rats, B16 melanoma in C57/Bl6 mice). Continuous prolonged administration of GrB-SPIONs via programmable subcutaneously implanted mini-pump system iPrecio further enhanced the therapeutic benefit of magnetic conjugates. Moreover, significant therapeutic response was achieved in immunocompromised mice models (advanced U87 brain tumor, small lung cancer H1339 with brain metastasis) with a high tumor burden. Combinatorial regimens employing stereotactic radiotherapy and/or magnetic targeting with immune checkpoint inhibitors (anti-CTLA-4 monoclonal antibodies) are found to further enhance the therapeutic efficacy of GrB-SPIONs in different tumor mouse models. The study was funded by RFBR, project № 19-08-00024; DFG grant SFB824/3, Germany, TaGoNaX DFG project № 336532926, STA1520/1-1. Citation Format: Maxim Shevtsov, Susanne Kaesler, Stefan Stangl, Luidmila Yakovleva, Ruslana Tagaeva, Yaroslav Marchenko, Boris Nikolaev, William Khachatryan, Oleg Galibin, Emil Pitkin, Gabriele Multhoff. Granzyme B functionalized nanocarriers targeting membrane-bound Hsp70 for multimodal cancer therapies [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 2878.
Abstract 1762: Dual HDAC-BET proteins inhibition by TW9 hold promise for breast cancer
Authors: Pedro Luiz P. Xavier, Romain Lucas, Tim Weiser, Stefan Knapp, Heidge Fukumasu, Susanne Müller
Journal: Cancer Research (2020)

Abstract Epigenetic proteins play a key role in gene expression regulation and cellular states and, consequently, abnormalities in these mechanisms result in the development and progression of several types of cancer. Thus, inhibitors against epigenetic targets have recently entered clinical trials as potential and innovative therapies against this disease. Both histone deacetylases (HDACs) and bromodomain and extraterminal proteins (BET) inhibitors have been shown to be efficient against several different cancer types, including breast cancer. Although synergistic effects of HDAC and BET inhibitors have been observed in different cancer types, few studies have been performed in breast cancer. However, combination studies often result in increased toxicity, thus new strategies are necessary to overcome these limitations. Therefore, we designed and synthesized a dual HDAC-BET inhibitor, TW9. In this study, we determined the effects of TW9 on two HR-positive cell lines MCF7 and T-47D and two triple-negative breast cancer cell lines, MDA-MB-231 and HCC1806 in 2D and 3D in vitro models. To determine the cytotoxic effects, cells were treated with (+)-JQ1 (BET inhibitor), CI994 (HDAC inhibitor) and TW9 (dual HDAC-BET inhibitor). After 72h, cell viability was tested using XTT assay. Primary and secondary tumorspheres were grown in ultra-low attachment multiwell plates and were treated with DMSO (control) or different concentrations of TW9. The triple-negative cell lines were more resistant to all inhibitors and TW9 was more potent compared to (+)-JQ1 or CI994 in all the breast cancer cells (p&amp;lt;0.05). Tumorspheres of MCF7 cells were treated with TW9 ranging from 100 nM to 500 nM. Significant decrease of primary and secondary tumorspheres was observed at all doses (p&amp;lt;0.0001). In addition, TW9 was able to inhibit the formation of secondary tumorspheres, even after removal of the treatment during dissociation of primary tumorspheres (p&amp;lt;0.0001), pointing to an epigenetic effect. In summary, our findings showed that dual HDAC-BET inhibition by TW9 shows positive effects regarding tumorigenicity and self-renewal of cancer cells and thus may provide a promising treatment against breast cancer, in particular for the more resistant triple-negative cells. Citation Format: Pedro Luiz P. Xavier, Romain Lucas, Tim Weiser, Stefan Knapp, Heidge Fukumasu, Susanne Müller. Dual HDAC-BET proteins inhibition by TW9 hold promise for 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 1762.
