bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C155: In-vitro multicellular 3D-spheroid model demonstrates the synergistic effect of 2-Domain soluble FMS-Like Tyrosine Kinase-1 (2d-sFlt-1) for breast cancer targeted therapies
Authors: Mutahar Adel Zaid I. , Salimath Bharathi 
Published: December 2023

Abstract
Using a conventional 2D-culture model, the anti-cancer drug failure rate was approximately 95%. Thus, incorporating in-vitro 3D models that better mimic in-vivo conditions became a central focus of drug discovery and regenerative medicine. Drug screening on triple-negative breast cancer (TNBC) with paclitaxel, doxorubicin alone or in combination with 2d-sFlt-1 revealed 28, 17, and 8-fold increase in the cytotoxicity effect using 2D-culture compared to 3D-spheroids. Tumor spheroids treated with 2d-sFlt-1 in combination with paclitaxel revealed a 13.5-fold higher response than paclitaxel alone. The targeted therapy was validated by a significant decrease in the formation of blood vessels either in tube formation or 3D-angiogenesis assays in endothelial-tumor cells co-cultured spheroids. The cytotoxicity effect of paclitaxel on 3D-tumor spheroids was enhanced with 2d-sFlt-1 (58% of dead cells) compared to (33% of dead cells) in paclitaxel alone. Furthermore, the antiproliferative effect of paclitaxel was significantly enhanced by combinatorial treatment with 2d-sFlt-1 (p&lt;0.0001) compared to bevacizumab (p&lt;0.05). Immunohistochemistry of 3D-tumor spheroids revealed inhibition in the expression of Ki-67 in combinatorial treatment. The increase in the migration rate of TNBC was significantly inhibited by combinatorial treatment as evidenced in 2D and 3D-invasion assays. Further, immunofluorescence of 3D-spheroids showed downregulation of EMT markers (E. Cadherin, vimentin, cortactin, and paxillin) in response to combinatorial treatment compared to paclitaxel alone. Moreover, inhibition of FAK expression upon 2d-sFlt-1 treatment was exhibited either in endothelial cells, MDA-MB231, or co-cultured spheroids. Expression of vascular endothelial growth factor (VEGF) was also decreased in combinatorial treatment as evidenced by ELISA. qPCR of 3D-spheroids revealed the downregulation of EMT genes (N-cadherin, SNAIL, and TWIST) and upregulation of E-cadherin in combinatorial treatment. These findings demonstrate the antiangiogenic and anti-metastatic properties of 2d-sFlt-1 on TNBC. We conclude that multicellular 3D spheroids for bioengineering tumor models are promising in vitro animal-free models for cancer therapies and regenerative medicine.
Citation Format: Adel Zaid I. Mutahar, Bharathi Salimath. In-vitro multicellular 3D-spheroid model demonstrates the synergistic effect of 2-Domain soluble FMS-Like Tyrosine Kinase-1 (2d-sFlt-1) for breast cancer targeted therapies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C155.
