tbuckley/cabot-search huggingface dataset:
Abstract 85: Puf60 drives tumor progression and therapy resistance in head and neck squamous cell carcinoma
Authors: Jung Je Park, Chae Dong Yim, Ji Hyun Seo, So Young Cheon
Journal: Cancer Research (2025)

Abstract Background: Head and neck squamous cell carcinoma (HNSCC) is a malignancy with high morbidity and mortality due to its invasive nature and frequent resistance to therapy. PUF60, a multifunctional RNA-binding protein, plays roles in transcription regulation and DNA repair, but its specific contributions to HNSCC pathogenesis remain unclear. This study investigates the role of PUF60 in tumor progression, oxidative stress responses, and resistance to therapeutic interventions. Methods: HNSCC cell lines were employed to study the functional effects of PUF60 overexpression and knockdown. Cellular assays assessed invasion, migration, and apoptosis under standard conditions and in response to oxidative stress, cisplatin, and radiation. DNA damage was analyzed using flow cytometry and Western blotting, while immunoprecipitation and subcellular fractionation were performed to explore interactions between PUF60 and vital regulatory proteins such as PTEN and Sirt6. Results: Overexpression of PUF60 significantly enhanced the invasive and migratory capabilities of HNSCC cells, while knockdown reduced these phenotypes. PUF60-overexpressing cells demonstrated resistance to cisplatin-induced apoptosis, accompanied by altered ROS production and decreased markers of DNA damage under oxidative stress. Radiation studies revealed a protective effect of PUF60, with reduced DNA damage and enhanced survival. Mechanistically, PUF60 modulated the subcellular localization of PTEN and interacted with Sirt6, highlighting its role in maintaining tumor cell viability under stress conditions. Conclusion: PUF60 is a crucial driver of HNSCC progression and therapy resistance, promoting tumor cell invasiveness, modulating responses to oxidative and genotoxic stress, and facilitating survival under therapeutic pressure. Targeting PUF60 may offer a novel approach to overcoming resistance and improving treatment outcomes in HNSCC. Citation Format: Jung Je Park, Chae Dong Yim, Ji Hyun Seo, So Young Cheon. Puf60 drives tumor progression and therapy resistance in 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 85.
Abstract 558: MUC1*-deruxtecan kills tumors that have acquired resistance to trastuzumab containing therapeutics
Authors: Cynthia C. Bamdad, Benoit J. Smagghe, Scott T. Moe, Kevin R. Yi, Trevor J. Grant, Mark G. Carter, Daniel S. Miller, Michael J. Nash, Jacy P. Marquez, Natalie K. Miller, JacLeen S. Nash, Robert McDermot, Andrew K. Stewart
Journal: Cancer Research (2025)

Abstract Purpose: To develop a treatment for HER2 positive patients whose tumors have stopped responding to Enhertu Methods: HER2 positive BT474 breast cancer cells were induced to become Herceptin resistant (trastuzumab resistant) in vitro via prolonged exposure to sub-lethal levels of the drug. Analysis of the trastuzumab-resistant cells showed that they had greatly increased expression of MUC1*, known to have anti-apoptotic and pro-growth properties. Recall that MUC1* (muk 1 star) is a growth factor receptor created after cleavage and release of the N-terminal portion of MUC1. The targeting antibody, huMNC2, has already demonstrated safety and cancer selectivity in a 1st-in-human CAR-T clinical trial for treatment of metastatic breast cancers. MNC2 is an IgG1 antibody that only recognizes the conformational epitope created when MUC1 is cleaved by specific tumor-associated enzymes. Confocal microscopy and pHrodo show that MNC2 is rapidly and robustly internalized by the cancer cells. We conjugated MNC2 to deruxtecan to yield an MNC2-deruxtecan with a DAR of 7.4. Female NSG mice were xenografted with either BT474-wt cells or the trastuzumab-resistant cells, BT474-Res2. Tumors were allowed to engraft then treated with trastuzumab or MNC2-deruxtecan. Results: Herceptin had little to no effect on BT474-Res2 implanted tumors. However, MNC2-deruxtecan potently killed the trastuzumab resistant tumors in a matter of weeks. MNC2 conjugated to other linker-payloads similarly killed the trastuzumab resistant tumors. Treated animals showed no obvious signs of toxicities. Conclusions: Patients with HER2 positive breast cancers have benefitted greatly from the new ADC Enhertu (fam-trastuzumab deruxtecan). However, most patients, develop resistance to HER2-directed therapies and experience progressive disease leaving them with few treatment options. Here we’ve shown that HER2 positive breast cancer cells acquire resistance to trastuzumab by increasing expression of the powerful growth factor receptor MUC1*. These MUC1*-targeting ADCs offer an effective treatment for these patients. These data support a conclusion that a MUC1*-ADC is safe and could have high therapeutic value for patients who have stopped responding to Enhertu. Citation Format: Cynthia C. Bamdad, Benoit J. Smagghe, Scott T. Moe, Kevin R. Yi, Trevor J. Grant, Mark G. Carter, Daniel S. Miller, Michael J. Nash, Jacy P. Marquez, Natalie K. Miller, JacLeen S. Nash, Robert McDermot, Andrew K. Stewart. MUC1*-deruxtecan kills tumors that have acquired resistance to trastuzumab containing therapeutics [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 558.