Abstract 1232: Synergistic roles played by autophagy and Hsp70 in cancer cell survival
Authors: Sara Sannino, Jeffrey L. Brodsky
Journal: Cancer Research (2020)

Abstract To avoid cell death, cancer cells adapt to extreme conditions. Chaperone upregulation, modulation of the unfolded protein response (UPR), and induction of protein degradation pathways are critical for cancer cell survival and metastasis in some cancers. Thus, it is not surprising that the molecular chaperone Hsp70 is upregulated in many cancers. For example, increased Hsp70 abundance correlates with metastasis formation and poor prognosis in breast cancer patients. We previously demonstrated that inhibition of Hsp70, by treating cells with a specific inhibitor known as MAL3-101, induces rhabdomyosarcoma cancer cell death due to induction of a UPR-mediated apoptotic response (Sabinis et al., 2016). Moreover, by taking advantage of a MAL3-101-resistant cell line, we established that protein degradation pathways act as a compensatory mechanism in MAL3-101 resistant rhabdomyosarcoma cells. In particular, we found that autophagy inhibition re-sensitized resistant cells to Hsp70 inhibition, suggesting that autophagy is a key compensatory mechanism for Hsp70 inhibition. Autophagy was further induced by MAL3-101 treatment in these cells, as evidenced by both autophagy related gene mRNA and protein accumulation as well as by autophagic-like structures detected by electron microscopy (Sannino et al., 2018). These data highlight a pro-survival role for autophagy induction upon exposure to an Hsp70 inhibitor in cancer, and provide a link between Hsp70, proteasome activity, the UPR, and autophagy in rhabdomyosarcoma. We next asked if other cancers might be dependent on Hsp70 activity and investigated the benefit of combined treatment with autophagy and/or proteasome inhibitors together with MAL3-101 in breast cancer cells. Our recent studies suggest that diverse breast cancer cell lines are either sensitive or resistant to Hsp70 inhibition. MAL3-101 resistant breast cancer cells have higher autophagy levels compared to MAL3-101 sensitive lines. Moreover, autophagy is upregulated upon Hsp70 inhibition in resistant breast cancer cells, again highlighting the potential benefit of combined treatment with autophagy and Hsp70 inhibitors. Overall, our work positions autophagy as a critical compensatory mechanism when molecular chaperone function is overwhelmed and misfolded proteins accumulate in cancer cells. Further investigations will reveal the potential for Hsp70 inhibitors and the role of protein degradation pathways in vivo in breast cancer. Citation Format: Sara Sannino, Jeffrey L. Brodsky. Synergistic roles played by autophagy and Hsp70 in cancer cell survival [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 1232.
Infarct Collagen Topography Regulates Fibroblast Fate via p38-Yes-Associated Protein Transcriptional Enhanced Associate Domain Signals
Authors: Darrian Bugg, Ross Bretherton, Peter Kim, Emily Olszewski, Abigail Nagle, Austin E. Schumacher, Nick Chu, Jagadambika Gunaje, Cole A. DeForest, Kelly Stevens, Deok-Ho Kim, Jennifer Davis
Journal: Circulation Research (2020)

Rationale: Myocardial infarction causes spatial variation in collagen organization and phenotypic diversity in fibroblasts, which regulate the heart’s ECM (extracellular matrix). The relationship between collagen structure and fibroblast phenotype is poorly understood but could provide insights regarding the mechanistic basis for myofibroblast heterogeneity in the injured heart. Objective: To investigate the role of collagen organization in cardiac fibroblast fate determination. Methods and Results: Biomimetic topographies were nanofabricated to recapitulate differential collagen organization in the infarcted mouse heart. Here, adult cardiac fibroblasts were freshly isolated and cultured on ECM topographical mimetics for 72 hours. Aligned mimetics caused cardiac fibroblasts to elongate while randomly organized topographies induced circular morphology similar to the disparate myofibroblast morphologies measured in vivo. Alignment cues also induced myofibroblast differentiation, as &gt;60% of fibroblasts formed αSMA (α-smooth muscle actin) stress fibers and expressed myofibroblast-specific ECM genes like Postn (periostin). By contrast, random organization caused 38% of cardiac fibroblasts to express αSMA albeit with downregulated myofibroblast-specific ECM genes. Coupling topographical cues with the profibrotic agonist, TGFβ (transforming growth factor beta), additively upregulated myofibroblast-specific ECM genes independent of topography, but only fibroblasts on flat and randomly oriented mimetics had increased percentages of fibroblasts with αSMA stress fibers. Increased tension sensation at focal adhesions induced myofibroblast differentiation on aligned mimetics. These signals were transduced by p38-YAP (yes-associated protein)-TEAD (transcriptional enhanced associate domain) interactions, in which both p38 and YAP-TEAD (yes-associated protein transcriptional enhanced associate domain) binding were required for myofibroblast differentiation. By contrast, randomly oriented mimetics did not change focal adhesion tension sensation or enrich for p38-YAP-TEAD interactions, which explains the topography-dependent diversity in fibroblast phenotypes observed here. Conclusions: Spatial variations in collagen organization regulate cardiac fibroblast phenotype through mechanical activation of p38-YAP-TEAD signaling, which likely contribute to myofibroblast heterogeneity in the infarcted myocardium.
