bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3698: Conditionally reprogrammed cells from patient-derived xenograft to model neuroendocrine prostate cancer development
Authors: Ci Xinpei , Hao Jun , Dong Xin , Xue Hui , Wu Rebecca , Haegert Anne M. , Collins Colin C. , Lin Dong , Wang Yuzhuo 
Published: August 2019

Abstract
Treatment-emergent neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of advanced prostate cancer that occurs via NE transdifferentiation of prostate adenocarcinomas in response to androgen receptor (AR)-inhibition therapy. Study of t-NEPC has been hampered by a lack of clinically relevant models. We previously established a unique and first-in-field patient-derived xenograft (PDX) model of adenocarcinoma (LTL331)-to-NEPC (LTL331R) transdifferentiation. In this study, we established conditionally reprogrammed (CR) cells from the adenocarcinoma PDX tumor line LTL331. These LTL331-derived CR (LTL331-CR) cells retained the same genomic mutations of the parental tumor and, can be genetically manipulated and continuously propagated in vitro. Further androgen deprivation treatment on LTL331-CR cells showed no effect on cell proliferation. Transcriptomic analyses of the LTL331-CR cells revealed profound downregulation of androgen response pathway, and enrichment of stem/progenitor-like marker genes, compared with the parental tumor LTL331. Notably, when grafted back into the subrenal capsule of male NOD/SCID mice, these LTL331-CR cells gave rise to NEPC tumors directly as manifested by histological expression of NE markers. Transcriptomic analyses of the newly developed NEPC tumors also demonstrated marked enrichment of NEPC signature genes and loss of AR signaling genes. This study provides a novel strategy to investigate the mechanisms underlying t-NEPC development with a unique PDX by enabling gene manipulation ex vivo and subsequent functional evaluation in vivo.
Citation Format: Xinpei Ci, Jun Hao, Xin Dong, Hui Xue, Rebecca Wu, Anne M. Haegert, Colin C. Collins, Dong Lin, Yuzhuo Wang. Conditionally reprogrammed cells from patient-derived xenograft to model neuroendocrine prostate cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3698.
Abstract 3700: Investigating the therapeutic potential of parthenolide for hematopoietic neoplasms in dogs
Authors: Schlein Lisa J. , Rose Barbara , Peterson Aubree , Thamm Douglas 
Published: August 2019

Abstract
The purpose of this research is to explore the therapeutic potential of parthenolide (PTL) to treat various hematopoietic neoplasms in dogs; additionally, some dog breeds are enriched for development of mast cell neoplasia and histiocytic sarcoma, providing translational study populations for rare and deadly human diseases. Growth inhibition assays were performed using a panel of canine mast cell, histiocytic sarcoma, lymphoma, and leukemia cell lines, with PTL alone or in combination with redox-perturbing standard-of-care therapeutics. Cell death was assessed using flow cytometry. Immunofluorescence and immunoblotting were used to assess NFκB localization and phosphorylation, respectively. All immortalized canine cell lines evaluated are sensitive to PTL therapy and undergo dose-dependent apoptosis following exposure to drug. PTL exposure leads to inhibition of NFκB, as evidenced by immunofluorescent nuclear exclusion and decreased p65 phosphorylation. Preliminary studies indicate that some standard-of-care therapeutics synergize with PTL. These initial studies show that PTL is a promising therapeutic for hematopoietic neoplasms in dogs. Murine modeling and investigation of redox perturbance are underway and will further investigate PTL’s potential in the clinical setting.
Citation Format: Lisa J. Schlein, Barbara Rose, Aubree Peterson, Douglas Thamm. Investigating the therapeutic potential of parthenolide for hematopoietic neoplasms in dogs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3700.
Abstract 3712: Proliferative and invasive colorectal tumors in pet dogs provide unique insights into human colorectal cancer
Authors: Wang Jin , Wang Tianfang , Sun Yanfang , Feng Yuan , Kisseberth William C. , Henry Carolyn J. , Mok Irene , Lana Susan E. , Dobbin Kevin , Northrup Nicole , Howerth Elizabeth W. , Zhao Shaying , Cai Houjian 
Published: August 2019

