bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5981: CAP70 suppresses the development of triple-negative breast cancer by inhibiting EGFR pathway activation
Authors: Zheng Junfang , Ma Yuanzhen , Qi Yijun 
Published: September 2020

Abstract
Background: Among all major subtypes of breast cancer, triple-negative breast cancer (TNBC) carries the worst prognosis for the patients. The poor clinical outcome of TNBC is further exacerbated by the lack of effective targeted therapies. Therefore, the identification of functional molecular targets for TNBC therapy is urgently needed. The goal of this study was to determine the role of CFTR-associated protein of 70 kDa (CAP70, also called PDZK1) in the development of TNBC and assess its value as a target for TNBC therapy.
Methods: Bioinformatics analysis and immunohistochemistry were performed to determine the expression of CAP70 in TNBC. The functions of CAP70 were demonstrated in a series of in vitro and in vivo experiments. GST Pull-down, mass spectrometry, co-immunoprecipitation, bioinformatics analysis, pharmacologic treatment, and western blotting were performed to elucidate the potential mechanisms of CAP70 activities.
Results: CAP70 was specifically downregulated in TNBC tissues and was related to tumor stage, lymph node metastasis, and patient survival. Functional assays showed that CAP70 suppressed TNBC carcinogenesis, progression, and metastasis by inhibiting EGFR signaling. Moreover, inhibition of EGFR signaling by CAP70 enhanced the sensitivity of TNBC to EGFR inhibitor erlotinib.
Conclusions: CAP70 suppresses TNBC development and enhances its sensitivity to erlotinib by inhibiting EGFR signaling. CAP70 is a significant prognostic factor of TNBC and a potential molecular therapeutic target for the treatment of this subtype of breast cancer.
Citation Format: Junfang Zheng, Yuanzhen Ma, Yijun Qi. CAP70 suppresses the development of triple-negative breast cancer by inhibiting EGFR pathway activation [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 5981.
Abstract 5990: The potential role of artificial lactate influx in remodeling cancer-specific metabolism of colorectal cancer
Authors: Jeong Keun-Yeong 
Published: September 2020

Abstract
Cancer cells have a specific metabolic pathway that produces a large quantity of lactate from glucose by abnormal aerobic glycolysis, it can provide a secondary path that meets the metabolic needs for persistent survival. Accordingly, regulating cancer-specific metabolism has important implications for the discovery of novel therapeutics. In this study, the possibility of an impact on colorectal cancer was investigated that focused on the remodeling of cancer-specific aerobic glycolysis by the artificial influx of lactate. Intracellular lactate levels were assessed in the colorectal cancer cells following lactate calcium salt treatment. Expression of lactate dehydrogenase and pyruvate dehydrogenase were confirmed to investigate the effect of the increased lactate influx. The nicotinamide adenine dinucleotide ratio and concentration of α-ketoglutarate were measured to confirm the tricarboxylic acid coupling. The tube formation and wound healing assay were performed as well as the expression of hypoxia-inducible factor-1α and vascular endothelial growth factor receptor to confirm the loss of malignancy. Xenograft animal models were established to evaluate the antitumor efficacy by monitoring changes in the tumor volume. We demonstrated that an artificial influx of lactate was increased in colon cancer cells under a hypoxic condition thereby reversible activation of lactate dehydrogenase reacting to lactate. Then, the conversion to pyruvate was promoted, and as a result of increased stimulation of pyruvate dehydrogenase, the tricarboxylic acid was coupled, showing an oxidative metabolism similar to normal cells. The malignancy of cancer cells was
lost by undergoing remodeling of such cancer-specific, and a significant decrease in tumor growth was confirmed as a result of the anticancer effect of artificial lactate influx. These findings suggest the unique mechanisms in which the artificial influx of lactate would have anticancer effects by regulating cancer-specific aerobic glycolysis.
Citation Format: Keun-Yeong Jeong. The potential role of artificial lactate influx in remodeling cancer-specific metabolism of colorectal 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 5990.
Abstract 6001: 6-Phosphofructo-2-kinase inhibition to increase the efficacy of ER and CDK4/6 inhibitors against ER+ breast cancer
Authors: Lanceta Lilibeth , Lypova Nadiia , Chesney Jasson , Imbert-Fernandez Yoannis 
Published: September 2020

