tbuckley/cabot-search huggingface dataset:
Abstract LB203: FER regulates endosomal recycling and is a candidate predictor for taxane benefit in breast cancer
Authors: Sandra Tavares, Nalan Liv, Milena Pasolli, Mark Opdam, Max Ratze, Manuel Saornil, Lilian Sluimer, Rutger Hengeveld, Robert van Es, Erik van Werkhoven, Harmjan Vos, Holger Rehmann, Boudewijn Burgering, Hendrika Oosterkamp, Susanne Lens, Judith Klumperman, Sabine Linn, Patrick Derksen
Journal: Cancer Research (2021)

Abstract To this day, targeted treatment options for patients with triple negative metastatic breast cancer (TNBC) are still virtually absent. Previously, we showed that elevated expression of the tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/TNBC patients. Here, we show that high FER levels are also associated with improved outcome after adjuvant taxane-based combination chemotherapy, in high-risk, HER2-negative patients. In TNBC cells, we observed a causal relation between high FER levels and sensitivity to taxanes. Our proteomics and mechanistic studies demonstrated that FER regulates endosomal recycling, a microtubule-dependent process that underpins breast cancer cell invasion. Using chemical genetics, we identified DCTN2 as a novel FER substrate. Our work indicates that the DCTN2 tyrosine 6 is essential for tubular recycling domains development in early endosomes and subsequent propagation of TNBC cell invasion in 3D. In conclusion, we show that high FER expression promotes endosomal recycling and represents a candidate predictive marker for benefit of adjuvant taxane-containing chemotherapy in high-risk patients, including TNBC patients. Citation Format: Sandra Tavares, Nalan Liv, Milena Pasolli, Mark Opdam, Max Ratze, Manuel Saornil, Lilian Sluimer, Rutger Hengeveld, Robert van Es, Erik van Werkhoven, Harmjan Vos, Holger Rehmann, Boudewijn Burgering, Hendrika Oosterkamp, Susanne Lens, Judith Klumperman, Sabine Linn, Patrick Derksen. FER regulates endosomal recycling and is a candidate predictor for taxane benefit in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB203.
Abstract 12237: Low-intensity Pulsed Ultrasound (LIPUS) Therapy Ameliorates DES-induced Coronary Hyperconstricting Responses Through Its Anti-inflammatory Effects in Pigs in vivo -A Novel Non-invasive Therapy for Coronary Inflammation-
Authors: Tasuku Watanabe, Yasuharu Matsumoto, Hirokazu Amamizu, Susumu Morosawa, Jun Sugisawa, Satoshi Tsuchiya, Kazuma Ohyama, Kensuke Nishimiya, Hiroaki Shimokawa
Journal: Circulation (2019)

Background: In the practice of coronary artery disease, residual inflammatory risk after statin therapy has attracted much attention. We have previously demonstrated that coronary adventitial infla...
Enhancement of hepatocarcinogenicity by MeIQx in thioacetamide-treated liver
Authors: Jin Seok Kang, Hideki Wanibuchi, Keiichirou Morimura, Atsushi Hagihara, Elsayed I. Salim, Shoji Fukushima
Journal: Cancer Research (2005)

5716  As there may be increasing risk of heterocyclic amines in liver cancer, we investigated the enhancement carcinogenic potential of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), one of heterocyclic amines, in rats liver damage induced by thioacetamide (TAA). Rats (n=280) were divided into 14 groups. Animals of groups 1-7 received TAA (0.03%) for the first 12 weeks, and animals of groups 8-14 received drinking water without TAA. After withdrawal of TAA, all animals received MeIQx at doses from 0, 0.001, 0.01, 0.1, 1, 10 to 100 ppm (either groups 1-7 or groups 8-14, respectively) in pellet basal diet for 16 weeks. Animals of all groups were sacrificed at week 28. Numbers and area of glutathione S-transferase placental form (GST-P) positive foci, which are preneoplastic lesions of the liver, were increased significantly in all the groups received TAA→MeIQx compared to the groups treated with MeIQx alone (p
Abstract 604: PTX-35, a potential first-in-class TNFRSF25 agonist, reduced the suppressive activity of regulatory T cells and enhanced CD4+ T cell effector responses, in the presence of tumor antigens, in a murine melanoma model
Authors: Khalid W. Kalim, Vikas Tahiliani, Jayalakshmi Miriyala, Patrick J. Dillon, Anh M. Trinh, Abra N. Chaney, Matthew M. Seavey, Eric P. Dixon, Rahul R. Jasuja, Jeff T. Hutchins
Journal: Cancer Research (2021)

