tbuckley/cabot-search huggingface dataset:
Combination therapy with B7H3-redirected bispecific antibody and Sorafenib elicits enhanced synergistic antitumor efficacy
Authors: Cheng Huang, Hongjian Li, Yunyu Feng, Xiaoling Li, Zongliang Zhang, Caiying Jiang, Jichao Wang, Chenli Yang, Yuying Fu, Min Mu, Shasha Zhao, Zeng Wang, Yi Kuang, Huan Hou, Yuelong Wang, Wenhao Guo, Jianguo Xu, Hui Yang, Liangxue Zhou, Aiping Tong, Gang Guo
Journal: Theranostics (2020)

Rationale: Current traditional treatment options are frequently ineffective to fight against ovarian cancer due to late diagnosis and high recurrence. Therefore, there is a vital need for the development of novel therapeutic agents. B7H3, an immune checkpoint protein, is highly expressed in various cancers, representing it a promising target for cancer immunotherapy. Although targeting B7H3 by bispecific T cell-engaging antibodies (BiTE) has achieved successes in hematological malignancies during recent years, attempts to use them for the treatment of solid cancers are less favorable, in part due to the heterogeneity of tumors. Sorafenib is an unselective inhibitor of multiple kinases currently being tested in clinical trials for several tumors, including ovarian cancer which showed limited activity and inevitable side effect for ovarian cancer treatment. However, it is able to enhance antitumor immune response, which indicates sorafenib may improve the efficiency of immunotherapy. Methods: We evaluated the expression of B7H3 in ovarian cancer using online database and validated its expression of tumor tissues by immunohistochemistry staining. Then, B7H3 expression and the effects of sorafenib on ovarian cancer cell lines were determined by flow cytometry. In addition, 2D and 3D ovarian cancer models were established to test the combined therapeutic effect in vitro. Finally, the efficiency of B7H3×CD3 BiTE alone and its combination with sorafenib were evaluated both in vitro and in vivo. Results: Our data showed that B7H3 was highly expressed in ovarian cancer compared with normal samples. Treatment with sorafenib inhibited ovarian cancer cell proliferation and induced a noticeable upregulation of B7H3 expression level. Further study suggested that B7H3×CD3 BiTE was effective in mediating T cell killing to cancer cells. Combined treatment of sorafenib and B7H3×CD3 BiTE had synergistic anti-tumor effects in ovarian cancer models. Conclusions: Overall, our study indicates that combination therapy with sorafenib and B7H3×CD3 BiTE may be a new therapeutic option for the further study of preclinical treatment of OC.
Abstract CT137: A pilot pharmacokinetic study of VAL413 in patients with recurrent pediatric solid tumors
Authors: James I. Geller, Dennis Brown, Jeffrey Bacha, Neil Sankar, Sarath Kanekal, Mark Leggas, Lars Wagner
Journal: Cancer Research (2020)

Abstract Background: Ewing's sarcoma (EWS) is the second most common malignant bone tumor affecting children, adolescents and young adults. Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also widely used off-label as salvage therapy for patients with recurrent EWS, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, and medulloblastoma. Prior adult and pediatric trials demonstrate that the combination of intravenous irinotecan and temozolomide has significant antitumor activity in advanced EWS. Recently, commercially available intravenous irinotecan has been administered orally (IRN-IVPO) in pediatric patients to reduce intravenous administration-related side effects, improve convenience and reduce clinic time and costs. Unfortunately, the taste of the iv preparation can be limiting, leading to poor compliance especially in pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. Methods: VAL-413 is novel formulation developed to improve tolerability of oral irinotecan for the treatment of cancer. This study (USIND#135675) aims to establish the recommended phase II dose of VAL-413 when given in combination with temozolomide. Secondary objectives include characterization of the pharmacokinetics of VAL-413 vs. conventional irinotecan given orally (IRN-IVPO), evaluating palatability of VAL-413, assessing the toxicity profile of VAL-413 in combination with temozolomide, and assessment of tumor response. Up to 20 patients &amp;gt= 1 to &amp;lt= 30 years of age with recurrent pediatric solid tumors will be enrolled at two different dose levels of VAL-413 in combination with fixed-dose temozolomide using a standard 3 + 3 design. During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of IRN-IVPO, together with 5 days of concurrent temozolomide. During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days. Up to 17 cycles of treatment may be administered on this study. This study design will test the hypothesis that VAL-413 will not have significant pharmacokinetic differences from IRN-IVPO using intra-patient comparison of pharmacokinetic profiles. The evaluation of two dose levels will help to formally define a recommended Phase II dose for further studies. Toxicity will be evaluated based on CTCAEv5 and tumor response based on RECISTv1.1. Citation Format: James I. Geller, Dennis Brown, Jeffrey Bacha, Neil Sankar, Sarath Kanekal, Mark Leggas, Lars Wagner. A pilot pharmacokinetic study of VAL413 in patients with recurrent pediatric solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT137.
Abstract 4963: Notch1 non-canonical pathway drives breast cancer stem cell function
Authors: Lufei Sui, Suming Wang, Danielle Sim, Randolph S. Watnick
Journal: Cancer Research (2020)

