tbuckley/cabot-search huggingface dataset:
Abstract 2437: Overexpression of MYL5 promotes cervical cancer cell metastasis through SLUG and HIF-1α signaling
Authors: Lan Zhang
Journal: Cancer Research (2017)

Abstract Myosin light chains (MLC) serve important regulatory functions in a wide range of cellular and physiological processes. Previous research found that MLC are also chromatin-associated nuclear proteins which regulate gene transcription. In this study, we show that the MLC member myosin regulatory light chain 5 (MYL5) controls metastasis in cervical cancer. We uncover this role of MYL5 through clinical cervical cancer samples and various in vitro and in vivo models of metastasis. MYL5 promotes metastasis by enhancing the transcription of SLUG and hypoxia inducible factor-1α (HIF-1α). Moreover, we reveal a bidirectional regulation between MYL5 and HIF-1α. HIF-1α specifically binds to the MYL5 promoter region, and hypoxia leads to increased levels of MYL5 in cervical cancers. Overexpression of MYL5 sustained HIF-1α expression in normoxic condition. Clinical data confirmed a positive correlation between MYL5 and HIF-1α. In summary, our observations suggest a potential application of MYL5 in prognosis prediction and cancer treatment. Citation Format: Lan Zhang. Overexpression of MYL5 promotes cervical cancer cell metastasis through SLUG and HIF-1α signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2437. doi:10.1158/1538-7445.AM2017-2437
Abstract 2397: Epigenetic silencing in clear renal cell carcinoma: <i>KEAP1</i> promoter hypermethylation
Authors: Federico Pio Fabrizio, Manuela Costantini, Massimiliano Copetti, Anna Maria la Torre, Angelo Sparaneo, Andrea Fontana, Maria Luana Poeta, Michele Gallucci, Steno Sentinelli, Paolo Graziano, Paola Parente, Vincenzo Pompeo, Laura De Salvo, Giuseppe Simone, Rocco Papalia, Francesco Picardo, Teresa Balsamo, Gerardo Paolo Flammia, Domenico Trombetta, Angela Pantalone, Klaas Kok, Paranita Ferronika, Lucia Anna Muscarella, Vito Michele Fazio
Journal: Cancer Research (2017)

Abstract The Keap1/Nrf2 pathway is a master regulator of the cellular redox state through the induction of several antioxidant defense genes implicated in chemotherapeutic drugs resistance of tumor cells. An increasing body of evidence supports a key role for Keap1/Nrf2 pathway in kidney diseases and renal cell carcinoma, but data concerning the molecular basis and the clinical effect of its deregulation remain incomplete. Here we performed a comprehensive genetic and epigenetic analysis of the KEAP1 gene in 37 tumor/normal paired tissues of clear cell Renal Carcinoma (ccRCCs). Promoter methylation analysis was performed by using a quantitative methylation specific PCR assay in real time, whereas mutation scanning was performed on FFPE tissues by direct sanger sequencing of the exons 4-7 codifying for the DGR domain of the Keap1 protein. A tumor-specific DNA methylation of the KEAP1 gene promoter region was found in 18 out of 37 ccRCCs (48,6%) and a direct effects on the modulation of Keap1 mRNA levels was confirmed by in vitro 5-azacytidine treatment on three different ccRCCs cell lines. Analysis of an independent TGCA data set corroborate the epigenetic findings and reveals a significant correlation in multivariate analysis of epigenetic KEAP1 silencing with Overall Survival in ccRCCs. Our results further suggest that epigenetic deregulation of the Nrf2/Keap1 system could play a pivotal role in the cancerogenesis of ccRCCs. In addition identifying patients with KEAP1 epigenetic abnormalities may contribute to disease progression prediction and response to therapy in ccRCC affected patients. Citation Format: Federico Pio Fabrizio, Manuela Costantini, Massimiliano Copetti, Anna Maria la Torre, Angelo Sparaneo, Andrea Fontana, Maria Luana Poeta, Michele Gallucci, Steno Sentinelli, Paolo Graziano, Paola Parente, Vincenzo Pompeo, Laura De Salvo, Giuseppe Simone, Rocco Papalia, Francesco Picardo, Teresa Balsamo, Gerardo Paolo Flammia, Domenico Trombetta, Angela Pantalone, Klaas Kok, Paranita Ferronika, Lucia Anna Muscarella, Vito Michele Fazio. Epigenetic silencing in clear renal cell carcinoma: KEAP1 promoter hypermethylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2397. doi:10.1158/1538-7445.AM2017-2397
Abstract 1327: CD147 contributes to extracellular matrix remodeling and degradation
Authors: Tiffany Tan, Beata Kosmider, Nathaniel Marchetti, Sudhir Bolla, Chenna Mandapati, Gerard Criner, Karim Bahmed
Journal: Cancer Research (2017)