Abstract Tumor cells evolve multiple mechanisms to escape immune surveillance, one of which is to establish a tolerogenic microenvironment by recruiting immune suppressive cell types such as regulatory T cells (Tregs). Tumor Necrosis Factor Receptor Super Family 25 (TNFRSF25), also known as Death Receptor 3 (DR3), is a potent costimulatory molecule and is preferentially expressed by activated and antigen-experienced T cells. PTX-35, a potential first-in-class TNFRSF25 agonist antibody, is currently in a Phase 1 clinical trial in patients with solid tumors. The purpose of this study was to characterize the impact of mouse PTX-35 (mPTX-35) on tumor growth as well as Treg stability and functionality, including propensity of Tregs to be converted to effector CD4+ T cell subtypes. In this murine melanoma model, C57BL/6 mice were subcutaneously injected with B16.F10-OVA tumor cells. Mice were administered various combinations of mPTX-35, a PD-1 inhibitor, and tumor antigens. When mPTX-35 was administered with tumor antigens, we observed: (1) reduction in the suppressive activity of Tregs, as reflected by decreased expression of CD25 and Nrp1 among Tregs in the peripheral blood and CTLA-4 in the tumor; (2) compromised Treg stability and increased Treg plasticity, including an increased percentage of RORγt+Foxp3+ unstable Tregs and increased conversion of Tregs to RORγt+Foxp3- Th17 cells; (3) increased effector IFNγ+ Th1 cells and effector IL17+ Th17 cells in blood and tumor microenvironment; and (4) elevation in effector IFNγ+ CD8+ T cells in the blood. Importantly, these changes in Treg stability and functionality were associated with delayed tumor progression. In conclusion, we demonstrate that mPTX-35, in the presence of tumor antigens, resulted in the reprogramming of the Treg cell phenotype, including reduced suppressive activity of Tregs and increased plasticity towards inflammatory Th1 and Th17 cells. PTX-35 has the potential to improve the efficacy of treatment regimens where tumor antigens are released. Citation Format: Khalid W. Kalim, Vikas Tahiliani, Jayalakshmi Miriyala, Patrick J. Dillon, Anh M. Trinh, Abra N. Chaney, Matthew M. Seavey, Eric P. Dixon, Rahul R. Jasuja, Jeff T. Hutchins. PTX-35, a potential first-in-class TNFRSF25 agonist, reduced the suppressive activity of regulatory T cells and enhanced CD4+ T cell effector responses, in the presence of tumor antigens, in a murine melanoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 604.
Abstract 3096: A novel ZIP4-NOTCH3-HDAC4 axis in ovarian cancer stem cells
Authors: Yan Xu, Qipeng Fan, Robert Emerson
Journal: Cancer Research (2021)

Abstract High grade serous ovarian cancer (HGSOC) is one of the most deadly and heterogenic cancers. We have recently shown that ZIP4 (gene name SLC39A4), a zinc transporter, is a novel cancer stem cell (CSC) marker in HGSOC. 100-200 ZIP4+, but not ZIP4-, cells from both PE04 and PEA2 cells formed larger tumors than those from 100-200 ALDH+ cells in mice. Mechanistically, we found that ZIP4 was an upstream regulator of another CSC-marker, NOTCH3, in HGSOC cells. NOTCH3 was functionally involved in spheroid formation in vitro and tumorigenesis in vivo in HGSOC. Drug-resistance is one of the main characteristics of CSCs, While ZIP4 converts drug-resistance to cisplatin (CDDP) and doxorubicin (DOX) as we reported previously, we unexpectedly found that ZIP4 induced a sensitization of HGSOC cells to histone deacetylase inhibitors (HDACis). In particular, only those HDACis against the Class IIa HDACs showed ZIP4-dependent sensitization. ZIP4 selectively up-regulated HDAC IIa HDACs, including HDAC4 and 5, with little or no effects to HDACs in other classes. ZIP4 knockout (KO) and HDAC4 knockdown (KD) increased cell resistance to LMK-235, a selective HDAC4/5 inhibitor. LMK-235 and HDAC4 knockdown (KD) inhibited spheroid formation in vitro and tumor development in vivo. Collectively, we revealed a novel ZIP4-NOTCH3-HDAC4 axis, which is functionally involved and important in CSC-related activities in vitro and tumorigenesis in vivo, and provide an innovative targeting strategy to CSC. Citation Format: Yan Xu, Qipeng Fan, Robert Emerson. A novel ZIP4-NOTCH3-HDAC4 axis in ovarian cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3096.
Novel function of SART1 in HNF4α transcriptional regulation contributes to its antiviral role during HBV infection
Authors: Yan Teng, Zaichao Xu, Kaitao Zhao, Youquan Zhong, Jingjing Wang, Li Zhao, Zhixin Zheng, Wei Hou, Chengliang Zhu, Xinwen Chen, Ulrike Protzer, Yong Li, Yuchen Xia
Journal: Journal of Hepatology (2021)
Abstract ND07: HER2-TTC: A Targeted thorium conjugate to treat HER2 expressing cancers with potent alpha radiation
Authors: Jenny Karlsson
Journal: Cancer Research (2021)

