tbuckley/cabot-search huggingface dataset:
Abstract 4455: Metabolic stress induces a double positive feedback loop between AMPK and p62 conferring dual activation of AMPK and NRF2 to synergize antioxidant defense
Authors: Eun-Ji Choi, Hyun-Taek Oh, Seon-Hyeong Lee, Chen-Song Zhang, Mengqi Li, Soo-Youl Kim, Sunghyouk Park, Tong-Shin Chang, Byung-Hoon Lee, Sheng-Cai Lin, Sang-Min Jeon
Journal: Cancer Research (2024)

Abstract Co-occurring mutations in KEAP1 in LKB1-mutant NSCLC activate NRF2 to compensate losing LKB1-AMPK activity during metabolic adaptation and survival. Here, we investigated the regulatory crosstalk between LKB1-AMPK and KEAP1-NRF2 pathways during metabolic stress. We found that metabolic stress activates NRF2 through the expression and phosphorylation of p62, causing the autophagic degradation of KEAP1. Intriguingly, the induction of p62 during metabolic stress is also required to activate AMPK by promoting AXIN-LKB1-AMPK complex formation and recruiting it to the lysosomal membrane. Importantly, the p62-driven dual-activation of AMPK and NRF2 was critical for tumour growth by synergizing antioxidant defences. In turn, the induction of p62 also required LKB1-AMPK activity, suggesting a double positive feedback loop between AMPK and p62. Mechanistically, the increase in lysosomal pH caused by low glucose metabolism and AMPK-dependent reduction of proton generation induced PP2A-dependent dephosphorylation of TFEB/TFE3 which increased the expression of p62. The increase of ROS caused by metabolic stress induced lysosomal MCOLN1-Ca2+ dependent activation of TAK1 which increased p62 phosphorylation. Protons provided by lactic acid abrogated all the effects caused by metabolic stress. This positive feedback loop between AMPK and p62 that activates AMPK and NRF2 can potentially explain why co-occurring mutations in LKB1 and KEAP1 occur and further provide promising therapeutic strategies for lung cancer. Citation Format: Eun-Ji Choi, Hyun-Taek Oh, Seon-Hyeong Lee, Chen-Song Zhang, Mengqi Li, Soo-Youl Kim, Sunghyouk Park, Tong-Shin Chang, Byung-Hoon Lee, Sheng-Cai Lin, Sang-Min Jeon. Metabolic stress induces a double positive feedback loop between AMPK and p62 conferring dual activation of AMPK and NRF2 to synergize antioxidant defense [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 4455.
Abstract 5770: Inhibition of KRAS G12D mutant with small molecules
Authors: Dae-Hee Lee, Ji Yoon Lee
Journal: Cancer Research (2024)

