tbuckley/cabot-search huggingface dataset:
Abstract 1490: Elucidating the effect of glutamine metabolism in breast to bone metastasis
Authors: Breelyn A. Karno, Yoonha Hwang, Rachelle Johnson, Jin Chen, Deanna Edwards
Journal: Cancer Research (2024)

Abstract Bone-metastatic lesions will develop in approximately 65-75% of patients with metastatic breast cancer and are associated with high morbidity and mortality. Despite our limited understanding of how breast-to-bone metastases form, the recent emergence of metabolic adaptation as a critical factor in metastasis is a promising development. Breast cancer cells are particularly reliant on glutamine, a key amino acid that is metabolized by the enzyme glutaminase (GLS) to facilitate many downstream metabolic processes. Bone-tropic breast cancer cell lines significantly enhance their glutamine uptake, suggesting that glutamine metabolism may be a significant factor in bone metastasis. In addition to tumor cells, glutamine metabolism is critical for osteoblasts, important bone-resident cells that contribute to the “vicious cycle” of bone destruction during metastatic outgrowth in the bone niche. In this study, we sought to evaluate the role of glutamine metabolism in breast cancer bone metastasis by examining the effect of GLS function in metastasizing tumor cells and bone-native osteoblasts. Using an intracardiac inoculation model of bone metastasis, we found that breast cancer cells lacking GLS (GLS KO) failed to effectively form bone metastatic tumors. We also observed that GLS KO bone tumors show a reduction in osteolysis using a direct intratibial injection model. Mechanistically, we have found that GLS KO breast cancer cells develop a “senescence-like” phenotype that may limit metastatic outgrowth within the bone. To investigate the importance of glutamine metabolism in the bone niche, we developed a conditional genetic mouse model to delete GLS in osterix-expressing in osteoblast progenitors and mature osteoblasts (GLSOBKO). Remarkably, we observed reduced bone destruction in GLSOBKO mice after intratibial injection of syngeneic breast cancer cells. We also report a reduction in the number of osteoclasts at the bone/tumor interface in these mice, suggesting that loss of osteoblast GLS could temporarily halt the “vicious cycle” of bone metastasis. Together, this work suggests that glutamine metabolism may promote breast-to-bone metastasis via both intrinsic and extrinsic mechanisms. These findings raise the possibility of using pre-existing cancer therapies targeting glutamine metabolism to ameliorate bone metastatic burden in breast cancer. Citation Format: Breelyn A. Karno, Yoonha Hwang, Rachelle Johnson, Jin Chen, Deanna Edwards. Elucidating the effect of glutamine metabolism in breast to bone metastasis [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 1490.
Abstract 4355: Characterizing HRD in ovarian cancer: Insights from copy number signatures
Authors: Aliah Hawari, Avraam Tapinos, Claire J. Kramer, Andreas J. Gruber, Richard Houlston, James Brenton, David Wedge
Journal: Cancer Research (2024)

Abstract Copy number changes are defining features in ovarian cancers. Two distinct methods by Steele et al. and Drews et al., published back-to-back in 2022, detail features and categories of copy number signatures. However, these methods have not been benchmarked for ovarian cancer. Mutational signatures are pivotal in understanding cancer biology and serve as predictive and prognostic biomarkers. This study aims to examine the landscape of copy number signatures to characterize the diversity of Homologous Recombination (HR) impairment within ovarian cancer. While assessing Homologous Recombination Deficiency (HRD) is crucial for targeted treatments, current HRD tests lack clarity. Using signature extraction tools SigProfilerExtractor and CINSignature, we analyzed whole-genome sequencing data (mean depth 100x) from 416 ovarian cases from Genomics England (GeL), employing both copy number signature methods. Among the signatures extracted, HRD signature CN17 from Steele et al. methodology was identified in 37% of the samples and primarily found in the high-grade serous ovarian cancer (HGSOC) subtype (77%). Additionally, higher exposure levels (median of 0.4 in n=154 compared to median of 0.29 in n=416) of Drews et al. methodology’s most complex HRD signature, CX3, was detected in samples exhibiting CN17 activity. This ongoing exploration of the copy number signatures landscape works towards identifying the spectrum of HR impairment, aiming to benchmark these two methods for a standardized diagnostic tool. This study contributes to our understanding of the mutational landscape of ovarian cancer and its potential implications for prevention and personalized treatment strategies. Citation Format: Aliah Hawari, Avraam Tapinos, Claire J. Kramer, Andreas J. Gruber, Richard Houlston, James Brenton, David Wedge. Characterizing HRD in ovarian cancer: Insights from copy number signatures [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 4355.
