tbuckley/cabot-search huggingface dataset:
Efficacy of bevacizumab monotherapy in first line treatment of metastatic melanoma, a preliminary report of four cases with treatment response
Authors: Oddbjorn Straume, Daniel Heinrich, Stephanie Geisler, Per Eystein Lonning, Lars Akslen, Jurgen Geisler
Journal: Cancer Research (2008)

LB-72  Background: Antiangiogenic treatment has been introduced in combination with chemotherapy in several tumor groups like colorectal cancer, breast cancer and lung cancer. With the exception of clear cell renal cancer, there are no reports of significant clinical benefit of antiangiogenic monotherapy in human cancers, and the general view is that antiangiogenic monotherapy does not work. It has been suggested that antiangiogenic drugs normalize the tumor vasculature, leading to better penetration and improved availability of chemotherapeutic drugs in the tumor tissue. Normalization or disruption of tumor vasculature is likely to be dependent on the dose of the antiangiogenic drug.  In addition, there is an urgent need of useful predictive markers of antiangiogenic treatment since these drugs are expensive and might have serious side effects. To find useful predictive markers of antiangiogenic treatment we designed a phase II clinical trial with bevacizumab for metastatic melanoma. Monotherapy was chosen to enable us to identify markers specifically important for the antiangiogenic effect.  Study Design: An open label, single center, two stage clinical phase II trial was established. According to ethical principles, patients were initially included in second line, following progression on dacarbazine. After having observed objective, clinical responses on bevacizumab monotherapy 10 mg/kg q14 d in second line, we subsequently enrolled patients in first line according to protocol. Endpoints are response rates (RECIST), time to progression, overall survival and toxicity. In stage one, 12 patients were included, then after having observed more than two objective responses, we now plan to include 23 more patients in stage two, planning to include 35 altogether.  Preliminary results: Here, we report four cases with objective responses according to RECIST criteria on bevacizumab monotherapy. Male (66), with melanoma metastasis to the liver, skeleton and skin had initially a 25% regression of liver metastases with subsequent stabilization, his skin lesions continues to regress even after 52 weeks on the treatment. Woman (40), with metastases to lungs, as well as ascites and WHO performance grade II-III by inclusion, has complete response in the lungs after 16 cycles and no more ascites production. The other two responders have long lasting stabilization of the disease after periods of rapid growth before inclusion. At this time 4 out of 13 patients responded to the treatment and enrollment continues until the planned sample size is reached. The treatment is well tolerated and no serious adverse events have been recorded so far.  Conclusion: Our four reported cases illustrate in principal that antiangiogenic monotherapy with bevacizumab can be efficient and give clinically meaningful responses without severe toxicity in selected metastatic melanoma patients.
Abstract 14693: Deficiency of Bone Morphogenetic Protein-3b Increases the Activity of the C/ebpα Promoter and Adipogenesis
Authors: Ingrid Marti-Pamies, Robrecht Thoonen, Alexia Vite, Alex Caplan, Jesus Tamez, Wei Han, Emmanuel S Buys, Donald Bloch, Marielle Scherrer-Crosbie
Journal: Circulation (2019)

Introduction: Bone morphogenetic proteins (BMP) are critical for the regulation of the endocrine system and cardiovascular (CV) structure and function. The objective of this study was to investigat...
