bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract C099: Establishment and characterization of an NUP98-KDM5A-driven AML XPDX model
Authors: III Armando Diaz , Simonson Alyssa , Flores Johnnie , Holahan Joseph , Papadopoulos Kyriakos P , Lund Jim , Rasco Drew , Patnaik Amita , Wick Michael J
Published: December 2023

Background: Acute myeloid leukemia (AML) with NUP98 fusions is associated with poor prognosis in adults and especially children. Pediatric AML is a rare and heterogeneous disease characterized by a high prevalence of gene fusions as driver mutations, including the NUP98-KDM5A fusion found in a particular subgroup of patients with complex karyotypes.  To better understand this subtype of AML, we established and characterized a XPDX model designated ST1653 representing NUP98-KDM5A-driven disease from a previously treated AML patient.  We performed DNA and RNA-based sequencing of the model.  Further we evaluated in vivo sensitivity towards cytarabine and inhibitors targeting the JAK and CDK6 pathways, which have been shown to be important in NUP98-KDM5A-driven AML. Methods: ST1653 was established from a bone marrow aspirate collected from a 63-year-old Caucasian male who had AML recurrence following high dose cytarabine.  The sample was injected subcutaneously into a triple-deficient mouse and the P0 model passaged after seventy days into CB-17 SCID and athymic nude mice and further developed until stable.  WES and RNAseq were then performed.  For in vivo studies, ST1653 was evaluated against cytarabine and the JAK inhibitors ruxolitinib, baricitinib and tofacitinib and the CDK4/6 inhibitors palbociclib, abemaciclib and ribociclib.  Endpoints in all studies included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a T/C of ≤ 20% versus control was considered sensitive.  Tumor regression (%T/C<0%) versus Day 0 tumor volume was also reported. Results: Growth of the ST1653 AML XPDX model was similar in CB-17 SCID or athymic nude mice with a median time to endpoint of forty-five days, although the take rate in the SCID strain was superior.  Sequencing identified the presence of the NUP98-KDM5A fusion and chimeric protein expression was confirmed.  In vivo, ST1653 was insensitive to cytarabine and the JAK inhibitors but demonstrated limited sensitivity to CDK4/6i treatment. Conclusion: We have established and characterized a XPDX model of NUP98-KDM5A-driven AML including sequencing and in vivo evaluation.  This model is an important tool for developing novel therapies to this high-risk leukemia subtype.

Citation Format: Armando Diaz III, Alyssa Simonson, Johnnie Flores, Joseph Holahan, Kyriakos P Papadopoulos, Jim Lund, Drew Rasco, Amita Patnaik, Michael J Wick. Establishment and characterization of an NUP98-KDM5A-driven AML XPDX model [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 C099.
Abstract C110: miR195 - A potential therapeutic molecule for breast cancer: Present and future
Authors: Purohit Paresh , Saini Neeru
Published: December 2023

Breast cancer is the leading cause of death in women worldwide (Globocan 2020). Surgery, chemotherapy as well as radiation therapy are the commonly used modes of treatment and the treatment depends on the tumor type. Patients develop resistance and demonstrate poor prognosis after prolonged treatment. Hence there’s is always a need for new diagnostics and therapeutics. miRNAs are 18-22 nucleotides small RNAs known to play a role in development and disease.  Deregulation of miRNAs in diseased conditions can be harnessed as potential therapeutics by miRNA mimics or miRNA inhibition by antimiRs. Till date, several miRNA-targeted therapeutics have reached clinical development. Our laboratory has shown that miR-195 not only down regulates anti-apoptotic protein bcl-2 but also key genes of lipid metabolism (FASN, HMGCR) which are upregulated in breast cancer. The altered calcium signaling is deleterious to cells and is also known to be associated with different hallmarks of cancer. We recently observed that miR-195 perturbs calcium homeostasis in breast cancer cells by down-regulating a major calcium efflux pump present on the plasma membrane. Experimental validation has been performed in breast cancer cells and spheroids using western blotting, qRT-PCR, dual luciferase assay, calcium measurements using flow cytometry and immunofluorescence. MiR-195 alters calcium homeostasis leading to ER stress and autophagy in breast cancer. The current work describes recent advances in our understanding of miRNA-195 in breast cancer.