Abstract C157: Targeting PIK3CA and CDKN2A alterations in Esophageal Adenocarcinoma with Alpelisib and Palbociclib
Authors: Rustgi Naryan , Ryan Thomas , Cho Jin , Moy Ryan , Yoon Sam , Ryeom Sandra , Yoon Changhwan 
Published: December 2023

Abstract
Our study investigates the efficacy of targeted therapies for Esophageal Adenocarcinoma (EAC) tumors harboring an activating PIK3CA mutation and inactivating CDKN2A mutation. We tested the small molecule inhibitors alpelisib, which targets the Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit (PIK3CA), and palbociclib, which targets Cyclin D kinase 4/6 (CDK4/6), in EAC in vitro organoid and in vivo mouse models. EAC and Gastric cancer (GC) organoid models were treated with single agent alpelisib or palbociclib on a log scale to determine their IC50 values. An EAC organoid harboring activating PIK3CA E545K and inactivating CDKN2A D74A mutations demonstrated more significant growth inhibition when treated with each agent alone versus standard of care chemotherapy. Subsequent experiments involved combination treatment of our EAC-mutant organoid with alpelisib and palbociclib as well as a representative GC organoid and EAC organoids lacking these specific mutations as controls. We confirmed PIK3CA downstream target engagement after alpelisib treatment by qPCR, western blot analysis and immunofluorescence analysis. Once in vitro efficacy was confirmed, EAC-mutant organoids were transplanted into mice by either subcutaneous or orthotopic injections and treated with chemotherapy, alpelisib and palbociclib alone or in combination. Our data demonstrate that a PIK3CA/CDKN2A mutated patient-derived EAC organoid is sensitive to alpelisib and palbociclib in a dose dependent manner, and analysis of PIK3CA downstream targets by western and qPCR was consistent with growth inhibition of treated organoids. These findings offer support for the use of alpelisib and palbociclib in the treatment of EAC patients with PIK3CA/CDKN2A mutations.
Citation Format: Naryan Rustgi, Thomas Ryan, Jin Cho, Ryan Moy, Sam Yoon, Sandra Ryeom, Changhwan Yoon. Targeting PIK3CA and CDKN2A alterations in Esophageal Adenocarcinoma with Alpelisib and Palbociclib [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C157.
Abstract IA005: Emerging insights from the tebentafusp clinical program
Authors: Berman David M. 
Published: December 2023

Abstract
A majority of proteins that are specific for solid tumors are intracellular and thus can only be accessed by TCR-based therapeutics. Tebentafusp, a bispecific (gp100 x CD3) ImmTAC, is the first TCR therapeutic to demonstrate an overall survival benefit for any solid tumor. In the Phase 3 IMCgp100-202 study in HLA-A*02:01+ adult patients with previously untreated metastatic uveal melanoma [NCT03070392], tebentafusp significantly improved overall survival (OS) and progression free survival compared to investigator’s choice [HR 0.51 and HR 0.73, respectively]. Emerging insights from this first-in-class TCR therapeutic may be instructive to future development of other therapies in the same class.
Citation Format: David M. Berman. Emerging insights from the tebentafusp clinical program [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr IA005.
Abstract IA007: Design of next generation precision medicine trials using artificial intelligence
Authors: Tourneau Christophe Le 
Published: December 2023

Abstract
A better understanding of cancer biology has enabled the development of molecularly targeted therapies matching molecular alterations that induce tumor proliferation and metastases. Over the last decades, dozens of drugs were approved in various cancer types based on molecular alterations, often producing prolonged efficacy. More recently, some molecular alterations were found to be relevent across cancer types, such as NTRK translocations, thereby defining novel ontologies of cancer populations that are no longer defined by their cancer type but only a molecular alteration/signature. Although drug development is being challenged by these novel ontologies, patient stratification remains quite straightforward with unidimentional treatment algorithms (1 drug for 1 alteration, across or within cancer types). However, the relevance of some other alterations present in several cancer types sometimes differs across cancer types, but also among patients with a same cancer type, highlithing the issue of cancer heterogeneity. This later much more frequent situation supports a precision medicine approach that takes into account comprehensive molecular profiling. What I will try to explain during my talk is that the move from stratified medicine to precision medicine, defined as the individual selection of a treatment based on comprehensive molecular profiling, can only be done by using artificial intelligence. In order to illustrate this provocative statemen, I will review some initiatives that have used artificail intelligence in their study designs. I will finish by presenting the SENTIER project (Strategies to Expedite and Navigate Therapeutic Innovations through patient-centric and knowledge-Enhanced Research), an integrated research platform for early drug development that pursues the aim to accelerate drug development by connecting data from different early phase clinical trials in order to accelerate drug development.
Citation Format: Christophe Le Tourneau. Design of next generation precision medicine trials using artificial intelligence [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr IA007.
