tbuckley/cabot-search huggingface dataset:
Abstract 6720: The role of the Co-chaperone UNC45A in breast and prostate cancer
Authors: Asif Elahi, Taoufik Llbiyi, Vamsi Krishna Kommalapati, Yasmeen Jilani, Ahmed Chadli
Journal: Cancer Research (2025)

Abstract UNC45A is a key co-chaperone supporting cancer cell proliferation and tumorigenesis. Interestingly, UNC45A is essential for cancer cells but not for normal cell proliferation. However, the mechanism underlying UNC45A regulatory function is not well studied. We have previously shown that UNC45A functions as a glucocorticoid receptor (GR) co-activator to drive the mitotic kinase NEK7 gene transcription. NEK7 is essential for centrosome separation, mitotic spindle formation, and cytokinesis. GR has been implicated in promoting aggressive prostate tumor growth and resistance to therapy. Indeed, GR upregulation is an established mechanism to bypass the androgen receptor blockade therapy in metastatic-resistant prostate tumors. Here, we tested the hypothesis that UNC45A promotes GR-mediated resistance to hormonal therapy. To this end, we used shRNA-mediated gene silencing to evaluate the impact of UNC45A loss on PC3 prostate tumor progression. Our results show that silencing UNC45A reduces cell proliferation in vitro and tumor growth in vivo. TUNEL analysis and Ki67 staining show that loss of UNC45A triggers DNA damage, reduced cell proliferation, and apoptosis in PC3 tumors grown in the NOD SCID mice model. Immunofluorescence analysis shows a remarkable disorganization of centrosomes in tumor cells expressing UNC45A shRNA. The importance of UNC45A in promoting enzalutamide resistance is being tested in tridimensional spheroid culture and in vivo and will be discussed in this meeting. Overall, our results support the hypothesis that UNC45A is a promising cancer therapeutic target and highlight the need for developing UNC45A small molecule inhibitors to treat aggressive diseases such as prostate and breast cancers. Citation Format: Asif Elahi, Taoufik Llbiyi, Vamsi Krishna Kommalapati, Yasmeen Jilani, Ahmed Chadli. The role of the Co-chaperone UNC45A in breast and prostate 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 6720.
Abstract 7085: Analysis of gene expression pattern of glycosphingolipid synthases using tumor tissues from breast cancer patients to identify key targets for early diagnosis and protection of recurrence
Authors: Kanchan Chakma, Robiul Hasan Bhuiyan, Farhana Yesmin, Koichi Furukawa
Journal: Cancer Research (2025)

Abstract Breast cancer become the most common types of cancer in Bangladesh (female), and accounted 13028 new cases and 6783 deaths in 2020. No efficient therapy has been developed although anti-HER2 antibody therapy has been tried, showing some effects. We need to detect breast cancers at early stage of evolution and also of recurrence, and develop more effective way than the current approaches to eradicate breast cancers. In order to achieve these purposes, it seems essential to find breast cancer-specific antigens as a marker and/or therapeutic targets. Recently, some interesting and promising findings on breast cancers have been reported. For example, ganglioside GD2 was reported to be a marker of breast cancer stem cels, and also play roles in the carcinogenesis. GD3, Gb3 have an association in tumorigenesis as well as cel proliferation, adhesion and migration. More important marker antigens of breast cancers might be present. Aims of the study are to identify novel breast cancer-associated glycolipids including their synthetic enzyme genes, using many surgical specimens and sera from breast cancer patients. Tumor and healthy tissues were collected after surgical resection from hospitals and clinics. Samples are immediately transferred to the laboratory. mRNA was extracted using TRIzol method. cDNA was converted from mRNA using Reverse Transcriptase. qRT-PCR was performed to analyze glycosyltransferase gene expression pattern. Expression of glycolipid GD3-synthase (ST8SIA1), GD2-synthase (B4GALNT1), and Gb3 synthase (A4GALT) are analyzed by RT-PCR using tumor tissues from breast cancer patients. GD2-synthase expression level found significantly higher in tumor tissues compared to healthy tissues. GD3 and Gb3 synthases did not show significant difference between tumor tissues and healthy tissues. GD2 are upregulated in breast cancer patients. This gene may be a novel biomarker for breast cancer and may be useful to design therapeutic drug. Citation Format: Kanchan Chakma, Robiul Hasan Bhuiyan, Farhana Yesmin, Koichi Furukawa. Analysis of gene expression pattern of glycosphingolipid synthases using tumor tissues from breast cancer patients to identify key targets for early diagnosis and protection of recurrence [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 7085.
Abstract 7043: HMGA1 Epigenetic Regulators Drive Relapse in Pediatric B-Cell Leukemia By Amplifying ETV5 and Stemness Networks
Authors: Linda M. S. Resar, Jung-Hyun Kim, Andrei Thomas-Tikonenko, Sarah Tasian
Journal: Cancer Research (2025)