Abstract HER2-TTC (BAY 2701439) is a new representative of the Targeted Thorium Conjugates (TTCs), a novel class of radiotherapeutics for the treatment of cancer. It is comprised of the α-particle emitter thorium-227 complexed to a 3,2-HOPO chelator and conjugated to a human epidermal growth factor receptor 2 (HER2) targeted monoclonal antibody derived from trastuzumab. The targeted binding of HER2-TTC exposes tumor cells that express HER2 to a cytotoxic dose of alpha radiation. The high energy alpha-particles induce clustered double-strand DNA damage in targeted and adjacent tumor cells, which have a high likelihood to result in cell death in a cell cycle-independent fashion. Alpha particles have a short range of &amp;lt; 100 μm (less than 10 cell diameters), which minimizes damage to surrounding healthy tissue. The mechanism of action for TTCs is not dependent on any specific tumor type or affected by known resistance mechanisms provided that the target tumor epitope continues to be expressed. Potential combinations with inhibitors of DNA damage response (DDR) pathways may lead to synergistic anti-tumor activity. Preclinically, HER2-TTC has demonstrated substantial and selective anti-tumor activity in different models including breast, gastric, lung, bladder, colorectal cancer, with a range of HER2 expressions (IHC scores of 1+ to 3+). These included trastuzumab and T-DM1 resistant models, and models with low HER2 expression (IHC2+/ISH- or IHC1+). HER2-TTC has also demonstrated synergistic efficacy in combination with olaparib in a BRCAmut model. Preclinical data also support potential combinations with immune oncology agents, likely due to immunogenic cell death induced by alpha radiation. HER2-TTC has recently entered a First in Human study (NCT04147819) in patients with advanced tumors that express HER2. These include HER2 high expressing (IHC3+ or ISH+) breast and gastric/gastroesophageal carcinoma relapsed/refractory to trastuzumab/T-DM1, cancers with low HER2 expression, and other tumors that express HER2 such as colorectal cancer, non-small cell lung cancer, salivary, bladder and endometrial tumors. Citation Format: Jenny Karlsson. HER2-TTC: A Targeted thorium conjugate to treat HER2 expressing cancers with potent alpha radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr ND07.
Abstract 2936: Ago2 induces Kras signaling and promotes tumor progression in mouse models of lung adenocarcinoma
Authors: Jean C. Tien, Seema Chugh, Andrew E. Goodrum, Yunhui Cheng, Lisha Wang, Rahul Mannan, Xiaoming Wang, Vijaya L. Dommeti, Yuping Zhang, Alice Xu, Fengyu Su, Xuhong Cao, Sunita Shankar, Arul M. Chinnaiyan
Journal: Cancer Research (2021)

