bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5358: Involvement of solute carrier transporters SLC25A17 and SLC27A6 in metabolic reprograming of castration-resistant prostate cancer
Authors: Kushwaha Prem P. , Verma Shiv S. , Shankar Eswar , Lin Spencer , Gupta Sanjay 
Published: June 2022

Abstract
Enzalutamide (XTANDI®), an antiandrogen, is used for the treatment of advance-stage prostatecancer. Approximately, 60% of patients receiving enzalutamide show initial remission followedby disease relapse with the emergence of highly aggressive castration-resistant prostate cancer.Solute carrier (SLC) transporters play a critical role in cancer drug resistance by altering cellularmetabolism. We have recently reported the predominance of SLC25A17 and SLC27A6 duringenzalutamide resistance (Cells 9(12):2535, 2020) by generating enzalutamide resistant (C4-2B-Enzu) cells exposing human prostate cancer C4-2B cells in the presence of increasingconcentration of enzalutamide (1-20 µM) and maintained in the same condition for six months.However, the role of these molecules during metabolic reprogramming have not beenelucidated. Knockdown of SLC25A17 and SLC27A6 gene by sgRNA transfection suppressedcell proliferation, and migration in C4-2B-Enzu cells. Analysis of cell cycle showed that in theabsence of SLC25A17 and SLC27A6 there is induction of G1/S cell cycle arrest and reductionin the protein expression of checkpoint factors viz. Cyclin D1, CDK6, CDK4, and CDK2.SLC25A17 and SLC27A6 knockdown resulted in downregulation of acetyl-CoA carboxylase(ACC), fatty acid synthase (FASN) and Acyl-CoA synthetase long chain family member 5(ACSL5) with simultaneous decrease in the levels of lactic acid, triglyceride and citric acid in C4-2B-Enzu cells. In addition, SLC25A17 knockdown resulted in marked increase in apoptosis asevident by increase in protein expression of RIPK3 and BAX, compared to SLC27A6 knockdownin C4-2B-Enzu cells. Taken together, our results demonstrate that solute carriers SLC25A17and SLC27A6 play an important role in the development of enzalutamide resistance throughmetabolic reprogramming and loss of these molecules results in cell death. Thus, SLC25A17and SLC27A6 may serve as a therapeutic target for enzalutamide resistant prostate cancer.
Citation Format: Prem P. Kushwaha, Shiv S. Verma, Eswar Shankar, Spencer Lin, Sanjay Gupta. Involvement of solute carrier transporters SLC25A17 and SLC27A6 in metabolic reprograming of castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5358.
Abstract 5371: Repurposing erbb2 (HER2/neu) as a neoantigen target for neu-negative tumors using a novel erbb2-encoding lentivirus
Authors: Gabriel Emmanuel M. , Necela Brian , Bahr Deborah , Kaplan Jamie , Attwood Kristopher , Knutson Keith 
Published: June 2022

Abstract
INTRODUCTION: HER2/neu is a potent biomarker for which anti-HER2/neu antibodies offer significant responses. However, many cancers, such as melanoma, have less than 5% expression of HER2/neu. The purpose of this study was to determine whether induced expression of erbb2 (mouse HER2/neu analogue) could function as a neoantigen target for anti-erbb2 antibody.
METHODS: RT-PCR was used to construct a rat erbb2-encoding vector using the live, non-replicating lentivirus pLenti6.3. erbb2-encoding pLenti6.3 was transfected in vitro into the B16 mouse melanoma cell line, which has less than 5% endogenous expression of erbb2. The generated erbb2+ B16 cell line was designated B16/neu. Anti-erbb2 antibody (7.16.4) was used to treat C57Bl/6 male and female mice bearing B16/neu (200 ug intraperitoneally three times per week for 3 weeks). To confirm activity of 7.16.4, this antibody (100 ug per T75 flask) was co-cultured with B16/neu in vitro, and cell growth/confluence was measured.