Abstract
Deregulation of the estrogen receptor (ER)-cyclin D1-CDK4/6 pathway is a hallmark of ER+ breast cancer that has prompted the development of CDK4/6 inhibitors. Although administration of CDK4/6 inhibitors to patients with ER+ advanced breast cancers have resulted in an improvement in progression free survival, almost all patients invariable develop resistance and relapse over time. Activation of glucose metabolism upon CDK4/6 inhibition is becoming increasingly evident. A key stimulator of glycolysis is the PFKFB3 enzyme which synthesizes fructose 2,6-bisphosphate (F2,6BP), a potent allosteric activator of the rate-limiting 6-phosphofructo-1-kinase (PFK1). F2,6BP controls flux throughout the entire glycolytic pathway and, as a result is required for the proliferation of cancer cells. In preliminary studies, we provide evidence that PFKFB3 expression and activity is increased in response to CDK4 inhibition in ER+ breast cancer cells and that a PFKFB3 inhibitor, PFK-158, increases the anti-tumor activity of anti-CDK4 targeted therapy in vitro. Importantly, we found that ER+ cancer cells with acquired resistance to palbociclib have increased levels of PFKFB3 and are highly susceptible to the effects of PFK-158. Our studies provide a clear rationale to propose the use of PFKFB3 inhibitors in combination with CDK4/6 inhibitors as an effective strategy to increase the efficiency and/or overcome resistance to CDK4/6 inhibition.
Citation Format: Lilibeth Lanceta, Nadiia Lypova, Jasson Chesney, Yoannis Imbert-Fernandez. 6-Phosphofructo-2-kinase inhibition to increase the efficacy of ER and CDK4/6 inhibitors against ER+ breast 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 6001.
Abstract 6036: The clinicopathological significance of nerves and NGF receptors in esophageal cancer
Authors: Griffin Nathan , Gao Fangfang , Jobling Phillip , Wills Vanessa , Walker Marjorie M. , Faulkner Sam , Hondermarck Hubert 
Published: September 2020

Abstract
Recent developments in oncology have revealed that nerve outgrowth in the tumor microenvironment is essential to the progression of many human cancers. In esophageal cancer, the presence and role of nerves and is unclear. In this study, nerves were identified within the tumor microenvironment of esophageal cancer and were associated with the squamous subtype of the disease (p=0.044). Additionally, the surrounding or invasion of nerves by cancer cells (perineural invasion) was detected in 12% of esophageal cancers and was associated with poor patient survival (p=0.038). Nerves were found to express the TrkA and p75NTR receptors for nerve growth factor (NGF) and an association was observed between high production of NGF by cancer cells and the presence of nerves (p=0.022). In vitro, esophageal cancer cells were able to induce neurite outgrowth in PC12 neuronal cells and this neurotrophic activity was inhibited by anti-NGF blocking antibodies. In squamous cell carcinoma tissues, TrkA expression was found to be strongly increased in compared to both adenocarcinoma and normal oesophageal tissue (p&lt;0.0001). The selective pharmacological inhibitor of NTRK1, GNF-5837, induced a decreased esophageal cancer cell proliferation, invasion and migration. Together, these data demonstrate that innervation is a significant feature in esophageal cancers that may be driven by cancer cell-released NGF. Therefore, this study reveals that interventions against the NGF-TrkA signaling pathway may have the potential to target cancer cells and inhibit cancer neurogenesis.
Citation Format: Nathan Griffin, Fangfang Gao, Phillip Jobling, Vanessa Wills, Marjorie M. Walker, Sam Faulkner, Hubert Hondermarck. The clinicopathological significance of nerves and NGF receptors in esophageal 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 6036.
Abstract 6072: MUC16-Cter cleavage increases the metastatic potential in pancreatic cancer
Authors: Marimuthu Saravanakumar , Lakshmanan Imayavaramban , Muniyan Sakthivel , Atri Pranita , Jain Maneesh , Ponnusamy Moorthy P. , Batra Surinder K. 
Published: September 2020