Abstract 3166: Lipid nanoparticles as an efficient transfection method for the delivery of elephant TP53 and retrogene9 into osteosarcoma cells
Authors: Madison Sanborn, Aaron Rogers, Gareth Mitchell, Ryan Kennington, Miranda Sharp, Joshua D. Schiffman, Lisa M. Abegglen
Journal: Cancer Research (2024)

Abstract Lipid nanoparticles (LNPs) continue to be at the forefront of nanotechnology research due to their versatile and effective ability to deliver DNA, RNA, and small molecules through the cell membrane. Since LNPs are formulated with lipids found naturally in cells, they generate a lower risk for immunogenic response and cause significantly less cell death than traditional transfection methods, such as electroporation. Our microfluidics assembled LNPs have shown transfection efficiencies over 80%, substantially higher than observed with other transfection techniques, and continues to increase over the first 72 hours. We previously reported that elephant TP53 (EP53) induces apoptosis in cancer cells at higher rates than human TP53 (huTP53), and elephant TP53 RETROGENE9 (EP53-R9) contributes to apoptosis through transcription independent mechanisms. To further characterize the effectiveness of these genes, osteosarcoma cell lines were transfected with huTP53, EP53, and EP53-R9 nanoplasmid and mRNA loaded LNPs. Cells treated with EP53 and huTP53 nanoplasmid-loaded LNPs had significantly increased caspase activity and cell death compared to those treated with the empty vector control (P&amp;lt;.0001), with over 90% of all cells treated with either type of p53 dead after 72 hours. Immunocytochemistry was performed to image cells using confocal microscopy, which showed a 36-fold increase in TP53 signal in the nucleus of nanoplasmid LNP treated cells after 72 hours as compared to untreated osteosarcoma cells. In contrast, cells treated with the mRNA LNPs had a 7-fold increase in TP53 signal over 72 hours, though the transfection efficiency was equivalent to the nanoplasmid treated cells. Future studies will assess the efficacy of EP53 and EP53-R9 LNPs in vivo in osteosarcoma mouse models. These results demonstrate the potential of LNP mediated delivery of EP53 and EP53-R9 to be developed as a new treatment approach for cancer patients. Citation Format: Madison Sanborn, Aaron Rogers, Gareth Mitchell, Ryan Kennington, Miranda Sharp, Joshua D. Schiffman, Lisa M. Abegglen. Lipid nanoparticles as an efficient transfection method for the delivery of elephant TP53 and retrogene9 into osteosarcoma 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 3166.