Citation Format: Paresh Purohit, Neeru Saini. miR195 - A potential therapeutic molecule for breast cancer: Present and future [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 C110.
Abstract C123: Alloferon inhibits migration of pancreatic cancer by regulating the expression of IL-22Rα
Authors: Jo Hyejung , Kim Yejin , Shin Seulgi , Kang Jae Seung
Published: December 2023

Pancreatic cancer frequently metastasizes into one or more organs and tissues located near the pancreas. Metastasis contributes to make curative approach unachievable and bring poor prognosis. Therefore, it is important to develop a strategy to regulate the metastasis of pancreatic cancer. Recent research has reported that IL-22 increases the factors involved in migration and invasion to support the development of pancreatic cancer. The binding of IL-22 to IL-22 receptor exerts its biological effects and, IL-22 receptors are heterodimer receptor complex composed of IL-22Rα and IL-10Rβ. Previously we showed that alloferon, known as the immune modulator, increases chemosensitivity in pancreatic cancer by downregulating the SLC6A14, a transporter of glutamine. In this study, we identified that alloferon is a potential adjuvant therapeutic agent for pancreatic cancer by regulating the expression of IL-22Rα. We found that IL-22 has essential role in migration and invasion of pancreatic cancer by increasing the chemokine receptors such as CXCR3 and CXCR4. In addition, alloferon decreased the expression of IL-22Rα in pancreatic cancer cell line. Therefore, the expression of CXCR3 and CXCR4 decreased in AsPC-1 in presence of alloferon even upon the treatment with recombinant IL-22. To evaluate the effect of alloferon on tumor migration, the migration and invasive capacity were measured in pancreatic cancer cells in absent or present of alloferon. It was observed that alloferon significantly inhibit the migration of AsPC-1 toward ligand of CXCR3 and CXCR4, CXCL10 and CXCL12. These findings established that the expression of IL-22Rα associated with metastasis is likely related to overexpression of CXCR3 and CXCR4 in pancreatic cancer. Taken together, it is suggested that alloferon could be used as an adjuvant therapy to inhibit the metastasis of pancreatic cancer by regulating the expression of IL-22Rα.

Citation Format: Hyejung Jo, Yejin Kim, Seulgi Shin, Jae Seung Kang. Alloferon inhibits migration of pancreatic cancer by regulating the expression of IL-22Rα [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 C123.
Abstract C125: Development of attenuated orf virus as a new generation oncolytic viral vector
Authors: Yamada Yumiko , Hsu Wei-Li , Wang Yu-Chih , Liu Hao-Ping
Published: December 2023

The orf virus (ORFV) possesses remarkable qualities that make it a potential viral vector for cancer therapy. Recently, the cancer-killing properties of ORFV have been demonstrated in a variety of human cancers, including nasopharyngeal carcinoma (NPC). Initially, we found that the ORFV-bearing wild-type genome was successful in eliminating two NPC cell lines derived from patients in Hong Kong and Taiwan, HK-1 and TW02, respectively.  To make viral vectors safer for medical use, the oncolytic effects of two live attenuated ORFVs, which were created by removing one of the virulent factors, VEGF or CBP, were further evaluated in these two cell lines. Despite this attenuation, the two recombinant ORFVs were still able to effectively infect and kill NPC cells, particularly HK-1 cells. ORFV infection caused pyroptosis in NPC cells through GSDME cleavage, resulting in significant cell detachment and reduction in FAK and AKT activation during the early stages of infection. The innate immune response is also affected by ORFV infection, as shown by the increased chemotaxis of NK cells and synergistic effect of NK on the cytotoxicity of NPC cells caused by ORFV infection. Infection with both wild-type and CBP-deleted ORFVs significantly reduced HK-1 tumor growth in a xenograft mouse model, suggesting its potential as a therapeutic agent for NPC treatment. To maximize its therapeutic use, it is essential to comprehensively understand the mechanisms that drive the oncolytic activity of ORFV.