Abstract Despite advances in therapy for pediatric B-cell acute lymphoblastic leukemia (pB-ALL), relapse remains a leading cause of death in children with cancer. The gene encoding the High Mobility Group A1 (HMGA1) chromatin regulator is highly expressed in stem cells and hematologic malignancies where high levels portend poor outcomes. In pB-ALL, HMGA1 is overexpressed with highest levels at relapse. Transgenic mice overexpressing Hmga1 in lymphoid cells develop aggressive leukemia. To determine how HMGA1 functions in relapsed pB-ALL, we performed multiomic analyses. Here, we uncover a previously unknown role for HMGA1 as an epigenetic gatekeeper of stemness transcriptional networks at relapse. Strikingly, silencing HMGA1 expression via CRISPR or short hairpin RNA decreases proliferation and clonogenicity in vitro while disrupting engraftment and prolonging survival in vivo. Multiomics analyses revealed transcriptional networks governed by HMGA1 that regulate proliferation (G2M checkpoint, E2F), RAS/ERK signaling, hematopoietic stem cells (HSCs), and ETS variant 5 transcription factor (ETV5) targets. CRISPR-mediated ETV5 gene silencing recapitulates effects of HMGA1 silencing in pB-ALL cell lines. Further, restoring ETV5 expression in pB-ALL cell lines with HMGA1 silencing partially rescues anti-leukemogenic effects of HMGA1 depletion. Mechanistically, HMGA1 binds to AT-rich regions within the ETV5 promoter and recruits activating histone marks to induce ETV5. Moreover, HMGA1 and ETV5 are co-expressed and up-regulated in primary blasts from children with relapsed pB-ALL where high HMGA1 correlates inversely with time to relapse. Artificial intelligence predicted that the histone deacetylase inhibitor (HDACi), vorinostat, targets HMGA1-ETV5 gene networks. In PDX models with pB-ALL blasts from relapse, we found that vorinostat enhances responses to standard B-ALL therapy (dexamethasone, vincristine), depleting circulating blasts and disrupting leukemic engraftment. Our findings reveal HMGA1 as an epigenetic switch that activates ETV5 and HSC gene networks in relapsed pB-ALL and rational therapeutic target to treat or prevent relapse. Citation Format: Linda M. S. Resar, Jung-Hyun Kim, Andrei Thomas-Tikonenko, Sarah Tasian. HMGA1 Epigenetic Regulators Drive Relapse in Pediatric B-Cell Leukemia By Amplifying ETV5 and Stemness Networks [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 7043.
Abstract 6990: Profiling Ras inhibitors for effects on GTP hydrolysis using the Transcreener GDP assay
Authors: Camdon Yemm, Robert Lowery
Journal: Cancer Research (2025)

