bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4473: Targeting matrix metalloproteinase-3 (MMP-3) in high-grade serous ovarian cancer
Authors: Reyes-Burgos Víctor G. , Hernández-O'Farrill Eliud , Quiñones Luis E. Vazquez , Flores-Colón Marienid , Valiyeva Fatima , Vivas-Mejía Pablo E.
Published: March 2024

High-Grade Serous Ovarian Cancer (HGSOC) is the most aggressive and lethal gynecological malignancy. Surgery and chemotherapy (with platinum compounds) are the main treatments. Many patients relapse and develop chemotherapy resistance, limiting the therapeutic utility of these therapies. This persistent resistance makes HGSOC treatment difficult. Cisplatin-resistant ovarian cancer cells upregulate Matrix Metalloproteinase-3. MMP3 is an enzyme involved in active tissue remodeling and extracellular matrix protein breakdown during dynamic physiological processes. The structure of MMP3 includes the prodomain, the catalytic domain and the hemopexin domain. We showed that MMP3 protein levels are higher in cisplatin resistant as compared with cisplatin sensitive HGSOC cells. Our research team showed that small interference RNA (siRNA)-mediated MMP3 knockdown reduced cisplatin-resistant ovarian cancer cell growth and invasion. This data indicates that MMP3 may be a promising HGSOC treatment target. Targeting MMP3 with small chemical inhibitors (SCI) could represent a better option than siRNA because SCI are more stable and easier to deliver. The purpose of this project is to design SCI of MMP3 in the propeptide, catalytic, and hemopexin domains of MMP3. We used in silico methods to identify MMP3 inhibitors in these domains. The ZINC20 database of commercially compounds was used for virtual screening using Python Prescription (PyRx) software. We identified 25 ligands out of 370,000 with the greatest affinity for each MMP3 functional domains. SwissADME was then used to evaluate in silico absorption, distribution, metabolism, pharmacokinetics, drug-likeliness, and medicinal chemistry. This research lays the groundwork for HGSOC therapeutic strategies to improve treatment efficacy, especially for chemotherapy-resistant patients.

Citation Format: Víctor G. Reyes-Burgos, Eliud Hernández-O'Farrill, Luis E. Vazquez Quiñones, Marienid Flores-Colón, Fatima Valiyeva, Pablo E. Vivas-Mejía. Targeting matrix metalloproteinase-3 (MMP-3) in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4473.
Abstract 4474: Novel analogs of 4-substituted pyrrolo[2,3-d]pyrimidines as dual-targeted mEGFR/AURKA inhibitors for lung cancer
Authors: Kurup Sonali , Carpenter Gabe , Satawa Samantha , Amissah Felix , Lisabeth Erika , Giletto Matthew , Ellsworth Edmund
Published: March 2024

Small molecule, mutant epidermal growth factor receptor kinase (mEGFR) inhibitors such as osimertinib and erlotinib constitute the recommended therapy for mEGFR-positive non-small cell lung cancer (NSCLC). However, mEGFR inhibitors are ineffective in NSCLC over time due to mutations within mEGFR and redundant signaling pathways such as mutant KRAS (mKRAS) that bypass mEGFR inhibition. Simultaneous inhibition of multiple kinases has been suggested to provide synergistic effects on tumor growth inhibition and tumor resistance. Studies have shown that resistance to mEGFR inhibitors was overcome when mEGFR inhibitors were combined with aurora kinase (AURK) inhibitors. Additionally, mEGFR inhibitors were found to retain their anticancer effects in mKRAS-positive NSCLC cells if given concurrently with AURK inhibitors. Kurup et al. previously reported a series of 4-substituted pyrrolo[2,3-d]pyrimidines as dual mEGFR/AURKB inhibitors. Novel analogs of 1-5 have been designed to incorporate AURKA inhibition while maintaining mEGFR inhibition. Molecular modeling was utilized to guide selectivity for AURKA over AURKB. This study led to the identification of novel dual-targeted mEGFR/AURKA inhibitors with demonstrated inhibition of mKRAS+ NSCLC and mEGFR+ NSCLC. The design, synthesis, kinase inhibitory activities, and anticancer effects for these novel analogs will be presented. Structure-activity relationships for dual mEGFR/AURKA inhibition will be defined.

Citation Format: Sonali Kurup, Gabe Carpenter, Samantha Satawa, Felix Amissah, Erika Lisabeth, Matthew Giletto, Edmund Ellsworth. Novel analogs of 4-substituted pyrrolo[2,3-d]pyrimidines as dual-targeted mEGFR/AURKA inhibitors for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4474.
Abstract 4532: Discovery of DAT-1000A, a potent Polθ inhibitor that significantly enhances anti-tumor efficacy in combination with PARP inhibitor in homologous-recombination-deficient tumors
Authors: Yan Dan , Zhang Yao , Zhang Yan , Zhang Jingxi , Wang Bin , Chen Huixian , Shi Jingxue , Lin Xiaoling , Zhuo Jincong , Zhou Kevin
Published: March 2024