Abstract Chronic obstructive pulmonary disease (COPD) is an incurable, progressive lung disease characterized by shortness and difficulty in breathing. Patients with COPD are at higher risk of developing lung cancer and often are associated with poor outcome of lung cancer diagnosis and treatment. Extracellular matrix (ECM) remodeling and degradation is one of the common hallmarks between cancer and COPD. It contributes to degradation of air sacs (emphysema) or small airways (obstructive bronchiolitis). It is also involved in cancer initiation and progression to assist tumor expansion and cancer cell migration. In this study, we analyzed lung tissue and primary alveolar type II (ATII) cells isolated from patients with emphysema and control organ donors. ATII cells secrete and store pulmonary surfactant and restore the epithelium after damage. We performed RNA sequencing in ATII cells to identify dysregulated proteins, which are involved in ECM degradation in emphysema. To further study the mechanism involved in the ECM degradation in this disease, we analyzed the expression of selected proteins and we focused on the role of extracellular matrix metalloproteinase inducer (CD147). CD147 is a cell membrane protein involved in inducing the production of extracellular matrix metalloproteinases (MMPs). First, we found that cells isolated from patients with emphysema have higher expression of CD147 in ATII cells in comparison with controls as detected by western blotting and RT-PCR. This may explain high ECM degradation in this disease. Second, we observed higher MMPs levels in plasma obtained from individuals with this disease. Third, we found significantly higher expression of cathepsin B in ATII cells isolated from emphysema in comparison with controls. Cathepsin B is an enzyme that facilitates a direct degradation of ECM proteins and activate other proteases capable of degrading ECM. Fourth, our data indicate that CD147 interacts with cathepsin B, which may lead to the activation of MMPs and emphysema progression. In summary, our results show for the first time the important role of CD147 in emphysema development. Moreover, we found that cathepsin B may contribute to CD147-mediated disease progression. Further studies will elucidate its role in lung cancer development in patients with emphysema. Note: This abstract was not presented at the meeting. Citation Format: Tiffany Tan, Beata Kosmider, Nathaniel Marchetti, Sudhir Bolla, Chenna Mandapati, Gerard Criner, Karim Bahmed. CD147 contributes to extracellular matrix remodeling and degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1327. doi:10.1158/1538-7445.AM2017-1327
Drug-induced amino acid deprivation as strategy for cancer therapy
Authors: Marcus Kwong Lam Fung, Godfrey Chi-Fung Chan
Journal: Journal of Hematology & Oncology (2017)