RESULTS: The novel B16/neu cell line expressed approximately 50% erbb2 in vitro on flow cytometry analysis, compared to 2% errb2 expression in naïve B16. Erbb2/neu expression was confirmed on fluorescent Western blot. Anti-erbb2 antibody (7.16.4) slowed the growth of B16/neu in vitro, confirming the suppressive effects of 7.16.4. In B16/neu-bearing mice, 7.16.4 resulted in effective control of tumor growth and a complete tumor response rate of 35.7%, (5/14 mice) compared to placebo controls (p &lt; 0.01). Interestingly, B16/neu tumors demonstrated slower growth kinetics compared to naïve B16 tumors (p = 0.013), suggesting immune recognition of erbb2 in naïve C57Bl/6 mice as a neoantigen target. No adverse reactions were observed with 7.16.4. In vivo inoculation of erbb2-encoding pLenti6.3 in naïve B16 tumors and treatment of in vivo transfected B16/neu tumors with 7.16.4 comprise ongoing experiments.
CONCLUSIONS: erbb2 expression on B16 melanoma was successfully achieved using a novel erbb2-encoding lentivirus. Induced erbb2 served as a neoantigen target for anti-erbb2 antibody. This preclinical study provides translational evidence that induced HER2/neu expression may be utilized to repurpose anti-HER2 antibodies for human malignancies that do not normally express high levels of HER2/neu.
Citation Format: Emmanuel M. Gabriel, Brian Necela, Deborah Bahr, Jamie Kaplan, Kristopher Attwood, Keith Knutson. Repurposing erbb2 (HER2/neu) as a neoantigen target for neu-negative tumors using a novel erbb2-encoding lentivirus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5371.
Abstract 5384: Cell growth of sunitinib-resistant renal cell carcinoma was inhibited by Shikonin through necroptosis induction and Akt/mTOR signaling inhibition
Authors: Juengel Eva , Markowitsch Sascha D. , Vakhrusheva Olesya , Akele Yasminn , Kitanovic Jovanna , Schupp Patricia , Slade Kimberly S. , Thomas Anita , Tsaur Igor , Mager Rene , Efferth Thomas , Haferkamp Axel 
Published: June 2022

Abstract
Despite the establishment of new therapy options during the last decades, advanced renal cell carcinoma (RCC) remains an uncurable disease, due to evolving drug-resistance. New, more efficient treatment strategies are still in urgent demand. Shikonin (SHI) from Traditional Chinese Medicine has exhibited anti-tumor properties in several tumor entities. Thus, in the current investigation we evaluated the impact of SHI on progressive growth and metastatic behavior, not only in therapy-sensitive (parental) but also in therapy-resistant RCC cells. Parental and sunitinib-resistant RCC cells, Caki-1, 786-O, KTCTL-26, and A498, were treated with SHI. Tumor cell growth, proliferation, clonogenic capacity, cell cycle phase distribution, induction of cell death (apoptosis and necroptosis) and the expression and activity of regulating and signaling proteins were evaluated. Moreover, the adhesion and chemotactic activity of the RCC cells after exposure to SHI were investigated. SHI did not affect cell motility but led to significant inhibition of progressive tumor cell growth in both therapy-sensitive and therapy-resistant RCC cells. Thereby, SHI significantly inhibited the growth, proliferation and clone formation in parental and sunitinib-resistant RCC cells by G2/M phase arrest through down-regulation of cell cycle activating proteins, blocking cell division. Furthermore, SHI induced apoptosis and necroptosis by activating necrosome complex proteins. Concomitantly, SHI impaired the Akt/mTOR pathway, pivotal for cell survival and growth. Thus, SHI may hold promise as an additive option in treating patients with advanced and therapy-resistant RCC.
