tbuckley/cabot-search huggingface dataset:
Abstract 1629: Targeting HSBP1 Cys137 residue by 4-Iodobutyl acetate selectively kills triple-negative breast cancer
Authors: Ruei-Chen Hung, Chiou-Feng Lin, Yuan-Feng Lin
Journal: Cancer Research (2025)

Abstract Background: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancers and has a higher mortality rate because of metastatic character as compared to the non-TNBC subtypes. Chemotherapy is a non-selective anti-cancer treatment and currently remains as a first-line regimen for TNBC patients. As a result, identifying a more effective and selective drug target is urgently needed for TNBC. The aim of this study was made to discover the iodoacetamide derivative-targetable cysteine (Cys) residues of protein which is involved in the specific protein-protein interactions (PPIs) that are critical for TNBC survival. Methods: MTT assay was used to discover the iodoacetamide derivative that has a cytotoxic effectiveness on TNBC cell line HCC1806 better than normal mammary cell line MCF10A. Mass spectrometric analysis was utilized to identify the iodoacetamide derivative-targetable proteins and Cys residues. Site-directed mutagenesis was employed to validate the specific incorporation of iodoacetamide derivative candidate into the identified protein Cys residue. Cell-based assays and mouse models were established to determine the anti-TNBC effectiveness of iodoacetamide derivative candidate. Pulldown assay was performed to determine the specific PPIs of iodoacetamide derivative candidate-targeted protein in TNBC cells. Results: MTT assays revealed that 4-Iodobutyl Acetate (IBA) is able to selectively kills HCC1806 cells with half maximal inhibitory concentration (IC50) at 0.01 µM which is much lower than that of MCF10A cells (IC50 = 7.91 µM). Mass spectrometric analysis indicated that IBA incorporates into the Cys137 residue of HSPB1 protein and thereby induces cell apoptosis in HCC1806 cells. Either the removal of iodo-group from IBA or the mutation of Cys137 to Ser significantly abolished its cytotoxic effects on HCC1806 cells both in vitro and in vivo. Pulldown assay demonstrated that the incorporation of IBA into Cys 137 leads to the disruption of HSPB1 PPIs with Akt, Cytochrome c and Caspase-3, which ultimately results in the loss of metastatic ability and induction of cell apoptosis in HCC1806 cells. Conclusion: Our results provide a novel, selective and even more safe therapeutic strategy for combating TNBC via targeting the pocket surrounding the Cys137 of HSPB1 protein. Citation Format: Ruei-Chen Hung, Chiou-Feng Lin, Yuan-Feng Lin. Targeting HSBP1 Cys137 residue by 4-Iodobutyl acetate selectively kills triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1629.
Abstract 1287: Clinical relevance and translatability of NSCLC patient-derived xenograft (PDX) models for evaluating cMET-targeted therapies
Authors: Nathlie Leger, Kayla Tyskiewicz, Hanna Koster, Paul Heverly, Mara Gilardi, Stefano Cairo, Frank Smith
Journal: Cancer Research (2025)

Adoption of tyrosine kinase inhibitors (TKIs) has improved outcomes for Non-Small Cell Lung Cancer (NSCLC) by disrupting tumor-promoting growth factors, but patients develop resistance to these therapies through acquired alterations in other receptors. MET amplification is a common mechanism of resistance to FDA-approved small molecule EGFR inhibitors. Antibody Drug Conjugates (ADCs), such as c-MET targeting telisotuzumab-vedotin, are emerging as a promising therapy for EGFR inhibitor-progressed NSCLC, but understanding ADC efficacy across diverse profiles of advanced tumors remains a challenge. There is a need to develop more translational preclinical models to understand next-generation experimental agent efficacy prior to clinical trial enrollment. Here, we investigate the therapeutic potential of an experimental anti-cMET ADC in a panel of NSCLC low-passage patient-derived xenograft (PDX) models derived from patients pre-treated with EGFR therapies.10 NSCLC PDX models from Champions Oncology’s tumor bank were established In Vivo from patient tumors and maintained at a low passage. Genomic and pharmacologic profiling was conducted on established models to characterize EGFR resistance. Models were then treated with 1 or 3 mg/ kg experimental agent every 4 days for 8 doses, with tumor volume and survival data collected over a 4-week treatment period. The experimental anti-cMET ADC demonstrated a range of tumor growth inhibition across the selected models, which is reflective of the heterogeneity seen in NSCLC patients in the clinic. Several cMET-amplified models showed significant tumor regression, while other cMET-amplified models exhibited more variability ranging from partial response to full resistance to treatment. The use of low-passage NSCLC PDX models is essential in preserving the clonal heterogeneity and molecular landscape of patient tumors, making them highly relevant for the preclinical evaluation of novel therapies. Notably, Champions low-passage models preserved the molecular and histological features of the original patient tumors, including mutations and copy number variations, which were critical for understanding the response to therapy. Our study highlights the translational potential of Champions PDX models, serving as a platform for investigating the efficacy and mechanisms of resistance to targeted therapies. Citation Format: Nathlie Leger, Kayla Tyskiewicz, Hanna Koster, Paul Heverly, Mara Gilardi, Stefano Cairo, Frank Smith. Clinical relevance and translatability of NSCLC patient-derived xenograft (PDX) models for evaluating cMET-targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1287.
Abstract 4707: Electrochemotherapy for the treatment of head and neck squamous cell carcinoma
Authors: Felipe H. Maglietti, Sebastian D. Michinski, Lorna A. Evans, Raquel Lertora
Journal: Cancer Research (2025)