Abstract Background: RAS mutations are occurring at a high rate in colorectal cancer, lung cancer, and pancreatic cancer. RAS is family of small GTPase proteins with important roles in cell growth, differentiation, proliferation, and survival. There are three types of RAS genes: HRAS, KRAS, and NRAS. The The RAS gene is the most commonly found oncogene in human cancer. KRAS exhibits a highest mutation rate compared to those of HRAS and NRAS in various cancer types. Methods: Colorectal cell line LIM1215, SW48 and NSCLC cell line NCI-H1975, NCI-H838 were used for MTT assays. Apoptosis assay was performed using the annexin V-FITC apoptosis detection kit (BioBud, Cat. LS-02-100). Colony forming assay was performed with 6-well culture plates by seeding 500 cells/well. The expression levels of proteins involved in Q2a-induced signaling pathway were determined by Western blot. In vivo study was performed with tumor xenografts. HT-29 cells were implanted into the right flank of 5-week-old BALB/c nude mice. Tumor size was determined by measuring the diameter (width, length) of the tumor every two days with a digital caliper. All group mice sacrificed at day 19. Results: Patients with cancer involving KRAS mutations are resistant to therapeutics that target epidermal growth factor receptor and show poor outcomes. In addition, effective treatments that target G12D in KRAS have not been developed. Thus, therapeutic agents targeting the G12D mutation in KRAS are needed. In this study, we identified the Q2a compound, a quinazoline-based derivative that specifically acts on the KRAS G12D mutation. This compound induced cell apoptosis by reducing phosphorylation of AKT in the PI3K pathway downstream of KRAS. Q2a compound specifically inhibited the growth of KRAS G12D mutant cells. In addition, cells with the KRAS G12D mutation were more sensitive to Q2a compound compared to the sensitivity of wild-type cells and those with other KRAS mutations, resulting in apoptosis. Treatment with the Q2a compound also decreased C-RAF phosphorylation in the MAPK pathway, which is downstream of KRAS. In KRAS G12D-mutated colorectal cancer xenografts, Q2a compound inhibited tumor production without significant liver toxicity. Conclusion: Q2a compounds show potential as therapeutic agents that target KRAS G12D mutations in colorectal and pancreatic cancers. Kyewords: Anti-Cancer Drug, KRAS G12D Mutant, apoptosis, colon cancerJi Yoon Lee, Dae-Hee Lee*Department of Marine Bio Food Science, Gangneung-Wonju national University Citation Format: Dae-Hee Lee, Ji Yoon Lee. Inhibition of KRAS G12D mutant with small molecules [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 5770.
Abstract 4129: Mitochondria-targeted antioxidant MitoQ inhibits human breast cancer metastasis in mice
Authors: Tania Capeloa, Pierre Sonveaux
Journal: Cancer Research (2024)

Abstract In oncology, the occurrence of distant metastases often marks the transition from curative to palliative care. Such outcome is highly predictable for triple-negative and HER2-positive breast cancer patients, even if tumors are detected early, and there is no treatment to prevent metastasis. Here, considering that mitochondria are bioenergetic sensors of the tumor microenvironment, we report in preclinical mouse models that human breast cancer relapse is not a fatality: local recurrence and metastatic dissemination can be prevented by MitoQ, a mitochondria-targeted antioxidant that already underwent Phase I safety and Phase II efficacy trials in humans for pathologies other than cancer. Metastatic prevention was confirmed in the MMTV-PyMT model of spontaneously metastatic mouse breast cancer. After oral delivery, MitoQ was effective at nanomolar concentrations at which nonmalignant cells were spared. In anticipation of future clinical trials, a robust signature of the response to MitoQ was defined, applicable to bulk primary tumor biopsies. Citation Format: Tania Capeloa, Pierre Sonveaux. Mitochondria-targeted antioxidant MitoQ inhibits human breast cancer metastasis in mice [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 4129.
Abstract 5769: Target identification of T-cell activating immunomodulatory tetrahydrothiazepines: DGKα and DGKζ inhibitors
Authors: Thomas Luebbers, Adrian Britschgi, Veronica Costa, Thomas Friess, Jean-Christophe Hau, Gordon Heidkamp, Holger Kuehne, Laetitia J. Martin, Filip Roudnicky, Manuel Tzouros, An Vandemeulebroucke
Journal: Cancer Research (2024)

Abstract We became interested in bicyclic tetrahydrothiazepine derivatives described in a Patent (WO 2016/139181) having immunomodulatory activities on CD3-activated T cells (CD4+ &amp; CD8+) and NK cell increasing the secretion of several cytokines such as, e.g., IL-2, IFN-γ and/or TNF-α whereas corresponding unstimulated immune cells do not respond. Surprisingly - in contrast to what has been described in the patent - the N-H of the Amides 1 and 2 described in the patent was not required for potency and the oxadiazoles 1 and 2 were significantly more potent in T-cell proliferation and IL-2 release. Compound 1 was in vivo active in a single dose PD study in mice after CD3 activation and in a MC38 xenograft mice model showing single agent activity. Amide 1 and Amide 2 were identified in a phenotypic screen and the mode of action was unknown. Because of the promising pharmacological profile and in vivo activity, we were interested in the target. Here we describe how we identified the potential targets DGKα and DGKζ. Citation Format: Thomas Luebbers, Adrian Britschgi, Veronica Costa, Thomas Friess, Jean-Christophe Hau, Gordon Heidkamp, Holger Kuehne, Laetitia J. Martin, Filip Roudnicky, Manuel Tzouros, An Vandemeulebroucke. Target identification of T-cell activating immunomodulatory tetrahydrothiazepines: DGKα and DGKζ inhibitors [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 5769.
Abstract 5785: Shedding light on PARP1-E2F1 interaction by Cryo-EM
Authors: Pablo Iglesias, Ester Casajus-Pelegay, Maria Moreno-Morcillo, Lara González-Rendo, Laura Porres-Ventin, Victor M. Arce, Rafael Fernandez-Leiro, Jose A. Costoya
Journal: Cancer Research (2024)