Cancer is caused by uncontrollable growth of neoplastic cells, leading to invasion of adjacent and distant tissues resulting in death. Cancer cells have specific nutrient(s) auxotrophy and have a much higher nutrient demand compared to normal tissues. Therefore, different metabolic inhibitors or nutrient-depleting enzymes have been tested for their anti-cancer activities. We review recent available laboratory and clinical data on using various specific amino acid metabolic pathways inhibitors in treating cancers. Our focus is on glutamine, asparagine, and arginine starvation. These three amino acids are chosen due to their better scientific evidence compared to other related approaches in cancer treatment. Amino acid-specific depleting enzymes have been adopted in different standard chemotherapy protocols. Glutamine starvation by glutaminase inhibitior, transporter inhibitor, or glutamine depletion has shown to have significant anti-cancer effect in pre-clinical studies. Currently, glutaminase inhibitor is under clinical trial for testing anti-cancer efficacy. Clinical data suggests that asparagine depletion is effective in treating hematologic malignancies even as a single agent. On the other hand, arginine depletion has lower toxicity profile and can effectively reduce the level of pro-cancer biochemicals in patients as shown by ours and others’ data. This supports the clinical use of arginine depletion as anti-cancer therapy but its exact efficacy in various cancers requires further investigation. However, clinical application of these enzymes is usually hindered by common problems including allergy to these foreign proteins, off-target cytotoxicity, short half-life and rapidly emerging chemoresistance. There have been efforts to overcome these problems by modifying the drugs in different ways to circumvent these hindrance such as (1) isolate human native enzymes to reduce allergy, (2) isolate enzyme isoforms with higher specificities and efficiencies, (3) pegylate the enzymes to reduce allergy and prolong the half-lives, and (4) design drug combinations protocols to enhance the efficacy of chemotherapy by drug synergy and minimizing resistance. These improvements can potentially lead to the development of more effective anti-cancer treatment with less adverse effects and higher therapeutic efficacy.
Abstract 4168: Altering cisplatin sensitivity by manipulating the cellular metallome
Authors: Lauren Amable, Eric Shide
Journal: Cancer Research (2017)

Abstract The cellular metallome serves as an important reservoir to meet the biological needs of the cell, serving as enzyme co-factors and ensuring proper protein folding. Recent studies have suggested that cancer cells adapt their metallome in order to accommodate rapid cellular growth and metabolism pathways. Thus, altering the cancer metallome may yield new avenues to target cancer and change the responsiveness to chemotherapy. Here, we aim to characterize and understand how changes in the ovarian cancer metallome affect sensitivity to the chemotherapy drug cisplatin. Five ovarian cancer cell lines were used in experiments: A2780, A2780/CP70, SKOV3, OVCAR3, and CAOV3. The metallome was manipulated by treating cells with either zinc, copper, magnesium, calcium, iron, manganese, or the metal chelator tetrathiomolybdate. Cisplatin sensitivity after metal treatment was measured by WST-1 cell proliferation assays. Metallomes were quantitated by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) by measuring the following metals: zinc, copper, magnesium, calcium, molybdenum, manganese, iron, phosphorous, and sulfur. Cellular metal concentrations were normalized to sulfur levels. Changes in cisplatin sensitivity were evaluated by measuring cellular cisplatin uptake by ICP-MS. Treatment of ovarian cancer cells with various metals resulted in differences in cellular proliferation and metallome composition. The changes in the metallome were not singular in nature because altering one metal resulted in changes in multiple metals. Cisplatin sensitivity was additionally affected under different metal treatments. Preliminary data suggest that cisplatin uptake was altered as a mechanism to mediate the cellular response to cisplatin, however other mechanisms such as DNA repair might also play a role. In conclusion, we demonstrate that perturbations of the cancer metallome result in changes of various metals, cellular proliferation, and sensitivity to the chemotherapy drug cisplatin. The data lend further insight into how an individual’s metallomic status, a combination of nutritional and harmful metal exposure, might result in the development and progression of cancer and affect the response to chemotherapy. Citation Format: Lauren Amable, Eric Shide. Altering cisplatin sensitivity by manipulating the cellular metallome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4168. doi:10.1158/1538-7445.AM2017-4168
Abstract 3631: Delivery of a CD20 transferrin receptor VNAR bispecific antibody to the brain for CNS lymphoma
Authors: Frank S. Walsh, Krzysztof Wicher, Jaroslaw Szary, Pawel Stocki, Michael Demydchuk, Lynn Rutkowski
Journal: Cancer Research (2017)