Abstract Squamous cell carcinoma (SCC) is the second most prevalent type of skin cancer after basal cell carcinoma, with the highest incidence occurring in sun-exposed regions of the body, particularly the head and neck. Approximately 300,000 new cases are diagnosed each year, imposing significant financial burdens on healthcare systems due to treatment costs and on the economy due to productivity losses. Surgery remains the primary treatment option; however, patients, particularly those with advanced-stage disease, may decline surgery due to concerns about functional and cosmetic outcomes. Other effective treatments include cryosurgery, radiotherapy, topical therapies, photodynamic therapy, and Mohs micrographic surgery. Recently, electrochemotherapy (ECT) has emerged as a novel treatment option. ECT involves administering bleomycin followed by electric pulses targeted at the tumor and surrounding margins, inducing transient cell membrane permeabilization. This enhances drug uptake and amplifies cytotoxic effects by over 1,000-fold. Since 2006, ECT has been a standard therapy in Europe and was introduced in Argentina in 2020, offering a new approach for patients who are unsuitable for or decline other treatments. In this study, we present outcomes from six patients with head and neck SCC treated with ECT on an outpatient basis. Most patients required only a single 60-minute treatment session. Observed side effects included grade 1-2 edema, pain, and flu-like symptoms per CTCAE 4.0. Tumor response was assessed using RECIST criteria, with results showing 71.4% complete response (5 of 7 lesions), 14.3% partial response (1 lesion), and 14.3% progressive disease, yielding an objective response rate of 85.7%.In conclusion, electrochemotherapy proved to be a safe and effective treatment for select head and neck SCC patients who are not candidates for surgery, providing a promising alternative in the therapeutic landscape. Citation Format: Felipe H. Maglietti, Sebastian D. Michinski, Lorna A. Evans, Raquel Lertora. Electrochemotherapy for the treatment of head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4707.
Abstract 1851: Development of a smart nanocarrier system for prostate cancer immunotherapy
Authors: Imani Roundtree, Angelo Altenor, Rodney Valdivia, Tovah St. Ignac, Alexandra Esposito, Karelys DiazDavila, Richard Lamptey, John Fetse
Journal: Cancer Research (2025)

Abstract Prostate cancer (PCa) is characterized by the overexpression of monoamine oxidase-A (MAO-A), a driver of tumor growth, metastasis, and treatment resistance. Monoamine oxidase inhibitors (MAOIs), such as phenelzine, have shown promise as repurposed agents for PCa therapy. However, systemic administration of phenelzine at effective doses carries significant risks of neuropsychiatric side effects, including aggression, seizures, and suicidal ideation, highlighting the need for a targeted delivery approach. This study aims to develop a smart nanocarrier system for the co-delivery of phenelzine (PHE) and the anti-programmed death ligand 1 (PD-L1) peptide (C7), enhancing therapeutic efficacy while reducing off-target effects. The nanocarrier employs a pH-sensitive hydrazone bond and a matrix metalloproteinase-2 (MMP-2) cleavable linker to achieve site-specific drug release. The system integrates polyethylene glycol-hydrazone-phenelzine (PEG-HZ-PHE) and an MMP-2cleavable linker tethered to the anti-PD-L1 peptide (C7-MMP2), into a lipid nanocarrier platform. Characterization using dynamic light scattering (DLS) revealed a particle size of 190.0 ± 3.9 nm, a polydispersity index (PDI) of 0.17 ± 0.02, and a zeta potential of -33.6 ± 1.3 mV. pH-dependent release studies showed that phenelzine release was highest at pH 5.4 (74.7 ± 0.6%) and lowest at pH 7.4 (11.3 ± 0.1%) after 18 hours, with a 42.3 ± 0.6% release at pH 6.4. Enzyme cleavage studies demonstrated that 73.8 ± 14.5 % of C7 was released within 4 hours of incubation with MMP-2 enzyme, with only 20.3 ± 2.1% of C7-MMP2 remaining after the same period. Cytocompatibility assessment using a red blood cell (RBC) hemolysis assay showed no significant hemolytic activity compared to the negative control (PBS buffer), while the positive control (0.5% Triton X-100) caused significant hemolysis. In conclusion, the developed dual-responsive nanocarrier is stable at physiological pH (7.4) but efficiently releases therapeutic agents in acidic and MMP-2 enzyme-rich environments, offering potential for improved PCa therapy by minimizing off-target effects. Citation Format: Imani Roundtree, Angelo Altenor, Rodney Valdivia, Tovah St. Ignac, Alexandra Esposito, Karelys DiazDavila, Richard Lamptey, John Fetse. Development of a smart nanocarrier system for prostate cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1851.
Abstract 5415: Identifying telomere-related molecular signatures in <i>H. pylori</i> infection and exploring plant-based potential telomerase inhibitors: An <i>in-silico</i> analysis
Authors: Trupti Patel, Ujjayini Chakraborty
Journal: Cancer Research (2025)