Citation Format: Eva Juengel, Sascha D. Markowitsch, Olesya Vakhrusheva, Yasminn Akele, Jovanna Kitanovic, Patricia Schupp, Kimberly S. Slade, Anita Thomas, Igor Tsaur, Rene Mager, Thomas Efferth, Axel Haferkamp. Cell growth of sunitinib-resistant renal cell carcinoma was inhibited by Shikonin through necroptosis induction and Akt/mTOR signaling inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5384.
Abstract 5385: Multiple modes of action of the CD38 x ICAM-1 bispecific antibody
Authors: Chen Xiaocheng , Wong Oi Kwan , Post Leonard 
Published: June 2022

Abstract
The cluster of differentiation 38 (CD38) is a well validated target for treating multiple myeloma. Although the anti-CD38 monoclonal antibody treatment has resulted in outstanding responses in patients with multiple myeloma, a significant portion of patients still failed to respond and nearly all patients eventually relapsed. The mechanism of resistance has been partially associated with downregulation of CD38 expression. In addition, CD38 is broadly expressed on normal lymphoid, myeloid, as well as red blood cells (RBCs). To effectively target CD38 on tumor cells, we hypothesize that a bispecific antibody against a tumor associated guide antigen (TAG) and CD38 could achieve tumor specificity and improve potency. ICAM-1, an Ig-like cell adhesion molecule, is highly expressed in multiple myeloma, lymphoma and a subset of solid tumors. Antibody against ICAM-1, bersanlimab (BI505, BioInvent), was well-tolerated, but only showed limited clinical efficacy in MM patients. We generated bispecific CD38 x ICAM-1 antibodies with different formats and geometries and compared their in-vitro activities on ICAM1high tumor cells with low to medium CD38 expression. Our results showed that the asymmetric 1+1 format has potent ADCC and ADCP activities on ICAM-1+CD38medium or ICAM-1+CD38low cells. Fc modifications further improved ADCC activities of the bispecific antibody. To further understand the impact of antigen densities, we tested ADCC activities on a selected set of myeloma and lymphoma cell lines with a range of CD38 and ICAM-1 expressions. We observed superior ADCC activity on cells with extremely low CD38 expression. Moreover, we showed that the bispecific antibody reduced NK fratricide and RBC binding comparing to the bivalent CD38 antibody. Most importantly, the CD38 x ICAM1 bispecific antibody demonstrated potent tumor inhibition activities in in-vivo myeloma and lymphoma models. These studies suggested that CD38 x ICAM-1 bispecific antibody has multiple modes of action for treating lymphoma and multiple myeloma.
Citation Format: Xiaocheng Chen, Oi Kwan Wong, Leonard Post. Multiple modes of action of the CD38 x ICAM-1 bispecific antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5385.
Abstract 5389: Exploring potential predictive biomarkers for the responsiveness to CTX-712 by in vivo drug sensitivity analysis on PDX models
Authors: Morishita Daisuke , Yagishita Shigehiro , Mizutani Akio , Yamakawa Hiroko , Ebara Shunsuke , Hamada Akinobu 
Published: June 2022

Abstract
Cancer’s remarkable diversity had been understood through a logical framework of six key hallmarks. Additionally, several equally prevalent hallmarks have been identified in recent analyses of cellular phenotypes as the stress phenotypes of cancers. A novel hallmark of cancer RNA deregulation has been newly proposed as another hallmark of cancer within this group of stress phenotypes. However, the development of cancer therapies targeting RNA deregulation has only just begun. Indeed, small molecules that attack the RNA maturation processes and produce aberrant RNA are currently under development. We developed orally available, selective, and a first-in-class pan- CDC-like kinase (CLK) inhibitor, CTX-712, currently in phase 1 clinical trials for advanced, relapsed or refractory malignant cancers. CTX-712 dephosphorylates serine and arginine-rich proteins and induces primarily skipped exon type of splicing changes, resulting in the generation of RNA deregulation stress. In multiple preclinical models, excessive RNA deregulation stress caused cancer cell death and tumor growth inhibition. To explore the patient selection biomarkers for CTX-712, in vivo efficacy survey analysis has been conducted on breast, ovarian, colorectal, pancreatic, gastric and lung cancer models from patient derived xenograft (PDX) library with a detailed clinical information. Besides the efficacy investigation, the preclinical pharmacokinetics (PK) and pharmacodynamics (PD) analysis on tested PDX models were also performed to confirm plasma/tumor PK and PD (target CLK inhibition in xenografted tumors). Importantly, tested PDX models could be divided to sensitive (T/C on the most sensitive model = -71.1) and insensitive (T/C on the least sensitive model = 67.7), and the correlated tendency was observed between the efficacy and the inhibition magnitude of intratumor PD marker, production of exon skipped aberrant mRNA. To clarify the differences of sensitivity among tested PDXs will lead us to identity patient selection biomarkers of CTX-712. Therefore, whole transcriptome RNA sequencing, exome sequencing, and other approaches have been applied to reveal the differences of sensitivity among tested PDXs. Through this study on multiple PDXs, integration of drug responsiveness, and genomic/transcriptomic profiling may provide prediction markers for treatment responsiveness of CTX-712.