Abstract Penetration of the blood brain barrier (BBB) remains a significant hurdle in the development of biologic therapeutics for CNS-related cancers. Antibody-based molecules typically do not cross the BBB in amounts required for therapeutic efficacy. Receptor-mediated transporters in the luminal membrane of brain capillary endothelium, which normally transport circulating endogenous peptides and proteins, offer a non-invasive approach for the delivery of therapeutic molecules to the brain.Using a combination of in vitro and in vivo phage display technology, we isolated a panel of cross species (rodent, primate and human) binders to the transferrin receptor 1 (TfR1) from synthetic libraries of shark variable antigen receptors (VNARs). Initially, the anti-TfR1 VNARs were fused to an immunoglobulin Fc backbone for testing in mice. At therapeutic (2 mg/kg) doses delivered by tail vein injection, high levels of the VNAR-Fc antibodies were found in the brain after 18 hours, which exceeded 5% of the plasma levels. Brain fractionation studies showed that the VNAR-Fc antibodies to TfR1 translocated to the brain parenchyma and were not retained in the capillaries. The lead anti-TfR1 VNAR was then used to target aberrant B cells in the brain for conditions such as cerebral lymphoma where existing CD20 therapies to not penetrate the CNS at therapeutic doses. A family of anti-CD20/TfR1 bispecific molecules were produced by linking the small VNAR to either the N- and C- terminus of heavy and light chains to create both monovalent and bivalent fusions . We used rituxan as the CD20 agent. The bispecifics were assessed for binding to the two cognate antigens and then tested for brain penetration after tail vein injection. At least 4 different formats gave excellent brain penetration 18 hours after dosing at 3.75mg/kg. Unmodified rituxan had a brain plasma ratio of 0.25 in line with published data while the best anti-TfR1-rituximab bispecific formats were between 2 to 5%. The bispecific formats also retain antibody-dependent cell-mediated cytotoxicity and will be further tested for brain penetration in non-human primates and in rodent models of CNS lymphoma. If these results successfully translate from rodents to larger animals, the peripheral delivery of a brain penetrant CD20/TfR1 bispecific antibody would provide a safer and more effective alternative to CD20 antibody delivery by the intrathecal route and could have broad utility in B cell driven brain cancer. Citation Format: Frank S. Walsh, Krzysztof Wicher, Jaroslaw Szary, Pawel Stocki, Michael Demydchuk, Lynn Rutkowski. Delivery of a CD20 transferrin receptor VNAR bispecific antibody to the brain for CNS lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3631. doi:10.1158/1538-7445.AM2017-3631
Abstract 225: Chemoproteomic evaluation of target engagement in clinical samples
Authors: Tyzoon K. Nomanbhoy
Journal: Cancer Research (2017)

Abstract One of the challenges during the clinical development of kinase inhibitors is understanding whether or not a compound is actually binding the kinase of interest, in the appropriate tissue, during the course of compound treatment. While compound concentration in blood can be determined from pharmacodynamics, there are very few approaches that directly measure whether or not the compound is binding the target kinase. Herein, we apply a chemoproteomics platform (KiNativ®) using a desthiobiotin ATP acyl phosphate probe (ATP probe), to monitor target engagement in clinical samples. As a proof of concept, we demonstrate that compound can be added to whole blood, after which peripheral blood mononuclear cells (PBMCs) are isolated, lysed, labeled with the ATP probe, and analyzed by mass spectrometry to determine whether or not compound treatment blocks the probe-labeling of the target. We successfully applied this approach in the analysis of both the reversible JNK inhibitor CC-930, as well as the covalent BTK inhibitor Ibrutinib (Imbruvica®). We then extended the study to monitor the inhibition of BTK by Ibrutinib in PBMCs isolated from patients undergoing drug treatment. Finally, we demonstrate that in addition to profiling kinases in PBMCs isolated from whole blood, this method can also be used to profile kinases in solid tumors. Thus, the chemoproteomics approach described here could be applied as a general method to monitor target engagement for inhibitors developed against a variety of different kinases in clinical samples. Citation Format: Tyzoon K. Nomanbhoy. Chemoproteomic evaluation of target engagement in clinical samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 225. doi:10.1158/1538-7445.AM2017-225
Abstract 3035: Decomposing oncogenic transcriptional signatures to generate maps of divergent cellular states
Authors: William J. Kim, William C. Hahn, Jill Mesirov, Pablo Tamayo
Journal: Cancer Research (2017)