Abstract LB_B11: Transmembrane chloride intracellular channel 1 (tmCLIC1) protein as akey regulator of colorectal cancers' aggressiveness
Authors: Cianci Francesca , Verduci Ivan , Tacconi Carlotta , Rey Guido , Roz Luca , Fantin Alessandro , Mazzanti Michele 
Published: December 2023

Abstract
Colorectal cancer is the third leading cause of death in developed countries. Although the huge progresses reached in therapeutically approach, metastases remain the main issue treating colorectal cancer. Ion channels have a prominent role in the acquirement of aggressive phenotype, but most of them are involved in normal physiological processes. Among all the new potential biomarkers, Chloride Intracellular Channel 1(CLIC1) is a promising candidate. As a matter of fact, in physiological homeostasis, CLIC1 is expressed by all cell types as a cytosolic monomer. CLIC1 is a metamorphic protein that coexist in both cytosolic and transmembrane form (tmCLIC1), the latter involved in several pathological states, including cancer. CLIC1 mRNA overexpression was identified in colorectal cancer cells and is related to a poor prognosis. In this scenario, the main aim of the present work is to understand the role of tmCLIC1 in tumorigenesis, invasion, and migration potential of colorectal cancer. We first investigated the level of expression of CLIC1 protein and the activity of its transmembrane form as an ion channel in several colorectal cancer cells at different stage of development. Our results have demonstrated that tmCLIC1 protein expression and activity is proportional to the level of aggressiveness of cells, and here its action is fundamental on cellular proliferation, migration, and invasion. The role of tmCLIC1 activity in colorectal cancer was confirmed also in in vivo models. Experiments performed in zebrafish and mice models have demonstrated that the silencing of CLIC1 results in the impairment of primary tumor development and a strong reduction of distal metastases formation. Moreover, many different metastatic genes are downregulated when CLIC1 protein is absent; in particular, genes related to oxidative stress conditions, typical of cancer cells. As a matter of fact, the peculiar activity of CLIC1 and its binding with glutathione makes this protein essential for redox balance of colorectal cancer cells. Altogether, all the results obtained might be considered a starting point to unveil a mechanism of action that could represent a new milestone in anticancer research.
Citation Format: Francesca Cianci, Ivan Verduci, Carlotta Tacconi, Guido Rey, Luca Roz, Alessandro Fantin, Michele Mazzanti. Transmembrane chloride intracellular channel 1 (tmCLIC1) protein as akey regulator of colorectal cancers' aggressiveness [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B11.
Abstract LB_B12: Phase 2, multicenter, open-label basket trial of nab-Sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2 (PRECISION I)
Authors: Haddox Candace , Iyer Gopa , Demeure Michael J. , Ding Li , Schmid Anita N. , Navarro Willis H. , Kwiatkowski David J. , Ahnert Jordi Rodon 
Published: December 2023

Abstract
BACKGROUND. nab-Sirolimus, approved in the US for patients with advanced malignant PEComa, is a novel albumin-bound mTOR inhibitor (mTORi) that inhibits the mTOR pathway via suppression of the mTORC1 complex. When TSC1 or TSC2 is inactivated via mutation or loss, the mTOR pathway may be aberrantly activated. Clinically, in an exploratory analysis of the pivotal AMPECT trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC2 and TSC1, respectively, had confirmed response (Wagner, J Clin Oncol, 2021). TSC1 and TSC2 alterations have been observed in patients with various cancers. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with mTORi-class adverse events. Based on the clinical observations from AMPECT and the underlying mechanism of action of nab-sirolimus, the PRECISION I trial (NCT05103358) was designed to assess the safety and efficacy of nab-sirolimus in a tumor-agnostic study of advanced cancers with TSC1 or TSC2 inactivating alterations.