Citation Format: Daisuke Morishita, Shigehiro Yagishita, Akio Mizutani, Hiroko Yamakawa, Shunsuke Ebara, Akinobu Hamada. Exploring potential predictive biomarkers for the responsiveness to CTX-712 by in vivo drug sensitivity analysis on PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5389.
Abstract 5395: DNA damage repair gene mutations predict the efficacy of platinum-based chemotherapy in colorectal cancer
Authors: Lin Yan , Zhang Jinyan , Liao Xiaoli , Zhang Yumei , Luo Min , Li Qian , Xie Mingzhi , Liang Chaoyong , Liao Sina , Zheng Yating , Hu Xue , Huang Mengli , Liang Rong , Li Yongqiang 
Published: June 2022

Abstract
Background: DNA damage repair (DDR) mutations are known to predict response to platinum-based chemotherapy in multiple solid tumors. However, their predictive value remained unknown in patients with colorectal cancer.
Methods: The genomic and survival datas from the TCGA-COAD and TCGA-READ cohorts of patients receiving platinum-based chemotherapy were used to analyze the predictive value of DDR mutations on platinum-based chemotherapy.
Result: The DDR genes were commonly mutated (85.82%) in the TCGA-COAD and TCGA-READ cohorts. The objective response rates (ORRs) were 80% for the patients with DDR mutations (DDRmut) subgroup and 56% for the DDR wild-type (DDRwt) subgroup (P&lt;0.05), and the disease control rates (DCRs) were 86% for the DDRmut subgroup and 56% for the DDRwt subgroup (P&lt;0.05). In patients with stage I, II and III colorectal cancer, there was no significant difference in the overall survival (OS) between DDRmut subgroup and DDRwt subgroup (Hazard Ratio=0.48, 95%CI 0.1−2.31, log-rank P=0.35). In patients with stage IV colorectal cancer, the OS was significantly better among the DDRmut patients than in the DDRwt subgroup (Hazard Ratio=0.21, 95%CI 0.06−0.8, P= 0.011).
Conclusions: DDR mutations may serve as a positive predictor of platinum-based chemotherapy therapy in patients with CRC and their clinical value warrants further investigation.
Citation Format: Yan Lin, Jinyan Zhang, Xiaoli Liao, Yumei Zhang, Min Luo, Qian Li, Mingzhi Xie, Chaoyong Liang, Sina Liao, Yating Zheng, Xue Hu, Mengli Huang, Rong Liang, Yongqiang Li. DNA damage repair gene mutations predict the efficacy of platinum-based chemotherapy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5395.
