tbuckley/cabot-search huggingface dataset:
Abstract 6295: Role of MAPK11 in the protective mechanisms against toxicity of tyrosine kinase inhibitors
Authors: Anna Pavlovna Hnatiuk, David Staudt, Mark Mercola
Journal: Cancer Research (2024)

Abstract Introduction and purpose of the study: Targeted therapies with Tyrosine Kinase Inhibitors (TKIs) have drastically improved the survival of cancer patients. However, long term exposure to TKIs has been associated with severe adverse events such as heart failure, impairing patient survival and life quality, and limiting treatment options. Cardioprotective effect of MAPK11 has been described against cardiac ischemic disease. In addition, MAPK11 has also been reported as an important mediator in cancer development and progression. Therefore the aim of this study is to evaluate the potential therapeutic and dual anti-cancer and cardio-protective effect of MAPK11 inhibition during TKI treatment. Experimental procedures: For this study we used the TKI ponatinib as a paradigm of cardiac toxicity. Ponatinib has been used as a gold standard therapy for the drug resistant type of Chronic Myeloid Leukemia (CML) due to T315I-ABL1 mutation, and has been associated with high risk of cardiac toxicity. We performed in vitro functional assays to evaluate the cardiotoxicity and cardiac protection using human iPSC-cardiomyocytes (hiPSC-CMs), and anti-cancer effect in T315I mutated KCL-22 CML cells. The cardiotoxicity was evaluated by impairment of cardiomyocytes contractile function during TKI (ponatinib) treatment, the cardiac-protection was evaluated by restoration of contractile function post-inhibition of MAPK11 with RNA silencing (siRNA) technique. The anti-cancer effect was evaluated using a cell viability and proliferation assay during inhibition of MAPK11 by siRNA and ABL1 inhibition as a positive control. Summary of unpublished data: Pretreatment with siRNA MAPK11 inhibition significantly improved the contractile function of the cardiomyocytes during treatment with ponatinib when compared to those that did not receive MAPK11 inhibition. Moreover, when compared to the positive control of siRNA ABL1 inhibition, the MAPK11 inhibition showed similar anti-cancer effect in the T315I mutated KCL-22 CML cells proliferation and survival assay. Conclusions: Our study suggests that the inhibition of MAPK11 is a potential druggable therapeutic target with dual action of anti-cancer effect for the mutant form of CML, as well as a substantial protective effect against the cardiac toxicity associated with the TKI ponatinib that could bring insights in the development of safer oncological drugs. Citation Format: Anna Pavlovna Hnatiuk, David Staudt, Mark Mercola. Role of MAPK11 in the protective mechanisms against toxicity of tyrosine kinase 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 6295.
Abstract 515: Endocycling cancer cells undergo multiple S phases while repressing myc activity
Authors: Michael A. Loycano, Kenneth J. Pienta, Sarah R. Amend
Journal: Cancer Research (2024)

Abstract Chemotherapy resistance remains a major challenge when treating patients with metastatic cancer. While intrinsic resistance to therapy has been well studied, phenotypic plasticity that drives entry and exit of resistant cell states is poorly understood. One of these plastic cell states used by cancer cells under chemotherapy treatment is characterized by the reprogramming of the mitotic cell cycle to enter a non-proliferative endocycle. Cells in this endocycling state decouple DNA synthesis from cell division by actively progressing through G1, S, and G2 phases of the cell cycle while repeatedly skipping mitosis. After a dormant period, cells can switch back to a mitotic cell cycle to repopulate a tumor. The underlying mechanisms that drive this cell cycle reprogramming remain unknown. C-myc is an oncogenic transcription factor that is dysregulated in ~70% of human cancers. C-myc is responsible for the activation of several cell cycle drivers, including cyclins and CDKs, and represses cell cycle inhibitors, such as CDK inhibitors. High levels of myc activity allow cells to move through the cell cycle quickly with a rapid doubling time. Documented endocycles in polyploid cells rely on high c-myc activity; however, our data shows that endocycling cancer cells have repressed levels of c-myc protein and transcriptional activity. Transcriptomic data shows that myc target genes are expressed at very low levels compared to the mitotic parental cells, and complementary data shows low protein levels. While myc downregulation is expected in non-proliferative cells, the compensatory mechanisms mediating the G1/S transition in the cancer endocycle remain unknown. Recent data has shown that myc suppression alone is not sufficient to induce a sustained endocycle at a population level, despite premature APCCdh1 activation during G2 in a subset of cells. We hypothesize that restoring myc activity to the levels of mitotic parental cells will drive endocycling cells to resume a proliferative mitotic cell cycle and produce mitotic progeny cells. Understanding the mechanisms that govern this transition is crucial to generate next-generation cancer therapeutics to disrupt endocycling cells, blocking acquired resistance and disease recurrence. Citation Format: Michael A. Loycano, Kenneth J. Pienta, Sarah R. Amend. Endocycling cancer cells undergo multiple S phases while repressing myc 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 515.