Abstract
Spontaneous tumors in pet dogs represent a valuable but undercharacterized cancer model. To better use this resource, we performed an initial global comparison between proliferative and invasive colorectal tumors from 20 canine cases and evaluated their molecular homology to human colorectal cancer (CRC). We sequenced 15 canine intestinal samples for WGS and 26 for RNA-seq. We investigated alterations in the genome and transcriptome, using state-of-the-art analysis tools. We aslso investigated their microbiome, by mapping WGS and RNA-seq read pairs that could not be placed onto the canine genome to two microbial genome databases: The Human Microbiome Project database and all bacterial genomic sequences. We performed the same analysis with TCGA (The Cancer Genome Atlas) colon cancer data. Based on our analysis, proliferative canine tumors harbor overactivated WNT/β-catenin pathways and recurrent CTNNB1 (β-catenin) mutations S45F/P, D32Y and G34E. Invasive canine tumors harbor prominent fibroblast proliferation and overactivated stroma. Both groups have recurrent TP53 mutations. We observed three invasion patterns in canine tumors: collective, crypt-like and epithelial-mesenchymal transition (EMT). We detected enriched Helicobacter bilis and Alistipes finegoldii in proliferative and crypt-like tumors, but depleted mucosa-microbes in the EMT tumor. Additionally, guided by our canine findings, we classified 79% of 478 human colon cancers from TCGA into four subtypes: primarily proliferative, or with collective, crypt-like or EMT invasion features. Their molecular characteristics match those of canine tumors. We showed that consensus molecular subtype 4 (mesenchymal) of human CRC should be further divided into EMT and crypt-like subtypes, which differ in TGF-β activation and mucosa-microbe content. Our canine tumors share the same pathogenic pathway as human CRCs. Dog-human integration identifies three CRC invasion patterns and improves CRC subtyping.
Citation Format: Jin Wang, Tianfang Wang, Yanfang Sun, Yuan Feng, William C. Kisseberth, Carolyn J. Henry, Irene Mok, Susan E. Lana, Kevin Dobbin, Nicole Northrup, Elizabeth W. Howerth, Shaying Zhao, Houjian Cai. Proliferative and invasive colorectal tumors in pet dogs provide unique insights into human colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3712.
Abstract 3715: Cancer as a consequence of breaking through evolutionary constraints on longevity
Authors: Modiano Jaime F. , Sarver Aaron L. 
Published: August 2019

Abstract
It is well known that the risk of cancer increases with age, but when viewed through a comparative lens, this risk is species specific and exists at a relatively low background in the animal kingdom. The exceptions, where cancer is a major cause of mortality, are humans and companion dogs and cats. Indeed, it is estimated that more than 50% of pet dogs that reach the age of 10-years will die from cancer. Colloquially, there is a perception that there is a “cancer epidemic” in dogs caused by exposures to real or perceived mutagens, but this hypothesis is based on presumptions for which supporting evidence is weak or absent. Here, we propose an alternative hypothesis, that replacing natural selection with artificial selection for form and function, and superimposing longevity that breaks the evolutionary constraints for that species inevitably creates cancer-prone phenotypes. Modern pet dogs have achieved a social status equivalent to human family members. With this have come better health care, reduced early mortality, and greater longevity. Although dogs were first domesticated15,000 to 20,000 years ago and breeds were derived over the last 200 to 400 years, significant gains in longevity and the recognition of cancer as a major cause of mortality in pet dogs have taken place over the past 40 to 60 years, coinciding with the transition of dogs from working animals to pets. Breaking through the evolutionary constraint on longevity comes at a price: long-lived species such as elephants, whales, mole rats, and others have acquired a diversity of cancer-protective mechanisms, achieving a balance between longevity and their reproductive and energetic investments over tens of millions of years. But no such cancer-protective mechanisms have been identified in dogs, or for that matter in humans. In both species, risk increases with age, but in dogs, risk is magnified by artificial selection. Osteosarcoma provides an example that can be generalized. The underlying causal factor is selective breeding for large size, but this is only able to manifest itself because modern pet dogs exceed their evolutionarily expected lifespan by at least 2 or 3 times. We conclude that appreciating the role of longevity as a major cause of cancer in pet dogs, as well as in other model organisms will improve our ability to design and interpret experiments that will show greater fidelity when translated to humans, where the same risk factors are operative, although they are partly masked by the influence of behavioral or occupational exposures to strong mutagens.
Citation Format: Jaime F. Modiano, Aaron L. Sarver. Cancer as a consequence of breaking through evolutionary constraints on longevity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3715.
Abstract 3901: Nonclinical safety evaluation of CA102N, a hyaluronic acid (HA) and nimesulide (Nim) conjugate, for colorectal cancer treatment
Authors: Tchaparian Eskouhie , Lin Louis , Hsu Elin , Chen Ivy , Wu Albert 
Published: August 2019