Epidermal growth factor (EGF)-based activatable probe for predicting therapeutic outcome of an EGF-based doxorubicin prodrug
Authors: Han Young Kim, Sang Hoon Um, Yejin Sung, Man Kyu Shim, Suah Yang, Jooho Park, Eun Sun Kim, Kwangmeyung Kim, Ick Chan Kwon, Ju Hee Ryu
Journal: Journal of Controlled Release (2020)
Abstract A38: ATM inhibitor synergizes with glycolysis inhibition in ovarian cancer cells
Authors: Chi-Wei Chen, Erika S. Dahl, Kelly E. Leon, Raquel Buj, Katherine M. Aird
Journal: Clinical Cancer Research (2020)

Abstract Epithelial ovarian cancer (EOC) is the deadliest gynecologic malignancy in the USA. While therapies such as inhibitors against poly (ADP-Ribose) polymerase (PARP) are emerging as the standard treatment for EOC patients, this strategy is limited to the subset of patients harboring particular genetic alterations in the DNA damage response pathway, making them homologous recombination (HR) deficient. Approximately 50% of EOC patients are HR proficient, which corresponds to PARP inhibitor resistance and worse patient survival. Therefore, novel therapies for this subset of patients are urgently needed. We found that the DDR gene ATM is upregulated in a subset of EOC patients, which is associated with worse progression-free survival. This suggests that targeting ATM may be beneficial for these EOC patients. Our previous publication demonstrated that inhibition of ATM alters cellular metabolism. Therefore, we aimed to explore ATM inhibitor-mediated metabolic vulnerabilities in EOC to develop them as novel therapeutic strategies. We found that inhibition of ATM increases glucose uptake but not lactate of multiple EOC cells using YSI Bioanalyzer and the fluorescent glucose analog 2NBDG by flow cytometry. Seahorse analysis further indicates that glucose is not being used for Warburg effect. Using an shRNA screen, we identified SLC2A11 and SLC2A12 as the transporters that mediate glucose uptake upon ATM inhibition. To determine whether the observed changes can be exploited for therapeutic benefit, we combined ATM inhibition with the known inhibitor of glycolysis, fenofibrate. We found that while neither ATM inhibition or fenofibrate alone had a robust effect on cell proliferation, the combination was synergistic. Mechanistically, we determined that the combination resulted in cellular senescence using SA-B-Gal assay and detected PML body by immunofluorescence. Using 53PB1 and gH2AX as DDR markers, we concluded that the combination causing synthetic lethal is DDR independent manner. In this study, we found that ATM-SLC2A11/12 axis mediating glucose uptake in EOC cells. Mechanistically understand the role of ATM beyond DDR. Together, our results suggest that metabolic changes induced by ATM inhibitors in EOC are a potential target for the treatment for EOC. Citation Format: Chi-Wei Chen, Erika S. Dahl, Kelly E. Leon, Raquel Buj, Katherine M. Aird. ATM inhibitor synergizes with glycolysis inhibition in ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A38.
Abstract IA05: Intratumor genetic heterogeneity as a predictive biomarker in head and neck squamous cell carcinoma
Authors: Edmund A. Mroz, James W. Rocco
Journal: Clinical Cancer Research (2020)

Abstract The presence of heritable genetic differences among cancer cells within a tumor, called intratumor genetic heterogeneity, has long been suspected of playing a role in the poor responses of some tumors to traditional therapies. Research over the past decade has now documented the existence of genetic heterogeneity within tumors of individual patients and acknowledged its potential clinical significance. The research methods for identifying intratumor genetic heterogeneity were not readily adaptable to widespread clinical application until the development of a quantitative measure (MATH—mutant allele tumor heterogeneity) based on whole-exome sequencing of individual tumor samples. MATH values could be readily derived from biopsy or surgical specimens prior to the decision to utilize adjuvant radiation or chemotherapy. MATH analysis has now been used in HNSCC genomic data sets, along with clinical outcome data, to document a relation of high intratumor genetic heterogeneity to shorter overall survival (OS) in a large, multi-institutional study. Recent analysis examining the impact of high and low heterogeneity as measured by MATH suggests that the relation of intratumor heterogeneity to OS likely depends on the specific type of adjuvant therapy used. Our results demonstrate that patients with high intratumor heterogeneity (high MATH scores) would benefit from adjuvant radiation even when NCCN clinical treatment guidelines suggest that it could be omitted. In contrast, patients with low MATH tumors should likely adhere to these guidelines. Our results also support that patients with high MATH tumors will likely not benefit from the addition of adjuvant chemotherapy to radiotherapy, and thus could be spared the additional morbidity of complications from combination therapy. Current HNSCC NCCN treatment guidelines are based on either clinical or pathologic tumor stage and in the postoperative setting the presence or absence of high-risk pathologic features such as positive or close margins and tumor extra nodal extension. Intratumor genetic heterogeneity as measured by MATH analysis has the potential to further inform stage- and pathology-based treatment decisions and consequently should be evaluated in controlled prospective trials that compare adjuvant radiation against chemoradiation following surgery for HNSCC. Citation Format: Edmund A. Mroz, James W. Rocco. Intratumor genetic heterogeneity as a predictive biomarker in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr IA05.