Abstract
Pancreatic cancer (PC) is one of the most lethal malignant tumors. Several membrane-bound mucins are overexpressed in PC, including MUC16. The role and molecular mechanism of MUC16 mucin, particularly carboxyl-terminal domain (MUC16-Cter) in metastasis of pancreatic cancer, are poorly understood. Therefore, we hypothesize that the “MUC16-Cter domain plays a vital role in facilitating metastasis in pancreatic cancer”. Here, we knockout MUC16 in Capan 1 PC cells and overexpressed MUC16-Cter (F114AA) domain in MiaPaCa2 PC cells to study its functional impact in PC. Capan-1 MUC16 knockout cells displayed a significant decrease in colony-forming by in vitro tumorigenicity assay, endothelial binding, and P-selectin binding ability compared to control cells. Whereas, MUC16-Cter domain overexpressed MiaPaCa2 cells showed a significant increase in colony formation as compared to vector control cells. These results suggest that MUC16 plays a role in promoting in vitro tumorigenicity and facilitating intravasation and circulation of PC cell by interacting with endothelial cells during the metastatic spread of PC cells. Interestingly, we observed that chemotherapeutic drug (gemcitabine) induces MUC16-Cter cleavage in PC cells. We generated a genetically engineered mouse model Muc16-/- with KrasG12D, Trp53R172H/+, Pdx1-Cre (KPCM) background to study the role of Muc16 in PC tumorigenesis and metastasis with existing KPC model. KPCM showed decreased the early onset of cancer formation compared to KPC. Further, the Kaplan Meier test showed an increased survival rate in Muc16 -/- with KPC background as compared to KPC mice. EMT markers showed decreased expression in KPCM compared to KPC tumors. KPCM cells showed a significant decreased in migratory potential, endothelial, and P-selectin binding ability KPC PC cells. In conclusion, our in vitro and in vivo findings confirm that MUC16 and its Cter domain might play an essential role during the PC tumorigenesis and metastasis. Therefore, targeting MUC16-Cter might be an ideal therapeutic strategy for inhibiting tumorigenesis and metastasis of PC.
Citation Format: Saravanakumar Marimuthu, Imayavaramban Lakshmanan, Sakthivel Muniyan, Pranita Atri, Maneesh Jain, Moorthy P. Ponnusamy, Surinder K. Batra. MUC16-Cter cleavage increases the metastatic potential in pancreatic 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 6072.
Abstract 6107: Stromal and immune changes in the aged lung microenvironment create a permissive niche for the metastatic outgrowth of melanoma
Authors: Fane Mitchell , Douglass Stephen , Alicea Gretchen , Webster Marie , Aguirre-Ghiso Julio , Weeraratna Ashani 
Published: September 2020