Abstract 7223: A triplet therapeutic strategy targeting MEK, BCL-XL, and EGFR, for KRAS-mutant pancreatic ductal adenocarcinoma
Authors: Gerik W. Tushoski-Alemán, Alexandra J. Crespin, Chibeze J. Oguejiofor, Jordan A. McKean, Kelly M. Herremans, Thomas J. George, Carmen J. Allegra, Steven J. Hughes, Song Han
Journal: Cancer Research (2024)

Abstract KRAS mutations drive over 90% of pancreatic cancers, but KRAS has been proven difficult to target. Downstream of KRAS, MEK inhibition in combination with BCL-XL inhibition is synthetically lethal and an effective treatment for gynecologic, but not colorectal malignancies. Like colorectal cancer, pancreatic cancer often exhibits aberrant HER/EGFR activity. We hypothesized that a triplicate regimen targeting MEK, BCL-XL, and EGFR/HER would be effective for pancreatic cancer. Trametinib (MEK inhibitor), Afatinib (pan-EGFR/HER inhibitor), and Navitoclax (BCL-XL inhibitor); or DT2216 (a BCL-XL/BCL-1 proteolysis targeting chimera, PROTAC) were explored using various combinatorial strategies. These drug combinations were tested using four primary human pancreatic cancer cell lines using live cell imaging (Incucyte) and an in vivo murine model. Group comparisons were analyzed using one-way ANOVAs, and adjusted p-values &amp;lt;0.05 were considered significant. We observed that no single-agent treatments were effective. MEK inhibition plus anti-BCL-XL (Trametinib + Navitoclax or Trametinib + DT2216) demonstrated efficacy in one of the four cell lines. We noted synergistic effects on reduced cell growth and increased cell death when EGFR/HER inhibition was included by the administration of Afatinib. The triplet combination resulted in synergistic effects in three of four cell lines with Navitoclax and four of four cell lines with DT2216 (q&amp;lt;0.05). This effect was confirmed with DT2216 inhibition of BCL-XL in an in-vivo murine model. In conclusion, our study shows that a combinatory strategy targeting MEK, BCL-XL, and pan-EGFR/HER receptor kinase shows significant synergistic effects in pancreatic cancer. Clinical trials that assess the efficacy and safety of this strategy for patients with KRAS-mutant pancreatic cancer are warranted. Our data also suggests that novel KRAS inhibitors as monotherapy are likely to fail. Citation Format: Gerik W. Tushoski-Alemán, Alexandra J. Crespin, Chibeze J. Oguejiofor, Jordan A. McKean, Kelly M. Herremans, Thomas J. George, Carmen J. Allegra, Steven J. Hughes, Song Han. A triplet therapeutic strategy targeting MEK, BCL-XL, and EGFR, for KRAS-mutant pancreatic ductal adenocarcinoma [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 7223.