Abstract 5297: CLN-619, a clinical stage MICA/B-specific hIgG1 monoclonal antibody, engages multiple immune effector cells to promote anti-tumor activity
Authors: Kerry A. Whalen, Catherine C. Henry, Kavya Rakhra, Kristan Meetze, Jennifer S. Michaelson, Patrick A. Baeuerle
Journal: Cancer Research (2024)

Abstract CLN-619 is a humanized IgG1 monoclonal antibody that targets MICA and MICB (MICA/B) and is currently in phase 1 clinical development in cancer patients (NCT05117476). MICA/B serve as activating signals on target cells for recognition by the NKG2D receptor, which is expressed on NK cells and a subset of T cell populations. MICA/B expression is induced in response to stressed conditions, thereby enabling NKG2D-mediated elimination of target cells. On NK cells, NKG2D is one of many receptors in the complex network of activating and inhibitory receptors, whereby NKG2D pathway activation results in cytokine production, enhancement of ADCC and target cell death. On CD8 T cells, the NKG2D axis plays a costimulatory role in lowering the threshold for lysis upon TCR engagement, and may also drive direct CD8-mediated killing following prior TCR activation. MICA/B is expressed broadly on a range of solid and hematological malignancies. However, tumor cells evade NKG2D-mediated elimination by shedding MICA/B ligand from the cell surface via proteases present in the tumor microenvironment (TME). CLN-619 functions by binding to MICA/B and preventing shedding, thereby increasing MICA/B cell surface expression to restore the NKG2D-MICA/B axis to promote tumor cell killing by NK cells and T cells. Additionally, CLN-619 can mediate ADCC and ADCP by NK cells and macrophages. In preclinical xenograft models, doses as low as 0.03 mg/kg inhibited tumor outgrowth. We investigated the effects of CLN-619 on a variety of primary immune cells including NK cells, T cells and macrophages. In the evaluation of NK cells, we measured CLN-619 modulation of cytokine production and cytotoxicity in the presence of MICA/B expressing target cells. In addition, we demonstrated the contribution of Fc-mediated functions of CLN-619. In the context of T cells, we explored the requirement of TCR co-stimulation or prior antigen exposure in the activation of the NKG2D pathway by CLN-619. In the context of macrophages, we measured the ability of CLN-619 to mediate ADCP against MICA/B-expressing target cells. These data highlight the potential of CLN-619 to engage multiple immune cell types within the TME, which may lead to greater and broader efficacy compared to IO therapies targeting a single immune cell type. Citation Format: Kerry A. Whalen, Catherine C. Henry, Kavya Rakhra, Kristan Meetze, Jennifer S. Michaelson, Patrick A. Baeuerle. CLN-619, a clinical stage MICA/B-specific hIgG1 monoclonal antibody, engages multiple immune effector cells to promote anti-tumor activity [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 5297.
Abstract 4372: Epithelial-to-mesenchymal transition-driven secretory program underlies vulnerabilities in lung cancer
Authors: Kevin L. Fulp, Oluwafunminiyi E. Obaleye, Guan-Yu Xiao
Journal: Cancer Research (2024)

Abstract Epithelial-to-mesenchymal transition (EMT) is a driving force behind lung adenocarcinoma (LUAD) progression. Although substantial evidence has been attained in the involvement of EMT and its regulatory mechanisms in cancer, few effective EMT-targeted therapies have been available in the clinic thus far. It is urgent to develop new therapeutic strategies for improving patient outcomes. We have identified RAB6A as a master regulator of EMT-driven secretory trafficking, which coordinates cancer cell invasion and immunosuppression in LUAD. We found that RAB6A expression was associated with a poor prognosis in LUAD patients and that RAB6A inhibition in our LUAD models reversed resistance to immune checkpoint inhibition with PD-L1 blockade, an emerging clinical problem. Thus, RAB6A machinery is a therapeutic target of interest in EMT-driven cancers. Screening approaches to identify selective RAB inhibitors are in their infancy, a challenge that can be overcome only by obtaining insights into the regulation of RAB6A. RAB6A is a small GTPase whose activity is controlled by guanine nucleotide exchange factors (GEFs) like RIC1 and RGP1, and GTPase activating proteins (GAPs) like RABGAP1, as well as other effector proteins. While these GEFs, GAPs, and effectors are all known regulators of RAB6A function and are frequently amplified in different cancer types, their specific functions in cancer progression are still unknown. To establish the causal relationship between these proteins and EMT-driven LUAD progression, we utilize human and murine LUAD cell lines that have been characterized with respect to EMT status. Our findings here show that the intervention of RAB6A activity via depletion of these regulators impairs the recruitment of RAB6A to the Golgi. We demonstrate that knocking down the GEFs, RIC1 and RGP1, significantly decreases invasion while having negligible effects on the migrative and proliferative abilities of these cells. RABGAP1 depletion, on the other hand, reduces cell proliferation but has no effects on the migration and invasion of the cells. Consistent with these results, inactivation of RAB6A abolishes the EMT-dependent pro-metastatic secretion. Mechanistically, the EMT activator, ZEB1, upregulates RGP1 via silencing miR-148a that targets this GEF to activate RAB6A. These findings elucidate the regulatory mechanisms underlying the EMT-driven secretory program, providing a foundation for therapeutic intervention to prevent the progression of LUAD. Citation Format: Kevin L. Fulp, Oluwafunminiyi E. Obaleye, Guan-Yu Xiao. Epithelial-to-mesenchymal transition-driven secretory program underlies vulnerabilities in 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 4372.