METHODS. Eligible patients are ≥12 years old and mTORi-naïve, possess advanced malignant solid tumors with TSC1 or TSC2 inactivating alterations identified using next-generation sequencing (NGS) in tumor tissue or liquid biopsy (confirmed by central review of NGS reports), and have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m2 will be given intravenously over 30 min on Days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using RECIST v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Enrollment began March 2022. Collaboration with leading NGS vendors will expedite the identification of patients with qualifying TSC1 and TSC2 mutations; ongoing study access is facilitated through a just-in-time approach to trial location activation. Based on the prevalence of TSC1 and TSC2 inactivating alterations, the most frequent tumor types expected are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric.
Citation Format: Candace Haddox, Gopa Iyer, Michael J. Demeure, Li Ding, Anita N. Schmid, Willis H. Navarro, David J. Kwiatkowski, Jordi Rodon Ahnert. Phase 2, multicenter, open-label basket trial of nab-Sirolimus for malignant solid tumors harboring pathogenic inactivating alterations in TSC1 and TSC2 (PRECISION I) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B12.
Abstract LB_B26: Efficacy and tolerability of a novel pan-RAS inhibitor with a unique mechanism of selectivity in mouse models of pancreatic cancer
Authors: Keeton Adam B , Maxuitenko Yulia Y , Foote Jeremy B , Huang Chung-Hui , Berry Kristy L , Fadlalla Khalda , Nagaraju Ganji P , Reddy Bandi DS , Chen Xi , El-Rayes Bassel F , Buchsbaum Donald J , Piazza Gary A 
Published: December 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death in the U.S. This is frequently due to advanced disease at time of diagnosis as well as the high prevalence of KRAS driver mutations. Currently available targeted therapeutics are designed to covalently inactivate only KRAS-G12C mutants, whereas the most common mutations in PDAC are KRAS-G12D, KRAS-G12V, and KRAS-G12R. Thus, the need for novel RAS-targeted therapeutics with efficacy in tumors with these more common mutations is of utmost urgency to reduce PDAC disease burden. Our novel class of pan-RAS inhibitors have unique biological and attractive drug-like properties. We synthesized an orally bioavailable prodrug, ADT-1004, which generates the active species, ADT-007, that inhibits growth of PDAC tumors. ADT-007 inhibits PDAC cell growth in vitro with IC50 as low as 2 nM regardless of RAS mutant allele, inhibits RAS activation, and downstream MAPK/AKT signaling. Differentiated normal epithelial cells, hepatic cells, and tumor cells with wild type RAS are insensitive to ADT-007 due to enzymatic detoxification providing unique selectivity for a pan-RAS inhibitor. ADT-1004 is well tolerated in vivo, producing sustained ADT-007 concentrations well above IC50 values in plasma. Daily oral ADT-1004 administration results in significant inhibiteion of tumor growth in both mouse orthotopic and PDX models of PDAC tumors accompanied by a reduction in RAS signaling.
Citation Format: Adam B Keeton, Yulia Y Maxuitenko, Jeremy B Foote, Chung-Hui Huang, Kristy L Berry, Khalda Fadlalla, Ganji P Nagaraju, Bandi DS Reddy, Xi Chen, Bassel F El-Rayes, Donald J Buchsbaum, Gary A Piazza. Efficacy and tolerability of a novel pan-RAS inhibitor with a unique mechanism of selectivity in mouse models of pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B26.