Abstract 817: A prospective, multi-center, phase IV study to evaluate safety and efficacy of Dr. Reddy’s bevacizumab (DRL_BZ) in patients with solid tumors
Authors: Narendra Maharaj, Ranjith K, Anand Eswaraiah, Pramod kumar Reddy, Gopichand M, Rajender Singh Arora, Krishna Chaithanya Puligundla, Ashok Kumar Diwan, Tanveer Mohibbhai Maksud
Journal: Cancer Research (2025)

Abstract Introduction: DRL_BZ is a biosimilar to the reference product, bevacizumab, and was approved in India and subsequently introduced in other markets for the use in various other solid tumors as single or combination therapy. This study was conducted as part of a post-marketing commitment to regulatory authority aimed to evaluate treatment safety (primary objective), and efficacy (secondary objective) in male and female patients with solid tumors. Methods: In this prospective, single-arm, multicenter, Phase IV study (BZ-01-002), a total of 200 patients with median age 54.0 years were enrolled with the following indications: mCRC (n = 59); NSCLC (n = 41); epithelial ovarian cancer (n = 27), and cervical cancer (n = 73). Patients received DRL_BZ either with chemotherapy or as monotherapy and followed up to disease progression, unacceptable toxicity, or death due to any cause, or up to 6 months from first dose whichever occurs earlier. Results: The overall median duration (days) of DRL_BZ treatment exposure for the enrolled patients was 151.5 (1.0 - 253) days. Of the 200 enrolled patients, 117 (58.5%) patients completed the study, while 83 (41.5%) patients were withdrawn from the study due to various reasons (majorly due to COVID-19 pandemic). Out of 454 TEAEs reported from 139 (69.5%) patients, 46 TEAEs in 25 (12.5%) patients were considered related to DRL_BZ administration. Thirteen (6.5%) TEAEs leading to permanent study drug discontinuation. A total of 13 SAEs in 12 (6%) patients were reported and four of them were related to study drug. As per mITT population, 153 patients were evaluable for efficacy, and the reported ORR was 23.1% (3/13) for 2-weekly mCRC patients, 25% (8/32) for 3-weekly mCRC patients, 45.7% (16/35) for NSCLC patients, 72.7% (16/22) for epithelial ovarian cancer patients, and 37.3% (19/51) for cervical cancer patients. Conclusions: The safety profile of DRL_BZ, in terms of reported adverse events, in patients with solid tumors is comparable and consistent with the known safety profile of bevacizumab in literature. Overall, findings from this Phase IV study indicate that the safety and efficacy of DRL_BZ in patients with solid tumors is as per the approved prescribing information. Citation Format: Narendra Maharaj, Ranjith K, Anand Eswaraiah, Pramod kumar Reddy, Gopichand M, Rajender Singh Arora, Krishna Chaithanya Puligundla, Ashok Kumar Diwan, Tanveer Mohibbhai Maksud. A prospective, multi-center, phase IV study to evaluate safety and efficacy of Dr. Reddy’s bevacizumab (DRL_BZ) in patients with solid tumors [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 817.