Abstract
Our previous data has indicated that while tumors grow more slowly in aged mouse skin, they form more lung metastases. We queried whether the lung microenvironment undergoes age-related changes that provide a permissive niche for metastatic outgrowth. Our previous data has implicated dermal fibroblasts as the drivers of age-related changes in the skin, and so we analyzed young vs aged healthy human lung fibroblasts. The secreted changes in aged lung fibroblasts suggest that the lung microenvironment evolves during aging to promote proliferation of melanoma cells. Specifically, these changes involve the secretion of factors such as sFRP1, that we find suppresses Wnt5A and AXL signaling, which typically drives a metastatic but slow-growing/dormant cancer phenotype. Interestingly, this switch promotes activation of the MER tyrosine kinase pathway, increasing proliferation. This switch is reinforced by the MER ligand PROS1, which is upregulated in the aged lung microenvironment. Consistent with this, our in vivo studies indicate that tumor cells disseminate to the lungs at the same rate in young and aged mice. However, they persist as single cell populations in the young mouse lungs, whereas they grow out rapidly in the aged mouse lung. We next queried whether the immune microenvironment also played a role in the differential outgrowth of lung metastases in young and aged mice. We find that aged lung fibroblasts secrete higher levels of immunosuppressive factors ARG-1 and CXCL1, which are both necessary for efficient metastatic outgrowth in vivo. Analysis of the aged lung microenvironment reveals that immunosuppressive MDSCs and Treg populations are significantly increased compared with the young lung, while effector CD4 and CD8 T cells are decreased. Importantly, depletion of MDSCs or Tregs in the aged lung both significantly decrease metastasis. Overall, we find that aged-induced changes in fibroblast secretory phenotypes and immune subpopulations promote efficient metastatic melanoma progression in the lung.
Citation Format: Mitchell Fane, Stephen Douglass, Gretchen Alicea, Marie Webster, Julio Aguirre-Ghiso, Ashani Weeraratna. Stromal and immune changes in the aged lung microenvironment create a permissive niche for the metastatic outgrowth 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 6107.
Abstract 6133: Rats support cancer studies
Authors: Adedeji Bisoye Towobola , Fallon Noto K. , Moody Sam , Steffey Valeriya , Brenzel Chris , Crawford Jack , Jamling Tseten Yeshi , Narla Goutham 
Published: September 2020

Abstract
The use of the most predictive model is essential in transferring scientific knowledge from bench to bedside. In In vivo cancer research, immunodeficient mice models are being used, but have been found with limitations. They fall short in tumor take rates, growth kinetics, and their ability to support the growth of some human Cancer cell lines.
To address these limitations, we produced an immunodeficient rat, a Sprague-Dawley Rag2/Il2rg double knockout (SRG OncoRat) rat that lacks mature B cells, T cells, and circulating NK cells. Using a variety of human cell lines (VCaP, LNCaP, 22RV1) which have poor or highly variable growth kinetics in commercially available immunodeficient mouse models, we demonstrated that the SRG rat has superior tumor take rates and growth kinetics, providing a more efficient model for drug efficacy studies. Enhanced take rates enable the use of fewer animals for studies, allows for faster timelines to drug efficacy data, and overall, may provide a better platform for reproducible drug efficacy results. In addition, the SRG rat developed larger tumor volumes, allowing for serial fine needle aspirate biopsy for PK, PD and molecular analysis in the same animal throughout the course of the study without significantly affecting normal tumor growth. The SRG OncoRat is a valuable addition to current available rodent xenograft models for evaluating novel therapies.
Citation Format: Bisoye Towobola Adedeji, Noto K. Fallon, Sam Moody, Valeriya Steffey, Chris Brenzel, Jack Crawford, Tseten Yeshi Jamling, Goutham Narla. Rats support cancer studies [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 6133.
Abstract 6159: Blocking neuropeptide Y Y5 receptor prevents hypoxia-induced Ewing sarcoma metastasis
Authors: Adnani Mina T. , Galli Susana , Hong Sung Hyeok , Tilan Jason U. , Kitlinska Joanna 
Published: September 2020