Abstract Cell division is orchestrated by a complex network of interactions between proteins involved in numerous signaling pathways that control cell proliferation. One of these main players is the E2F family of transcription factors. The role of these key players is to regulate the expression of several genes important in cell proliferation, particularly those involved in progression through G1 and into the S-phase of the cell cycle. In fact, cell cycle deregulation is a hallmark of cancer, and multiple studies have highlighted the critical role of E2F hyperactivation in tumor progression, angiogenesis, and metastasis. However, targeting a master regulator of cell growth will also have a pernicious effect on non-cancerous cells, thus limiting its applications. In order to overwhelm these restrictions, we propose a therapeutic approach in which E2F transcriptional activity is specifically reduced in cells with hyperactivation of the pathway, such as cancer cells.We and others have shown that poly (ADP-ribose) polymerase 1 (PARP1) is a transcriptional co-activator of E2F1 and, owing to this, loss of PARP results in cell cycle re-regulation and reduction of tumor growth. Interestingly, this effect of PARP1 does not depend on its enzymatic activity, thus opening a completely new strategic approach. Furthermore, considering that most oncogenic processes are associated with cell cycle deregulation, disruption of PARP1-E2F1 interaction could provide a new therapeutic target with a wide spectrum of indications in cancer. Currently, we lack comprehensive structural details regarding the PARP-1/E2F1 protein-protein interaction. To address this, we used cryo-EM to investigate both the standalone structure of PARP1 (full length) and its interaction with E2F1. This approach yielded high-resolution structural insights into the PARP1-E2F1 complex, enabling precise identification of the protein-protein interaction interface (PPI). Through this exploration of structural and molecular determinants governing this interaction, we aim to develop innovative strategies for designing drugs targeted at disrupting this complex. This work was supported by Agencia Estatal de Investigación (AEl/10.13039/501100011033), Xunta de Galicia (GPC GI-1862, ED431B 2020/26; ED431G 2019/02) and European Regional Development Fund-ERDF. Citation Format: Pablo Iglesias, Ester Casajus-Pelegay, Maria Moreno-Morcillo, Lara González-Rendo, Laura Porres-Ventin, Victor M. Arce, Rafael Fernandez-Leiro, Jose A. Costoya. Shedding light on PARP1-E2F1 interaction by Cryo-EM [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 5785.
Abstract 5863: Double-negative prostate cancer emerges through a mixed basal, club, and hillock cell identity driven by KLF5
Authors: Samuel Pitzen, Yinjie Qiu, Sarah Munro, Scott Dehm
Journal: Cancer Research (2024)