Cancers exhibiting homologous recombination (HR) repair deficiencies due to mutations in genes like BRCA1 or BRCA2 rely on alternative DNA damage response (DDR) pathways to uphold genomic integrity. This vulnerability allows for the targeted disruption of these pathways through synthetic lethality approaches. DNA polymerase theta (Polθ, encoded by POLQ) assumes a crucial role in mending DNA double-strand breaks (DSB) via microhomology-mediated end-joining (MMEJ), one of the principal pathways for repairing DNA DSB. Notably, Polθ expression is minimal in normal tissues but becomes upregulated in HR-deficient cancer cells, positioning Polθ as a prime target for synthetic lethality in HRD cancers. Reversion mutations in HR-related genes frequently employ micro-homology deletion mechanisms. Consequently, the inhibition of Polθ holds the potential to thwart the emergence of PARPi resistance, primarily driven by BRCA reversion mutations. In this context, we introduce DAT-1000A, a novel small-molecule Polθ inhibitor exhibiting potent activity with a single-digital nanomolar IC50 value. Its efficacy in MMEJ functional assays validates its on-target cellular activity. Assessments of cell viability in HR-deficient BRCA2-KO DLD-1 cells, compared to their parental counterparts, reveal a striking synthetic lethality window exceeding 500-fold. Additionally, DAT-1000A displays synergistic anti-proliferative effects when combined with PARP inhibitors in BRCA1/2-mutated cells. In BRCA1/2-mutated xenograft models, DAT-1000A demonstrates robust and sustained tumor regression, as evidenced by the level of γH2AX, a common marker for double-strand breaks, which closely correlates with anti-tumor efficacy. Importantly, high-dose DAT-1000A treatment in mice elicits no significant abnormalities, underscoring its excellent tolerability. Collectively, DAT-1000A emerges as a novel Polθ inhibitor, offering both potent activity and a favorable safety profile, and holds promise for advancing therapeutic options in the realm of HRD cancer treatment.

Citation Format: Dan Yan, Yao Zhang, Yan Zhang, Jingxi Zhang, Bin Wang, Huixian Chen, Jingxue Shi, Xiaoling Lin, Jincong Zhuo, Kevin Zhou. Discovery of DAT-1000A, a potent Polθ inhibitor that significantly enhances anti-tumor efficacy in combination with PARP inhibitor in homologous-recombination-deficient tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4532.
Abstract 4560: Assessing cancer drug combination efficacy across 900+ PRISM cell lines in a multiplexed screening assay
Authors: George Ashish Bino , Nair Shiker , Kocak Mustafa , Nguyen Ellen , Kalathungal Alvin , Fazio Anthony , Ponsi Cole , Golabi Aydin , Ronan Melissa A. , Rees Matthew G. , Roth Jennifer A.
Published: March 2024

Combination therapies are crucial in cancer care, yet identifying which combination will benefit a specific patient is challenging. The vast array of clinical, investigational, and tool anticancer agents and diverse cancer contexts makes investigating many drug combinations over a large number of cell lines infeasible. Here, we describe a multiplexed screening approach using the PRISM assay, where drug combinations are screened on >900 DNA-barcoded cancer cell lines. We analyze cell viability data in drug combinations and single agents using established metrics to describe the combined effects such as additivity, synergy, and antagonism. Quantifying and classifying combined effects will help prioritize specific combinations for follow-up investigations and provide biological and mechanistic insights, thus enabling rationally designed combination therapies. We illustrate our methodology through data from three drug combinations that exemplify synergy and antagonism. In the first combination, temozolomide+O6-benzylguanine (alkylating agent + MGMT inhibitor), we found that cell lines expressing MGMT were sensitized to temozolomide in the presence of O6-benzylguanine, thus illustrating synergy. In the second combination, we screened two anti-apoptosis compounds A-1331852+AZD5991 (BCL-xL + MCL1 inhibitor) and found that BCL-xL and MCL1 inhibition were also synergistic. In the third combination, ML210+ferrostatin-1 (GPX4 inhibitor inducing ferroptosis + ferroptosis inhibitor), we found that ferrostatin-1 antagonized the effects of ML210. Our analysis also reveals the importance of appropriate dose selection and analytical metrics for reliably measuring combined effects. In conclusion, the PRISM platform's multiplexed cell line screening is a robust method for characterizing rationally designed drug combinations, offering a systematic approach to enhance the precision of combination therapy development in cancer care.

Citation Format: Ashish Bino George, Shiker Nair, Mustafa Kocak, Ellen Nguyen, Alvin Kalathungal, Anthony Fazio, Cole Ponsi, Aydin Golabi, Melissa A. Ronan, Matthew G. Rees, Jennifer A. Roth. Assessing cancer drug combination efficacy across 900+ PRISM cell lines in a multiplexed screening assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4560.
Abstract 4575: FGFR3 altered bladder cancer exhibits a lineage-dependent vulnerability
Authors: Koleilat Mohamad Karim , Zhu Yan , Kwong Lawrence
Published: March 2024

