bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1655: Discovery of a novel PP2A activator as a potential therapeutic for FOLFOX resistant colon cancer
Authors: Johnson Hannah , Singh Amandeep , Raza Asif , Sha Congzhou M. , Dokholyan Nikolay V. , Narayan Satya , Sharma Arun K. 
Published: April 2023

Abstract
Protein phosphatase 2A (PP2A) is a diverse serine/threonine phosphatase that accounts for 50-70% of all serine/threonine phosphorylation in the cell. Due to the inactivation of PP2A in cancer, many of the cellular processes that PP2A regulates are aimed towards tumor progression. As such, the therapeutic targeting of PP2A in cancer is becoming a popular research avenue in the development of new chemotherapeutics. Currently, there have been a few PP2A activators observed to inhibit tumor progression in vitro and in vivo; however, these compounds have shown to have poor bioavailability, such as NSC49L, or uncertainty towards their ability to activate PP2A, as is the case with iHAP1. These hindrances demonstrate a need for further optimization of these molecules in order to produce a PP2A activator capable of inhibiting cancer without these limitations. As such, we have designed a series of compounds utilizing molecular modeling and fragment-based drug design based upon the known PP2A activators, NSC49L and iHAP1. These compounds were assessed for their ability to inhibit colon cancer (CRC) cells and FOLFOX-resistant CRC cells, where PPA24 was identified as the lead compound. The dose-response curves identified IC50 values in the range of 2.36-6.75µM for PPA24 across four CRC cell lines (HCT116, HT29, DLD1, and SW480) and two FOLFOX-resistant CRC cell lines (FOLFOX-HCT116 and FOLFOX-HT29), displaying more cytotoxicity than both the parent compounds and the other compounds in the series. Molecular docking recognized lower binding energies occurring during the association of PP2A with PPA24 than with either NSC49L or iHAP1. When examining the in vitro effect of PPA24 on stimulating PP2A activation, it was found that PPA24 significantly induced PP2A activity 2-3-fold higher than NSC49L or iHAP1. Likewise, PPA24 was able to induce apoptosis dose-dependently in both CRC and FOLFOX-resistant CRC cells. As PP2A is known for regulating the cell cycle progression, further exploration revealed PPA24 able to induce cell cycle arrest at the G2/M phase. And PP2A, being known as a regulator for many cellular processes, can be activated to assist in the degradation and inactivation of many signaling proteins such as c-myc, GSK3β, and ERK, which was observed in CRC cells treated with PPA24. Together, these results signify the potential of PPA24 to act as a novel PP2A activator in the treatment of CRC and FOLFOX-resistant CRC.
Citation Format: Hannah Johnson, Amandeep Singh, Asif Raza, Congzhou M. Sha, Nikolay V. Dokholyan, Satya Narayan, Arun K. Sharma. Discovery of a novel PP2A activator as a potential therapeutic for FOLFOX resistant colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1655.
Abstract 1679: Unraveling the function of TRAF2 and NCK interacting kinase (TNIK) in high-grade serous ovarian cancer
Authors: Puleo Noah , Cusato Michele , Carvette Dylan , Husdon Chantelle , DiFeo Analisa 
Published: April 2023

Abstract
The large majority of high grade serous ovarian cancer (HGSOC) patients will eventually become resistant to platinum-based chemotherapy, highlighting the urgent need to develop novel therapeutics targeting recurrent, platinum-resistant disease. To study this, our lab generated two patient derived platinum-resistant tumor spheres from platinum-sensitive primary patient cells to better understand the biology behind recurrent disease and identify novel therapeutic targets. Utilizing an artificial intelligence (AI) powered model, we screened a library that consisted of compounds predicted to target known or postulated resistance mechanisms and involved a novel therapeutic target. From this screen, we identified a TNIK kinase inhibitor as the only compound to effectively kill HGSOC spheres while sparing non-malignant fallopian tube cells. TNIK plays a key role in Wnt pathway activation, which our lab has previously shown to be critical in driving cancer stemness and epithelial ovarian cancer platinum resistance. Additionally, patient data shows that TNIK is amplified in ovarian cancer more than any other cancer type and is highly activated in ovarian cancer patients. We found that this compound was able to decrease overall Wnt activity in our platinum-resistant cells and could resensitize our platinum-resistant cells to cisplatin. This work demonstrates the abilities of using AI to expedite the drug discovery process as well as uncover novel therapeutic targets which may lead to future therapeutic strategies for HGSOC patients who no longer respond to standard of care platinum chemotherapy.