Abstract The systematic sequencing of the cancer genome has provided a powerful framework for identifying genetic alterations in cancer. However, a deeper understanding of the functional consequences of these alterations is necessary to guide appropriate therapeutic strategies. Here, we describe Onco-GPS (OncoGenic Positioning System), a data-driven analysis framework, and associated experimental and computational methodology, to organize individual tumor samples with shared oncogenic alterations onto a reference map defined by their underlying cellular states. Using this approach, we generated series of RAS/MAPK sub-signatures that reflect known and novel downstream pathways. These sub-signatures were then used to classify KRAS and BRAF mutant cancers into sub groups or cell states, as represented in the novel visual paradigm “OncoGPS map”. OncoGPS approach was first applied to cancers with BRAF mutations. The approach not only accurately classified three groups of BRAF mutant cancers that aligned with sensitivity to BRAF inhibitors, but also identified resistance mechanisms associated with each state, validating the overall approach. OncoGPS also identified four major cell states associated with KRAS mutant cancers. Further characterization of the four cell states showed that multiple molecular features representing epithelial-EMT states and activation of NF-κB pathway delineated two major “axes” of KRAS mutant cancers. In addition to the pathways and cell states defined in each group, the OncoGPS approach is able to identify effective drug combinations which was experimentally tested and confirmed. These results show that the Onco-GPS is an effective analytic framework to explore the complex landscape of oncogenic cellular states across cancers, and a powerful framework to summarize knowledge, establish relationships, and generate more effective disease models for research or as part of individualized precision medicine paradigms. Citation Format: William J. Kim, William C. Hahn, Jill Mesirov, Pablo Tamayo. Decomposing oncogenic transcriptional signatures to generate maps of divergent cellular states [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3035. doi:10.1158/1538-7445.AM2017-3035
Abstract 4541: Understanding the dose and schedule dependence of efficacy for the Wee1 inhibitor AZD1775 in xenograft and patient derived explant models by mathematical modelling
Authors: James W. Yates, Elaine Cadogan, Jennifer Hare, Adina Hughes, Urszula M. Polanska, Mark O'Connor, Susan E. Critchlow
Journal: Cancer Research (2017)

Abstract AZD1775 is a highly selective, small-molecule inhibitor of WEE1 being developed to treat patients with advanced solid tumors, as monotherapy and in combination with olaparib. Experimental Procedures Patient-derived explant (PDX) and xenografted models with a range of sensitivities to AZD1775 were tested for response to different doses and schedules of AZD1775. WEE1 inhibition was assessed by pCDK1 as a direct substrate of Wee1 and RRM2 as a surrogate of CDK2 activity. Concentration of AZD1775 in plasma was measured in the same animals. Mathematical models were developed to describe the relationship between drug exposure, biomarker modulation and resulting tumour growth inhibition. Results The PKPD relationship of both pCDK1 and RRM2 could be described by the mathematical model with significant delay between PK and RRM2 reduction due to this being a protein degradation event. Three factors influenced anti-tumour activity in the A427 xenograft and three TNBC PDX models, namely the AZD1775 dose, the number of consecutive days of dosing and the number of days between AZD1775 doses. The minimally effective preclinical dose with anti-tumour activity was 60 mg/kg od. TGI was seen to increase with increased days of consecutive AZD1775 dosing from 3 days on, such that a 5 days on/9 days off schedule was more efficacious than 3 days on/4 days off schedule for two weeks. A mathematical model successfully described this efficacy by using the predicted dose and schedule dependent reduction in pCDK1. Conclusions The insights from this predictive modelling informed the starting dose of 125mg BID AZD1775 on a 5 day on/9 day off schedule; with the clinical goal to optimize the days of consecutive AZD1775 dosing as well as the maximum tolerated dose. Citation Format: James W. Yates, Elaine Cadogan, Jennifer Hare, Adina Hughes, Urszula M. Polanska, Mark O'Connor, Susan E. Critchlow. Understanding the dose and schedule dependence of efficacy for the Wee1 inhibitor AZD1775 in xenograft and patient derived explant models by mathematical modelling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4541. doi:10.1158/1538-7445.AM2017-4541