Citation Format: Yumiko Yamada, Wei-Li Hsu, Yu-Chih Wang, Hao-Ping Liu. Development of attenuated orf virus as a new generation oncolytic viral vector [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 C125.
Abstract C133: BBT-4437, a novel, brain-penetrable, reversible pan-TEAD inhibitor targeting the Hippo signaling pathway in solid tumors
Authors: Revollo Leila , Brenneman Jehrod , Paudyal Sharad , Nguyen Toan , Lee Yong-Hee , Jin Taiguang Jimmy
Published: December 2023

The Hippo pathway regulates several cellular functions including cell lineage fate, proliferation, migration, apoptosis, maintenance of cell stemness and dedifferentiation, and organ size. TEA domain family members 1-4 (TEAD1-4) are evolutionarily conserved transcription factors and core components of the Hippo pathway. TEADs are functional partners of the oncoproteins YAP (Yes-associated protein) and its paralog TAZ (transcriptional co-activator with PDZ-binding motif). Mutations in components of the Hippo pathway have been implicated in several diseases, including cancer. YAP/TEAD activation has also been associated with resistance to targeted therapies by EGFR TKIs in EGFR-mutant NSCLC. Targeting TEAD transcription activity has emerged as a promising approach to addressing cancers with abnormalities in the Hippo pathway. BBT-4437 is a novel, brain-penetrable, reversible pan-TEAD inhibitor that exhibits excellent selectivity in blocking TEAD transcriptional activity in the TEAD reporter gene assay. It demonstrates nanomolar potency in inhibiting cell proliferation in NF2-deficient mesothelioma cells in vitro. BBT-4437 also inhibits the expression of downstream YAP-TEAD target genes (CCN1/CYR61, CCN2/CTGF and IGFBP3) in a concentration-dependent manner in vitro. Moreover, BBT-4437 shows synergistic effect in combination with osimertinib in the H1975 NSCLC cell line. Furthermore, daily oral administration of BBT-4437 leads to significant tumor regression in NF2-deficient H226 and H2373 mesothelioma xenograft models. BBT-4437 demonstrates favorable pharmacokinetic and ADME profiles, including excellent brain penetration.  Therefore, BBT-4437 has the potential to be a best-in-class TEAD inhibitor for targeting tumors with aberrant Hippo signaling and overcoming drug resistance caused by upregulation of the Hippo pathway in the clinic.

Citation Format: Leila Revollo, Jehrod Brenneman, Sharad Paudyal, Toan Nguyen, Yong-Hee Lee, Taiguang Jimmy Jin. BBT-4437, a novel, brain-penetrable, reversible pan-TEAD inhibitor targeting the Hippo signaling pathway in solid tumors [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 C133.
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

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<0.0001) compared to bevacizumab (p<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

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

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

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

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

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

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

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

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.
Abstract A075: Using social marketing principles to address lung cancer screening among Chinese Americans
Authors: Kwon Simona , Tan Yi-Ling , Chong Stella , Luu Binh , Tsai William , Ah-Yune Judy , Love Jamie , Vang Suzanne
Published: December 2023

Background: Lung cancer is the second and fourth most common cancer diagnosed among Chinese American men and women respectively. Screening can detect lung cancer in its early, most treatable stages. In 2022, the US Preventive Services Task Force (USPSTF) expanded their annual lung cancer eligibility criteria. Despite the disproportionately high rates of lung cancer among Chinese Americans, prior research suggest that screening rates in Chinese Americans remain low due to complex and systemic barriers. Objective: We seek to describe the development of a culturally and linguistically relevant project to provide education and outreach on lung cancer screening for Chinese Americans. Methods: The project was guided by the principles of participatory cultural adaptation and social marketing to develop sustainable education and outreach efforts and identify appropriate messaging and channels. This included a scoping review focusing on barriers to lung cancer screening in Chinese Americans and a survey of Chinese-serving physicians. A transdisciplinary advisory group guided the development and implementation of the project and design of the multi-media materials. We leveraged existing regional and national networks to maximize the outreach to Chinese American communities across the US. Results: Using social marketing principles, we developed culturally tailored multi-media materials to raise awareness of the eligibility criteria for lung cancer screening and address barriers toward screening in Chinese Americans. This included the following: 1) a bilingual website with information and resources for Chinese Americans, including an eligibility quiz; 2) digital stories featuring patient stories which directly address perceived barriers toward lung screening; and 3) materials for physicians. We will share the cultural adaptation process and present data on the reach of the social media outreach. Conclusion: There is a need to develop culturally and linguistically relevant education and outreach efforts to actively promote lung cancer screening and address barriers to screening among high-risk Chinese Americans, in order to reduce lung cancer disparities.