Abstract Lung cancer is the deadliest malignancy in the United States. Non-small cell lung cancer (NSCLC) accounts for 85% of cases, and is frequently driven by activating mutations in the gene encoding the KRAS GTPase (e.g. KRASG12D). Our previous work demonstrated that Argonaute 2 (AGO2)—a component of the RNA induced silencing complex (RISC)—physically interacts with KRAS and stabilizes it at the protein level. In multiple cell lines, AGO2 knockdown reduces KRAS protein level and attenuates cell proliferation. We therefore hypothesized that AGO2 could promote KRASG12D-dependent NSCLC in vivo. To test the hypothesis, we evaluated the impact of Ago2 knockout in the KPC mouse model of NSCLC. In KPC mice, intratracheal delivery of adenoviral Cre drives lung-specific expression of a stop-floxed KRASG12D allele and biallelic ablation of p53. Simultaneous biallelic ablation of floxed Ago2 inhibited KPC lung nodule growth while reducing proliferative index and improving pathological grade. We next applied the KPHetC model, in which the clara cell-specific CCSP-driven Cre activates KRASG12D and ablates a single p53 allele. In these mice, Ago2 ablation also reduced tumor size and grade. In both models, Ago2 knockout inhibited ERK phosphorylation in tumor nodules, indicating impaired KRAS signaling. Furthermore, RNA-seq analysis of KPC nodules demonstrated broadly reduced expression of Kras-related genes. Taken together, our data demonstrate a novel pathogenic role for AGO2 in KRAS-dependent NSCLC. Given the prevalence of this malignancy and current difficulties in therapeutically targeting KRAS signaling, our work has future translational relevance. Citation Format: Jean C. Tien, Seema Chugh, Andrew E. Goodrum, Yunhui Cheng, Lisha Wang, Rahul Mannan, Xiaoming Wang, Vijaya L. Dommeti, Yuping Zhang, Alice Xu, Fengyu Su, Xuhong Cao, Sunita Shankar, Arul M. Chinnaiyan. Ago2 induces Kras signaling and promotes tumor progression in mouse models of lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2936.
Abstract 2737: Clinical and epidemiologic predictors of clonal immune responses in colorectal cancer
Authors: Stephen B. Gruber, Joseph D. Bonner, Sidney S. Lindsey, Ya-Yu Tsai, Rebeca Sanz-Pamplona, M. Henar Alonso, Marilena Melas, Hedy S. Rennert, Kevin J. McDonnell, Gregory E. Idos, Christopher P. Walker, W. Martin Kast, Diane Da Silva, Harlan S. Robins, Joel K. Greenson, Victor Moreno, Stephanie L. Schmit, Gad Rennert
Journal: Cancer Research (2021)

Abstract The quantity and quality of immune responses in colorectal cancers (CRC) are widely variable and have important clinical, therapeutic, and prognostic implications. We studied clinical and epidemiologic factors that might influence T-cell quantity and clonality within colorectal adenocarcinomas to better understand the drivers of diverse immune responses. Incident cases of CRC from the Molecular Epidemiology of Colorectal Cancer Study (MECC) were interviewed, and 6,006 cases had complete epidemiologic data. Archived tumor blocks were retrieved from 3,865 (64.4%) cases, and all were reviewed by a single expert pathologist who quantified TILS/hpf. Sufficient tissue for macrodissection and measurement of TCR abundance and clonality using the immunoSEQ assay (Adaptive Biotechnologies) was available and completed for 2,750 cases. Logistic regression, negative binomial regression and linear regression models were used to evaluate potential associations between clinical and epidemiologic variables for: TILS/hpf, TCR abundance, and T-cell clonality. The stage distribution was representative of cancer incidence in the population, and the MSI-H phenotype was observed in 14.2% of cases. Clinical, pathologic, and epidemiologic variables including aspirin, alcohol, diet, hormone use, physical activity, smoking, and statins were assessed in relation to immune measures. Among other findings, &amp;gt;5 years of statins (p&amp;lt;0.001) and daily aspirin (p=0.037) were each strongly associated with T-cell clonality. Our study suggests that important parameters of the adaptive immune response may be mediated by modifiable factors. Mechanisms regulating immune responses in CRC may have implications for chemoprevention as well as immunotherapy. Citation Format: Stephen B. Gruber, Joseph D. Bonner, Sidney S. Lindsey, Ya-Yu Tsai, Rebeca Sanz-Pamplona, M. Henar Alonso, Marilena Melas, Hedy S. Rennert, Kevin J. McDonnell, Gregory E. Idos, Christopher P. Walker, W. Martin Kast, Diane Da Silva, Harlan S. Robins, Joel K. Greenson, Victor Moreno, Stephanie L. Schmit, Gad Rennert. Clinical and epidemiologic predictors of clonal immune responses in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2737.
Abstract 805: A germline mutation of gene ATM p.C1899* is associated with a family history of multiple cancers in a family in Yunnan province, China
Authors: Xianghua Sun, Hushan Zhang, Wanfu Zhang, Zhiping Zhang, Bo Li
Journal: Cancer Research (2021)