Citation Format: Noah Puleo, Michele Cusato, Dylan Carvette, Chantelle Husdon, Analisa DiFeo. Unraveling the function of TRAF2 and NCK interacting kinase (TNIK) in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1679.
Abstract 1688: Proton pump inhibitors as a potential combination therapy with existing chemotherapy for esophageal cancer
Authors: Morita Ryuichi , Ishikawa Takeshi , Matsumura Shinya , Sakakida Tomoki , Yoshida Juichiro , Doi Toshifumi , Hirose Ryohei , Inoue Ken , Dohi Osamu , Yoshida Naohisa , Uchiyama Kazuhiko , Takagi Tomohisa , Konishi Hideyuki , Naito Yuji , Itoh Yoshito 
Published: April 2023

Abstract
Introduction: V-ATPase is highly expressed in cancer cells and has been shown to be involved in the transformation of normal cells into cancer cells, invasion of tissues, survival of cancer cells, and the formation of drug resistance. The use of proton pump inhibitors (PPIs) as V-ATPase inhibitors has been shown to enhance the efficacy of chemotherapy in some cancers.
Material and Method: We investigated the effect of proton pump inhibitors on esophageal squamous cell carcinoma, one of the major causes of cancer mortality in Japan. First, three PPIs at various concentrations (lansoprazole, esomeprazole, and bonoprazan) and pyrimidine fluoride (5-FU), a key drug in chemotherapy for esophageal cancer, were used as basic medical agents. Human esophageal squamous cell lines, KYSE50 and KYSE70, were prepared and treated with the above drugs, and cell viability assays were performed using Cell Counting Kit 8 for 72 hours. We then performed a retrospective clinical study of 40 patients with clinical stage IV esophageal squamous cell carcinoma treated with the drugs at Kyoto Prefectural University of Medicine Hospital in Japan.
Result: In cell survival assays, PPIs showed significantly enhanced cytotoxic effects of pyrimidine fluoride on all cell lines compared with those not treated with PPIs. Clinical data showed no difference in the incidence of treatment-related adverse events between the PPI and non-PPI groups. The response rate after two courses of chemotherapy was 66.7% in the PPI group and 40.9% in the non-PPI group (p=0.102). Kaplan-Meier analysis showed improved OS in patients treated with PPIs (log rank test p=0.032), and multivariate analysis showed that PPI use was associated with a more favorable OS (p=0.009,HR 0.33,95% CI 0.12-0.76 ).
Conclusion: In the chemotherapy of esophageal squamous cell carcinoma, the use of PPIs may enhance the cytotoxic effect of the key drug, pyrimidine fluoride, while ensuring safety, and may lead to better therapeutic efficacy.
Citation Format: Ryuichi Morita, Takeshi Ishikawa, Shinya Matsumura, Tomoki Sakakida, Juichiro Yoshida, Toshifumi Doi, Ryohei Hirose, Ken Inoue, Osamu Dohi, Naohisa Yoshida, Kazuhiko Uchiyama, Tomohisa Takagi, Hideyuki Konishi, Yuji Naito, Yoshito Itoh. Proton pump inhibitors as a potential combination therapy with existing chemotherapy for esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1688.
Abstract 1747: Targeting metabolic and epigenetic programs to re-sensitize glioblastoma to chemotherapy
Authors: Rowland Emma , Walter Jordan , Jermakowicz Anna , Suter Robert , Riggins Rebecca , Ayad Nagi 
Published: April 2023

Abstract
Treatment options for glioblastoma (GBM) are limited. Prognosis remains dismal, with an 18 month on average survival rate following diagnosis due to treatment resistance and disease recurrence. The goal of this project is to investigate hallmarks of cancer progression that contribute to temozolomide (TMZ) resistance, a first tine treatment for GBM.