Fibroblast Growth Factor 3 (FGFR3) genomic alterations are oncogenic drivers in ~15% of bladder cancer patients. A novel FGFR inhibitor, Erdafitinib, was FDA approved in 2019 based off a Phase II trial with an overall response rate of 40%. However, the majority of patients rapidly relapse at a median of 6 months, requiring combination therapies to prevent drug resistance. We hypothesized that a genome-wide CRISPR screen would identify Erdafitinib-sensitizing co-targets. We screened UM-UC-14, an S249C FGFR3 mutated bladder cancer cell line, and identified Cyclin C as a top hit in addition to known MAPK effectors such as ERK2 and SHP2. Cyclin C is a non-cell cycle related cyclin and part of the CDK8/19 kinase module of Mediator. Pharmacological validation in 4 FGFR3 altered cell lines confirmed a high degree of synergy between Erdafitinib and the CDK8/19 inhibitor Sel120, while no effect was seen in 2 wildtype cell lines, suggesting strong specificity. Moreover, the synergy in FGFR3-mutant cells was superior to that of SHP2 inhibitor SHP099 or the ERK inhibitor BVD-523. Similarly, GATA3 and PPARG also scored highly in our CRISPR screen. These transcription factors have been shown to be sufficient to enforce a luminal identity but not necessarily to maintain it. We validated these 3 genes as sensitizers and show in luminal cells that loss of either GATA3 or PPARG leads to loss of luminal markers and gain of basal markers. In contrast, cells treated with Sel120 showed, on RNAseq, an increase in basal markers without loss of luminal markers. Interestingly, our data suggests that the gain of basal markers, commonly associated with a worse prognosis, is associated with a strong sensitization to FGFR inhibition in FGFR3 alteration driven bladder cancer. We conducted a xenograft experiment confirming that mice responded well to single agent Erdafitinib, but without frank tumor regression. By contrast, Sel120+Erdafitinib induced complete responses in 8/10 mice compared to 6/10 mice for SHP099+Erdafitinib. Remarkably, after 60 days of daily drugging and a 20-day washout, the tumors did not grow back in the complete responders. Importantly, no loss of body weight or other signs of morbidity were found. Our results suggest an immediate and promising benefit in combining either CDK8/19 or SHP2 inhibitors with Erdafitinib in treating patients with FGFR3 alteration driven bladder cancers. Furthermore, we identified a strategy in targeting lineage modulators as sensitizers to existing therapies.

Citation Format: Mohamad Karim Koleilat, Yan Zhu, Lawrence Kwong. FGFR3 altered bladder cancer exhibits a lineage-dependent vulnerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4575.
Abstract 4583: Development of selective HDAC6 inhibitors to improve cancer immunotherapy
Authors: Gajendran Nithya , Suresh Manasa , Quiceno David , Li Xintang , Durr Marie , Tan Karen , Noonepalle Satish Kumar Reddy , Villagra Alejandro
Published: March 2024

Histone Deacetylases (HDACs) are enzymes that modify histones and non-histone proteins. Our group has previously demonstrated that HDAC6 inhibitors (HDAC6is) modulate multiple immune pathways, including those that suppress the antitumoral M2 phenotype, leading to improved antitumor immunity. Despite the potential of HDAC6is, current inhibitors have poor selectivity and off-target effects and only work at micromolar concentrations. In this work, we designed a screening pipeline of HDAC6i, considering selectivity, potency, capacity to prevent the protumoral phenotype of macrophages, and low cytotoxicity on macrophages and other immune cells. This approach has not been tested before, as the standard screening method for antitumoral HDACis has focused on its cytotoxic effect on cancer cells. We initially designed in silico 980 compound derivatives from previously reported HDAC6i, such as SS208, Nexturastat A, and Suprastat. Twenty-four compounds with a high capacity to bind HDAC6 and chemical stability were screened by their ability to inhibit HDAC6 in cell-free conditions. Sixteen compounds demonstrated high potency and were further evaluated in murine macrophages by their cytotoxic effect using CellTox. The capacity to impede tubulin deacetylation was assessed by western blot and deacetylase activity by HDAC-Glo. The top six candidates were then evaluated by their selectivity compared to other HDAC members and by their effect on repressing the expression of protumoral M2 macrophages Arginase 1 and Fizz1, and activation of antitumoral markers TNFa and iNOS by western blot and qRT-PCR. The best three candidates were then evaluated at nanomolar concentrations to explore their immunomodulatory potential of M1 against M2 by performing antigen presentation (SIINFEKL presentation) and phagocytic capacity using microscopy. Two of these compounds, SM-06-09 and SM-05-947, will be further tested in syngeneic murine melanoma models for their ability in tumor regression and antitumor immunity. This study has yielded important insights into developing new and improved HDAC6is with minimal cytotoxicity, and we believe our work will help advance cancer research and ultimately lead to better patient outcomes.

Citation Format: Nithya Gajendran, Manasa Suresh, David Quiceno, Xintang Li, Marie Durr, Karen Tan, Satish Kumar Reddy Noonepalle, Alejandro Villagra. Development of selective HDAC6 inhibitors to improve cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4583.
Abstract 459: Exosomal miRNA 16-5p/29a-3p secreted from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysisExosomal miRNA 16-5p/29a-3p secreted from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysis
Authors: Tien Sui-Chih , Chang Chin-Chun , Chen I-Chih , Huang Ching-Hsuan , Peng Hsuan-Yu , Chang Yu-Ting , Chang Ming-Chu , Hu Chun-Mei , Lee Wen-Hwa
Published: March 2024