Abstract
CA102N is a conjugate of the biological polymer hyaluronic acid (HA) and Nimesulide (Nim), a cyclooxygenase-2 (COX-2) inhibitor that represents a promising new approach to addressing cancer treatment. Similar to an antibody-drug conjugate or a pro-drug, CA102N enhances the efficacy of Nim through targeting and binding of HA to CD44 receptors highly expressed in solid tumors. Pharmacological (in vitro and in vivo) studies indicated that CA102N exhibits apoptotic and tumor growth inhibitory activities against colorectal cancer. The MOA of CA102N was demonstrated to be related to apoptosis and disruption of the PI3K/Akt/mTOR pathway in addition to inhibition of the COX-2/PGE2 related pathways.
Safety of CA102N was assessed in acute dose range finding and repeat-dose intravenous toxicity studies in rats and beagle dogs. Three dose levels including the Maximum Tolerated Dose (MTD) from DRF study, a middle dose and a low dose equivalent to the proposed clinical dose were administered twice weekly (BID). A 28-day recovery group was also included in the rat study.
Overall CA102N was well tolerated in both species. CA102N did not induce any significant effects on the CNS, the cardiovascular and respiratory systems in animal models. Some changes in hematological parameters were observed only in rats at the highest dose (Std 10: ≥ 600 mg/kg/day ), however, most of these observations were reversible. No hERG inhibition (in vitro) was observed suggesting the risk of QT prolongation with CA102N is low. The Highest Non-Severely Toxic Dose (HNSTD) of CA102N in the dog was determined to be 280 mg/kg/day (7.24 mg/kg in Nim equivalents ) and the rat NOAEL was 400 mg/kg/day (10.16 mg/kg in Nim equivalents ). These doses are 2.3 times (rat) and 5.6 times (dog) of nimesulide dose to be evaluated (up to 0.72 mg/kg of nimesulide) in the proposed phase 1 study.
On the basis of the mechanism of action and the nonclinical safety profiles, toxicity associated risks to patients appear to be low at the proposed clinical dose levels. A Phase I study of CA102N in patients with locally advanced or metastatic colorectal cancer is ongoing.
Citation Format: Eskouhie Tchaparian, Louis Lin, Elin Hsu, Ivy Chen, Albert Wu. Nonclinical safety evaluation of CA102N, a hyaluronic acid (HA) and nimesulide (Nim) conjugate, for colorectal cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3901.
Abstract 3908: The combination of NVP-BEZ235 & endostatin exerts synergistic anticancer activity against triple-negative breast cancer in vitro and in vivo
Authors: Wang Xiaoshan , Zhang Xiao , Li Fanghua 
Published: August 2019