Abstract 5400: Detection of satellite tumor cells in peritumoral edema in myxofibrosarcoma and undifferentiated pleomorphic sarcoma using targeted gene sequencing
Authors: Principe Miguel Alfonso V. , Gokgoz Nalan , Prochazka Patrick , Ferguson Peter C. , Dewji Simin , Wunder Jay S. , Andrulis Irene A. , Dickson Brendan C. , Tsoi Kim M. 
Published: June 2022

Abstract
Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcomas (UPS) are soft tissue sarcomas with high local recurrence rates following resection. Common with these cancers is peritumoral edema, termed tumor tails, which our group has found could contain satellite tumor cells. A precise and accurate method of determining the presence of satellite tumor cells in this region is required to improve surgical planning, as the standard morphology-based technique is prone to misclassification. An emerging technology is targeted gene sequencing (t-NGS), a combination of whole genome or exome sequencing (WGS/WXS) comparing primary tumor and patient-matched blood, and digital droplet PCR (ddPCR). The objective of this study was to determine the viability of t-NGS in the detection of satellite tumor cells in the areas of edema surrounding MFS and UPS. A cohort of patients diagnosed with extremity MFS and UPS at Mount Sinai Hospital (Toronto, Canada) who underwent resection were retrospectively studied. Cases with available WGS/WXS data were used (n=8) to identify case-specific tumor-specific variants (TSV) to detect with the QX200 ddPCR platform. (n=4-5/case). Cases with a major TSV-positive droplet population in the tumor tails tissue indicated the presence of satellite tumor cells. Our quality analysis showed DNA above the ddPCR threshold of detection was extracted from the tumor tails of 6 of 8 cases. The ddPCR assay showed that a TSV-positive droplet population was detected within the tumor tails in 5 of 6 cases, while 1 of 6 cases showed no such population in the tumor tails. Overall, our results indicates that t-NGS has potential for TSV detection within tumor tails. A prospective study is underway to further test its validity and compare it with standard histology. The project aims to improve surgical planning by ensuring removal of satellite tumor cells while lowering the risk of wound complications.
Targeted gene-sequencing results of all cases within this study Case # Histology Pre-op Radiation DNA Extraction Successful TSV Probes (n) TSV+ Tumor TSV+ Tails TSV+ Normal 1 MFS N Y 5 4 4 0 2 MFS N Y 3 2 2 0 3 MFS Y Y* (normal insufficient) 3 3 0 N/A 4 UPS Y Y 3 2 0 1 5 MFS N Y 4 4 1 0 6 UPS N Y 3 3 3 1 7 MFS Y N N/A N/A N/A N/A 8 MFS Y N N/A N/A N/A N/A
Citation Format: Miguel Alfonso V. Principe, Nalan Gokgoz, Patrick Prochazka, Peter C. Ferguson, Simin Dewji, Jay S. Wunder, Irene A. Andrulis, Brendan C. Dickson, Kim M. Tsoi. Detection of satellite tumor cells in peritumoral edema in myxofibrosarcoma and undifferentiated pleomorphic sarcoma using targeted gene sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5400.
Abstract 5401: Fluoxetine inhibit osteosarcoma progression via RANK/RANKL signaling pathway
Authors: Tan Peggy , Hsu Fei-Ting , Chiang I-Tsang , Chang Yuan 
Published: June 2022

Abstract
Osteosarcoma (OS) is an aggressive malignant bone cancer commonly occurs on adolescent. OS was mostly found at sites of bone growth. Sixty percent OS cases happen at knee, 15% around hip, 10% shoulder and 8% jaw. Non-stop osteoclast cells differentiation by which osteoblasts secrete RANKL bind to RANK receptor on osteoclasts’ cell surface, stimulate rapid bone metabolism and considerable as an important signaling pathway correlate with OS progression.
Depressant is usually occurring in cancer patients. Several reports suggested that several anti-depressant drugs presented anti-tumour potential. Previous study has reported, fluoxetine, a prescription antidepressant can inactivate NF-κB and thus suppress hepatocellular carcinoma and non-small cell lung cancer progression. Furthermore, fluoxetine may inhibit DNA repair in non-small cell lung cancer.