Abstract Current treatment of triple negative breast cancer is hindered by a high incidence of chemoresistance (30-50%). The prevailing theory is that resistance and subsequent recurrence is driven by cancer stem cells. Unfortunately, the functional characterization of cancer stem cells at the molecular level is still incomplete. We show here, that within the canonical breast cancer stem cell population (CD24low/CD44+/ESA+) of triple negative breast cancer cells, a subset of cells characterized by high Notch1 expression possesses the tumor-initiating and chemoresistance properties associated with cancer stem cells. Moreover, the tumor initiating property of these Notch1-high expressing breast cancer stem cells is mediated by the repression of SIRT1. We also demonstrate that Notch1 represses SIRT1 through a non-canonical, cleavage independent pathway via PI3K/Akt/mTORC2. Strikingly, the repression of SIRT1 obviates the requirement for high Notch1 expression. These findings provide the first functional mechanistic requirements for breast cancer stem cell tumor initiation and chemoresistance. Our results also identify a novel non-canonical Notch1 signaling pathway regulating breast cancer stem cell function. We postulate that this pathway can be exploited as a potential therapeutic strategy to eradicate cancer stem cells and reduce the incidence of chemoresistance and recurrence. Citation Format: Lufei Sui, Suming Wang, Danielle Sim, Randolph S. Watnick. Notch1 non-canonical pathway drives breast cancer stem cell function [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 4963.
Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19
Authors: Bruno M. Tomazini, Israel S. Maia, Alexandre B. Cavalcanti, Otavio Berwanger, Regis G. Rosa, Viviane C. Veiga, Alvaro Avezum, Renato D. Lopes, Flavia R. Bueno, Maria Vitoria A. O. Silva, Franca P. Baldassare, Eduardo L. V. Costa, Ricardo A. B. Moura, Michele O. Honorato, Andre N. Costa, Lucas P. Damiani, Thiago Lisboa, Letícia Kawano-Dourado, Fernando G. Zampieri, Guilherme B. Olivato, Cassia Righy, Cristina P. Amendola, Roberta M. L. Roepke, Daniela H. M. Freitas, Daniel N. Forte, Flávio G. R. Freitas, Caio C. F. Fernandes, Livia M. G. Melro, Gedealvares F. S. Junior, Douglas Costa Morais, Stevin Zung, Flávia R. Machado, Luciano C. P. Azevedo
Journal: JAMA (2020)

Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) is associated with substantial mortality and use of health care resources. Dexamethasone use might attenuate lung injury in these patients.
Colchicine in Patients With Acute Coronary Syndrome
Authors: David C. Tong, Stephen Quinn, Arthur Nasis, Chin Hiew, Philip Roberts-Thomson, Heath Adams, Rumes Sriamareswaran, Nay M. Htun, William Wilson, Dion Stub, William van Gaal, Laurie Howes, Nicholas Collins, Andy Yong, Ravinay Bhindi, Robert Whitbourn, Astin Lee, Chris Hengel, Kaleab Asrress, Melanie Freeman, John Amerena, Andrew Wilson, Jamie Layland
Journal: Circulation (2020)