Abstract
Background: Triple-negative breast cancer(TNBC) take up 15% of invasive breast cancer. TNBC has no effective molecular targets & unfavourable prognosis. We investigated the effects of NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, a combine with or not an angiogenesis inhibitor Endostatin in the orthotopic TNBC model & explored its anti-tumor & anti-angiogenesis mechanisms.
Material & Methods: Assess sensitivity of the cells to the drug by MTT assays.Orthotopic xenografts were performed for tumor growth and survival studies. Additionally, Immunohistochemistry for VEGF and MVD(CD34) was performed using the EnVision/HRP technique,Serum VEGF was detected by ELISA method.
Results: BEZ235 effectively inhibited cell proliferation in vitro & provided additive effects when combine with Endostatin.Treatment with BEZ235 & Endostatin resulted in inhibition of tumor growth & prolongation of survival time of tumor-bearing mice in vivo.Immunohistochemical analysis revealed that intratumoral proliferation & angiogenesis was significantly suppressed. Furthermore, Changing of the number of Serum VEGF support the finding of angiogenesis inhibition too.
Conclusion: Our findings suggest that BEZ235 exerts antitumor effects against TNBC & enhances effects of Endostatin through inhibition of cell proliferation & tumor angiogenesis. This approach may represent a promising combination targeted therapy for TNBC treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Xiaoshan Wang, Xiao Zhang, Fanghua Li. The combination of NVP-BEZ235 & endostatin exerts synergistic anticancer activity against triple-negative breast cancer in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3908.
Abstract 393: Deoxymab: A targeted biologic that is synthetically lethal to TNBC brain metastases
Authors: Zhang Shenqi , May Christopher , Shirali Anupama , Dubljevic Valentina , Campbell James A. , Zhou Jiangbing , Hansen James E. 
Published: August 2019

Abstract
Brain metastases in triple-negative breast cancer (TNBC) harbor defects in homology-directed DNA repair that may be exploited to develop new therapeutic strategies. However, these tumors are protected by the blood-brain barrier (BBB), and mechanisms of DNA repair are sequestered in the nucleus. Methods to cross the BBB and target intranuclear processes are needed.
3E10 is a nuclear-penetrating lupus anti-DNA autoantibody that inhibits the DNA damage response to selectively kill cancer cells with defects in DNA repair. 3E10 localizes to DNA in tumor environments, and penetrates cells via the ENT2 equilibrative nucleoside transporter. ENT2 is expressed in the BBB, and 3E10 has previously delivered cargo proteins to the brain. We believe 3E10 can be turned against TNBC brain metastases, and used MDA-MB-231-BR brain-seeking human TNBC cells and tumors as a model system to test this hypothesis.
We re-engineered 3E10 into an optimized fragment, called Deoxymab-1 (DX1), to maximize effect on cancer cells and minimize toxicity. DX1 expressed in CHO cells was purified over a HiTrap Capto S column by FPLC, and purity and quality was confirmed by SDS-PAGE and SEC-HPLC. Immunostaining and colony formation assays demonstrated that DX1 penetrated the nuclei of ~100% of MDA-MB-231-BR cells in culture and was synthetically lethal to the cells, with doses of 5 and 10 μM reducing surviving fractions to 0.47±0.15 (P&lt;0.03) and 0.29±0.07 (P&lt;0.01), respectively.
TNBC brain metastases were established in nude mice by intracardiac injection of 1.75x105 MDA-MB-231-BR cells transfected with luciferase. One week later the presence of brain metastases was confirmed by IVIS. Mice were treated with tail vein injection of vehicle control (n=7) or DX1 (20 mg/kg) (n=7) 3x/week for 3 weeks. Tumor burden was monitored by weekly IVIS. DX1 significantly suppressed growth of the brain metastases (Table 1). These results establish proof of the novel concept of use of a modified lupus autoantibody against TNBC brain metastases.
Table 1:Brain Radiance Efficiencies (x105)TreatmentWeek 0Week 1Week 2Week 3Control1.2±0.22.5±0.45.1±0.720±5DX11.3±0.21.4±0.32.0±0.23.8±0.8Pns&lt;0.01&lt;0.01&lt;0.02
Citation Format: Shenqi Zhang, Christopher May, Anupama Shirali, Valentina Dubljevic, James A. Campbell, Jiangbing Zhou, James E. Hansen. Deoxymab: A targeted biologic that is synthetically lethal to TNBC brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 393.
Abstract 3944: MKI-1 is a small molecule inhibitor of MASTL with antitumor and radiosensitizer activity in breast cancer cells
Authors: Kim Ah-Young , Kim Jae-Sung 
Published: August 2019