SAT0551 INCIDENTAL FINDINGS OF TEMPOROMANDIBULAR JOINT DISORDERS ON STANDARD BRAIN MRIS: A CROSS-SECTIONAL STUDY
Authors: Tatiana Reitblat, Azaria Simonovich, Svetlana Kolontaevsky, Leonid Kalichman
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The temporomandibular joints (TMJ) changes is quite often ignored as a differential diagnosis in the evaluation of patients with suspicion on rheumatic and musculoskeletal disease such as temporal arteritis, fibromyalgia, rheumatoid arthritis. To understand whether TMJ changes have to be included in routine workup of patient's evaluation with the suspect to rheumatic disease, we assessed the prevalence of TMG changes incidental findings in standard brain MRI scan. In our experience, numerous incidental findings are found on a standard brain MRI scan, especially the elderly. A literature search revealed that no studies have reported the prevalence of these findings and their clinical relevance. <h3>Objectives</h3> To evaluate the prevalence of incidental TMJ findings on standard brain magnetic resonance imaging scans and assess if these findings are associated with symptoms. <h3>Methods</h3> Our sample comprised 65 males (47.1%) and 75 females (52.9%), mean age 54.75±17.45 (range: 18-87). Data collected from each TMJ included articular displacement, articular effusion, condyle flattering, condyle erosions, capsule enhancement, and bone marrow edema. Dichotomous data as to TMJ-related symptoms such as headaches, earaches, dizziness, clicking or grating sound, pain or soreness of the joint, limited mouth opening, locking of the jaw, facial muscle pain, unexplained teeth pain, neck pain or stiffness and difficulty swallowing, were acquired during telephone interviews. <h3>Results</h3> The most frequent finding was disc displacement (39.9% on the right side and 47.8% on the left), followed by condyle flattering (33.3% on the right side and 44.2% on the left). All findings, except bone marrow edema, were significantly more frequent on the left side than the right (Table 1). Significant associations were found between incidental findings in the TMJ and earaches (odds ratio 2.759, P=0.043), dizziness (odds ratio 2.325, P=0.031), a clicking or grating sound (odds ratio 6.492, P=0.002) and facial muscle pain (odds ratio 11.255, P=0.003)(Table 2). <h3>Conclusion</h3> Incidental findings of TMJ degenerative features were commonly found on standard brain magnetic resonance imaging. The high frequency of the findings and strong association with facial pain requires performing TMJ assessment in all patients who undergo medical inquiry for suspected rheumatic and musculoskeletal disease. <h3>Disclosure of Interests</h3> Tatiana Reitblat Consultant for: Abbvie, Eli Lilly, Azaria Simonovich: None declared, Svetlana Kolontaevsky: None declared, Leonid Kalichman: None declared
Abstract 1500: Understanding tumor cell community and its evolution by single cell analysis in liver cancer
Authors: Lichun Ma, Maria O. Hernandez, Yongmei Zhao, Monika Mehta, Bao Tran, Michael Kelly, Zachary Rae, Jonathan M. Hernandez, Jeremy L. Davis, Sean P. Martin, David E. Kleiner, Stephen M. Hewitt, Kris Ylaya, Bradford J. Wood, Tim F. Greten, Xin Wei Wang
Journal: Cancer Research (2020)

Abstract Tumor cell biodiversity is a major contributing factor to therapeutic failures and lethal outcomes of solid malignancies. Primary liver cancer, comprising mainly hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), is the second most lethal malignancy worldwide. To understand the biodiversity of tumor cell community in liver cancer, we performed single-cell transcriptome profiling of primary HCC and iCCA from 19 patients, who were enrolled at the NIH Clinical Center for immune checkpoint inhibition clinical trials. We found malignant cells differed within and between tumors, indicating both intratumor and intertumor heterogeneity. We developed a method to measure intratumor heterogeneity. Strikingly, the degree of intratumor diversity was associated with patient outcome where tumors with high