Abstract 3964: A cancer survival program against activated T cell attack
Authors: Michael X. Wang, Brandon E. Mauch, August F. Williams, Tania Barazande-Pour, Filipe Araujo Hoffmann, Sophie H. Harris, Cooper P. Lathrop, Claire E. Turkal, Michelle H. Paw, David A. Gervasio, Tiffany Tran, Theresa Guo, Gregory A. Daniels, Soo J. Park, Matthew J. Hangauer
Journal: Cancer Research (2024)

Abstract The immune-cancer interactions downstream of immune checkpoint inhibition present the next targetable interface of cancer immunity. Despite evidence for cytotoxic T lymphocyte (CTL) infiltration and cytolytic activity within immunotherapy-responsive tumors, partial responses and acquired resistance are common, indicating additional barriers for complete tumor elimination. We report a survival program engaged within residual cancer cells exposed to weeks of activated CTLs. Contrary to immune-evasion mechanisms, we observe a residual antigenic cancer cell subpopulation which activates CTLs, survives within IFNγ-high environments, and withstands CTL-induced apoptosis. This cancer survival program, termed immune-induced persistence, is reversibly-driven (non-genetic) and prevents the complete CTL-mediated elimination of cancer cell populations by supporting the survival of quiescent cancer ‘persister’ cells against activated CTL attack. Persister cells display sublethal caspase activity and caspase-dependent DNA damage, consistent with CTL-induced genomic instability, and depend on the inhibitors of apoptosis proteins for survival. Notably, immune-induced persistence presents a markedly distinct survival program than drug-induced persistence, including distinctive apoptotic profiles, stress response pathways, and vulnerabilities. Thus, cancer cell populations can transiently adopt non-redundant survival programs in response to various cytotoxic environments. Features of immune-induced persistence are observed within CTL-treated human cancer cell lines, immune-treated human tumor slice cultures, and intratumor transcriptional heterogeneity programs. Under continued CTL exposure, persistent cancer populations give rise to genetically distinct cancer clones, including stably resistant immune escape variants, modeling acquired resistance to cancer immunotherapies. We propose sublethal interactions between effector immune cells and cancer persister cells as a critical and targetable variable at the interface between activated immunity and cancer. Citation Format: Michael X. Wang, Brandon E. Mauch, August F. Williams, Tania Barazande-Pour, Filipe Araujo Hoffmann, Sophie H. Harris, Cooper P. Lathrop, Claire E. Turkal, Michelle H. Paw, David A. Gervasio, Tiffany Tran, Theresa Guo, Gregory A. Daniels, Soo J. Park, Matthew J. Hangauer. A cancer survival program against activated T cell attack [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 3964.