Over 80% of the patients with pancreatic ductal adenocarcinoma (PDAC) have cachexia, which is associated with reduced survival, decreased quality of life, and higher rates of metastatic disease. To date, the diagnostic and therapeutic options of PDAC-associated cachexia remain limited due to the lack of a complete understanding of the underlying pathological mechanism. Here, we demonstrate that fat loss is the earliest feature of cachexia induced by PDAC through its secreted exosomes. By analyzing exosomal components of normal and cancer-derived exosomes through small RNA-seq, we identify miR-16-5p, miR-21-5p, miR-29a-3p and miR-125b-5p enriched in pancreatic cancer-derived exosomes and in the exosomes from sera of mice or patients with pancreatic tumor. Among these, miR-16-5p and miR-29a-3p play a key role in fat loss by inhibiting adipogenesis through decreasing Erlin2 and CMPK1 expression leading to C/EBPβ and PPARγ downregulation. Synergistically, miR-29a-3p increases ATGL expression to facilitate lipolysis by suppressing MCT1 expression. Furthermore, PDAC-derived exosomes deprived of miR-16-5p and miR-29a-3p fail to induce fat loss, suggesting that these two exosomal miRs are required for PDAC-induced fat loss. These findings unravel a precise mechanism of how PDAC causes adipose atrophy via exosomal miRs and may provide new diagnostic and therapeutic strategies for PDAC-induced cachexia.

Citation Format: Sui-Chih Tien, Chin-Chun Chang, I-Chih Chen, Ching-Hsuan Huang, Hsuan-Yu Peng, Yu-Ting Chang, Ming-Chu Chang, Chun-Mei Hu, Wen-Hwa Lee. Exosomal miRNA 16-5p/29a-3p secreted from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysisExosomal miRNA 16-5p/29a-3p secreted from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 459.
Abstract 4613: Tumor-derived interleukin 35 facilitates the gemcitabine resistance in pancreatic adenocarcinoma by mediating the dissemination of chemoresistance among PDAC cells
Authors: Huang Chongbiao , Sun Huizhi , Chang Antao , Hao Jihui
Published: March 2024

Rapid drug resistance after chemotherapy is a key cause of treatment failure in human pancreatic ductal adenocarcinoma (PDAC). Here, we found that tumor-derived interleukin 35 (IL-35) mediated the rapid resistance of PDAC to gemcitabine (GEM). The role of IL-35 in GEM resistance was determined by molecular and cell biology approaches in PDAC cells and in patient-derived tumor xenograft (PDX) models. We used whole genome RNA sequencing, molecular cloning and other molecular biological methods to study the molecular mechanism of IL-35 mediated GEM resistance. An anti-IL-35 neutralizing antibody was used in mouse models to investigate the feasibility of targeting IL-35 to overcome drug resistance in pancreatic cancer. We observed the phenomenon that GEM resistance could spread from GEM resistant PDAC cells to GEM sensitive ones. The results of sequencing and experiments confirmed that the IL-35 secretion is responsible for the dissemination of chemoresistance. IL-35 secreted from GEM resistant cells activated the IL35 expression in GEM sensitive cells and upregulated SOD2 expression via GP130-STAT1 signaling, which scavenges reactive oxygen species (ROS) and then leads to GEM resistance.Furthermore, we found that a neutralizing antibody against IL-35 significantly enhanced the tumor suppressive effect of GEM. These findings collectively reveal that IL-35 plays crucial roles in mediating GEM resistance in pancreatic cancer. Moreover, IL-35 might serve as a promising therapeutic target for combating PDAC chemoresistance.

Citation Format: Chongbiao Huang, Huizhi Sun, Antao Chang, Jihui Hao. Tumor-derived interleukin 35 facilitates the gemcitabine resistance in pancreatic adenocarcinoma by mediating the dissemination of chemoresistance among PDAC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4613.
Abstract 4683: Suppression of ARL6ip1 inhibits malignant phenotypes of human colorectal cancer cells in vivo and > in situ
Authors: Lin Yinzhi , Karnan Sivasundaram , Ito Hideaki , Umezawa Kazuo
Published: March 2024

Introduction: Conophylline is an alkaloid isolated from the leaves of the Thai plant, Ervatamia microphylla. We isolated conophylline as an inhibitor of K-Ras functions and an activator of pancreatic β-cell differentiation. It ameliorates various disease models in animals, including cancer, diabetes mellitus, NASH, and hepatic cirrhosis. On the other hand, its molecular target was determined to be ADP-ribosylation factor-like 6-interacting protein 1 (ARL6ip1) using a conophylline-biotin conjugate. ARL6ip1 is located in the endoplasmic reticulum (ER) membrane, and conophylline binds to the cytoplasmic portion of ARL6ip1. Known functions of ARL6ip1 include inhibition of apoptosis, inhibition of glutamate transporter, and modulation of the ER structure. Previously, we knocked out ARL6ip1 in human colon carcinoma cells by CRISPR-Cas9 and found that either deletion of ARL6ip1 or addition of conophylline inhibited migration, invasion and tumorigenicity in cultured cancer cells. In the present research we have studied the in vivo anticancer effect of conophylline and ARL6ip1 knockout, and the mechanism of anticancer activity in cultured cells.