Background: Inflammation plays a crucial role in clinical manifestations and complications of acute coronary syndromes (ACS). Colchicine, a commonly used treatment for gout, has recently emerged as a novel therapeutic option in cardiovascular medicine owing to its anti-inflammatory properties. We sought to determine the potential usefulness of colchicine treatment in patients with ACS. Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial involving 17 hospitals in Australia that provide acute cardiac care service. Eligible participants were adults (18–85 years) who presented with ACS and had evidence of coronary artery disease on coronary angiography managed with either percutaneous coronary intervention or medical therapy. Patients were assigned to receive either colchicine (0.5 mg twice daily for the first month, then 0.5 mg daily for 11 months) or placebo, in addition to standard secondary prevention pharmacotherapy, and were followed up for a minimum of 12 months. The primary outcome was a composite of all-cause mortality, ACS, ischemia-driven (unplanned) urgent revascularization, and noncardioembolic ischemic stroke in a time to event analysis. Results: A total of 795 patients were recruited between December 2015 and September 2018 (mean age, 59.8±10.3 years; 21% female), with 396 assigned to the colchicine group and 399 to the placebo group. Over the 12-month follow-up, there were 24 events in the colchicine group compared with 38 events in the placebo group ( P =0.09, log-rank). There was a higher rate of total death (8 versus 1; P =0.017, log-rank) and, in particular, noncardiovascular death in the colchicine group (5 versus 0; P =0.024, log-rank). The rates of reported adverse effects were not different (colchicine 23.0% versus placebo 24.3%), and they were predominantly gastrointestinal symptoms (colchicine, 23.0% versus placebo, 20.8%). Conclusions: The addition of colchicine to standard medical therapy did not significantly affect cardiovascular outcomes at 12 months in patients with ACS and was associated with a higher rate of mortality. Registration: URL: https://www.anzctr.org.au ; Unique identifier: ACTRN12615000861550.
Abstract 6024: An integrin αvβ3+ stem-like tumor cell subset promotes breast cancer progression via c-Jun/AXL signaling
Authors: Qi Sun, Yufen Wang, Adam Officer, Olivier Harismendy, Jay S. Desgrosellier
Journal: Cancer Research (2020)

Abstract Breast cancer cells bearing similarities to normal mammary stem cells play a key role in tumor progression. Here, we characterize a unique stem-like tumor cell population that expresses the integrin αvβ3 and is associated with aggressive patient disease. We now show that αvβ3+ cells that also express EpCAMLow represent a functionally and transcriptomically distinct breast cancer cell type. Rare αvβ3+ cells enrich for stemness properties such as anchorage-independent colony formation, self-renewal, differentiation and tumor initiation at limiting dilution. Unbiased whole transcriptome analysis by RNA-Seq identified several genes specifically upregulated in αvβ3+ cells that are also enriched in normal adult mammary stem cells. Phospho-array profiling of major signaling pathways revealed increased activation of the proto-oncogene c-Jun in αvβ3+ stem-like cells. Inhibition of JNK/c-Jun signaling further identified the receptor tyrosine kinase AXL as a critical downstream target gene necessary for tumorsphere formation. Our findings reveal a c-Jun/AXL signaling pathway required for stemness properties in αvβ3+ tumor cells important for breast cancer progression. Citation Format: Qi Sun, Yufen Wang, Adam Officer, Olivier Harismendy, Jay S. Desgrosellier. An integrin αvβ3+ stem-like tumor cell subset promotes breast cancer progression via c-Jun/AXL signaling [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 6024.
Abstract 2044: Chemotherapy induced neutropenia in rats following administration of eflapegrastim or pegfilgrastim on the same day at three different timepoints and at 24 hours post-chemotherapy
Authors: Yu-Yon Kim, Eunjung Kim, Hyesun Han, Seungjae Baek, Shanta Chawla, Prasad Kolli, Gajanan Bhat, Francois Lebel
Journal: Cancer Research (2020)