In our study, the MTT assay demonstrated fluoxetine significantly reduced viability of U-2 OS cells. Next, target protein RANK/RANKL expression were also downregulated by fluoxetine in dose dependent manner. Besides, STAT3 mediated NF-κB activity, were also inactivated by fluoxetine. Additionally, the expression of PARP1 (DNA damage related, and several oncogenes such as XIAP and Cyclin D1 were also downregulated by fluoxetine in dose dependent manner. Moreover, the inhibition of tumour angiogenesis by fluoxetine has also proven by using aorta ring assay. Further in vivo experiment may need to be performed to identify anti-tumor efficacy of fluoxetine.
In sum, fluoxetine can be used anti-tumour adjuvant of OS therapy and the detailed mechanism or further combination strategy may be worth exploring.
Citation Format: Peggy Tan, Fei-Ting Hsu, I-Tsang Chiang, Yuan Chang. Fluoxetine inhibit osteosarcoma progression via RANK/RANKL signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5401.
Abstract 5406: Novel quatramer nano-formulation of dual-targeted PI3-Kδ/HDAC6 inhibitor, HSB-510, suppresses growth of triple negative breast cancer
Authors: Tiwari Sachchidanand , Liu Suiyang , Anees Mohammad , Mehrotra Neha , Thakur Ashish , Tawa Gregory , Grewal Gurmit , Stone Richard M. , Kharbanda Surender M. , Singh Harpal 
Published: June 2022

Abstract
Triple negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and a worse clinical outcome as compared with other breast cancer subtypes. Multiple studies have shown that progression of TNBC depends on more than one signalling pathways, suggesting that the therapies with multi-targeted anti-cancer agents will offer improved therapeutic benefit through synergistic effects in inhibiting cancer growth. Dual-targeted inhibitors of phosphoinositide 3-kinase (PI3-K) and histone deacetylase (HDAC) have emerged as promising cancer therapy candidates. However, poor aqueous solubility and bioavailability limited their efficacy in cancer and accordingly, improved delivery systems are needed. The present studies have investigated the encapsulation of PI3-Kδ/HDAC6 dual inhibitor into hybrid block co-polymers (polylactic acid-methoxy polyethylene glycol; polylactic acid-polyethylene glycol-polypropylene glycol-polyethylene glycol-polylactic acid) (HSB-510) as a delivery system to target PI3-Kδ and HDAC6 pathways in TNBC cells. The prepared HSB-510 Quatramer nano-formulation showed an average diameter of 96 ±3 nm, the zeta potential of -17±2 mV, and PDI of ˂0.1 with a slow and sustained release profile of PI3-Kδ/HDAC6 inhibitors in a non-physiological buffer. In vitro studies with HSB-510 have demonstrated substantial growth inhibition of TNBC cell lines, MDA-MB-468, SUM-149 and Ehrlich ascites carcinoma (EAC) as well as downregulation of phospho-AKT, phospho-ERK and c-MYC levels. Importantly, bi-weekly treatment of BALB/c wild-type mice harbouring EAC cells (syngeneic mouse model) with HSB-510 at a dose of 25 mg/kg resulted in significant (76%) tumor growth inhibition (TGI). The treatment with HSB-510 was without any significant effect on the body weights of the mice. These results demonstrate that a novel Quatramer nano-formulation of a novel PI3-Kδ/HDAC6 dual inhibitor (HSB-510) represents an approach for successful targeting of TNBC and potentially other cancer types.
Citation Format: Sachchidanand Tiwari, Suiyang Liu, Mohammad Anees, Neha Mehrotra, Ashish Thakur, Gregory Tawa, Gurmit Grewal, Richard M. Stone, Surender M. Kharbanda, Harpal Singh. Novel quatramer nano-formulation of dual-targeted PI3-Kδ/HDAC6 inhibitor, HSB-510, suppresses growth of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5406.