Abstract International Agency for Cancer Research categorizes Helicobacter pylori as a Class I carcinogen for its known role in gastric cancers, especially among the low-income groups of developing countries where stomach infections are very common. Chronic infection caused by these bacteria results in gastric inflammation that trigger molecular events ultimately leading to cellular transformation. CagA, a pathogenic gene of H. pylori can disrupt multiple molecular targets in human cells and may also interrupt with normal cell proliferation and survival. This study demonstrates the carcinogenic potential of H. pylori by interfering with the function of telomeric complex and contributing to cellular immortality. GEO datasets were used to identify genes that are differentially expressed and how their altered expression compromised the normalcy of shelterin, CST, and TERT-TERC complexes. This study also explores the role of selected proteins that hampers the functioning of double stranded break (DSB) repair at telomeres. Finally, we compare standard and traditional drugs that may interfere with telomerase activity in cancer cells. We found that CagA may trigger the hTERT activation via the AKT-pathway. The target proteins Cdh1 and Pik3ca showed higher binding affinity with phytochemicals then with the standard of care drugs and possible play a role in indirectly inhibiting telomerase. Despite advancements in stomach cancer treatment, the findings from this study attempts to make a useful contribution in understanding H. pylori infection and resultant trigger of cancer hallmarks. Citation Format: Trupti Patel, Ujjayini Chakraborty. Identifying telomere-related molecular signatures in H. pylori infection and exploring plant-based potential telomerase inhibitors: An in-silico analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5415.
Abstract 6153: Overcoming immunosuppression in pancreatic cancer: Efficacy of polyamine blockade and anti-PD-1 combinational therapy
Authors: Joseph A. Goode, Diana Gaete-Alvarez, Otto Phanstiel, Deborah Altomare
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive cancer, with an only a 13% 5-year survival rate. This low survival rate is due to its dense microenvironment, late-stage diagnosis, and limited treatment options. Polyamines, small molecules essential for cell growth, play a critical role here because their dysregulation is linked to PDAC's tumor growth, invasion, and metastasis. Additionally, the tumor microenvironment becomes increasingly “cold,” or resistant to immune responses. This resistance is driven by the recruitment of immunosuppressive populations and immune evasion mechanisms, such as the programmed death-1 (PD-1) pathway, which conceals PDAC from immune detection. This study aims to explore the interaction between polyamines, the PDAC immune microenvironment, and evaluate the effectiveness of combining Polyamine Blockade Therapy (PBT) with anti-PD-1 inhibitors as a novel immunotherapy strategy. Using an orthotopic mouse model of PDAC with syngeneic GFP-Luc2 cells, we assessed the impact of PBT, consisting of Difluoromethylornithine (DFMO) and the polyamine transport inhibitor (PTI) Trimer 44NMe (Trimer PTI), in conjunction with anti-PD-1 therapy. Tumor growth was monitored by bioluminescence in vivo and shifts in immune populations were assessed using flow cytometry. The combination of simultaneous PBT and anti-PD-1 treatment resulted in a significant reduction in tumor mass, decreased levels of immunosuppressive cells, and an increase in anti-tumor immune populations. The combination of Polyamine Blockade Therapy with anti-PD-1 inhibition shows promise as an effective immunotherapy for PDAC, potentially improving patient outcomes by disrupting the polyamine-mediated immunosuppressive network while enhancing anti-tumor immunity. Citation Format: Joseph A. Goode, Diana Gaete-Alvarez, Otto Phanstiel, Deborah Altomare. Overcoming immunosuppression in pancreatic cancer: Efficacy of polyamine blockade and anti-PD-1 combinational therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6153.
Abstract 1538: Impact of MCT1 inhibition on NSCLC metabolism and sensitivity to therapy
Authors: Robert Cameron, Massar Alsamraae, Maia G. Clare, Nia G. Hammond, Christine Bestvina, Marina Chiara Garassino, Brandon Faubert
Journal: Cancer Research (2025)

