tbuckley/cabot-search huggingface dataset:
Abstract A053: Dynamic regulation of pyruvate carboxylase is required for immune evasion and pulmonary metastasis
Authors: Mike Coleman, Eylem Kulkoyluoglu Cotul, Dorothy Teegarden, Stephen Hursting, Mike K Wendt
Journal: Cancer Research (2024)

Abstract Metabolic plasticity is an important mediator of tumor cell survival, growth in various microenvironments, and immune evasion. We present a dimorphic role for for the metabolic enzyme pyruvate carboxylase (PC) in pulmonary metastatic versus primary mammary tumors. Specifically, we demonstrate that PC is essential for metastatic outgrowth in the lungs. In contrast, depletion of PC in tumor cells promotes primary tumor growth. This affect was only observed in immune competent animals, leading us to address the hypothesis that repression of PC can suppress anti-tumor immunity. Exploring key differences between the pulmonary and mammary environments we demonstrate that hypoxia potently downregulated PC. Metabolomic analyses demonstrated that in the absence of PC, tumor cells produce more lactate and undergo less oxidative phosphorylation. Inhibition of lactate metabolism was sufficient to restore T cell populations to PC-depleted mammary tumors and drastcially inhibited primary tumor growth. Along these line, forced overexpression of PC decreased lactate production, increased immune inflitation, and prevented initiation of pulmonary metastases. These findings highlight a key contextual role for PC-directed lactate production as a metabolic nexus connecting hypoxia and antitumor immune suppression in primary tumors and intiating pulmonary metastases. However, following immune evasion and initiation of metastasis the return of PC expression is required for propagation of macroscopic pulmonary metastases. Citation Format: Mike Coleman, Eylem Kulkoyluoglu Cotul, Dorothy Teegarden, Stephen Hursting, Mike K Wendt. Dynamic regulation of pyruvate carboxylase is required for immune evasion and pulmonary metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A053.
Abstract B029: Combinations of metformin and BH3-mimetic drugs synergistically induce immunogenic cell death in breast cancer cells
Authors: Mariel Savelius, Linda Id, Johanna Anttila, Ruixian Liu, Ilida Suleymanova, Jani Saarela, Juha Klefström
Journal: Cancer Research (2024)

Abstract There is a compelling medical need for novel and safe treatment options for patients with advanced and difficult to treat breast cancer. Our previous findings have demonstrated that a combination of metformin and navitoclax (BCL-2/BCL-XL inhibitor) successfully prevents tumor growth in patient derived xenograft and syngrafted mouse models of aggressive MYC-driven breast cancer. This outcome is due to the synthetic lethal action of these drugs in tumors with elevated MYC expression. Here, we explored the combinations of metformin with all clinically applicable anti-apoptotic BCL-2 family protein inhibitors (BH3-mimetics) in a panel of 15 triple-negative breast cancer cell lines with distinct endogenous MYC levels, as well as inducible MYC models. We used cytotoxicity assays and analyzed the data with SynergyFinder, an interactive analysis and visualization tool, to calculate the degree of combination synergy utilizing Zero interaction potency reference model. Through these cytotoxicity assays, we defined which metformin and BH3-mimetic drug combination induces most synergistic cell death in a MYC-synthetic lethal manner. Additionally, we used DAMP reporter cell lines and peripheral blood mononuclear cell-based dendritic cell activation assays to evaluate the immunogenic potential of combination-induced cell death. We show that targeting MCL-1 or BCL-2/XL with BH3-mimetics MIK-665 and navitoclax, respectively, and combining them with metformin, induces synergistic cell death in MYC-high cancer cells. We also show that cell death caused by these drug combinations promotes maturation of dendritic cells. In conclusion, targeting MYC-high tumors with synthetic lethal strategies, including BH3-mimetics and metformin, may offer new opportunities to combine with immunotherapies for the treatment of breast cancer. Citation Format: Mariel Savelius, Linda Id, Johanna Anttila, Ruixian Liu, Ilida Suleymanova, Jani Saarela, Juha Klefström. Combinations of metformin and BH3-mimetic drugs synergistically induce immunogenic cell death in breast cancer cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B029.
Abstract IA003: Composing each patient's equation: Deciphering brain tumor dynamics and evolution by integrating multi-regional image-localized biopsies
Authors: Kristin R. Swanson
Journal: Cancer Research (2024)