Abstract Background: Ataxia-telangiectasia mutated (ATM) is a gene that plays role in cell cycle checkpoints and DNA damage response, heterozygous germline mutations in ATM are considered as one of risk factor of breast cancer (BC). There are also some reports that ATM mutations are related to other tumor types, such as prostate cancer. Several pathogenic germline mutations in ATM have been reported included missense mutations, nonsense mutations, frameshift deletions, in-frame deletion, large deletion. Here, we report a family history of multiple cancers related to germline mutation of ATM p.C1899* in a family in Yunnan province, China. Methods: The proband is a 58-year old male patient with colon cancer. Both tumor tissue samples and peripheral blood sample of the proband was subjected to next generation sequencing (NGS) analysis by 3D Medicines Inc., Shanghai, China, a laboratory accredited by College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA). A novel germ-line mutation was identified, that was heterozygous ATM p.C1899* mutation (c.5697C&amp;gt;A). Peripheral blood sample of other family members have been collected and send to 3D Medicines Inc., for NGS analysis. Results: In total of 6 members of the family underwent NGS analysis, results showed that these members were carry a germline mutation of gene ATM p.C1899*, one uncle was patient with gastric cancer, and one aunt was patient with pancreatic cancer, which means this germline mutation was related with three different cancer in a family. Conclusion: The mutation of ATM, especially germline mutation, may associated with multiple cancers, such as gastric cancer, colorectal cancer and pancreatic cancer. Accurate genetic testing should be given more attention to better control the risk of familial cancer. Citation Format: Xianghua Sun, Hushan Zhang, Wanfu Zhang, Zhiping Zhang, Bo Li. A germline mutation of gene ATM p.C1899* is associated with a family history of multiple cancers in a family in Yunnan province, China [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 805.
Abstract LB184: Induction of ulk1 regulated autophagy by a novel antipsychotic drug leads to apoptosis in pancreatic cancer cells
Authors: Sharavan Ramachandran, Sanjay K. Srivastava
Journal: Cancer Research (2021)

Abstract Pancreatic cancer patients have limited treatment options in spite of several advanced treatment strategies. Pancreatic tumors exhibit high basal autophagy compared to other cancers. Several studies including from our lab reported that enhanced autophagy leads to apoptosis in cancer cells. In this study, we have demonstrated that pimavanserin (PVT) suppresses pancreatic tumor growth by inducing autophagy-mediated apoptosis. Our results indicated that PVT induced 1.8 - 5 fold autophagy in pancreatic ductal adenocarcinoma (PDAC) cells, as evaluated by increased acridine orange staining. Furthermore, accumulation of double-membrane vesicles (autophagosomes) and formation of autophagolysosomes were observed with PVT treatment. Genomic analysis by R2 &amp;GEPIA database revealed that PDAC patients exhibited reduced levels of autophagy initiator gene, ULK1. PVT induced the expression of autophagy markers ULK1, FIP200, Atg101, Beclin-1, Atg5, and LC3A/B in several pancreatic cancer cells. In addition, phosphorylation of ULK1 atSer757 was inhibited with PVT treatment. Apoptotic effects of PVT in pancreatic cancer cells were validated by increase in cleavage of caspase3. ULK1 agonist LYN-1604 enhanced the autophagic and apoptotic effects of PVT. On the other hand, autophagy inhibitors chloroquine and bafilomycin blocked the autophagic and apoptotic effects of PVT in pancreatic cancer cells. Our in vivo findings demonstrated that chloroquine abrogated the growth-suppressive effects of PVT by 21% in sub-cutaneously implanted BxPC3 tumor xenografts. Moreover, chloroquine reduced the effects of PVT in inducing the expression of ULK1 and the cleavage of caspase 3 as evaluated by western blotting. Oral administration of PVT suppressed BxPC3 tumor xenografts by 50% in athymic nude mice. In another in vivo experiment, PVT treatment inhibited the growth of orthotopically implanted PANC1 tumors by 77%. Chronic administration of PVT did not exhibit any general signs of toxicity or behavioral side effects in mice. Moreover, long-term administration of PVTdid not altered the clinical chemistry parameters like ALT, AST, total serum protein, calcium, creatinine, BUN, and albumin. Collectively, our results indicate that PVT-mediated pancreatic tumor growth suppression was associated with the induction of autophagy-mediated apoptosis. Since PVT is already available in the clinic with an established safety profile, our results will accelerate its clinical development for pancreatic cancer therapy. Citation Format: Sharavan Ramachandran, Sanjay K. Srivastava. Induction of ulk1 regulated autophagy by a novel antipsychotic drug leads to apoptosis in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB184.