Sex-Specific Associations Between Chemotherapy, Chronic Conditions, and Neurocognitive Impairment in Acute Lymphoblastic Leukemia Survivors: A Report From the Childhood Cancer Survivor Study
Authors: Ellen van der Plas, Weiyu Qiu, Brian J Nieman, Yutaka Yasui, Qi Liu, Stephanie B Dixon, Nina S Kadan-Lottick, Christopher B Weldon, Brent R Weil, Lisa M Jacola, Todd M Gibson, Wendy Leisenring, Kevin Oeffinger, Melissa M Hudson, Leslie L Robison, Gregory T Armstrong, Kevin R Krull
Journal: JNCI Journal of the National Cancer Institute (2020)

The purpose was to examine associations between treatment and chronic health conditions with neurocognitive impairment survivors of acute lymphoblastic leukemia (ALL) treated with chemotherapy only.This cross-sectional study included 1207 ALL survivors (54.0% female; mean age 30.6 years) and 2273 siblings (56.9% female; mean age 47.6 years), who completed the Childhood Cancer Survivor Study Neurocognitive Questionnaire. Multivariable logistic regression compared prevalence of neurocognitive impairment between survivors and siblings by sex. Associations between neurocognitive impairment with treatment exposures and chronic conditions (graded according to Common Terminology Criteria for Adverse Events) were also examined. Statistical tests were 2-sided.Relative to same-sex siblings, male and female ALL survivors reported increased prevalence of impaired task efficiency (males: 11.7% vs 16.9%; adjusted odds ratio [OR] = 1.89, 95% confidence interval [CI] = 1.31 to 2.74; females: 12.5% vs 17.6%; OR = 1.50, 95% CI = 1.07 to 2.14), as well as impaired memory (males: 11.6% vs 19.9%, OR = 1.89, CI = 1.31 to 2.74; females: 14.78% vs 25.4%, OR = 1.96, 95% CI = 1.43 to 2.70, respectively). Among male survivors, impaired task efficiency was associated with 2-4 neurologic conditions (OR = 4.33, 95% CI = 1.76 to 10.68) and with pulmonary conditions (OR = 4.99, 95% CI = 1.51 to 16.50), and impaired memory was associated with increased cumulative dose of intrathecal methotrexate (OR = 1.68, 95% CI = 1.16 to 2.46) and with exposure to dexamethasone (OR = 2.44, 95% CI = 1.19 to 5.01). In female survivors, grade 2-4 endocrine conditions were associated with higher risk of impaired task efficiency (OR = 2.19, 95% CI = 1.20 to 3.97) and memory (OR = 2.26, 95% CI = 1.31 to 3.92).Neurocognitive impairment is associated with methotrexate, dexamethasone, and chronic health conditions in a sex-specific manner, highlighting the need to investigate physiological mechanisms and monitor impact through survivorship.