Citation Format: Simona Kwon, Yi-Ling Tan, Stella Chong, Binh Luu, William Tsai, Judy Ah-Yune, Jamie Love, Suzanne Vang. Using social marketing principles to address lung cancer screening among Chinese Americans [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 A075.
Abstract A083: Initiation and persistence of hormone therapy in endocrine positive breast cancer at an urban safety-net hospital
Authors: Solfisburg Quinn S. , Beaulieu-Jones Brendin R. , Cassidy Michael R. , Ko Naomi Y.
Published: December 2023

Background: Evidence demonstrates inequities in receipt and persistence of hormone therapy among breast cancer patient populations based on race, ethnicity, insurance, and language. Institutions where patients seek cancer care may have an impact on receipt of treatment. It is unknown whether safety net hospitals, servicing a vulnerable patient population, exhibit inequities in receipt of hormone therapy for breast cancer.   Study Design: We performed a retrospective study of patients diagnosed with all stages of hormone positive (ER+ and/or PR +) breast cancer treated at a safety net institution over the five year period from January 1, 2009 to December 31, 2013. The initiation of and persistence of hormone therapy were assessed by race, ethnicity, insurance status, and primary language. Persistence of therapy was defined as defined as at least 3 prescriptions (90 day supply) or more than 1 visit after start of treatment documenting taking treatment.   Results: A total of 599 women were identified. The median age was 59 years, 58% were non-White, 32% were non-English-speaking, and 35% had Medicaid or no insurance. A total of 506 (84%) were started on hormone therapy. In multivariate regression analysis, the rate of endocrine therapy initiation was associated with higher stage at diagnosis, post-menopausal status, and HER2 negative status. Non-white race, Hispanic/Latino ethnicity, non-English-language, and Medicaid/no insurance were not significantly associated with or without initiation of hormone therapy. 93% of patients started on hormone therapy had evidence of continued treatment, 91% had evidence of continued treatment at 1 year, 75% finished their recommended course of hormone therapy.   Conclusion:  At an urban safety-net hospital, we do not observe inequities in the initiation of endocrine therapy for breast cancer by race, ethnicity, insurance, or language. Persistence of therapy was similar to nationally reported data. Additional research by hospital type, and granular reasons for non-adherence are warranted.

Citation Format: Quinn S. Solfisburg, Brendin R. Beaulieu-Jones, Michael R. Cassidy, Naomi Y. Ko. Initiation and persistence of hormone therapy in endocrine positive breast cancer at an urban safety-net hospital [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 A083.
Abstract A105: Healthy behaviors among non-Hispanic Black and Hispanic people affected by cancer during the post-treatment survivorship
Authors: Seven Memnun , Moraitis Ann Marie , Hammer Marilyn J. , Pearlman Jessica , Reid Allecia , Sturgeon Susan , Wenzel Jennifer
Published: December 2023