Abstract 4488: Newly developed organoiridium(III) complexes containing N,P-ligands possess antiproliferative activity in selected cancer cell lines
Authors: Renata Hezova, Jan Hosek, Nicol Strakova, Pavlina Simeckova, Josef Masek, Simona Kajabova, Pavel Starcha
Journal: Cancer Research (2024)

Abstract In conventional cancer treatment, platinum-based cytostatics are considered as standard therapy; however, they possess severe side effects. This fact leads to a constant effort to develop new non-platinum metallodrugs with different mechanism of action (MoA). In our study we developed new half-sandwich organoiridium(III) complexes, of general formulas [Ir(η5-Cp*)Cl(LNP)]PF6 (1-3) and [Ir(η5-Cpph)Cl(LNP)]PF6 (4-6) involving three different N,P-donor phosphinoalkylamines (LNP), which we tested on 2D and 3D cancer models; HCp* = pentamethylcyclopentadiene, HCpph= (2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)benzene. The most effective complexes 3 and 6 bearing 3-(diphenylphosphanyl)propan-1-amine had the highest cytotoxic effect against various cancer cell lines (THP-1, HeLa, SW982, A549, MOR) including a cisplatin-resistant lung carcinoma cell line (MOR/CPR) with IC50 values between 3.1 and 9.1 μM for specific cell lines. The cytotoxic effect was further demonstrated on 3D spheroids of lung cancer cells that revealed anti-cancer and anti-migration potential of complexes 3 and 6. Cell cycle and cell death analysis showed a different mechanism compared to the effect of cisplatin. Moreover, complex 3 did not decrease cell viability of non-cancerous cells (peripheral blood mononuclear cells and porcine chondrocytes) under 50% at a concentration of 20 µM. In addition, we report for the first time that organoiridium complexes showed high cytotoxic activity on cancer cell lines, including cisplatin-resistant cell line, with different MoA from cisplatin. They trigger expression of stress-related genes associated with oxidative stress, DNA damage, and endoplasmic reticulum stress and, moreover, complex 3 showed cytotoxic selectivity towards cancer cells. This work was supported by the Czech health research council of the Ministry of Health of the Czech Republic (AZV Project NU22-08-00236). Citation Format: Renata Hezova, Jan Hosek, Nicol Strakova, Pavlina Simeckova, Josef Masek, Simona Kajabova, Pavel Starcha. Newly developed organoiridium(III) complexes containing N,P-ligands possess antiproliferative activity in selected cancer cell lines [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 4488.
Abstract 2347: Zuclopenthixol as an inhibitor of glioblastoma-induced neuronal hyperexcitability
Authors: Mikias B. Negussie, Saritha Krishna, Ying Wei, Cesar Nava Gonzales, Mulki Mehari, Shawn L. Hervey-Jumper
Journal: Cancer Research (2024)

Abstract Introduction Drug repurposing serves as a promising avenue for glioblastoma treatment, especially as new evidence emerges about the role of neuronal activity dependent tumor proliferation. Structure based drug discovery with virtual screening requires highly accurate 3D information about the target of choice. Recent developments in machine learning based protein structure prediction have allowed for the exploration of chemical space with virtual screening tools not previously accessible via traditional methods. Netrin-G1 (NTNG1) is an axonal guidance molecule implicated in glioblastoma with high functional connectivity to the cortex. In this study, we explore pharmacologic inhibition of NTNG1 with a clinically approved compound. Methods We perform protein structure predictions with AlphaFold2, followed by structure relaxation in an explicit solvent environment with NAMD 2.14. A final confirmation of NTNG1 was used as input to an AutoDock Vina based virtual screening platform. Zuclopenthixol (ZP) was chosen from a list of hits for microelectrode array (MEA) experiments in a mouse neuron/patient-derived tumor cell co-culture environment. Results A list of clinically approved compounds were returned from our virtual screen. ZP was chosen for validation studies, as it readily crosses the blood-brain barrier and occupies the entire TSP1 binding site in NTNG1. Preliminary results from MEA studies suggest ZP reduces tumor-mediated hyperexcitability and adequately modulates a protein-protein interaction between NTNG1 and TSP1. Conclusion By demonstrating that ZP decreases tumor-mediated hyperexcitability, this study offers evidence for the novel application of ZP to reduce glioblastoma proliferation. Further work will focus on survival analyses in mice treated with ZP and validation of experimental compounds that are structurally similar to ZP. Citation Format: Mikias B. Negussie, Saritha Krishna, Ying Wei, Cesar Nava Gonzales, Mulki Mehari, Shawn L. Hervey-Jumper. Zuclopenthixol as an inhibitor of glioblastoma-induced neuronal hyperexcitability [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 2347.