Two signaling pathways were investigated in TMZ-sensitive and -resistant GBM cell lines and in primary and recurrent patient-derived xenograft (PDX) tumor cells by genetically and pharmacologically inhibiting methionine adenosyltransferase 2A (MAT2A) and adenosylhomocysteinase (AHCY). Cell growth and survival were assessed by measuring protein expression of proliferation, oxidative stress and cell cycle arrest markers. EPIC array analysis and targeted bisulfite sequencing were conducted to identify changes in genome-wide and specific CpG island methylation. The Seahorse XF Analyzer measured mitochondrial respiratory capacity and oxidative metabolism. Induced pluripotent stem cell organoids were co-cultured with PDX tumor cells to determine if treatments mitigate tumor cell invasiveness.
Compared to parental cells (PC), MAT2A gene expression was increased by 1.7-fold in acquired resistant and de novo resistant GBM cells (RC) [(transcript per million): PC, 7386 ± 412; RC, 12941 ± 1023; n=2; p=2.10e-8].Compared to TMZ-sensitive cells (TS), TMZ-resistant cells (TR) demonstrated a 56% increase in baseline oxygen consumption rate [(pmol/min): TS, 179 ± 6.7; TR, 279 ± 13; n=18; p=.0012] and 64% increase in maximal respiratory capacity [(pmol/min): TS, 403 ± 29; TR, 659 ± 35; n=6; p&lt;.0001]. Both primary and recurrent GBM cells were subject to select MAT2A and AHCY inhibitor compounds and EC50s were determined. Recurrent cells demonstrated a vulnerability to TMZ-generated cell death both by genetically knocking down and pharmacologically inhibiting MAT2A and AHCY.
MAT2A and AHCY contribute to TMZ resistance and recurrence by dysregulating methylation programs and upregulating antioxidant programs, respectively. These findings provide a foundation for developing novel combinatory therapeutic strategies and inform clinical studies intended to augment the practically negligible rate of remission for GBM and improve treatment outcomes for cancer patients.
Citation Format: Emma Rowland, Jordan Walter, Anna Jermakowicz, Robert Suter, Rebecca Riggins, Nagi Ayad. Targeting metabolic and epigenetic programs to re-sensitize glioblastoma to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1747.
Abstract 1809: ACT-1002-4391 - A novel potent antagonist of the prostaglandin E2 receptors EP2 and EP4 with excellent duality
Authors: Jeay Sébastien , Diethelm Stefan , Knopf Agnes , Goxe Marie , Daugan Marie , Erupathil Julie , Pothier Julien , Pozzi Davide , Sifferlen Thierry , Wyder Lorenza , Lyothier Isabelle , Corminboeuf Olivier , Lehembre Francois , Renz Imke , Meyer Dominique 
Published: April 2023

Abstract
Prostaglandin E2 (PGE2) binds to four G-protein-coupled EP receptors, of which both EP2 and EP4 are abundantly expressed by tumor-infiltrating immune cells including DCs, NK cells, Tregs, cytotoxic T cells and TAMs. Signaling via EP2 and EP4 is immunosuppressive, preventing the mounting of effective anti-tumor immune responses leading to tumor immune escape and tumor progression. Currently, several EP4 selective antagonists and an EP2/4 dual antagonist are being developed for anti-cancer immunotherapy. Using a combination of EP2 and EP4 selective antagonists in different tumor mouse models, we could demonstrate that dual EP2/EP4 blockade is more effectively activating anti-tumor immunity compared to targeting either receptor alone. The concurrent inhibition of EP2 and EP4 resulted in tumor regression and induction of immunological memory. Together with published data showing similar findings, our results suggest that simultaneous targeting of EP2 and EP4 could be a promising new therapeutic approach to overcome cancer immune evasion. Idorsia Pharmaceuticals has identified ACT-1002-4391 as a novel, potent antagonist of EP2 and EP4 receptors with an excellent duality profile. In vitro, ACT-1002-4391 is capable of modulating immune cell proliferation and/or function and is superior to EP2 or EP4 selective inhibition in that respect. In vivo, ACT-1002-4391 displays strong and dose-dependent single agent anti-tumor efficacy in a syngeneic mouse tumor model. Based on the excellent selectivity and duality profile, ACT-1002-4391 will be advanced into clinical development by Idorsia Pharmaceuticals.