Abstract
Ewing sarcoma (ES) is the second most prevalent malignant bone tumor after osteosarcoma in children and adolescents. While survival of patients with localized ES has improved, patients with metastatic ES still lack adequate therapies, which results in poor survival rates. Thus, there is an important need for new therapies targeting ES metastases and preventing its dissemnation. Previously, we have shown that ES cells constitutively express high levels of NPY and its receptors - Y1R and Y5R. However, tumor hypoxia changes expression pattern and functions of NPY system, leading to the activation of its Y2R and Y5R, which stimulate ES cell motility and invasiveness under these conditions. Hence, the goal of this study was to determine the role of NPY in hypoxia-induced ES metastases. Here, we focused on Y5R, since our data from other malignancies implicated this receptor as the major mediator of NPY's pro-metastatic effects. To this end, we used doxycycline (DOX)-inducible CRIPSR/Cas9 system to create an SK-ES1/Y5R knockout (KO) cell line. The Y5R KO significantly decreased motility of SK-ES1 cells. To determine the impact of this phenomenon on ES metastases, SK-ES1/Cas9/Y5RsgRNA cells were injected into gastrocnemius muscles of SCID/bg mice and the animals were fed with DOX+ or control diet. The Y5R KO did not affect primary tumor growth. Once the xenografts reached a volume of 0.25cm3, a femoral artery ligation (FAL) was performed in the tumor-bearing limbs to induce hypoxic conditions. Both primary tumors and their corresponding metastases were sequenced to confirm the efficiency of gene editing. Notably, majority of metastases arising in mice bearing SKES-1/Y5RsgRNA+DOX xenografts were initiated by the clones without Y5R gene modification, confirming the role of Y5R in ES dissemination. The frequency of metastases with efficient Y5R KO originating from hypoxic tumors was markedly decreased, as compared to the control group (-DOX). Moreover, Y5R KO prevented hypoxia-induced increase in osseous metastases previously reported by our group. Collectively, these data validate NPY/Y5R axis as a crucial mediator of the hypoxia-induced ES metastasis and implicate Y5R receptor as a novel target for therapies preventing ES dissemination. Importantly, the Y5R antagonist is already available and used in clinical trials.
Citation Format: Mina T. Adnani, Susana Galli, Sung Hyeok Hong, Jason U. Tilan, Joanna Kitlinska. Blocking neuropeptide Y Y5 receptor prevents hypoxia-induced Ewing sarcoma metastasis [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 6159.
Abstract 6161: PARP inhibition enhances radiotherapy of SMAD4 deficient human head and neck squamous cell carcinomas in experimental models
Authors: Young Christian D. , Hernandez Ariel L. , Bian Li , Karam Sana D. , Raben David , Wang Xiao-Jing 
Published: September 2020

Abstract
Purpose: SMAD4 loss causes genomic instability and the initiation/progression of head and neck squamous cell carcinoma (HNSCC). Here, we study if SMAD4 loss sensitizes HNSCCs to olaparib (PARP inhibitor) in combination with radiotherapy (RT).
Experimental Design: We analyzed HNSCC TCGA data for SMAD4 expression in association with FANC/BRCA family gene expression. Human HNSCC cell lines were screened for sensitivity to olaparib. Isogenic HNSCC cell lines were generated to restore or reduce SMAD4 expression and treated with olaparib, radiation, or the combination. HNSCC pretreatment specimens from a Phase I trial investigating olaparib were analyzed.
Results: SMAD4 levels correlated with levels of FANC/BRCA genes in HNSCC. HNSCC cell lines with SMAD4 homozygous deletion were sensitive to olaparib. In vivo, olaparib or RT monotherapy reduced tumor volumes in SMAD4 mutant but not SMAD4 positive tumors. Olaparib with RT dual therapy sustained tumor volume reduction in SMAD4 deficient (mutant or knockdown) xenografts, which exhibited increased DNA damage and cell death compared to vehicle treated tumors. In vitro, olaparib or in combination with radiation caused lower clonogenic survival, more DNA damage-associated cell death and less proliferation in SMAD4 deficient cells than in SMAD4-positive (endogenous SMAD4 or transduced SMAD4) cells. Applicable to clinic, 5 out of 6 SMAD4-negative HNSCCs and 4 out of 8 SMAD4-positive HNSCCs responded to a standard treatment plus olaparib in a Phase I clinical trial, and SMAD4 protein levels inversely correlated with DNA damage.
Conclusion: SMAD4 levels are causal in determining sensitivity to PARP inhibition in combination with RT in HNSCCs.
Citation Format: Christian D. Young, Ariel L. Hernandez, Li Bian, Sana D. Karam, David Raben, Xiao-Jing Wang. PARP inhibition enhances radiotherapy of SMAD4 deficient human head and neck squamous cell carcinomas in experimental models [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 6161.