Abstract Glioblastoma is a uniquely challenging and aggressive cancer that is practically considered uniformly fatal. This aggressiveness is driven by heterogeneity between and within patients and the diffuse invasion of tumor cells deep into the normal appearing brain tissue surrounding the frank tumor abnormality. We use our unique collection of 1000+ image-localized biopsies across nearly 200 patients to detect sex-distinct patterns of mapping between regional imaging features and underlying regional tumor biology. Specifically, we build mathematical models that fuse locoregional changes on MRI to underlying changes in tumor biology. We apply the resultant spatio-temporal models to serial imaging of patients receiving a variety of standard of care and novel therapeutics to track tumor dynamics under said therapies. This allows us unprecedent insight into the dynamics of each patients tumor under therapy. This includes detecting clonal loss through targeted therapies as well as shifts in the tumor ecosystem under immunotherapies. In this presentation, I will demonstrate how these methods can be brought together to help us detect, decipher and predict tumor dynamics and evolution in patients. Specifically, I will demonstrate the value of these novel combined resources in predicting response to treatment for EGFR-targeted therapies in 3 clinical trials and differentiating response to novel dendritic cells vaccines and CAR T-cell therapies in 2 additional clinical trials. Taken together, these complimentary approaches provide a platform to incorporate inter- and intra- tumoral heterogeneity into accurate predictive models that advance evolutionary- and ecologically-adaptive precision oncology for glioblastoma patients. Citation Format: Kristin R. Swanson. Composing each patient's equation: Deciphering brain tumor dynamics and evolution by integrating multi-regional image-localized biopsies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr IA003.
Abstract A061: Grb7 is dispensible for normal development and ERBB2-driven mammary tumorigenesis, but maternal Grb7 deletion causes lactational insufficiency
Authors: Kristopher A. Lofgren, Peter Feiszt, Paraic A. Kenny
Journal: Cancer Research (2024)

Abstract Growth factor receptor-bound 7 (Grb7) is an adaptor protein implicated in signal transduction downstream of multiple receptor tyrosine kinases, including ERBB, FGFR and PDGFR pathways. Experimental studies have implicated Grb7 in regulating cell proliferation, survival, migration, and invasion through its large repertoire of protein-protein interactions. Here, we describe the generation and characterization of a Grb7 knockout (KO) mouse. These mice are viable and fertile. A lacZ knock-in reporter was used to visualize Grb7 promoter activity patterns in adult tissues, indicating widespread Grb7 expression in glandular epithelium, the central nervous system and other tissues. The sole defect observed in these animals was a failure of Grb7 KO females to successfully raise pups to weaning age, a phenotype that was independent of both paternal and pup genotypes. These data suggest a regulatory role for Grb7 in mammary lactational physiology. Grb7 is genomically adjacent to ERBB2 and commonly co-amplified with ERBB2 in human breast cancer. This adaptor protein physically interacts with ERBB2 and has been implicated in oncogenic signal propagation to intracellular pathways. We intercrossed Grb7 KO and MMTV-Neu mice to determine whether Grb7 is required for ERBB2-driven tumorigenesis. Surprisingly, there was no difference in time to tumor detection between cohorts, indicating that Grb7 is not obligately required for ERBB2-driven tumorigenesis. In conclusion, despite a considerable body of literature suggesting key roles for Grb7 in signal transduction pathways involved in both normal and malignant processes, our analysis of Grb7 KO mice demonstrates that Grb7 is largely dispensable for both development and ERBB2-driven tumorigenesis. These data raise the possibility that other Grb family members, Grb10 and Grb14, might compensate for Grb7 loss. Accordingly, a comprehensive assessment of all Grb family members may be needed to fully clarify their physiological roles. Citation Format: Kristopher A. Lofgren, Peter Feiszt, Paraic A. Kenny. Grb7 is dispensible for normal development and ERBB2-driven mammary tumorigenesis, but maternal Grb7 deletion causes lactational insufficiency [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A061.
Abstract B030: ABC101-1, a novel microtubule inhibitor antibody-drug conjugate targeting HER2, has potent anti-tumor activity in a breast cancer model
Authors: Seo Woo Kim, Hana Yu, Geon Ho Lee, Tae Gyu Lim, Minji Jeong, Hyeonjoo Hwang, Jee Eun Moon, Yong Beom Lee, Sung-Ha Jin, Jin Hyun Jeong
Journal: Cancer Research (2024)