Abstract 5980: Cancer therapeutic and prevention strategy targeting mutated mitochondria DNA
Authors: Hiroki Nagase
Journal: Cancer Research (2024)

Abstract As the energy factory for the cell, the mitochondrion, through its role of ATP production by oxidative phosphorylation, can be regarded as the guardian of well regulated cellular metabolism; the integrity of mitochondrial functions, however, is particularly vulnerable in cancer due to the lack of superstructures such as histone and lamina folds to protect the mitochondrial genome from unintended exposure, which consequently elevates risks of mutation. In cancer, mechanisms responsible for enforcing quality control surveillance for identifying and eliminating defective mitochondria are often poorly regulated, and certain uneliminated mitochondrial DNA (mtDNA) mutations and polymorphisms can be advantageous for the proliferation, progression, and metastasis of tumor cells and disseminated into microenvironment cells through extracellular vesicle and tunnel nano tube. Such pathogenic mtDNA aberrations are likely to increase and frequently be homoplasmic in metastatic cancer cells and, intriguingly, in normal cells in the tumor microenvironments as well. Distinct characteristics of these abnormalities in mtDNA may provide a new path for cancer therapy. We recently tested this hypothesis with a few PIP-TPP conjugates targeting mtDNA mutations to induce mutants reduction in heteoplasmic cells or apoptosis in homoplasmic or near homoplasmic cells in vivo model without major adverse effects. This finding reaffirms the feasibility of such a PIP-TPP-based mtDNA-targeting approach for anticancer therapy as well as perhaps cancer risk prevention. However, the absence of known mtDNA mutation hotspots limits the clinical application of somatic mutation-targeted PIP-TPPs. Thus, we designed CCCh-1005-TPP to selectively target a frequent ATP6 gene variant and often oncogenically homoplasmic in the associated with hypertrophic cardiomyopathy, colon, breast and ovarian cancer risk and found its anticancer effect in mouse xenograft models. Here we study preclinical trial of CCCh-1005-TPP, a promising novel anti-cancer agent for clearing abnormal mtDNA by reactivating mitochondrial quality control surveillance of mitophagy. Given those mechanistic insights may provide a promising therapeutic or maybe preventive approach of the pathogenic mtDNA removal in homoplasmic or heteroplasmic cells. Additional caveat is that this strategy may also use not only for cancer but also many other mitochondria related diseases, such as neurodegenerative, diabetic, renal, muscle and hearing loss diseases as well as aging. Citation Format: Hiroki Nagase. Cancer therapeutic and prevention strategy targeting mutated mitochondria DNA [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 5980.