Abstract 303: Discovery of autophagy-inhibiting compounds as a novel class of senolytics
Authors: Martin Mistrik, Matthew Lacey, Lucie Beresova, Alzbeta Srovnalova, Josef Srovnal, Petr Dzubak, Marian Hajduch
Journal: Cancer Research (2025)

Abstract Introduction: Senolytics are compounds capable of selectively eliminating senescent cells, holding promise for therapies targeting age-related diseases and cancer. To identify novel senolytic agents, we screened a chemical library using cellular models of replicative senescence induced by replication stress. This screen yielded several hits, including MCOPPB, a known nociceptin receptor agonist. Subsequent in vivo studies in a murine model confirmed the potent senolytic activity of MCOPPB. Surprisingly, further investigations revealed that this activity was independent of nociceptin receptor signaling, suggesting an off-target mechanism. Methods: To explore the underlying mechanism, we performed a cell-painting assay, which phenotypically links compounds based on their cellular effects. MCOPPB clustered closely with another senolytic hit from the screen, Daurisolin, a natural autophagy inhibitor. Autophagy inhibition by MCOPPB was validated through assays measuring LC3 accumulation and other markers. Additional studies with known autophagy inhibitors, including Dauricin and Chloroquine, demonstrated both senolytic activity and clustering with MCOPPB in the cell-painting assay. Results: Our findings establish autophagy inhibition as the common mechanism of senolytic action for this newly identified class of compounds. MCOPPB, Daurisolin, and related inhibitors displayed consistent phenotypes in cell-painting assays and induced selective clearance of senescent cells. The clustering of these compounds in phenotypic assays provides a powerful approach for identifying senolytics with similar mechanisms of action. Conclusion: This study highlights autophagy inhibition as a novel senolytic mechanism and identifies a unique chemical cluster of autophagy-inhibiting senolytic compounds. These insights could drive the development of targeted therapies for conditions associated with cellular senescence. Acknowledgements: This work was supported by the Technology agency of the Czech Republic project PERMED: T2BA (TN02000109) and the National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102). Infrastructure was supported by projects CZ-OPENSCREEN (LM2023052), EATRIS-CZ (LM2023053) and Czech Bioimaging (LM2023050) Citation Format: Martin Mistrik, Matthew Lacey, Lucie Beresova, Alzbeta Srovnalova, Josef Srovnal, Petr Dzubak, Marian Hajduch. Discovery of autophagy-inhibiting compounds as a novel class of senolytics [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 303.
Abstract 552: Fenretinide enhances trastuzumab efficacy in trastuzumab-resistant HER2+ breast cancer cell lines
Authors: Debbie O'Reilly, John Crown, Denis M. Collins
Journal: Cancer Research (2025)

Abstract Introduction: HER2-positive (HER2+) breast cancer (BC) treatments have significantly improved patient outcomes, but treatment resistance remains a critical challenge, often driven by breast cancer stem cells (BCSCs). These resilient cells evade targeted therapies, leading to disease relapse and progression. Fenretinide (Fen), a synthetic retinoic acid (RA) derivative, has shown promise in acute myeloid leukemia by promoting cellular differentiation. Given BCSCs' similarities to embryonic cells, RA-based approaches may induce BCSC differentiation, reducing their resistance to HER2-targeted therapies. This project aims to identify BCSC markers in resistant HER2+ BC cell lines and evaluate the effects of Fen induced differentiation. Methods: RNA-Seq gene expression data was downloaded from CCLE and analysed using RStudio (R version 4.1.2). HER2+ BC cell lines with innate (HCC1569, HCC1954) or acquired (SKBR3-T, BT474-T) trastuzumab (Tras) resistance were studied. Acquired resistance was induced by continuous exposure to 10 ng/mL Tras for 6 months. Cells were treated with 1 µM Fen for 24 hours. qPCR analysis employed the comparative Ct method (ΔΔCt), expressed as fold change to control. Statistical significance was determined using the Student’s t-test or one-way ANOVA with Dunnett’s multiple comparison. Results are presented as the mean of biological triplicate experiments ± standard deviation. Results: DepMap analysis showed enhanced CD44 expression in innate-resistant HCC1569 and HCC1954 compared to parental SKBR3 and BT474. qPCR confirmed significantly higher CD44 levels in HCC1569 than SKBR3 (p = 0.0318) and significantly lower CD24 levels in HCC1569 and HCC1954 compared to SKBR3 (p = 0.008 for both). Acquired-resistance models SKBR3-T and BT474-T exhibited reduced BCSC markers compared to their parental lines. Fen had no significant effect on the expression of BCSC markers in innate or acquired resistant cell lines. Fen significantly decreased colony formation (CFA) across all cell lines and enhanced the growth-inhibitory effect of Tras in the SKBR3-T cell line in a dose-dependent manner. Conclusions: Preliminary findings indicate that Fen influences CFA in both innate and acquired Tras-resistant HER2+ BC cell lines and enhances Tras efficacy in acquired resistant SKBR3-T. However, its impact on BCSC markers is limited. Further investigation is needed to elucidate the role of Fen in overcoming Tras resistance mechanisms in HER2+ BC. Citation Format: Debbie O'Reilly, John Crown, Denis M. Collins. Fenretinide enhances trastuzumab efficacy in trastuzumab-resistant HER2+ breast cancer cell lines [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 552.