Abstract The purpose of this study was to characterize the phenotypes and drivers of therapy-induced lineage plasticity during the development of castration resistant prostate cancer (CRPC). While the majority of localized prostate cancer can be cured with surgery or radiation, metastatic disease is lethal. Therapies targeting the androgen receptor (AR) are initially effective, but eventually men will develop CRPC. About 70-75% of CRPC displays restored AR signaling (ARPC), while the remaining 25-30% display lineage plasticity evidenced by the emergence of AR-negative subtypes including those that display neuroendocrine (NE) markers, or double negative CRPC (DNPC) lacking both AR and NE markers. AR independent manifestations of CRPC represent a clinical challenge because no effective therapies are available and therapeutic targets are largely unknown. We analyzed publicly available bulk and single-cell RNA-seq datasets derived from clinical CRPC specimens to characterize the cellular identity of AR-negative tumors. Using a database of all known transcriptional regulators, we identified potential drivers of these phenotypes. We performed siRNA-mediated knockdown experiments in a model of DNPC to explore the extent to which the candidate regulators maintain AR-negative cell identity and sustain growth of DNPC prostate cancer cells. We identified a subset of CRPC tumors that co-express gene sets defining basal, club, and hillock cells in the benign prostate. This data supports the existence of epithelial cell lineage plasticity manifesting within CRPC tumors, as well as individual CRPC tumor cells, wherein AR-positive tumor cells transform to a phenotype encompassing basal, club, and hillock cell identities. We nominated the stem cell transcription factor KLF5 as a regulator of basal, club, and hillock cell identities in CRPC. In cell line models of DNPC, knock down of KLF5 inhibited cell growth and reduced the expression of genes defining basal, club, and hillock cell identities. This work links a prevalent and poorly-defined subtype of AR-negative CRPC to AR-negative epithelial cell types in benign prostate tissue. Inhibition of KLF5 and its downstream effectors could represent a therapeutic strategy to prevent or delay lineage plasticity and thereby extend patient response to AR-targeted therapies. Citation Format: Samuel Pitzen, Yinjie Qiu, Sarah Munro, Scott Dehm. Double-negative prostate cancer emerges through a mixed basal, club, and hillock cell identity driven by KLF5 [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 5863.
Abstract 1547: Melanotransferrin (<i>MELTF</i>, CD228) as a determinant of melanomagenesis: <i>MELTF</i> expression attenuates melanoma progression in the A375-luc2 murine metastasis model and human patients
Authors: Jana Jandova, Georg T. Wondrak
Journal: Cancer Research (2024)

Abstract The cell-surface glycoprotein melanotransferrin (MELTF, CD228) is a member of the iron-binding transferrin superfamily expressed in human melanocytes and other cell types. Dysregulated MELTF expression in malignant melanoma has been reported before but its specific role in tumorigenesis has remained elusive. Following our interest in the role of the transferrin receptor (TFRC) in melanomagenesis, our initial TCGA-analysis suggested that high MELTF expression is associated with increased melanoma patient survival. In order to explore the mechanistic role of MELTF in melanoma we performed CRISPR/Cas9-based MELTF deletion in A375-luc2 human malignant melanoma cells. ICP/MS-analysis indicated no difference in iron-content between MELTF_WT and MELTF_KO cells. NanoString nCounterTM ('PanCancer-Progression-Panel'; 770 genes) comparative transcriptomic profiling (MELTF_KO versus MELTF_WT) demonstrated an upregulation of EMT-related expression networks in MELTF_KO cells, an observation consistent with phenotypic detection of enhanced matrigel invasiveness; likewise, inclusion of recombinant glycosylated MELTF (Gly20-Gly711 His-tag; 92 kDa; 10-100 nM) attenuated invasiveness of MELTF_KO cells. In SCID mice, subcutaneous growth of MELTF_KO exceeded that of MELTF_WT xenografts, and intracardial injection followed by non-invasive bioluminescent monitoring revealed an increase in lung metastatic burden associated with decreased survival of the MELTF_KO group. These data support a heretofore unrecognized tumor-suppressive function of MELTF expression in melanoma progression, a mechanistic role consistent with a potential survival benefit associated with high MELTF expression observed in human melanoma patients. Citation Format: Jana Jandova, Georg T. Wondrak. Melanotransferrin (MELTF, CD228) as a determinant of melanomagenesis: MELTF expression attenuates melanoma progression in the A375-luc2 murine metastasis model and human patients [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 1547.
Abstract 3116: Bioluminescent 3D tumors with immune cell co-culture for high throughput screening (HTS)
Authors: Fu-Ju Chou, Samaneh Kamali, Mara Gilardi, Brandon Walling, Abhay Andar, Karin Abarca-Heidemann, Maria Mancini
Journal: Cancer Research (2024)