Abstract Background: ABC101-1 is an antibody-drug conjugate (ADC) targeting receptor tyrosine-protein kinase erbB-2, also known as HER2. ABC101-1 consists of a humanized IgG1 monoclonal antibody called trastuzumab conjugated to a microtubulin inhibitor, DM1, through interchain cysteines with a drug-to-antibody ratio (DAR) of 8. Our novel non-cleavable linker platform using maleimide as a connector enabled the construction of homogeneous ABC101-1 with DAR of 8, via a straightforward process resulting in high conjugation yield. Employing non-cleavable linkers may ensure that the cytotoxic drug is delivered stably to tumor cells, enhancing the therapeutic efficacy of ADC. Herein, we describe anti-breast cancer activity through in vitro cytotoxicity and in vivo efficacy, pharmacokinetics, and binding affinity of ABC101-1. Methods: In vitro cytotoxicity of ADC and linker-payload was evaluated by measuring cell viability using Cell Count Kit-8 (CCK8) analysis. In vivo anti-tumor activity was investigated using SKBR3 cell line-derived xenograft (CDX) model. A pharmacokinetic (PK) profile was assessed by performing indirect ELISA to determine concentrations of total mAb in the serum. The binding affinity of ABC101-1 to HER2 protein was assessed using the indirect ELISA measuring the concentrations of total mAb. Results: In this study, ABC101-1 exhibited potent in vitro cytotoxicity with picomolar activity on HER2-positive breast cancer cell line. In the CDX breast cancer model, ABC101-1 led to stronger tumor growth inhibition in both early and late phases than ado-trastuzumab emtansine (DAR 3.5) at the same dose. Also, the favorable pharmacokinetic profile of ABC101-1 was observed, along with the preserved antigen-binding ability upon the conjugation to linker-payload. Conclusions: ABC101-1 displayed preclinical efficacy in in vitro and in vivo studies as well as a favorable PK, thereby suggesting its therapeutic potential as an anti-tumor drug in breast cancer therapy. This study would reveal that our novel linker platform is a promising and efficient strategy to develop effective and homogeneous ADCs with DAR 8. Our finding may support the further pre-clinical evaluation of ABC101-1. Citation Format: Seo Woo Kim, Hana Yu, Geon Ho Lee, Tae Gyu Lim, Minji Jeong, Hyeonjoo Hwang, Jee Eun Moon, Yong Beom Lee, Sung-Ha Jin, Jin Hyun Jeong. ABC101-1, a novel microtubule inhibitor antibody-drug conjugate targeting HER2, has potent anti-tumor activity in a breast cancer model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B030.
Abstract PR10: Mammary epithelial architecture modulates field cancerization
Authors: Hendrik A Messal, Cindy Cleyp0ol, Catrin Lutz, Stefan Hutten, Esther Lips, Jos Jonkers, Jelle Wesseling, Ronald Bleys, Ben Simons, Colinda Scheele, Jacco van Rheenen
Journal: Cancer Research (2024)