Citation Format: Sébastien Jeay, Stefan Diethelm, Agnes Knopf, Marie Goxe, Marie Daugan, Julie Erupathil, Julien Pothier, Davide Pozzi, Thierry Sifferlen, Lorenza Wyder, Isabelle Lyothier, Olivier Corminboeuf, Francois Lehembre, Imke Renz, Dominique Meyer. ACT-1002-4391 - A novel potent antagonist of the prostaglandin E2 receptors EP2 and EP4 with excellent duality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1809.
Abstract 1871: Novel conditionally active bispecific HER2 x CD3 T cell engager targeting solid tumors
Authors: Cugnetti Ana Paula , Liu Haizhen , McNeeley Patricia , Wheeler Christina , Lucas Matthew , Xing Charles , Joyner Solmarie , Johnson Kyrie , Woodard Kathryn , Zhou Wei , Chang Cathy , Frey Gerhard , Boyle William J. , Short Jay M. 
Published: April 2023

Abstract
Human epidermal growth factor receptor 2 (HER2) is overexpressed in multiple cancers and is associated with poor prognosis. Despite the outstanding improvement in survival with the introduction of anti-HER2 therapies, therapeutic benefit is limited by many resistance mechanisms and toxicities. Clinical trials of therapeutics redirecting T cell activity to HER2+ tumors have highlighted the apparent risk of on-target, off-tumor adverse effects for this target, as HER2 is also expressed in normal epithelia. Using BioAtla’s Conditionally Active Biologic (CAB) platform, we have developed a HER2 x CAB-CD3 bispecific antibody that was engineered to bind with high affinity to the CD3 receptor and induce T cell activation under conditions that mimic the tumor microenvironment, but with reduced binding in physiological conditions. Both in vitro and in vivo efficacy data for a CAB T cell engager (TCE) targeting HER2 will be presented. Our data will demonstrate that HER2 x CAB-CD3 bispecific antibody promotes cytotoxicity of HER2+ cancer cells in vitro and induces complete regression of tumor growth in vivo. The HER2 x CAB-CD3 bispecific antibody has higher potency in inducing primary T cell activation measured by means of cytokine release and cancer cell cytotoxicity under acidic conditions compared to the non-CAB benchmark bispecific antibody. The generation of CAB bispecific antibodies with activity in the disease microenvironment minimizes on-target, off-tumor toxicities, thereby enabling higher potency-TCEs for targeting drug resistant, low expressing-HER2+ tumors. In summary, the use of CAB technology expands the universe of targets for drug development by generating a new class of potent CAB T-cell engagers with increased safety margin for potentially enhanced therapeutic indices in the clinic.
Citation Format: Ana Paula Cugnetti, Haizhen Liu, Patricia McNeeley, Christina Wheeler, Matthew Lucas, Charles Xing, Solmarie Joyner, Kyrie Johnson, Kathryn Woodard, Wei Zhou, Cathy Chang, Gerhard Frey, William J. Boyle, Jay M. Short. Novel conditionally active bispecific HER2 x CD3 T cell engager targeting solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1871.
Abstract 188: Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy development
Authors: Mardpour Soura , Beaurivage Claudia , Sun Jane , Jahn Lorenz , Overmeer Rene , Fielmich Lars-Eric , Hombrink Pleun , Pourfarzad Farzin , Boj Sylvia F. 