Materials and Methods: Conophylline was isolated from the leaves of Ervatamia microphylla. We employed HCT116 and DLD1 cell lines as human colorectal cancer cells. Cellular migration was measured by a wound-healing assay. The activity of Akt was measured by the phospho-Akt antibody. BALB/cSlc-nu/nu mice were used for the animal experiment.

Results: Colon adenocarcinoma tissue microarray comparing tumor and adjacent normal tissues revealed that ARL6ip1 expression was significantly higher in cancer than in normal tissues. Intraperitoneal administration of conophylline and knockout of ARL6ip1 both inhibited the growth of HCT116 in mice. Neither influenced the bodyweight of animals. Conophylline and deletion of ARL6ip1 both inhibited the migration. Rescue of ARL6ip1 canceled the effect of ARL6ip1 deletion on migration in HCT116 and DLD1 cells. As the mechanism, either conophylline or ARL6ip1 knockout inhibited the Akt activity, which was canceled by the rescue of ARL6ip1 in both cell lines.

Conclusion: ARL6ip1 was found to be highly expressed in the tumor tissue in colorectal cancer. CRISPR-Cas9 knockout of ARL6ip1 showed a similar anticancer activity as treatment with conophylline in the animal experiment. It is likely that the anticancer activity of conophylline would be mediated by Akt. Thus, ARL6ip1 would be a useful molecular target for the treatment of cancer.

Citation Format: Yinzhi Lin, Sivasundaram Karnan, Hideaki Ito, Kazuo Umezawa. Suppression of ARL6ip1 inhibits malignant phenotypes of human colorectal cancer cells in vivo and > in situ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4683.
Abstract 4718: Reclaiming a dirty drug: What is the context of vulnerability to arsenic trioxide in glioblastoma
Authors: Shaffer Charles , Tang Nanyun , Hao Yue , Fink Karen , Snipes George , Mickey Bruce , Berens Michael
Published: March 2024

Glioblastoma (GBM) is the most prevalent type of malignant tumor within the central nervous system. There is a growing demand to develop and adapt new therapeutic options in order to combat the five-year survival rate of 6.8% and improve patient quality of life. Arsenic trioxide (ATO) is the standard of care for myelodysplasia and relapsed or refractory acute promyelocytic leukemia. While currently being classified to have an idiopathic mechanism of action, two specific cytotoxic consequences of ATO have emerged: MNK1 activity and oxidative stress. Across six GBM PDX models a 20-fold difference in sensitivity manifests, indicative of underlying innate sensitivity or resistance to ATO. To correlate this to the proposed mechanisms of action, we observed ATO’s effect on MNK1 activity through eIF4E phosphorylation and glutathione (GSH) levels following treatment. A subset of GBM models exhibited a marked upregulation of eIF4E phosphorylation following treatment with 2 uM ATO. Of the six models, three were chosen to undergo further testing to observe whether this upregulation showed a consistent dose-dependent relationship across the models and correlated with vulnerability to ATO. Combination therapy with the MNK1 inhibitor, ETC-206, displayed mild to moderate synergy on overall cell viability and strong synergy when observing its effects on the glioma stem cell population. This preferential effect on the GSC populations suggests that MNK1i based combination strategies may show greater effectiveness in vivo than indicated by our previous in vitro studies. Nutraceuticals targeting GSH synthesis, Chrysin and Silibinin, displayed a 0.95 to 1.4-fold decrease in ATO IC50 values across all 6 models. To observe whether each nutraceutical impacted GSH levels consistently across all of the tested models, we measured GSH levels following treatment for each individual compound and their combination treatments. These findings further implicate MNK1 activity and cellular response to oxidative stress as markers of ATO sensitivity, however they are not the sole determinates of response. Understanding of the mechanism of action for idiopathic compounds may allow for the discovery of molecular signatures of sensitivity, improving patient selection for clinical trials and the development of new combination approaches to combat resistance in other tumor types.

Citation Format: Charles Shaffer, Nanyun Tang, Yue Hao, Karen Fink, George Snipes, Bruce Mickey, Michael Berens. Reclaiming a dirty drug: What is the context of vulnerability to arsenic trioxide in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4718.
Abstract 4797: Impact of COVID-19 pandemic on breast cancer screening and diagnosis stage in a large midwestern United States academic medical center
Authors: Johnson Kimberly J. , Waken RJ , O'Connell Caitlin P. , Brown Derek
Published: March 2024

Background: Access to breast cancer screening mammogram services decreased in association with the COVID-19 pandemic. There is also evidence for increases in late-stage breast cancer diagnoses. Our objectives were to determine: 1) the COVID-19-affected period on mammogram screening, 2) the proportion of pandemic-associated missed or delayed mammogram screening visits overall and by race/ethnicity and age group, and 3) evidence for pandemic-associated shifts in diagnosis stage.

Methods: Screening mammogram encounter data between 1-1-2019 and 12-31-2022 were extracted from EPIC for females ≥ 40 years old for the screening analysis. We used Bayesian state space models to describe weekly screening mammogram counts, modeling an interruption that phased in and out from 3-1-2020 to 9-1-2020. We used the posterior predictive distribution to simulate differences between a predicted, uninterrupted process and the observed screening mammogram counts. Breast cancer diagnoses at ≥ 21 years from the tumor registry between 12-1-2018 and 11-30-2021 were included in the stage analysis. We used logistic regression models to estimate late-stage diagnosis odds comparing matched three-month periods during the pandemic to before the pandemic.