Abstract 5262: MBO enhances anti-tumor immunity in pancreatic ductal adenocarcinoma by inducing immunogenic apoptosis
Authors: Shreyas Ramchandra Gaikwad, Sanjay K. Srivastava
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) poses significant therapeutic challenges due to its aggressive nature and limited treatment options. In this study, we explored the anti-cancer potential of MBO, a compound selected through drug repurposing strategy based on its cytotoxic ability and modulation of key survival pathways in PDAC. Our preliminary in vitro experiments demonstrated MBO's potent cytotoxicity against various PDAC cell lines, inhibiting cellular growth and clonogenicity. MBO induced G1 phase cell cycle arrest in a concentration-dependent manner. In the next step, in vivo, studies using xenograft and orthotopic mouse models confirmed MBO's ability to suppress tumor growth and increase CD8+ T cell infiltration. MBO demonstrated a favorable tumor suppressive activity wherein it suppressed tumor growth by approximately 49% and 56% in xenograft and orthotopic models, respectively. A CD8+ T cell depletion experiment revealed partial dependence on CD8+ T cells for MBO's overall anti-tumor efficacy. Further, combining MBO with anti-PD1 therapy exhibited a synergistic effect, enhancing overall T cell infiltration, particularly CD8+ T cells. Our mechanistic studies revealed that MBO induced immunogenic apoptosis, as evidenced by increased expression of immunogenic cell death markers (HSP90 and calreticulin) and apoptotic markers. To further delineate the mechanism, we performed RPPA profiling. RPPA analysis indicated MBO's impact on mitochondrial gene expression and stress response pathways, suggesting its involvement in disrupting cellular survival mechanisms along with stress-induced immunogenic marker expression. Overall, this study demonstrates MBO as a promising anti-cancer agent with the potential to serve as an immune adjuvant. Particularly, in combination with immunotherapies, MBO can serve as a potential option to improve immunotherapeutic response in PDAC tumors providing valuable insights for developing novel therapeutic strategies in PDAC. Citation Format: Shreyas Ramchandra Gaikwad, Sanjay K. Srivastava. MBO enhances anti-tumor immunity in pancreatic ductal adenocarcinoma by inducing immunogenic apoptosis [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 5262.
Abstract 5283: Polyamine blockade therapy: A strategy to block immunosuppression in pancreatic cancer
Authors: Joseph A. Goode
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients and is characterized by a dense tumor microenvironment (TME) which impedes tumor entry of immune cells and delivery of therapeutics. Immunosuppressive myeloid populations of PDAC, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), are known to not only support PDAC development but also impede the anti-tumor immune response elicited by therapeutic agents. To improve prognosis while maintaining tolerability, this study aims to target polyamine metabolism that is upregulated in the immunosuppressive myeloid populations and cancer cells to disrupt their contribution to PDAC progression and the immunosuppressive TME. We previously demonstrated that polyamine blockade therapy (PBT), via blocking biosynthesis with difluoromethylornithine (DFMO) and transport with a novel inhibitor (Trimer44NMe), elicits an anti-tumor response and improves median survival in PDAC engrafted immunocompetent mice. In the current study, PBT was found to lead to a selective reduction of the dominant MDSC subtype in PDAC, polymorphonuclear (PMN) MDSCs. Upon co-culturing of MDSCs with CD8+ T cells, PBT dampened MDSC-mediated suppression of T cell activity. These findings were corroborated by tracking Arginase 1, a driver of MDSC-mediated immunosuppression, which exhibited a significant decrease in response to PBT at both the activity and gene expression level. Ex-vivo generated M2 macrophages and TAMs treated with PBT also demonstrated a shift from the M2 pro-tumor phenotype towards the anti-tumor M1 macrophage phenotype. In summary, these findings support that PBT is effective at reducing myeloid-mediated immunosuppression through subtype specific modulation and supports the use of PBT for treatment of PDAC in combination with other immunomodulatory therapeutics. Citation Format: Joseph A. Goode. Polyamine blockade therapy: A strategy to block immunosuppression in pancreatic 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 5283.