Abstract Introduction: Despite the advent of targeted therapies, prognosis of lung of non-small cell lung cancer (NSCLC) remains poor. Thus, identifying metabolic programs in aggressive disease may allow for the development of novel treatment strategies. Prior work in early-stage NSCLC has demonstrated that lactate import via monocarboxylate transporter 1 (MCT1) is associated with higher recurrence and mortality. However, the potential for targeting MCT1 in treatment efficacy and resistance remains unknown. Methods: NSCLC cells were cultured in standard RPMI or, to better model in vivo metabolism, human plasma-like media (HPLM). MCT1 was inhibited genetically (CRISPR-KO) or pharmacologically (AZD3965). Isotope tracing experiments were performed using [U-13C]glucose or [U-13C]lactate. DNA damage was assessed via the protein expression of γH2AX. MCT1 inhibition was combined with pemetrexed, and cell viability/cell death was measured using annexin V/propidium iodide. Combinatorial/synergy effects were assessed using synergyfinderplus.org. Results: H1299 cells incorporate lactate into tricarboxylic acid cycle (TCA) intermediates in both standard and physiologic culture media. Lactate incorporation into the TCA was decreased by treatment with AZD3965. Both genetic and pharmacologic inhibition of MCT1 increased the expression of the DNA damage marker γH2AX. Following 24 hours of pemetrexed treatment, pemetrexed alone significantly decreased cell viability in RPMI but not HPLM. The addition of AZD3965 decreased cell viability in both conditions, but decreases were less pronounced in HPLM cultured cells. In both media conditions, combinatorial dosing of AZD3965 and pemetrexed led to increases in cell death, and these were more pronounced at increasing doses of AZD3965. AZD3965 did not confer additional cytotoxic effect to cells treated with paclitaxel. Conclusions: MCT1 inhibition decreases lactate import and oxidation in vitro and causes DNA damage to enhance the cytotoxic effects of pemetrexed. Metabolic reprogramming in NSCLC leads to the use of alternate carbon sources, such as lactate, and this can be modeled in both standard and physiologic culture conditions. Notably, this does not appear to be a general sensitization to cell death. Further studies are ongoing to identify the metabolic underpinnings of these effects and how they translate to in vivo systems. Citation Format: Robert Cameron, Massar Alsamraae, Maia G. Clare, Nia G. Hammond, Christine Bestvina, Marina Chiara Garassino, Brandon Faubert. Impact of MCT1 inhibition on NSCLC metabolism and sensitivity to therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1538.
Abstract 4046: Role of kaiso in androgen receptor signaling and castration resistance
Authors: Oceane Kircha Nana, Huixian Lin, Isra Elhussin, Md. Abu Siddique, Omna Hayyat, Moray Campbell, Clayton Yates
Journal: Cancer Research (2025)

Abstract Metastatic PCa patients are treated with androgen deprivation therapy (ADT) alone or ADT together with antiandrogens such as enzalutamide (Enza). ADT/Enza targets AR-expressing PCa cells; therefore, the mechanisms underlying ADT/Enza resistance involve AR genomic alterations, AR splice variants, and persistent AR signaling even under castrated conditions. Our lab recently identified Kaiso, a BTB-POZ methyl-binding transcriptional regulator, as a crucial player in AR signaling networks. However, it is known how Kaiso potentially influences progress and treatment outcomes. Firstly, we established that Kaiso expression levels increased, as well as a cytoplasmic to nuclear localization occurred during Enza treatment. Additionally, utilizing ChIP and Cut-n-Run assays we observed that Kaiso directly binds to the methylated regions within the AR promoter. Utilizing AR-specific methylation-sequencing, we further observed that CGCG-rich regions in the AR promoter can be modulated utilizing both Kaiso depleted (sh-Kaiso) and Kaiso (overexpression) OE cell lines. Furthermore, modulation of Kaiso expression levels influences both AR and PSA. RNA-seq of Kaiso OE cells demonstrate significant AR and PSA overexpression, as well as GSEA enrichments highlight that androgen receptor signaling, epithelial to mesenchymal transition, and MYC signaling as the most significant pathways. Finally, sh-Kaiso cells displayed increased sensitivity to both Enza and ABi, while Kaiso OE cell lines displayed a complete lack of response to both compounds. In summary, our findings suggest that Kaiso levels may significantly influence androgen sensitivity and highlight Kaiso as a therapeutic target to improve conventional AR-directed therapies. Citation Format: Oceane Kircha Nana, Huixian Lin, Isra Elhussin, Md. Abu Siddique, Omna Hayyat, Moray Campbell, Clayton Yates. Role of kaiso in androgen receptor signaling and castration resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4046.