Abstract
Although microtubule-associated serine threonine kinase like (MASTL) is an emerging target for selective anticancer treatment, a small-molecule inhibitor of MASTL with antitumor activity had not been reported yet. This study showed the new MASTL inhibitor, MKI 1 (MASTL Kinase Inhibitor 1), with antitumor activity and radiosensitizing effect in breast cancer in vitro and in vivo. MKI 1 was identified and validated its inhibitory activity to MASTL by in silico and in vitro analysis, respectively. MKI 1 inhibited phosphorylated ENSA, a direct substrate of MASTL, but not the other AGC kinases such as Akt signaling in breast cancer cells. In addition, MKI 1 reduced various oncogenic properties of breast cancer cells rather than normal breast cells. Furthermore, MKI 1 increased the radiosensitivity of breast cancer cells and breast cancer stem cells in response to irradiation. We also confirm the in vivo antitumor activity and radiosensitizing effects of MKI 1 in breast tumor xenograft model. Therefore, our results provide the new line of a small-molecule inhibitor of MASTL, MKI 1, with the antitumor and radiosensitizer activity in breast cancer in vitro and in vivo.
Citation Format: Ah-Young Kim, Jae-Sung Kim. MKI-1 is a small molecule inhibitor of MASTL with antitumor and radiosensitizer activity in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3944.
Abstract 3963: Deep serial analysis of the TCR/BCR CDR3 adaptome repertoire in peripheral blood of pancreatic cancer patients in a randomized study of neoadjuvant chemotherapy with or without autophagy inhibition
Authors: Wang Yue , Lotze Michael T. 
Published: August 2019

Abstract
Pancreatic cancer has a paucity of dendritic cells and almost no T lymphocytes. Here, we used Next Generation Sequencing following dimer avoidance multiplexed PCR (DAM-PCR) immune repertoire to study the characteristics and diversity of the TCR repertoire among PDAC (Pancreatic Ductal Adenocarcinoma) patients who underwent chemotherapy with or without Hydroxycholoroquine followed by surgical extirpation. We sequenced the TCR α,β,γ, and δ chains and the B-cell receptor (BCR) heavy chain (IgH) complementary-determining region 3 (CDR3) repertoire in peripheral blood mononuclear cells (PBMCs) from 10 PDAC patients before (Pre-chemo) and after chemotherapy (Post-chemo) and following operation (Postop). The distribution of CDR3, VD indel, and DJ indel lengths were similar among the Prechemo, Postchemo and Postop groups. The TCR repertoire diversity of PDAC patients was much lower compared to healthy donors (HD). The diversity index (D50) of TCR α and β’s in PDAC patients who received HCQ during chemotherapy was less than in patients without HCQ (p&lt;.05). TRBV expression increased and some public sequences diminished at individual time points following chemotherapy and postop. Full analysis of an ongoing study will be presented.
Citation Format: Yue Wang, Michael T. Lotze. Deep serial analysis of the TCR/BCR CDR3 adaptome repertoire in peripheral blood of pancreatic cancer patients in a randomized study of neoadjuvant chemotherapy with or without autophagy inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3963.
Abstract 3966: Combined Rho-kinase inhibition and immunogenic cell death triggers and propagates immunity against cancer
Authors: Kim In-San , Kim Gi Beom , Nam Gi-Hoon , Hong Yeonsun 
Published: August 2019

Abstract
Activation of T-cell immune response is critical for the therapeutic efficacy of cancer immunotherapy. Current immunotherapies have shown remarkable clinical success against several cancers; however, significant responses remain restricted to a minority of patients. Here, we show a therapeutic strategy that combines enhancing the phagocytic activity of antigen-presenting cells with immunogenic cell death to trigger efficient antitumour immunity. Rho-kinase (ROCK) blockade increases cancer cell phagocytosis and induces antitumour immunity through enhancement of T-cell priming by dendritic cells (DCs), leading to suppression of tumour growth in syngeneic tumour models. Combining ROCK blockade with immunogenic chemotherapy leads to increased DC maturation and synergistic CD8+ cytotoxic T-cell priming and infiltration into tumours. This therapeutic strategy effectively suppresses tumour growth and improves overall survival in a genetic MMTV/Neu tumour model. Collectively, these results suggest that boosting intrinsic cancer immunity using immunogenic killing and enhanced phagocytosis is a promising therapeutic strategy for cancer immunotherapy.
Citation Format: In-San Kim, Gi Beom Kim, Gi-Hoon Nam, Yeonsun Hong. Combined Rho-kinase inhibition and immunogenic cell death triggers and propagates immunity against cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3966.