Results: A total of 319,492 encounters among 146,644 women were included. Model-estimated screening mammograms dropped by 98.8% (95% CI 95.1 to 100) between 3-15-2020 and 5-24-2020, returning to pre-pandemic levels or higher after this period. Drops in screening mammogram encounters did not vary significantly by race/ethnicity or age group (p > .75). Among 4,669 breast cancer diagnoses, we found no significant differences in the odds of late-stage diagnoses for any period vs. the same period before the pandemic (Table).

Conclusions: These data suggest a short-term pandemic effect on screening mammograms. Evidence for increases in late-stage diagnoses is limited. These results may inform future pandemic planning.

OR (95% CI) Period comparison 1.19 (0.74 to 1.91) 3/2020 to 5/2020 vs. 3/2019 to 5/2019 1.05 (0.69 to 1.60) 6/2020 to 8/2020 vs. 6/2019 to 8/2019 1.14 (0.73 to 1.78) 9/2020 to 11/2020 vs. 9/2019 to 11/2019 0.92 (0.60 to 1.41) 12/2020 to 2/2021 vs. 12/2019 to 2/2020 1.08 (0.71 to 1.65) 3/2021 to 5/2021 vs. 3/2019 to 5/2019 0.89 (0.59 to 1.33) 6/2021 to 8/2021 vs. 6/2019 to 8/2019 1.31 (0.84 to 2.04) 9/2021 to 11/2021 vs. 9/2019 to 11/2019

Citation Format: Kimberly J. Johnson, RJ Waken, Caitlin P. O'Connell, Derek Brown. Impact of COVID-19 pandemic on breast cancer screening and diagnosis stage in a large midwestern United States academic medical center [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4797.
Abstract 4822: Disparities in receiving non-surgical therapy impact outcomes in non-metastatic gastric cancer in Louisiana
Authors: Hartupee Conner D. , Maupin Kyla , Danos Denise M. , Moaven Omeed
Published: March 2024

Background: Given the history of evolving medical therapies and advancements in cancer treatments over the last decades, resectable gastric cancer has presented multiple strategies for care. Previous literature indicates historically decreased use of multimodal therapies in minority populations. This study aims to evaluate Louisiana patient populations for rates of definitive treatment, inequities in access to care, and evaluating its impact on the outcomes of minorities and underserved population.

Methods: Patients with non-metastatic primary invasive gastric cancer, with T2-4 or any T status with positive lymph nodes, were identified in the Louisiana Tumor Registry using ICD-O codes and AJCC staging system. Receipt of non-surgical therapy was modeled using logistic regression. Overall survival (OS) was modeled using a Cox proportional hazards model.

Results: The study included 561 patients, of which 37.6% (n=211) did not receive surgical treatment and 16.2% (n=91) did not receive non-surgical therapy. A subset of the cohort received no definitive treatment, (6.8%, n=38). In a demographic only multivariable model, adjusting for age, sex, and race, age 70 and over [OR (95%CI) =0.18 (0.08-0.42), p<0.001] and female sex [OR (95%CI) =0.48 (0.28-0.85), p=0.011] was associated with decreased rates of non-surgical therapy. Black [OR (95%CI) = 0.54 (0.31-0.93), p=0.027] and Hispanic [OR (95%CI) = 0.38 (0.13-1.08), p=0.070] race was associated with decreased receipt of non-surgical therapies. However, after adjusting for domestic partner, insurance status, rurality, area poverty, and surgery status, racial disparities were no longer significant compared to whites: Black [OR (95% CI) = 0.59 (0.33-1.06), p=0.075]; Hispanic [OR (95% CI) = 0.52 (0.17-1.66), p=0.272]. In multivariable analyses, receipt of surgery [HR (95% CI) = 0.3 (0.23 - 0.38), p<0.001) and any non-surgical therapy [HR (95% CI) = 0.43 (0.31 - 0.60), p<0.001) were associated with increased overall survival.

Conclusion: A significant number of patients did not receive all modalities of the multidisciplinary treatment that is recommended for patients with non-metastatic gastric adenocarcinoma. Black patients and females are less likely to receive non-surgical modalities for gastric cancer in Louisiana, which is, at least, partially driven by socioeconomic determinants. Identifying patients with these risk factors is a crucial step in allocating resources to increase access the care and improve outcomes.

Citation Format: Conner D. Hartupee, Kyla Maupin, Denise M. Danos, Omeed Moaven. Disparities in receiving non-surgical therapy impact outcomes in non-metastatic gastric cancer in Louisiana [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4822.
Abstract 4831: Racialized economic segregation and disparities in late-stage diagnosis, treatment and mortality among patients with non-small cell lung cancer
Authors: Shrestha Pratibha , Lian Min , Liu Ying
Published: March 2024

Importance: Little is known about the impact of residential segregation on early detection, treatment, and prognosis among patients with non-small cell lung cancer (NSCLC), a predominant type of lung cancers.

Objective: To examine the associations of racialized economic segregation with the risks of late-stage diagnosis, non-adherence to guideline-recommended treatment, and mortality among non-Hispanic White (NHW) patients and non-Hispanic Black (NHB) patients with NSCLC.