diversity was associated with poor prognosis while tumors with low diversity was linked to good prognosis. The link between intratumor diversity and patient prognosis was also observed in bulk genomic and transcriptomic profiles for hundreds of HCC as well as iCCA patients. We found a polarization of the diverse landscapes of tumor microenvironment (TME) from low diversity and high diversity tumors. By searching upstream regulators of TME, we found an increased VEGF expression in high diversity tumors linked to diversity-related polarization of stromal and immune cells. Additionally, tumor evolutionary trajectory was uncovered by single-cell transcriptomic profiles generated from tumor biopsies collected from patients at baseline and after treatment with immune checkpoint inhibitors. Our results offer insight into the diverse ecosystem of HCC and iCCA and determine an impact of tumor cell biodiversity on patient prognosis, which may further benefit the prediction of clinical response to immune therapy. Citation Format: Lichun Ma, Maria O. Hernandez, Yongmei Zhao, Monika Mehta, Bao Tran, Michael Kelly, Zachary Rae, Jonathan M. Hernandez, Jeremy L. Davis, Sean P. Martin, David E. Kleiner, Stephen M. Hewitt, Kris Ylaya, Bradford J. Wood, Tim F. Greten, Xin Wei Wang. Understanding tumor cell community and its evolution by single cell analysis in liver 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 1500.
Abstract 3777: The role of IFITMs in maintaining glioma stem cells
Authors: Erisa Nita, Bernard Evers, Marta Nekulova, Gillian Morrison, Kathryn Ball
Journal: Cancer Research (2020)

Abstract Glioblastoma (GBM), one of the most lethal and heterogeneous primary brain tumors, contains cellular hierarchies with both quiescent and self-renewing highly tumorigenic glioblastoma stem cells (GSCs). Cancer stem cells within the context of the brain likely contribute to a lack of progress in patient survival time as they appear to have an innate resistance to both chemotherapeutic drugs and radiotherapy. The aim of this study is to elucidate how constitutive expression of interferons (IFNs) and their downstream signalling pathways maintain GSCs thereby supporting treatment resistance and tumor reoccurrence. To understand the mechanism of action of a subset of IFN regulated genes, originally characterized as a signature for radiation and chemotherapy resistance (IRDS), a panel of patient derived glioma stem cells was generated and manipulated using CRISPR/Cas9 mediated gene-editing. Phenotypic changes in growth, viability and drug resistance were characterised in the edited cells and linked to molecular level events using transcriptomic and proteomic techniques. Using this approach, in conjunction with patient tissue analysis, signalling under basal as well as IFN-activated conditions was studied in the context of GSC status. Immunohistopathology of a glioma tissue micro-array identified an increased expression of IFN induced transmembrane receptors (IFITMs), which co-localised with Nestin, around the blood vessels suggesting that IFITM positive cells were in the stem cell niche. Further analysis showed the presence of both IFITM1 and IFITM3 in GSCs and established that loss of IFITM function impacted on growth rate and cell cycle progression as well as treatment sensitivity. By using wild-type and gene-edited GSC to focus on the relationship between IFITM1 and IFITM3, we have compelling phenotypic and molecular evidence that IFN-induced changes in the localisation of IFITMs impact on the ability of stem cells to ‘escape' normal growth control mechanisms. Taking into consideration the constitutive expression of interferons in the tumor microenvironment, our study provides evidence that IFITMs regulate glioma stem cell self-renewal and are involved in maintaining a quiescent population which can escape chemotherapy. Citation Format: Erisa Nita, Bernard Evers, Marta Nekulova, Gillian Morrison, Kathryn Ball. The role of IFITMs in maintaining glioma stem 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 3777.