Abstract Background: Eflapegrastim is a long-acting G-CSF that is comprised of a G-CSF analog and a recombinant IgG4 Fc fragment conjugated at their N-termini via a short polyethylene glycol linker. Currently, G-CSF products are administered 24 hours after chemotherapy. We compared the duration of neutropenia (DN) after treatment with eflapegrastim and pegfilgrastim given on the same-day, at three different timepoints, and after 24 hours in chemotherapy-induced neutropenic rats. Method: Neutropenia was induced in rats via intraperitoneal administration of cyclophosphamide and docetaxel (TC) chemotherapy. Rats (5 animals per group) were assigned to dose groups of either vehicle or equivalent doses (based on human clinical doses) of pegfilgrastim (103.3 µg/kg) or eflapegrastim (61.8 µg/kg as G-CSF) on the same day as chemotherapy at 0, 2, and 5 hours or 24 hours after chemotherapy. The primary endpoint was the difference in DN after TC treatment and administration of eflapegrastim or pegfilgrastim at the specified timepoints. Results: In the vehicle group, the TC regimen induced neutropenia in all animals with an ANC nadir occurring on approximately Day 4 and a mean DN of nearly 7 days. The mean DN values for treatment with eflapegrastim on the same day, at 0, 2, and 5 hours, and after 24 hours were similar and the mean DN values for eflapegrastim were significantly lower than for pegfilgrastim at all dosing timepoints (Table). Time after Chemotherapy(hours)Mean Duration of Neutropenia (days)Difference (95% CI)Eflapegrastim Time vs 24 hoursDifference (95% CI)EflapegrastimPegfilgrastim00.62.2-1.6 (-3.067, -0.133)0.4 (-0.08, 1.28)20.21.8-1.6 (-2.84, -0.36)0 (-0.19, 0.59)50.01.2-1.2 (-1.20, -1.20)-0.2 (0, 0)240.21.8-1.6 (-2.84, -0.36)NA Conclusions: The DN for same-day treatment with eflapegrastim at 0, 2, and 5 hours was similar to that of the treatment after 24-hours. However, the mean DN values were significantly lower for eflapegrastim than pegfilgrastim at all time points. Further exploration of the potential advantage of same-day dosing with eflapegrastim in patients undergoing chemotherapy is warranted. Citation Format: Yu-Yon Kim, Eunjung Kim, Hyesun Han, Seungjae Baek, Shanta Chawla, Prasad Kolli, Gajanan Bhat, Francois Lebel. Chemotherapy induced neutropenia in rats following administration of eflapegrastim or pegfilgrastim on the same day at three different timepoints and at 24 hours post-chemotherapy [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 2044.
Abstract 4959: Targeting of the eukaryotic translation initiation factor 4A against breast cancer stemness
Authors: Sangita Sridharan, Megan Robeson, Diwakar Tukaramrao Bastihalli, Cory Howard, Boopathi Subramaniyan, Augustus Tilley, Dayanidhi Raman
Journal: Cancer Research (2020)

Abstract Chemoresistance is a clinically significant issue in triple-negative breast cancer (TNBC) patients, leading to minimal residual disease. The surviving breast cancer stem cells (BCSCs) undergo multilineage differentiation and repopulate a more aggressive primary tumor leading to metastasis and subsequent mortality. Not only are BCSCs innately chemo/radioresistant but also contribute to therapy failure through interconversion between BCSCs and bulk tumor cells. Therefore, it is imperative to co-target BCSCs and bulk tumor cells simultaneously. Identifying novel molecular targets is key to eliminate both bulk tumor cells and BCSCs. The eukaryotic protein translation initiation machinery, the eIF4F complex, is a convergence point for many oncogenic signaling pathways. This complex plays a vital role in translation of many oncogenic mRNAs implicated in cell cycle, tumor progression, chemoresistance and metastasis. We have previously demonstrated that the mRNA helicase eIF4A1, of the eIF4F complex, might serve as a vulnerable node to kill TNBC cells. In the current study, we hypothesized that targeting of eIF4A1 would reduce/eliminate both bulk tumor cells and BCSCs and overcome chemoresistance. In order to evaluate the effects of targeting eIF4A1 in BCSCs, we isolated BCSCs based on aldehyde dehydrogenase activity and CD44 expression by Fluorescence Activated Cell Sorting and characterized for stemness. Through pharmacological targeting (Rocaglamide A) and genetic ablation (CRISPR-Cas9) of eIF4A1, we demonstrated that there was a statistically significant reduction in the self-renewal ability indicated by the reduction in primary and secondary mammosphere formation efficiency (MFE) of BCSCs, levels of the pluripotency transcription factors (SOX2, OCT4 and NANOG), expression of drug transporters (ABCG2, ABCB1 and ABCC1) and increased induction of apoptotic cell death. Overall, we demonstrated that targeting eIF4A1 is effective in eliminating BCSCs through reduction in the levels of stemness factors and drug transporters. This sets up a stage to employ small molecule inhibitors against eIF4A1 in co-targeting strategic therapies. Citation Format: Sangita Sridharan, Megan Robeson, Diwakar Tukaramrao Bastihalli, Cory Howard, Boopathi Subramaniyan, Augustus Tilley, Dayanidhi Raman. Targeting of the eukaryotic translation initiation factor 4A against breast cancer stemness [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 4959.
Abstract 6078: Suppression of tumor-intrinsic IFNγ signaling in ARF6-mediated metastatic progression of melanoma
Authors: Coulson P. Rich, Aaron Rogers, Jae Hyuk Yoo, Roger Wolff, Shannon J. Odelberg, Sheri L. Holmen, Allie H. Grossmann
Journal: Cancer Research (2020)