Abstract Ras family GTPases are the most frequently mutated proteins in human cancers, most notably missense mutations at G12 and G13 that prolong the activated, GTP-bound state of the protein. Inhibitors that shift the equilibrium toward GDP-bound Ras, such as sotorasib, are proving effective clinically, and efforts to expand upon this strategy are widespread. Current strategies for biochemical screening and analysis of Ras inhibitors rely on the use of fluorescent GTP and GDP analogs to detect effects on GDP release and GTP binding. Though robust and widely used, these methods do not provide information on GTP hydrolysis, a critical part of the GTPase signal transduction process. We have developed methods for detecting GTP hydrolysis by small GTPases using the Transcreener GDP2 assay, a homogenous, competitive immunoassay for GDP with far-red fluorescence readout. Because GDP release is generally rate limiting, stimulation by GEFs can also be measured by monitoring GDP formation. We have optimized these assays for initial velocity detection of GTPase activity for wild type (WT) and mutant Ras proteins with robustness suitable for high throughput screening and tested a number of compounds reported to inhibit GTP and/or GDP binding. Consistent with expectations, the Ras G12C-specific covalent inhibitor, Sotorasib, potently inhibited KRas G12C (IC50 = 9.6 nM) and did not inhibit the wild-type enzyme. MRTX1133, which binds noncovalently to GDP-bound KRas G12D, inhibited the G12D mutant with an IC50 of 8.4 nM, and was less potent with the G12V and WT enzymes; IC50 = 48 nM and 69 nM, respectively. BI-2865, a pan KRas inhibitor, showed much weaker inhibition of all KRas variants tested, with IC50 values of 427 nM, 228 nM and 236 nM for WT, G12D and G12V KRas. We note that these GTPase assays require nanomolar concentrations of protein, and therefore cannot be used to accurately determine the potency of covalent inhibitors, such as sotorasib, that bind with picomolar affinity. However, for non-covalent inhibitors, such as MRTX1113 and BI-2865, measuring GTPase activity is a robust approach for selectivity profiling and may yield mechanistic insights different from those gleaned from guanine nucleotide binding/release assays or biophysical methods, e.g. SPR. Citation Format: Camdon Yemm, Robert Lowery. Profiling Ras inhibitors for effects on GTP hydrolysis using the Transcreener GDP assay [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 6990.
Abstract 2830: Aurora kinase B phosphorylates ZBP1 to drive PANoptosis following treatment with a combination of PARP and ATR inhibitors
Authors: Wenjian Gong, Zhiqi Liao, Shennan Shi, Fan Xiong, Mengshi Luo, Yuewen Zhang, Qiuyang Xu, Yijie Wu, Linghui Wang, Li Zhu, Dong Kuang, Marilyne Labrie, Xuejiao Zhao, Gordon B Mills, Ding Ma, Guangnian Zhao, Qinglei Gao, Yong Fang
Journal: Cancer Research (2025)

Background: The combination of DNA damage response inhibitors (DDRis) to induce unrepaired DNA damage entry into mitosis prematurely has emerged as a promising strategy for anticancer therapy. However, the efficacy is often limited by their tolerability due to associated toxicities. Method &amp; Result: Here we demonstrate that combining poly (ADP-ribose) polymerase (PARP) and ATR inhibitors induces PANoptosis in both cancer and non-cancer cells as a result of abnormal mitotic progression. This is highly dependent on CDK1 activity. Furthermore, ZBP1-dependent PANoptosome (ZBP1-RIPK1-CASP8-CASP6) mediated PARP and ATR inhibitors combination therapy induced PANoptosis. Further exploration revealed that the kinase activity of aurora kinase B (AURKB) was essential for ZBP1-mediated PANoptosis following the treatment. ZBP1 could be phosphorylated by AURKB during mitosis, and phosphorylated ZBP1 subsequently facilitates the assembly and activation of PANoptosome. Finally, our findings were validated in an ovarian cancer patient-derived xenograft (PDX) model in which PARPi and ATRi combination induced PANoptosis in both tumor and normal tissue Importantly, the toxicity to normal tissues was mitigated in ZBP1-knockout mice. Conclusion: Overall, these results suggest that phosphorylation of ZBP1 by AURKB triggers the activation of ZBP1-dependent PANoptosome after treatment with PARPi and ATRi combination, leading to cell-intrinsic antineoplastic activity and toxicity. Our study elucidates the specific mechanisms underlying cell fate determination during aberrant mitosis progression resulting from PARPi and ATRi combination therapy. These findings provide a theoretical foundation for understanding their anticancer effects and toxicity, crucial for optimizing the use of DDRis combination approaches in the clinic. Citation Format: Wenjian Gong, Zhiqi Liao, Shennan Shi, Fan Xiong, Mengshi Luo, Yuewen Zhang, Qiuyang Xu, Yijie Wu, Linghui Wang, Li Zhu, Dong Kuang, Marilyne Labrie, Xuejiao Zhao, Gordon B Mills, Ding Ma, Guangnian Zhao, Qinglei Gao, Yong Fang. Aurora kinase B phosphorylates ZBP1 to drive PANoptosis following treatment with a combination of PARP and ATR inhibitors [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 2830.
Abstract 6890: Knockdown of CD82 sensitizes adult T cell leukemia cells to anti-cancer agents-induced growth inhibition
Authors: Koichiro Fukuchi, Takayuki Ikezoe, Ikuko Ogahara, Songji Zhao
Journal: Cancer Research (2025)