Methods: This population-based retrospective cohort study included patients with NSCLC as a first primary malignancy diagnosed at age 20 and older between January 2007 and December 2015, followed through December 2016, and identified from the Surveillance, Epidemiology, and End Results (SEER) dataset released in April 2019. County-level racialized economic segregation was estimated using the Index of Concentration at the Extremes (ICE). We used multilevel logistic regression and multilevel Cox regression accounting for county-level clustering to estimate odds ratios (ORs) for late-stage diagnosis and non-adherence to guideline-recommended treatment, and hazard ratios (HRs) for overall mortality and lung cancer-specific mortality.

Results: Of 203, 441 patients, 85.8% were NHW and 14.2% were NHB. Compared with patients living in the most privileged (lowest ICE quintile―segregated, high-income NHW) counties, patients living in the least privileged (highest ICE quintile―segregated, low-income NHB) counties had higher risks of late-stage diagnosis (OR=1.09, 95% CI: 1.02-1.16; Ptrend <.001), non-adherence to guideline-recommended treatment (OR=1.28, 95% CI: 1.16-1.41; Ptrend <.0001), lung cancer-specific mortality (HR=1.10, 95% CI: 1.07-1.14; Ptrend <.0001), and overall mortality (HR=1.12, 95% CI: 1.09-1.16; Ptrend <.0001). The association of segregation with treatment underutilization was stronger in NHW patients than NHB patients (Pinteraction =0.02). There was no significant difference in the segregation-related risk of late-stage diagnosis, lung cancer-specific mortality, or overall mortality between NHW and NHB patients.

Conclusions: Living in segregated, low-income NHB counties was associated with increased risks of late-stage diagnosis, suboptimal treatment, and mortality among patients with NSCLC. Future research should investigate contributors to the adverse impact of residential segregation on lung cancer care and outcomes.

Citation Format: Pratibha Shrestha, Min Lian, Ying Liu. Racialized economic segregation and disparities in late-stage diagnosis, treatment and mortality among patients with non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4831.
Abstract 486: Paclitaxel nanoformulation attenuates pancreatic tumor desmoplasia and alter tumor immune responses
Authors: Kashyap Vivek K. , Darkwah Godwin P. , Chauhan Neeraj , Sikander Mohammed , Ghali Eswara N. , Kolli Meghana , Hafeez Bilal B. , Yallapu Murali M. , Chauhan Subhash C.
Published: March 2024

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer with a 5-year survival rate of less than 13% due to the lack of effective diagnostic/therapeutic modalities. Paclitaxel (PTX) has been tested in pancreatic cancer (PanCa) therapy with marginally better clinical outcomes, but remains limited by its poor hemocompatibility, biodistribution, and intracellular accumulation in tumor cells. Gemcitabine (GEM) is the most effective therapy for PanCa. However, it shows only a marginal survival benefit of 6 months. The poor therapy response is attributed to high desmoplasia, unfavorable tumor microenvironment (TME), and excessive recruitment of immune suppressive cells. We have recently engineered a multi-layered Pluronic F127 and polyvinyl alcohol stabilized and poly-L-lysine coated paclitaxel loaded poly(lactic-co-glycolic acid) nanoparticle formulation (PPNPs), which effectively inhibits pancreatic tumor. In this study, we demonstrate that PPNPs effectively sensitize tumor cells to GEM via attenuation of tumor desmoplasia. Our findings also show that PPNPs synergize GEM therapy response in cell lines and in vivo mouse models. Mechanistically, PPNPs target the TME via inhibition of the sonic hedgehog (SHH) pathway and other oncogenic signaling axis that inhibits bidirectional tumor-stromal cell interaction as determined by qPCR and Western blot analyses. In addition, PPNPs effectively target tumor-associated macrophages (TAM) by repolarizing M2 into M1 phenotype via inhibiting expression of M2 markers and an increase in M1 markers in mouse macrophage cell line RAW264.7. M2 polarization of RAW264.7 cells were induced by culture with IL-4 (20 ng/mL) in the presence of PPNPs or vehicle control. Furthermore, PPNPs effectively increase phagocytic capacity in murine macrophages as determined by phagocytosis assay (Vybrant Phagocytosis Assay Kit). In conclusion, we observed that our novel PPNP nano formulation effectively targets TME, and facilitates GEM uptake by inhibiting the activation of SHH signaling and reprograming the tumor immune surveillance mechanisms. This study suggests that PPNPs have great potential for future clinical use in management of pancreatic cancer.