Abstract 823: Combination therapy of HDAC inhibitors with HSP90 and TRAP1 targeting the hypoxia pathway in triple-negative breast cancer
Authors: Golnaz Asaadi Tehrani, Becca Kubick, Andrew Gutierrez, Terin D'Amic, Hailey Sanders, Brian Blagg, Bradley Smith, Meenal Datta
Journal: Cancer Research (2025)

Abstract Triple-negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer that more than 50% of cases present with hypoxia, which induces chemotherapy resistance and fuels treatment failure. While various therapies targeting components of the hypoxia signaling cascade have been identified, those focusing on specific targets often fail to produce lasting clinical responses. Therefore, there is a critical need for novel hypoxia inhibitors that combine potency, specificity, low toxicity, and favorable druggability. In this study, we evaluated the efficacy of novel drug combinations involving Heat Shock Protein 90 inhibitor (HSP90i) NDNB-25, Tumor Necrosis Factor Receptor-Associated Protein 1 inhibitor (TRAP1i) NDNT-34, and histone deacetylase inhibitors (HDACis) such as CAY10603, suberoylanilide hydroxamic acid (SAHA), and Valproic acid (VPA). The goal was to suppress the hypoxia pathway in TNBC and assess impacts on cell viability, metastasis, and hypoxia-related gene expression using 2D and 3D TNBC models. Our results demonstrated a strong synergistic effect of SAHA/NDNB-25 and SAHA/NDNT-34 combination therapies. Specifically, NDNB-25/SAHA combination significantly down-regulated HIF1A expression in 2D- cultures. While NDNB-25 and NDNT-34 mono-therapies only reduced HIF2A and TRAP1 expression, the NDNB-25/NDNT-34 combination down-regulated HIF1A, HIF2A, VEGFA, TRAP1, and HSP90 in 3D cultures. Moreover, the NDNB-25/NDNT-34 combination, at lower concentrations (250 nM and 5 µM), inhibited cell migration more effectively than mono-therapies at higher concentrations (500 nM and 10 µM). Fluorescent imaging revealed more distribution of hypoxia signals using a labeled hypoxia probe and the localization of TRAP1i, tagged with rhodamine B, in TNBC-derived mammospheres compared with luminal subtype. These findings suggest that combining epi-drugs and targeted therapies to modulate the hypoxia pathway could inform the development of innovative clinical strategies against TNBC. Citation Format: Golnaz Asaadi Tehrani, Becca Kubick, Andrew Gutierrez, Terin D'Amic, Hailey Sanders, Brian Blagg, Bradley Smith, Meenal Datta. Combination therapy of HDAC inhibitors with HSP90 and TRAP1 targeting the hypoxia pathway in 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 823.