Abstract CD82 belongs to the tetraspanin family and regulates several intracellular signaling pathways. We previously found that CD82 is aberrantly expressed on acute myeloid leukemia (AML) cells and plays a role in the adhesion of these cells to the bone marrow microenvironment. Adult T-cell leukemia (ATL) is a lethal peripheral T-cell malignancy in which HTLV-1-infected T cells transform and proliferate by various mechanisms. This study found that ATL cells expressed aberrant CD82 compared to T cells isolated from a healthy volunteer, as assessed by immunocytochemistry. Interestingly, MTT assay found that MT-1 cells derived from ATL patient became more susceptible to growth inhibition mediated by doxorubicin and etoposide when CD82 was knocked down using the CRISPR-Cas9 technique, although the doubling time of CD82 knockdown MT-1 cells was compatible with parental MT-1 cells. These observations suggest that CD82 may be a promising therapeutic target in ATL. Further experiments are required to elucidate the role of CD82 in ATL cells. Citation Format: Koichiro Fukuchi, Takayuki Ikezoe, Ikuko Ogahara, Songji Zhao. Knockdown of CD82 sensitizes adult T cell leukemia cells to anti-cancer agents-induced growth inhibition [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 6890.
Abstract 2923: Targeting DNA repair mechanisms to overcome CIC::DUX4 undifferentiated sarcomas
Authors: Zeinab Kosibaty, Cuyler Luck, Ross A. Okimoto
Journal: Cancer Research (2025)

Abstract Transcription factor (TF) fusion oncoproteins represent cancer specific alterations that arise from chromosomal rearrangements. Through target gene recognition, TF fusions can disseminate transcriptional responses that collectively work to drive tumorigenesis. Thus, identifying the molecular targets that operate as a disease driving network can potentially uncover key actionable dependencies. We have taken this strategy to dissect the underlying biological mechanism by which CIC::DUX4, a fusion oncoprotein associated with dismal outcomes, drives sarcomagenesis. We and others have defined a CIC::DUX4 fusion mediated network that dysregulates cell-cycle and DNA replication checkpoints. Specifically, CIC::DUX4-mediated CCNE1 upregulation compromises the G1/S transition leading to high DNA replication stress and conferring a dependence on the G2/M checkpoint kinase, WEE1. WEE1 provides a molecular brake to enable effective DNA repair prior to mitotic entry. Importantly, the mechanism by which CIC::DUX4 regulates DNA repair remains unknown. Here we show that the catalytic subunit of DNA polymerase epsilon (POLE) is essential for DNA integrity and cellular division in CIC::DUX4 sarcoma. Mechanistically, POLE loss increases DNA damage and induces p21-mediated cellular senescence to limit CIC:DUX4 tumor growth in vitro and tumor formation in vivo. Collectively, we credential POLE as a CIC::DUX4 target and further characterize a functional network through which CIC::DUX4 operates to drive tumor progression and survival. Citation Format: Zeinab Kosibaty, Cuyler Luck, Ross A. Okimoto. Targeting DNA repair mechanisms to overcome CIC::DUX4 undifferentiated sarcomas [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 2923.
Abstract 6891: Tumor treating fields with imipridone ONC206 in murine model of colorectal cancer
Authors: Leiqing Zhang, Maryam Ghandali, Connor Purcell, Lanlan Zhou, Wafik S. El-Deiry
Journal: Cancer Research (2025)