Published: April 2023

Abstract
Recent advances in cancer immunotherapy had a positive impact on the life expectancy of patients for a large range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. We developed an innovative alternative, built on the discovery that adult stem cells proliferate and organise into three-dimensional organotypic structures when they are embedded into extracellular matrix. Patient specific organoids are generated from healthy and malignant tissues and stored as biobanks with high quality and reproducibility. HUB Organoids recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity, and morphological and functional traits. Since cancer progression and responses to immunotherapy are governed by immune cell interactions in the tumor microenvironment, we developed an assay in which colorectal (CRC) and non-small cell lung cancer (NSCLC) tumor organoids are co-cultured with simultaneously expanded paired tumor infiltrating lymphocytes (TIL) as a source of tumor reactive cells. Our system allows robust expansion of TIL with preserved T-cell receptor repertoires and has an establishment rate of 75%. Paired resources allow for screening of immune-modulatory therapies under physiologic conditions not depending on peptide-pulsing and allo-reactivity. For this purpose, we developed a organoid-TIL co-culture system which quantifies and characterizes tumor organoid apoptosis by combining image-based analysis with flow cytometry and cytokine release assays as measurements of T-cell cytotoxicity against tumor (and normal-matched) organoids. Our system offers a powerful tool for the development and validation of cancer immunotherapy and may help to stratify cancer patients for susceptibility of various types of immunotherapies.
Citation Format: Soura Mardpour, Claudia Beaurivage, Jane Sun, Lorenz Jahn, Rene Overmeer, Lars-Eric Fielmich, Pleun Hombrink, Farzin Pourfarzad, Sylvia F. Boj. Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 188.
Abstract 1882: SCR-9171, a MUC17-targeted bispecific T cell engager molecule for gastrointestinal cancer
Authors: Cheng Guangcun , Fu Yayuan , Zheng Hua , Li ng , He Xiaolei , Jiao Xi , Luan Shuhui , Wang Shuai , Jiang Lei , Li Wenjing , Zhang Yun , Liu Lei , Tang Renhong 
Published: April 2023

Abstract
Background: Although advances treatments have significantly improved the survival of patients with gastrointestinal cancer in recent decades, there is still an unmet medical need for more effective treatments. A promising strategy is the use of bispecific antibodies that recruit T cells to kill cancer cells by simultaneously binding to CD3 on T cells and tumor associated antigens. CD3-based T cell engagers are highly potent therapeutic molecules with T cell cytotoxicity activities. But high CRS risk and T cell exhaustion has been observed for high affinity CD3-based T cell engagers in clinicals. Effective and safe use of these therapeutics depends on selective targeting of cancer cells and optimal CD3 affinity. MUC17, a member of the mucin family, is a transmembrane glycoprotein only expressed on the apical membrane of normal gastrointestinal mucosal epithelial cells. MUC17 is overexpressed in 23%-52% of patients with gastric cancer. Compared to the adjacent normal tissues, the expression of MUC17 protein is consistently higher in gastric cancer tissues, suggesting that MUC17 is an attractive therapeutic target for gastric cancer.
Method & Results: We created MUC17/CD3 T cell engaging bispecific antibodies by starting with a nanobody humanized from camel and a low affinity CD3 antibody. Here we report the design and the promising preclinical activity of SCR-9171 molecule in vitro and in vivo. SCR-9171 induced T cell activation and had potent cytotoxicity of MUC17 positive tumor cells in vitro. However, the cytokine release was much lower than the positive control, which established with a high affinity CD3 antibody. Importantly, in mouse models with reconstituted human immune cells, SCR-9171 showed strong antitumor efficacy against MUC17-positive tumors through the activation of T cells. Tolerability and pharmacokinetics of MUC17/CD3 bispecific antibody are being assessed in cynomolgus monkey. The results demonstrated that SCR-9171 was well tolerated in a one-month repeat-dose toxicology study at 3mg/kg with no associated clinical signs or changes in body weight.
Conclusion: These findings suggest that MUC17/CD3 bispecific antibody is a potential therapeutic molecule for MUC17-positive solid tumor.
Citation Format: Guangcun Cheng, Yayuan Fu, Hua Zheng, ng Li, Xiaolei He, Xi Jiao, Shuhui Luan, Shuai Wang, Lei Jiang, Wenjing Li, Yun Zhang, Lei Liu, Renhong Tang. SCR-9171, a MUC17-targeted bispecific T cell engager molecule for gastrointestinal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1882.