Abstract LB_C18: A novel WNT-RIP1 signaling pathway promotes colorectal cancer metastasis via induction of EMT
Authors: KANG A-RAM , KIM DO HOON , PARK JONG KUK 
Published: December 2023

Abstract
We identified new potential roles of RIP1 (receptor-interacting protein kinase 1) in controlling WNT signaling to enhance metastasis of colorectal cancer (CRC). First, we showed that WNT3A treatment sequentially increased the expression of RIP1 and β-catenin. Next, Immunohistochemical analyses of human CRC tissue arrays consisting of normal, primary, and metastatic cancers showed that elevated RIP1 expression might be related to β-catenin expression and it also indicated inductions of carcinogenesis and metastasis. In in vivo experiments with mice, intravenous injection of RIP1 over-expressed CRC cells has demonstrated that RIP1 may promote metastasis. These results implied RIP1 might be major component of WNT signaling. Next, we performed immunoprecipitation (IP) to revealed intracellular signaling mechanism that WNT3A treatment could induce direct binding between RIP1 and β-catenin, and observed direct binding and stabilization of the β-catenin protein via regulation of RIP1 ubiquitination by a downregulation of the E3 ligase, cIAP1/2. Down-regulation of cIAP1/2 expression with siRNA treatment and inhibition of its ubiquitinase activity with pharmacological inhibitor treatment could enhance WNT3A-induced RIP1 and β-catenin protein expression and binding. These results also enhance the migration and invasion of CRC cells in vitro via induction of endothelial-mesenchymal transition (EMT). The in vitro binding assay and IP of exogenous RIP1-containing CRC cells additionally result in the direct binding of RIP1 and β-catenin. The enhanced RIP1 expression can destroy the β-catenin–β-TrCP complex. Additionally, we also identified GDF15 (Growth and differentiation factor 15) is located at down-stream of WNT3A-RIP1 pathway and involved in EM induction. Taken together, these results suggest an identification of novel WNT-RIP1 pathway to enhance EMT and suggest GDF15 also might contribute CRC malignancy.
Citation Format: A-RAM KANG, DO HOON KIM, JONG KUK PARK. A novel WNT-RIP1 signaling pathway promotes colorectal cancer metastasis via induction of EMT [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C18.
Abstract A019: Busting myths in healthcare: Establishment of a bilingual health education platform in a border community
Authors: Mansour Sara , Fernandez Lorena , Allen Jesse , Garikiparthy Veeravenkata , Renovato Laura , Land Maria , Belmares Ricardo , Hogg Tanis , Holland Nathan , Chacon Jessica 
Published: December 2023

Abstract
Introduction: The Texas Tech University Health Sciences Center (TTUHSC) El Paso Health Education and Awareness Team (EP-HEATTM) was established in 2020, focusing on disseminating bilingual (English/Spanish) health education material to the border community. A co-production effort was established with EP-HEAT consisting of TTUHSC El Paso students, faculty, and Promotoras, also known as Community Health Workers. These events allow students to interact directly with the community and serve as healthcare educators to better prepare them for the community-facing aspects of being a physician and developing a professional identity. The goal of this project was to provide an environment where community members, students, Promotoras and healthcare experts work together to identify and dispel myths in healthcare. Methods: The EP-HEAT students and Promotoras work collaboratively with community members to identify myths in healthcare field, including cancer and treatment for the Hispanic population.​ Students then identify experts in the healthcare field who can address the myths. The promotoras invite community members to attend the event and finally, the Myth Busters event occurs in a pseudo-talk-show manner. Students and Promotoras, serve as the hosts, interviewing the expert in the field in a bilingual (English/Spanish format), with the audience being he community members. Results: Community members who attended the Myth Buster events received a survey to obtain demographic data, identify the motivation behind attendance, and evaluate the benefit and effectiveness of the event. Our results showed that 81% of our attendees identified as Hispanic, with 45% older than 46 years old. Discussion: An unanswered question that is pending is whether attending the Myth Buster events enabled community members to seek out additional resources for the identified healthcare topics (such as vaccinations, antibiotics, and Diabetes/healthy living) for example. We also need to determine whether students’ professionalism and networking increased as a result of the events.
Citation Format: Sara Mansour, Lorena Fernandez, Jesse Allen, Veeravenkata Garikiparthy, Laura Renovato, Maria Land, Ricardo Belmares, Tanis Hogg, Nathan Holland, Jessica Chacon. Busting myths in healthcare: Establishment of a bilingual health education platform in a border community [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A019.