Abstract The architecture of the human breast undergoes extensive remodelling throughout puberty, the menstrual cycle, pregnancy, and involution with a risk of accumulating genetic alterations and tissue changes. Cells with mutations in cancer driver genes are abundant in tissues of healthy individuals, but rarely develop into tumors. However, the underlying mechanisms that prevent tumor formation are largely unknown. We utilized tissue clearing and imaged 15 disease-free human breasts and cancer resections with subcellular resolution to unravel the 3D architecture of thousands of mammary ducts per individual. Surprisingly, our analysis revealed that disease-free breasts carry a high burden of microscopic tissue lesions indicating widespread abnormal cell behaviour. Distinct mammary trees from the same breast differed in the kind and frequency of lesions, which coevolved scattered along the ductal routes. Combining 3D imaging of FFPE archived breast cancer resections with spatial CNV-seq revealed that, in half the cases, disease-free ductal segments neighbouring early cancer lesions contain molecular alterations. To resolve the mechanisms that regulate mutation spread, we compared the clonal behavior of cells with oncogenic mutations and neutral mutations in the mouse mammary gland epithelium. From the analysis of the clonal dynamics, we find that local tissue remodeling during the estrous cycle leads to the elimination of the majority of mutant clones, while accelerating the expansion of surviving clones. Thus, oncogenic mutations can spread along entire ducts before signs of transformation become apparent. Our data provides understanding of the earliest stages of epithelial evolution preceding disease. Citation Format: Hendrik A Messal, Cindy Cleyp0ol, Catrin Lutz, Stefan Hutten, Esther Lips, Jos Jonkers, Jelle Wesseling, Ronald Bleys, Ben Simons, Colinda Scheele, Jacco van Rheenen. Mammary epithelial architecture modulates field cancerization [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr PR10.
Abstract IA23: "NO Target for Cancer Stem Cells"
Authors: Jenny C. Chang
Journal: Cancer Research (2024)

Abstract Developing novel therapies that target cancer metastasis, chemoresistant cancer stem cells, and augment the efficacy of systemic chemo/radiotherapies is crucial to reducing cancer-associated mortality. A protein within the tumor microenvironment that has gained interest as a promising therapeutic target is nitric oxide synthase (NOS). Our previous findings have shown that increased inducible nitric oxide synthase (iNOS) expression is a poor prognostic indicator and associated with worse overall survival in triple negative breast cancer (TNBC) patients. Nitric oxide (NO) is a unique molecule in its ability to target multiple oncogenic pathways in a spatial and temporal manner, such as PI3K, extracellular signal-regulated kinase (ERK), β-catenin pathway, transforming growth factor beta (TGFβ) signaling, and hypoxia-inducible factor (HIF). Growing evidence has also suggested that hyperactivation of the phosphoinositide-3-kinase (PI3K) survival signaling pathway may be one of the most common oncogenic aberrations in certain TNBC subsets, in particular metaplastic breast cancer (MpBC). We will summarize the role of NO in PI3K-Akt pathway activation in human TNBC, as well as data from The Cancer Genome Atlas of the role of iNOS and PI3K-Akt interaction. This review discusses the current knowledge of the roles of nitric oxide (NO) in tumor progression and cancer metastasis, and promising preclinical studies that evaluated NOS inhibitors as an anti-cancer therapy. Lastly, we will offer a perspective on utilizing NOS inhibitors in the clinical setting, highlighting the prospects and outstanding challenges. Citation Format: Jenny C. Chang. "NO Target for Cancer Stem Cells" [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA23.
Abstract B045: Novel Small Molecule Inhibitors Targeting Proinflammatory Cytokines in Metastatic Breast Cancer
Authors: Cody L Wolf, Clyde Pruett, Darren Lighter, Cooper McGrath, Andrea Feci, Joseph Tuccinardi, Simion Dinca, Ken Tawara, Matthew King, Lisa Warner, Don Warner, Cheryl L. Jorcyk
Journal: Cancer Research (2024)