Abstract 6407: A live cell method to assess E3 ligase and target protein occupancy for PROTACs
Authors: James Vasta, Cesear Corona, Jennifer Wilkinson, Morgan R. Ingold, Chad Zimprich, Marie Schwinn, Thomas Machleidt, Jim Hartnett, Mei Cong, Frank Fan, Richard L. Somberg, Matthew Robers
Journal: Cancer Research (2020)

Abstract Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that hijack ubiquitin E3 ligases and induce degradation of intracellular proteins through a tightly regulated proteosomal mechanism. Although several successful PROTACs have been developed against key intracellular target classes including bromodomains, kinases, and nuclear hormone receptors, these bivalent molecules often suffer from poor cell permeability due to high molecular weight. To enable a high-throughput, quantitative readout for PROTAC permeability and E3 ligase occupancy in living cells, we have developed a panel of target engagement (TE) assays for key E3 ligase including CRBN, VHL, XIAP, cIAP, and MDM2. These intracellular assays are the first biophysical method to enable the quantitative determination of compound occupancy, potency, and residence time for specific target proteins inside living cells. The assays provide a direct measure of compound binding or occupancy to a target under physiological conditions using bioluminescent resonance energy transfer (BRET). Citation Format: James Vasta, Cesear Corona, Jennifer Wilkinson, Morgan R. Ingold, Chad Zimprich, Marie Schwinn, Thomas Machleidt, Jim Hartnett, Mei Cong, Frank Fan, Richard L. Somberg, Matthew Robers. A live cell method to assess E3 ligase and target protein occupancy for PROTACs [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 6407.
Abstract 1776: Exploring anetumab ravtansine in a preclinical model of thymic carcinoma
Authors: Vincent Chen, Anette Sommer, Christoph Schatz, Sabine Zitzmann-Kolbe, In-Kyu Kim, Giuseppe Giaccone
Journal: Cancer Research (2020)

Abstract Thymic epithelial tumors (TETs) are a group of rare tumors (0.13 per 100,000 persons), comprised of thymomas and thymic carcinoma, arising from the epithelial cells of the thymus. The biology of these tumors is not well understood, and there are no approved targeted therapies against TETs. One promising drug target is mesothelin (MSLN), which is a surface glycoprotein that is cleaved to produce two proteins: mature MSLN (mMSLN) and megakaryocyte potentiating factor (MPF). In normal physiology, expression of MSLN is limited to mesothelial cells lining the pleura, pericardium, and peritoneum. Its expression is also present in various cancers, including thymic carcinoma, where it is expressed in 79% of cases. In this study, we investigate the ability of the MSLN targeting, fully human monoclonal antibody-drug conjugate (ADC) anetumab ravtansine (ARav) to inhibit growth of thymic carcinoma in in-vitro and in-vivo models. We utilized immunoblotting and RT-qPCR to characterize MSLN expression in human thymoma and thymic carcinoma derived cell lines. Binding of anetumab, the antibody moiety in ARav, to thymoma and thymic carcinoma cell lines was assessed by flow cytometry. In-vitro, ARav's effect on cell proliferation was tested against MP57 cells (thymic carcinoma), stably transfected with MSLN, utilizing CellTiter-Glo. ARav's activity in-vivo as a monotherapy, and as a combination therapy with cisplatin, was tested against MSLN expressing T1889 xenograft tumors in athymic nude mice and compared to vehicle, isotype control ADC, and standard-of-care (SoC) cisplatin. Using the anetumab antibody, thymoma (T1682) and thymic carcinoma (T1889) cell lines were shown to express MSLN on the cell surface. In-vitro, ARav was effective at inhibiting growth of MP57 cells stably transfected with mMSLN. In-vivo, 15 mg/kg ARav inhibited T1889 xenograft tumor growth more efficaciously than vehicle, the isotype control ADC (all given every 2 weeks), and 4 mg/kg cisplatin (given every week). Combining ARav at a dose of 7.5 mg/kg with 4 mg/kg cisplatin yielded an additive effect on inhibiting tumor growth. MSLN is expressed in thymoma and thymic carcinoma derived cell lines. Anetumab ravtansine inhibits growth of MSLN positive thymic carcinoma in our preclinical model; when combined with SoC cisplatin, ARav confers enhanced tumor growth inhibition. Citation Format: Vincent Chen, Anette Sommer, Christoph Schatz, Sabine Zitzmann-Kolbe, In-Kyu Kim, Giuseppe Giaccone. Exploring anetumab ravtansine in a preclinical model of thymic carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1776.