Abstract In the past decade, cancer immunotherapy has revolutionized the cancer treatment strategy. Immune-oncology (IO) drugs play an important role in treating various malignancies. Immunotherapies work by re-educating and boosting patients’ immune systems to recognize and eliminate cancer cells. The immune co-culture assay provides invaluable information to understand the tumor microenvironment (TME) and observe the immune response after IO drug treatment. Recent advancements in the Champions TumorGraft3D (CTG3D) platform provides more consistent and accurate information for preclinical drug evaluation, but also efficiently simulate the tumor-Immune microenvironment (TIME) and interactions between cancer organoids and immunocyte. However, current analytic approaches in organoid-immune co-culture studies are still highly reliant on flow cytometry and high-resolution confocal imaging endpoints to provide the study outcome. There is a need for a fast and cost-effective co-culture platform to help set up experimental conditions. Easily traceable tags (e.g. bioluminescent and fluorescent) can quickly help establish reliable the effector (E) cell to tumor (T) cell conditions, thus enabling the user to test multiple immune-cell activator or engagers concentrations in a cost-effective and rapid manner. At Champions Oncology we provide stable Luc/GFP-tagged CTG3D models. We have built a reliable CTG3D-immune co-culture platform with various indications (including colon, prostate, gastric, non-small cell lung cancer, and leukemia) which can be used in co-culture with autologous TIL, allogenic TIL and NK cells, thus providing users a fast and cost-effective option to optimize the E:T ratio and monitor the drug performance. Citation Format: Fu-Ju Chou, Samaneh Kamali, Mara Gilardi, Brandon Walling, Abhay Andar, Karin Abarca-Heidemann, Maria Mancini. Bioluminescent 3D tumors with immune cell co-culture for high throughput screening (HTS) [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 3116.
Abstract 5613: Study of long non-coding RNA TUG1 kinetics under replication stress conditions in cancer cell
Authors: Tomoya Fujita, Miho Suzuki, Osamu Masui, Keiko Shinjo, Yutaka Kondo
Journal: Cancer Research (2024)

Abstract Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that are not translated into proteins. In contrast to protein-coding mRNAs, certain lncRNAs carry out their functions within the nucleus. A detailed elucidation of the kinetics of lncRNAs contributes to a comprehensive understanding of their bona fide biological characteristics. Consequently, advancements in the in vivo visualization of lncRNAs have continued. Currently, various techniques, including RNA imaging technologies, have been employed to facilitate real-time tracking and visualization of RNA molecules within living cells. Taurine upregulated gene 1 (TUG1) is an oncogenic lncRNA, playing a pivotal role in cancer cells by resolving R-loops formed at stalled replication forks, particularly under replication stress conditions such as Hydroxyurea (HU) treatment. Despite its significance, the dynamic regulation of TUG1 under replication stress conditions remains largely unknown. In this study, we developed a stem loop-based live imaging system enabling real-time visualization of TUG1, providing insights into its subcellular localization and dynamic roles in physiological contexts. Upon treatment with HU, a chemical that interferes with replication, TUG1 expression was rapidly upregulated in the nucleus within 20 minutes. Additionally, we observed TUG1 molecules relocating close to the nuclear membrane. Considering the reported relocation of collapsed forks to the nuclear pore complex, this suggests that TUG1 may be involved in this relocation structure. These data indicate that TUG1 is associated with the fork restore mechanism occurring at the relocated collapsed forks, and the current live-cell imaging system holds potential for further uncovering the critical roles of TUG1 in cancer cells. Our stem loop-based imaging may contribute to a more precise understanding of RNA dynamics in live cells. Citation Format: Tomoya Fujita, Miho Suzuki, Osamu Masui, Keiko Shinjo, Yutaka Kondo. Study of long non-coding RNA TUG1 kinetics under replication stress conditions in cancer cell [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 5613.