Abstract Breast cancer is currently the most commonly diagnosed and second leading cause of cancer-related deaths among women in the Unites States. For the past several years, research has focused on the role of inflammatory cytokines such as interleukin-6 (IL-6) and their role in cancer. Increasing evidence suggests that breast cancer patients with high levels of proinflammatory modulators have an overall worse prognosis. Research performed by our lab and others has also shown that oncostatin M (OSM) promotes breast cancer progression and metastasis by inducing circulating tumor cell (CTC) numbers, and metastasis to distant sites in vivo. While efforts have been made to develop FDA approved therapeutics for OSM, previous studies have all utilized monoclonal antibodies and none have survived clinical trials. For the first time, our research group has developed a stepwise approach towards designing and testing novel small molecule inhibitors (SMIs) against OSM. To determine viable candidates, in silico computational screening of compound libraries towards OSM revealed top potential compounds that interact with the receptor binding region and inhibit biological function. These top candidate inhibitors were then analyzed for direct interaction with cytokines using fluorescent quenching and chemical shift perturbation NMR (CSP-NMR). In vitro efficacy of each SMI was then analyzed by measuring inhibition of all signaling cascades activated by OSM using enzyme-linked immunosorbent assays (ELISA) and immunoblot assays. From these in silico and in vitro methods, SMIs were then structurally modified with effective functional groups to increase efficacy of binding interaction and reduce toxicity for living systems. Finally, our most promising small molecule inhibitor that has been sufficiently tested for efficacy was examined in vivo utilizing a novel estrogen receptor-positive (ER+) mouse model of metastatic breast cancer, and treatment with our SMI proved to decrease tumor burden and metastasis, particularly to the lung when compared to vehicle control. In conclusion, our lab has generated the first ever SMI aimed to inhibit OSM-mediated cancer progression. Our continued efforts aim to develop a novel FDA approved therapeutic to improve outcomes for breast cancer patients. Citation Format: Cody L Wolf, Clyde Pruett, Darren Lighter, Cooper McGrath, Andrea Feci, Joseph Tuccinardi, Simion Dinca, Ken Tawara, Matthew King, Lisa Warner, Don Warner, Cheryl L. Jorcyk. Novel Small Molecule Inhibitors Targeting Proinflammatory Cytokines in Metastatic Breast Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B045.
Abstract B033: Targeting CaMKK2 inhibits actin cytoskeletal assembly to suppress cancer metastasis
Authors: Debarati Mukherjee, Rebecca A Previs, Corinne N Haines, Muthana Al Abo, Patrick K Juras, Kyle C Strickland, Binita Chakraborty, Regina Whitaker, Steven R Patierno, Jennifer A Freedman, Ching-Yi Chang, Donald P McDonnell
Journal: Cancer Research (2024)

Abstract Triple-negative breast cancers (TNBCs) tend to become invasive and metastatic at early stages in their development. Despite some treatment successes in early stage localized TNBC, the rate of distant recurrence remains high, and long-term survival outcomes remain poor. In a search for new therapeutic targets for this disease, we observed that elevated expression of the serine/threonine kinase calcium/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) is highly correlated with tumor invasiveness. In validation studies, genetic disruption of CaMKK2 expression or inhibition of its activity with small molecule inhibitors disrupted spontaneous metastatic outgrowth from primary tumors in murine xenograft models of TNBC. High-grade serous ovarian cancer (HGSOC), a high-risk, poor prognosis ovarian cancer subtype, shares many features with TNBC, and CaMKK2 inhibition effectively blocked metastatic progression in a validated xenograft model of this disease. Mechanistically, CaMKK2 increased the expression of the phosphodiesterase PDE1A which hydrolyzed cyclic guanosine monophosphate (cGMP) to decrease the cGMP-dependent activity of protein kinase G1 (PKG1). Inhibition of PKG1 resulted in decreased phosphorylation of vasodilator stimulated phosphoprotein (VASP), which in its hypophosphorylated state binds to and regulates F-actin assembly to facilitate cell movement. Together, these findings establish a targetable CaMKK2-PDE1A-PKG1-VASP signaling pathway that controls cancer cell motility and metastasis by impacting the actin cytoskeleton. Further, it identifies CaMKK2 as a potential therapeutic target that can be exploited to restrict tumor invasiveness in patients diagnosed with early-stage TNBC or localized HGSOC. Citation Format: Debarati Mukherjee, Rebecca A Previs, Corinne N Haines, Muthana Al Abo, Patrick K Juras, Kyle C Strickland, Binita Chakraborty, Regina Whitaker, Steven R Patierno, Jennifer A Freedman, Ching-Yi Chang, Donald P McDonnell. Targeting CaMKK2 inhibits actin cytoskeletal assembly to suppress cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B033.