Abstract 2569: Uncovering metabolic bottlenecks in KEAP1 mutant lung cancer
Authors: Sarah E. LeBoeuf, Warren Wu, Triantafyllia Karakousi, Robert Wild, Thales Papagiannakopoulos
Journal: Cancer Research (2020)

Abstract During tumorigenesis cancer cells continuously encountermetabolic bottlenecks as a result of accelerated growth, overall increased metabolic demand and increased oxidative stress due to the formation of reactive oxygen species. We use a combination of genetically-engineered mouse models, an accelerated CRISPR/Cas9-based experimentalplatformand biochemical approaches to identify metabolic liabilities that can be exploited using novel targeted therapies.Lung cancer, the leading cause of cancer-related deaths worldwide,is the most common cancer type to acquire mutually exclusive gain-of-function mutations in the anti-oxidant transcription factor NRF2or loss-of-function mutations in its negative regulator KEAP1. Loss of Keap1activates Nrf2, increases antioxidant production and dramatically accelerates KRAS-driven lung cancer. Our data are in line with mounting evidence demonstrating that antioxidants promote cancer progression. Our studies focus on elucidating the mechanisms underlying novel metabolic dependencies in KEAP1mutant tumors and explore the therapeutic potential of targeting metabolism in highly relevant pre-clinical mouse and human lung cancer models. We observe that the ability of KEAP1mutant tumors to divert their metabolism towards antioxidant production comes with a cost, generating multiple metabolic vulnerabilities, including a dependency on glutamine metabolism that can be therapeutically exploited using DRP-104, a novel broad acting glutamine antagonist which inhibits all glutamine-consuming reactions. In addition, we have extended our findings to demonstrate that cancers with high antioxidant capacity exhibit a general dependency on exogenous non-essential amino acids (NEAAs) that is driven by the Nrf2-dependent secretion of glutamate through system xc-(XCT), which limits intracellular glutamate pools that are required for NEAA synthesis. This dependency can be therapeutically targeted by dietary restriction or enzymatic depletion of individual NEAAs. Importantly, limiting endogenous glutamate levels by glutaminase inhibition can sensitize tumors without alterations in Keap1/Nrf2 pathway to dietary restriction of NEAAs. Our findings identify a metabolic strategy to therapeutically target cancers with genetic or pharmacologic activation of the Nrf2 antioxidant response pathway by restricting exogenous sources of NEAAs. Citation Format: Sarah E. LeBoeuf, Warren Wu, Triantafyllia Karakousi, Robert Wild, Thales Papagiannakopoulos. Uncovering metabolic bottlenecks in KEAP1 mutant lung 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 2569.
Abstract 1808: Loss of BAP1/BRCA1 counteracts spindle assembly checkpoint activation by the anti-mesothelin antibody drug-conjugate anetumab ravtansine
Authors: Anita Singh, Jin-li Luo, Sara Busacca, Alan Dawson, Krishna Kalyan Kolluri, Samuel Janes, Andrew Fry, Anette Sommer, Dean Fennell
Journal: Cancer Research (2020)

Abstract Mesothelioma is a rapidly lethal cancer with limited treatment options. Spindle poisons have demonstrated clinical usefulness in mesothelioma, however, predictive biomarkers are lacking. Anetumab ravtansine (ARav) is an antibody drug-conjugate (ADC) comprising a mesothelin targeting antibody coupled to the payload, DM4, a microtubule destabilizer. We have recently identified BRCA1 as a direct regulator of the spindle assembly checkpoint (SAC), which is activated by spindle poisons and mediates mitotic arrest. BAP1 is one of the most frequently inactivated tumor suppressors in mesothelioma and it interacts with and regulates expression of BRCA1. We therefore hypothesized that BAP1 inactivation may confer resistance to ARav, highlighting a potential opportunity to refine personalization with this ADC. Three primary cell lines were derived from mesotheliomas resected during pleurectomy decortication expressed mesothelin (MSLN) and further characterized via whole exome sequencing. Two of the three primary cell lines have BAP1 mutation (R417 frameshift (fs); E631fs) and show reduced BRCA1/MAD2 protein expression. MSLN expression was found to be independent of BAP1 inactivation status or BRCA1 expression level. BAP1 mutant primary cell lines exhibited resistance to ARav by overriding the mitotic arrest with continued cell cycle progression, indicating a defective SAC whereas the cell line with wt BAP1 underwent mitotic arrest followed by cell death. Increase in mitotic index was also observed in primary cell line with wt BAP1 following ARav treatment without any significant change in BAP1 mutant cell lines. Resistance to ARav in BAP1 deleted cell line NCI-H226 was reversed by stable expression of wildtype BAP1 in NCI-H226 indicating critical regulation of SAC by BAP1. Vinorelbine resistant cell line RVR with a defective SAC also exhibited resistance to ARav compared to the parental REN with no change in MSLN expression suggesting that an active SAC is required for prolonged mitotic arrest and subsequent cell death. Wildtype BAP1 and MSLN is critical for efficacy of ARav. Inactivation of BAP1 correlates with loss of BRCA1 expression and dysregulation of the SAC. Citation Format: Anita Singh, Jin-li Luo, Sara Busacca, Alan Dawson, Krishna Kalyan Kolluri, Samuel Janes, Andrew Fry, Anette Sommer, Dean Fennell. Loss of BAP1/BRCA1 counteracts spindle assembly checkpoint activation by the anti-mesothelin antibody drug-conjugate anetumab ravtansine [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 1808.