Abstract ARF6 is a small GTPase that controls the subcellular location of proteins to regulate invasion, proliferation and tumor microvesicle shedding. ARF6 is aberrantly activated in cutaneous melanoma and stimulates invasion in BRAFV600E-melanoma by controlling localization and activation of beta-catenin and PI3K/AKT. In uveal melanoma, ARF6 facilitates GNAQQ209L signaling to drive tumor growth by trafficking GNAQ to cytoplasmic vesicles. Although distinct diseases, pharmacologic inhibition of ARF6 reduces disease progression in both uveal and cutaneous melanoma models. These data underscore the importance of intracellular trafficking mechanisms in cancer and highlight the potential clinical utility of targeting this machinery by inhibiting ARF6. In order to genetically dissect the role of ARF6 in melanomagenesis, we utilized RCAS-mediated delivery of Cre recombinase, with or without constitutively activated ARF6 (Arf6Q67L), specifically to melanocytic cells to induce constitutive activation of BRAFV600E (BrafCA), deletion of Cdkn2a (Cdkn2af/f) and (Arf6f/f). Activation of ARF6 accelerates spontaneous metastasis while loss of Arf6 delays tumor onset and reduces tumor incidence and growth, dramatically improving survival of BrafCA;Cdkn2af/f mice, including in the presence of Pten loss. Unexpectedly, tumors expressing ARF6Q67L show significantly reduced expression of interferon-gamma (IFNγ) response genes, reduced CD8 (T cell) transcripts and an anti-apoptotic proteomics profile. Knockdown of Arf6 sensitizes BRAFV600E melanoma cells to IFNγ treatment reducing cell viability in vitro. Together these data demonstrate that ARF6 modulates BRAFV600E-driven tumor progression and suggest that ARF6 activation suppresses tumor intrinsic IFNγ signaling to evade the anti-tumor immune response during metastatic progression. Our in vivo models provide a new paradigm for understanding vulnerabilities in BRAF-mediated oncogenesis and implicate intracellular trafficking mechanisms as potentially actionable machinery in melanoma development, immune evasion and disease progression. Citation Format: Coulson P. Rich, Aaron Rogers, Jae Hyuk Yoo, Roger Wolff, Shannon J. Odelberg, Sheri L. Holmen, Allie H. Grossmann. Suppression of tumor-intrinsic IFNγ signaling in ARF6-mediated metastatic progression of melanoma [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 6078.
Abstract 4400: Translational drug interaction database (TDID): A knowledgebase for drug interactions
Authors: Shijun Zhang, Heng-Yi Wu, Rohith Vanam, None chien-WeiChiang, Lei Wang, Lang Li
Journal: Cancer Research (2020)

Abstract To help physicians and basic scientists in identifying drug-drug interaction mechanisms (DDI) and associated toxicity, we developed ‘The Translational Drug Interaction Database (TDID)', which is a fully searchable web-based resource that has a large collection of drug interaction data. The current TDID is seeded with pharmacokinetics (PK) or pharmacodynamics (PD) based drug interaction evidences that are extracted and classified from PubMed (from 1975 to 2015) via text mining. The DDI evidences are further classified into the following categories: PK in vitro, PD in vitro, PK in vivo, PD in vivo, clinical safety, and case report. Most importantly, cancer drug interaction clinical safety data are mined and manually curated from full-text articles. TDID also includes PK or PD DDI statements from DrugBank, and DDI-ADE associations from FAERS. Altogether, TDID integrates 88,500 pieces of DDI evidences from PubMed, 1,048,000 DDI statements from DrugBank, and over 100,000,000 DDI-ADE pairs from FAERS. Specifically, TDID has 1,480 pieces of cancer DDI toxicity evidences. These cancer DDI toxicity evidences are annotated with patient characteristics, treatment plan including dosages, and toxicity level. The database can be searched by drug name (i.e. single drug, drug pair), and the DDI query results can be sorted by study type. The Translational Drug Interaction Database (TDID) offers user-friendly browsing, searching, and filtering functions. The Translational Drug Interaction Database is available at https://tdid.bmi.osumc.edu. Citation Format: Shijun Zhang, Heng-Yi Wu, Rohith Vanam, chien-WeiChiang, Lei Wang, Lang Li. Translational drug interaction database (TDID): A knowledgebase for drug interactions [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 4400.