Abstract Colorectal Cancer is the third leading cause of cancer-related death in men and the fourth leading cause of cancer-related death in women in the United States. Treatment options include surgery, Chemotherapy, Radiation therapy, and immunotherapy. Despite multiple treatment options, colorectal cancer treatment remains a challenge. Tumor Treating Fields (TTFields) Therapy are FDA-approved for the Treatment of glioblastoma (GBM), Mesothelioma and metastatic NSCLC after platinum-based therapy, and showed preclinical and clinical efficacy in multiple cancer types. TTFields use alternating electric fields to induce cellular damage, suppress tumor growth and activate integrated stress response. Imipridones, TRAIL pathway-inducing compounds, activate the integrated stress response, especially through the eIF2α/ATF4 pathway. We hypothesized that combining TTFields and Imipridone ONC206(DRD2 antagonist and ClpP agonist) can increase treatment efficacy in colorectal cancer through common pathways like integrated stress response. Animal experiments were performed using the inovivo system that allows to treat mice with TTFields, The MC38 cell line was injected into the flanks of C57BL/6 mice, The mice were closely monitored for changes in weight, general appearance, and movement. Treatments were initiated once the tumor volume reached 75-100 mm3 and continued for 12 days. The mice were divided into four groups: sham heat control (N=4), sham heat and ONC206 (100 mg/kg weekly)(N=4), TTFields (N=3) , and TTFields and ONC206 (100 mg/kg weekly)(N=4). We observed a decrease in tumor volume following treatment with ONC206 and Tumor Treating Fields compared to sham heat control with a Pvalue of 0.0233; No significant percentage weight loss was observed in treatment groups. Our ongoing studies further explore the effect of synergy on common pathways. Our results suggest an effective novel combination of Imipridone ONC206 and TTFields for the treatment of colorectal cancer. Citation Format: Leiqing Zhang, Maryam Ghandali, Connor Purcell, Lanlan Zhou, Wafik S. El-Deiry. Tumor treating fields with imipridone ONC206 in murine model of colorectal 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 6891.
Abstract 6989: Advancing AOH1996: Enhanced anticancer activity of next-generation small molecule PCNA inhibitors
Authors: Pouya Haratipour, Maryam Zangi, Mahshid Yaghoubi, Long Gu, Jennifer Jossart, John J. Perry, Linda H. Malkas, Robert J. Hickey
Journal: Cancer Research (2025)

Abstract Proliferating cell nuclear antigen (PCNA) plays a critical role in at least nine distinct cellular pathways, including DNA replication and repair, transcription, cell cycle control, apoptosis induction, transcription-replication conflict resolution, and immune surveillance. Tumor cells express an acidic isoform of this protein (caPCNA), whereas non-cancer cells express only a basic isoform (nmPCNA). The absence of the caPCNA isoform in non-cancer cells makes it an ideal target for selectively killing cancer cells while preserving the viability of non-cancer cells. To this end, we developed a small molecule, AOH1996, that selectively inhibits the caPCNA isoform in cancer cells, inducing cell death in these cells while showing no detectable effects on non-cancer cells. AOH1996 directly binds to caPCNA, stabilizes its trimer structure, reduces chromatin association, and selectively inhibits tumor cell growth. Currently, in several phase I and phase Ib clinical trials, AOH1996 exhibits highly selective anti-cancer properties with essentially no off-target toxicities. This study describes our efforts to improve the clinical characteristics, potency, and stability of AOH analogues through a scaffold-hopping strategy that employs structure-activity relationship (SAR) studies and bioisostere replacement. SAR analysis and modification of four unique scaffolds related to AOH1996 led to the discovery of several additional analogues exhibiting enhanced potency, selectivity, and metabolic stability compared to the clinical lead. Over one hundred AOH analogues were designed, synthesized, and initially evaluated for effects on cell growth across eight tumor cell lines. Our results identify top analogues featuring unsymmetrical 3-methoxy-5-methyl groups on the terminal phenoxy moiety, combined with fluorine, nitrile, or chlorine substitutions at the #6 position of 1-naphthoic acid. Among these, AOH-3M5Me-6F and AOH-3M5Me-6CN emerged as the lead analogues, demonstrating up to nine- and seven-fold improved potency and 38% and 68% higher liver microsome stability, respectively. These findings position these analogues for further development as selective PCNA-targeting cancer therapies. Citation Format: Pouya Haratipour, Maryam Zangi, Mahshid Yaghoubi, Long Gu, Jennifer Jossart, John J. Perry, Linda H. Malkas, Robert J. Hickey. Advancing AOH1996: Enhanced anticancer activity of next-generation small molecule PCNA inhibitors [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 6989.