Citation Format: Vivek K. Kashyap, Godwin P. Darkwah, Neeraj Chauhan, Mohammed Sikander, Eswara N. Ghali, Meghana Kolli, Bilal B. Hafeez, Murali M. Yallapu, Subhash C. Chauhan. Paclitaxel nanoformulation attenuates pancreatic tumor desmoplasia and alter tumor immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 486.
Abstract 4879: Delineating lymphocyte aggregates from tertiary lymphoid structures using spatial transcriptomics
Authors: Krull Jordan , Byappanahalli Anjali , Jiang Yi , Gunderson Andrew , Ma Qin
Published: March 2024

Tertiary Lymphoid Structures (TLSs) are ectopic lymphoid structures that form in chronically inflamed non-lymphoid tissue. The presence of TLSs in tumors is largely associated with favorable outcomes among patients and also exhibit positive associations with response to immune checkpoint blockade. Although mainly comprised of lymphocytes (B cells and T cells), they are considered a separate entity from lymphocyte aggregates within tissue. Lymphocyte aggregates are fairly routine to identify in H&E stained tissue sections, but delineating TLSs from simple lymphocyte aggregates is subjective and not clearly defined. Additionally, the definition of TLSs is only recently being elucidated, so a clear molecular definition of both TLSs and lymphocyte aggregates is needed. To address this problem, we leveraged open-source spatial transcriptomics (ST) data from 17 samples across 7 cancer types. High resolution H&E images were manually evaluated for lymphocyte aggregates by identifying dense pockets of lymphocytic-appearing nuclei. Suspected aggregates were detected in 10 of 17 samples. We then applied a visium spot-level signature scoring method for 4 well published TLS signatures. Of the spots identified, 62% had enhanced signature expression for at least 2 of the signatures, although most of the incorrect annotations came from the lone gastric cancer sample. Differential expression between a TLS-sig- suspected lymphoid aggregate and a TLS-sig+ region not identified by H&E enriched primarily for B cell identity genes, suggesting B-cell-rich TLSs may not always appear as lymphoid aggregates in histology. [AG1] Strikingly, ST revealed strongly positive enhancements in the TLS signatures, where no annotations were made, and no obvious lymphoid aggregation was present, suggesting manual annotation from H&E is inadequate for identifying TLSs. Together, these results demonstrate that literature derived TLS signatures can correctly identify lymphoid aggregates as TLSs and that cellular and molecular differences between standard lymphoid aggregates and TLSs may be smaller than is currently accepted.

Citation Format: Jordan Krull, Anjali Byappanahalli, Yi Jiang, Andrew Gunderson, Qin Ma. Delineating lymphocyte aggregates from tertiary lymphoid structures using spatial transcriptomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4879.
Abstract 4896: A high throughput method of identifying cells with increased genomic content across diverse cancer tissues
Authors: Nair Shilpa Priyadarsini , Pienta Kenneth J. , Amend Sarah R.
Published: March 2024

Cancer cells with increased genomic content have been associated with recurrence and poor patient outcomes. The current manual identification of these rare cells by pathologists is time-consuming and labor intensive, given their scarcity within tissue samples. This study introduces a robust methodology for the automated identification of cancer cells with increased genomic content within prostate cancer tissues. Leveraging Qupath software integrated with the Stardist extension, our approach combines precise nuclear segmentation with threshold setting using a Python script. This methodology enables the specific identification of noncancerous small cells, cancerous cells, and those exhibiting genomic content significantly surpassing the average cancer cell (3x to 5x), complemented by thresholds based on hematoxylin intensity for enhanced result accuracy. Thus, our methodology offers an efficient solution to streamline the identification processes for these challenging cells.

We have extensively validated our method across diverse models, including animal and human models, transgenic and subcutaneous models, and Human Tissue Microarrays (TMAs), to identify cancer cells with increased genomic content. The rarity of these cells within tissue samples underscores the practical significance of our research, providing a solution to the current difficulties faced by researchers and clinicians in their identification.

The integration of this methodology aims to improve efficiency in cancer tissue analysis. Ongoing efforts are directed towards the evaluation of this high-throughput methodology using animal models and TMAs with known outcomes, further substantiating its applicability and potential clinical relevance.

Citation Format: Shilpa Priyadarsini Nair, Kenneth J. Pienta, Sarah R. Amend. A high throughput method of identifying cells with increased genomic content across diverse cancer tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4896.
Abstract 4901: High-resolution spatial transcriptomics identifies candidate genes facilitating perineural invasion
Authors: Olgun Deniz Guney , Wang Peter L. , Zhao Ryan , Gong Dennis H. , Hwang William L.
Published: March 2024

Perineural invasion (PNI), or the invasion of cancer to the space surrounding nerves, is associated with poor prognosis, but the underlying molecular factors that drive its initiation and progression are poorly understood. To explore this systematically, we applied a 6000-plex spatial transcriptomic panel with subcellular resolution to curated microarrays from 5 pancreatic ductal adenocarcinoma (PDAC) patients spanning different stages of tumor-nerve involvement. With this preliminary cohort, we explored malignant cell signatures associated with invasion and adaptation to the intraneural environment. Strikingly, we observed enrichment of a classical-like malignant transcriptional program marked by genes involved in glucose and lipid metabolism in nerve-invading malignant cells. Despite the known association of chemoresistance with serine dependence, these cells also exhibited upregulation of genes involved in serine biosynthesis, suggesting that intraneural invasion may offer an orthogonal path of treatment evasion. Overall, our findings indicate that nerve-invasive cancer cells adopt a unique transcriptomic signature within the neuronal microenvironment. Further studies will aim to uncover the relevance of these signatures to survival within the nerve environment and treatment resistance.

Citation Format: Deniz Guney Olgun, Peter L. Wang, Ryan Zhao, Dennis H. Gong, William L. Hwang. High-resolution spatial transcriptomics identifies candidate genes facilitating perineural invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4901.