Abstract 5976: R9: A novel NuRD complex inhibitor for targeted therapy in triple negative breast cancer (TNBC)
Authors: Kun Zhang, Sheeba Jacob, Mikhail Dozmorov, Ivan Babic, Elmar Nurmemmedov, Anthony C. Faber
Journal: Cancer Research (2024)

Abstract Triple Negative Breast Cancer (TNBC) is a highly aggressive breast cancer subtype, disproportionately affecting young and African American populations. TNBC constitutes up to 15% of breast cancers that lack effective targeted therapy. The Nucleosome Remodeling and Deacetylase (NuRD) complex, a pivotal chromatin remodeling entity, plays a crucial role in cancer development and progression. Specifically, the NuRD complex associates with SALL4 in cancer cells, contributing to the silencing of tumor-suppressor genes like PTEN. In this study, we discover R9, a novel small-molecule nucleotide analog, a first-in-class NuRD inhibitor. Utilizing computational and cellular methods, R9 demonstrated selective engagement with RBBP4, a key NuRD complex subunit. Cellular target engagement technology has been utilized to verify direct interaction of R9 with NuRD complex as well as to guide medicinal chemistry efforts. Mass spectrometry thermal proteome profiling (TPP) affirmed RBBP4 as the primary target of R9 with minimal off-target effects. In vitro studies reveal R9 displaying robust toxicity in TNBC cells, while sparing normal tissue derived cells. Encouragingly, R9 effectively impeded TNBC tumors growth in mice without inducing toxicity. Mechanistically, we demonstrate R9 induces DNA damage in sensitive TNBC cells, and the sensitivity correlates to DNA damage-vulnerable cancer cells, indicating DNA damage is a major effector of NuRD complex inhibition in TNBCs. We further demonstrate that R9 induces DNA damage through a c-MYC dependent manner. Ongoing studies aim to elucidate key transcription factors involved in NuRD complex inhibition and the role of MYC and DNA damage in response to NuRD complex inhibition. This research positions R9 as a promising candidate for targeted therapy in TNBC, offering potential insights into the intricate molecular pathways involved in TNBC tumor progression. Citation Format: Kun Zhang, Sheeba Jacob, Mikhail Dozmorov, Ivan Babic, Elmar Nurmemmedov, Anthony C. Faber. R9: A novel NuRD complex inhibitor for targeted therapy in triple negative breast cancer (TNBC) [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 5976.
Abstract 7156: Targeting the β-catenin signaling axis in osteosarcoma
Authors: Marina Curcic, Shreyas Gaikwad, Sanjay K Srivastava
Journal: Cancer Research (2024)

Abstract Osteosarcoma, an aggressive bone malignancy predominantly affecting children, poses a formidable challenge for therapeutic interventions. Here we evaluated a recently approved FDA drug, PCT, for potential anti-cancer effect in osteosarcoma model. Initial assessments of cytotoxicity encompassing various human and murine osteosarcoma cell lines—OS-17, OS-25, U2OS, SAOS2, MG63, and K7M3—revealed an IC50 ranging 1-3 µM. Subsequent investigations demonstrated significant anti-clonogenic activity and G2M phase cell cycle arrest. Annexin-PI assay showed a notable apoptotic effect of PCT, shedding light on the mode of cell death. Given the pivotal role of β-catenin signaling in human osteosarcoma pathogenesis and metastasis, targeting β-catenin components holds promise for therapeutic intervention. In silico docking studies suggested that PCT may have similar anti-cancer effect compared to β-catenin inhibitors (e.g., MSAB, ICG001). Our western blot analyses in multiple osteosarcoma cell lines demonstrated that PCT inhibits β-catenin pathway. Fluorescence microscopy and PCR analyses substantiated PCT's ability to hinder the nuclear translocation of β-catenin, providing mechanistic insights into its anti-tumor properties. Our preliminary data also suggests that AXL, an upstream regulator of β-catenin pathway, was modulated by PCT. In summary, our findings indicate that PCT exhibits therapeutic potential against osteosarcoma by targeting the β-catenin pathway. Further mechanistic studies are currently underway in our lab. Citation Format: Marina Curcic, Shreyas Gaikwad, Sanjay K Srivastava. Targeting the β-catenin signaling axis in osteosarcoma [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 7156.