Abstract 1011: Transposable element patterns across genetic ancestries in prostate cancer patients
Authors: Nicholas Korvink, Lucas Ueta, Hannah Park, Vinay Kumar, Farah Rahmatpanah
Journal: Cancer Research (2025)

Abstract Introduction: Prostate cancer (PCa) is a significant burden to American men with African ancestry (AA). The mechanism of how ancestry contributes to aggressive PCa in AA patients is not well understood. We have identified a difference between races in endogenous retroviruses (ERVs) expression. In prostate and cervical cancer, we have demonstrated that ERV expression signatures are useful for identifying patients at the greatest risk of disease progression. There is consistency in mortality rates for black men in the US, Caribbean, and Sub-Saharan Africa suggesting that shared ancestry is a common risk factor. Using ERVcaller we investigated polymorphic transposon elements (TE) and ERV insertions unique to tumor cells compared to normal blood in prostate cancer patients of African (AF) and European ancestry (EU). Method: ERVcaller software detects retrotransposons including Alu, LINE1, SVA, and HERV-K types using whole genome sequencing (WGS). We gathered publicly available WGS data (FASTQ files) from the European Nucleotide Archive (SRA accession SRP119289). These were derived from paired blood and tumor samples from 6 AF and 9 EU PCa patients. We processed this data with ERVcaller, revealing TE insertions present in each patient sample (i.e., blood or tumor). We identified tumor-exclusive and blood-exclusive insertions by excluding overlapping TE insertions between tumor and blood samples. These insertions were then analyzed for differences using a T-test in R Studio. Results: Statistical analysis revealed significant differences in the number of TE insertions in the tumors of AF patients (mean = 50.00) compared to their EU (mean = 31.89) counterparts (p-value &amp;lt; 0.0038). In addition, we found no significant differences in TE insertions in blood samples of AF patients (mean = 35.50) relative to EU patients (mean = 32.78; p-value &amp;gt; 0.56), suggesting that this differential insertion pattern is isolated to the affected tumor region. Conclusion: ERVs have previously demonstrated important roles in the development of various diseases. Our findings demonstrate significant variations in TE insertions in tumors of PCa patients across genetic ancestries. Citation Format: Nicholas Korvink, Lucas Ueta, Hannah Park, Vinay Kumar, Farah Rahmatpanah. Transposable element patterns across genetic ancestries in prostate cancer patients [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 1011.
Abstract 853: PDL1-PRAME dual antigen cancer vaccine inhibits melanoma growth in syngeneic mouse model and induces antigen-specific immune responses
Authors: Kin-Tak Chan, Hsin-Wei Chen, Pi-Hui Liang, You-Yu Lin, Tristan Zhang, Melvin Toh
Journal: Cancer Research (2025)

Abstract Preferentially expressed antigen in melanoma (PRAME) is a cancer/testis antigen frequently expressed in various types of cancer, especially in melanoma, and its overexpression is associated with aggressive tumor progression. PRAME-specific T-cells found in cancer patients recognize and specifically lyse cancer cells, positioning PRAME as a promising target for cancer immunotherapy. PDL1 represents one of the most important immune checkpoint antigens frequently overexpressed on tumor cells to suppress T-cell mediated anti-cancer immunity. Several anti-PDL1 antibodies have been approved for clinical use through passive immunization. We had developed PDL1-PRAME dual antigen cancer vaccines and reported their promising tumor growth inhibition effects against syngeneic mouse hepatocellular carcinoma in 2023. In the present study, anti-cancer efficacy of the PDL1-PRAME dual antigen cancer vaccine was evaluated in an aggressive mouse melanoma model. Subcutaneous administration of the cancer vaccine formulated with alum-CpG oligodeoxynucleotides (ODNs) prior to tumor implantation significantly inhibited tumor growth by 91.5% (P&amp;lt;0.01) and prolonged the median survival time from 23.5 days to 40.5 days (P&amp;lt;0.01), compared to adjuvant treated control. To further optimize the vaccine formulation, another in vivo study was conducted with the PDL1-PRAME vaccine protein formulated with different adjuvants, including a novel synthetic saponin based adjuvant IAS-01, to evaluate the vaccine-induced antigen-specific immune responses in C57BL/6 mice. IAS-01, developed by ImmunAdd, is a liposome-based adjuvant incorporating two potent immunostimulants, a fully synthetic monophosphoryl Lipid A and a fully synthetic truncated QS-21 analogue, IA-05, devoid of hemolytic toxicity. Both alum-CpG ODN and IAS-01 obviously enhanced the vaccine-induced T-cell response against PRAME and elevated the anti-PDL1 antibody response. In particular, the highest anti-PDL1 antibody response was found with the IAS-01 adjuvant, compared to all the other adjuvants tested. Our study highlighted the prospect of developing the PDL1-PRAME dual antigen cancer vaccine for cancer immunotherapy. The vaccine efficacy is being further optimized in terms of its protein structure, adjuvant formulation, and administration route for potential clinical testing. Citation Format: Kin-Tak Chan, Hsin-Wei Chen, Pi-Hui Liang, You-Yu Lin, Tristan Zhang, Melvin Toh. PDL1-PRAME dual antigen cancer vaccine inhibits melanoma growth in syngeneic mouse model and induces antigen-specific immune responses [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 853.