Background: Racial and ethnic minoritized people, historically experience inequities, are disproportionately affected by suboptimal body weight, diet, and sedentary lifestyle. However, limited studies focus on cancer survivors' experiences developing and maintaining healthy behaviors, particularly in Non-Hispanic Black (NHB) and Hispanic people. Objective. This study aimed to understand the experiences of NHB and Hispanic people affected by cancer in developing and maintaining positive health behaviors beyond a cancer diagnosis. Methods. The data was collected in a mixed-method study through semi-structured interviews with 29 NHB and Hispanic cancer survivors between June- October 2022. Conventional content analysis was used. Results. The lived experiences of cancer survivors were narrated in three themes; 1- Impact of a cancer diagnosis on oneself, 2- Facilitators and Barriers to health and health behaviors, and 3- Utilization of available sources for health. Facilitators and barriers to health and health behaviors were further explored as biological (e.g., symptoms, comorbidities), behavioral (e.g., help-seeking behavior, sleep pattern), physical/built environment (e.g., available sources, neighborhood), and sociocultural environment (e.g., income, transportation, knowledge, culture, upbringing, household and community composition, social and family network), and healthcare system-related factors (e.g., insurance coverage, personal preferences, perceived discrimination, and stigma). Conclusion. NHB and Hispanic people affected by cancer, specifically those living in disadvantaged neighborhoods with limited sources or where they feel discriminated and stereotyped, those with limited income and transportation, and those with physical, social, or mental health problems, appeared to have challenges prioritizing health behaviors and maintaining healthy living. Implications for Practice. Biological, behavioral, and psychosocial determinants of health behaviors should be addressed through multilevel collaborations among different levels of partners. Keywords. Cancer survivorship, health behaviors, racial disparities, non-Hispanic Black and Hispanic people

Citation Format: Memnun Seven, Ann Marie Moraitis, Marilyn J. Hammer, Jessica Pearlman, Allecia Reid, Susan Sturgeon, Jennifer Wenzel. Healthy behaviors among non-Hispanic Black and Hispanic people affected by cancer during the post-treatment survivorship [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 A105.
Abstract A132: Time to treatment by neighborhood among endometrial intraepithelial neoplasia and endometrial cancer patients
Authors: Wang Victoria , Reid Hadley , Pelletier Andrea , Russell Trinity , Chen Lucy , Marsh Reagan , Feltmate Colleen , Wright Alexi , Elias Kevin
Published: December 2023

Objective: To examine interval wait time for surgery in EIN and Endometrial Cancer patients at a single institution and identify potential disparities in access to care Methods: At this single institution, five priority neighborhoods where medically underserved populations reside have been designated from a Community Health Needs Assessment. We performed a retrospective chart review of patients with EIN or endometrial cancer at a single institution between 2016-2019. Patients from one of five priority neighborhoods were compared with patients from other zip codes within the same state. Results: 100 patients from priority neighborhoods and 104 patients from other neighborhoods within the same state were identified. Mean age was similar (59.74 vs 58.15 yrs, p 0.372) and rates of private insurance status were similar (66% vs 52%, p 0.08). Priority neighborhood patients were more likely to identify as Black or Hispanic (30.0% vs 4.81%; 18.0% vs 0%, p <0.001), and were more likely to speak a non-English primary language (19.0% vs 2.88%, p 0.005). Priority neighborhood patients had a higher Charlson Deyo co-morbidity score (2.44 vs 2.49, p 0.809). Patients had a similar rates of advanced stage disease (Stage III or IV 16 vs 16, p 0.213) and histologic subtype (Endometrioid 47.5% vs 59.6%; Serous or Clear Cell 13.46% vs 14.75%, p 0.962). The mean interval to treatment by primary surgery from referral visit was 68.9 days for non-priority neighborhood patients compared to 80.12 days for priority neighborhood patients (p 0.478). In univariate analysis, race/ethnicity, primary language, and insurance status were not significant factors impacting time to treatment.   Conclusion: Interval wait time to primary surgery among a single institution cohort was longer for priority neighborhood patients. This study highlights potential barriers to healthcare access that are unaddressed by current systems.

Citation Format: Victoria Wang, Hadley Reid, Andrea Pelletier, Trinity Russell, Lucy Chen, Reagan Marsh, Colleen Feltmate, Alexi Wright, Kevin Elias. Time to treatment by neighborhood among endometrial intraepithelial neoplasia and endometrial cancer patients [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 A132.