tbuckley/cabot-search huggingface dataset:
Abstract 5725: The potent and selective PARP1 inhibitor and trapper SNV1521 exhibits combination activity with targeted and chemotherapeutics
Authors: Mingming Gao, Qipeng Fan, Zhentian Li, Jun Pan, Renxu Chang, Liangxing Wu, Wenqing Yao, Phillip CC Liu
Journal: Cancer Research (2025)

SNV1521 is clinical stage PARP1 inhibitor and trapper with excellent potency and selectivity against other MARP and PARP proteins. Although several first generation non-PARP1 selective inhibitors have been approved primarily as monotherapy for BRCA-associated tumors, they have not fully realized the potential of PARP inhibition as a mechanism for potentiation of chemo-, DNA damage response, and radiation therapy because of overlapping toxicities including hematologic suppression. SNV1521 shows exquisite selectivity for PARP1 over PARP2 and other related proteins in biochemical assays compared with both first-generation PARPi and saruparib. In colony formation assays using normal donor HSPCs, SNV1521 exhibited significantly less suppression of the proliferation of both myeloid and erythroid lineages compared with these inhibitors. When comparing with the target efficacious concentration using a BRCA2-deficient cell line versus the NOEL for suppression of heme progenitors, SNV1521 showed an expanded margin versus either olaparib or saruparib. These data support the potential of SNV1521 to combine more effectively with approved and experimental oncology drugs. In cell-based combination experiments, SNV1521 strongly synergized with topoisomerase-1 inhibitors as well ADCs utilizing topo-1 based warheads. Importantly, the combination benefit extended to cell lines that were not intrinsically sensitive to PARP inhibitors suggesting activity in cell models beyond those with functional defects in homologous recombination. In a PDX model of breast cancer, the combination of topotecan with SNV1521 showed deeper tumor regression than either agent alone. Moreover, this activity showed durable anti-tumor activity after cessation of dosing. In summary, these data support the continued clinical development of SNV1521 as monotherapy and also in combination with drugs that are mechanistically synergistic but cannot be effectively combined with less selective PARP1 inhibitors because of overlapping toxicities. Citation Format: Mingming Gao, Qipeng Fan, Zhentian Li, Jun Pan, Renxu Chang, Liangxing Wu, Wenqing Yao, Phillip CC Liu. The potent and selective PARP1 inhibitor and trapper SNV1521 exhibits combination activity with targeted and chemotherapeutics [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 5725.
Abstract 5283: Decoding and disrupting the coupled cellular plasticity and myeloid cell instigation in metastatic prostate cancer
Authors: Tianhe Huang, Yaoyin Li, Jun Wan, Liang Cheng, Xin Lu
Journal: Cancer Research (2025)

Abstract Prostate cancer (PCa) metastasis significantly worsens patient prognosis, particularly when it spreads to the lungs. Understanding the mechanisms underlying PCa metastasis is crucial for developing effective therapies. Here, we developed a genetically engineered mouse model by activating MAPK pathway in the PB-Cre Pten p53 Smad4 mice, creating a model that mimics the aberrant cell signaling associated with human metastatic PCa and exhibits strong metastatic phenotype. We observed dynamic changes in epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) during metastasis: circulating tumor cells (CTCs) displayed mesenchymal characteristics, while lung metastases regained epithelial features. Transcriptomic profiling of primary tumors, CTCs, and lung metastases revealed that lung metastatic cells (LM) upregulated pro-inflammatory cytokines, notably IL-1α. This cytokine profile correlated with increased recruitment and activation of neutrophils in the premetastatic lung niche, as confirmed by single-cell RNA sequencing and flow cytometry. Functional experiments demonstrated that depleting neutrophils using anti-Ly6G antibodies or inhibiting their recruitment and activation via a CXCR1/2 antagonist (currently in clinical trials) significantly reduced lung metastasis and extended survival in mice. Similarly, IL-1 receptor knockout mice showed decreased neutrophil infiltration and fewer metastatic nodules, indicating the pivotal role of IL-1 signaling in neutrophil-mediated metastasis. Mechanistically, we identified the transcription factor KLF4 as the master regulator of both the EMT-to-MET plasticity and IL-1α expression in metastatic cells. Chromatin immunoprecipitation confirmed KLF4 binding to the IL-1α promoter, leading to the upregulation of neutrophil-recruiting cytokines. Knockdown of KLF4 in LM cells reduced IL-1α levels and metastasis, while overexpression enhanced them. Co-culture of tumor cells with neutrophils increased KLF4 expression and cytokine production, suggesting a feedback loop promoting metastasis. Clinical data analysis showed that high levels of KLF4 and IL-1α correlate with increased neutrophil infiltration and poorer disease-free survival in PCa patients. Our findings identify the crucial role of the KLF4/IL-1α axis and neutrophil recruitment in PCa lung metastasis. Targeting neutrophil activation or the KLF4/IL-1α signaling pathway may offer new therapeutic strategies for preventing or treating metastatic prostate cancer. Citation Format: Tianhe Huang, Yaoyin Li, Jun Wan, Liang Cheng, Xin Lu. Decoding and disrupting the coupled cellular plasticity and myeloid cell instigation in metastatic 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 5283.
Abstract 6367: CHD1 loss hijacks SREBP2-mediated cholesterol biosynthesis to fuel SPOP-deficient prostate cancer and confers resistance to castration
Authors: Feiyu Chen, Haoyan Li, Yin Wang, Ximing Tang, Kevin Lin, Qidong Li, Chenling Meng, Wei Shi, Javier Leo, Xin Liang, Jie Zhang, Vivien Van, Iqbal Mahmud, Bo Wei, Philip L. Lorenzi, Maria G. Raso, Ana Aparicio, Yue Lu, Daniel E. Frigo, Boyi Gan, Di Zhao
Journal: Cancer Research (2025)

Abstract Despite receiving surgical or medical castration, most prostate cancer (PCa) patients eventually progress to castration-resistant prostate cancer (CRPC), where the androgen receptor (AR) continues to drive disease progression. Genomic studies have identified a unique subtype of PCa marked by mutations in speckle-type BTB/POZ protein (SPOP), which lead to the stabilization of AR and its co-activators and have been associated with prolonged responses to androgen deprivation therapies and favorable prognoses. However, SPOP mutations frequently co-occur with the loss of chromodomain helicase DNA-binding protein 1 (CHD1), and the impact of concurrent CHD1 loss on SPOP-mutated PCa remains unclear. In this study, we developed a novel genetically engineered mouse model with CHD1 deletion and SPOP mutation to recapitulate this specific molecular subtype of PCa. Our findings provide genetic evidence that CHD1 loss accelerates the progression of SPOP-mutated PCa in males and confers resistance to castration in this context. By integrating single-cell transcriptomic, lipidomic, epigenetic, and proteomic analyses, we uncovered a non-canonical role of CHD1 in gene repression through its interaction with the ACF complex and demonstrated that CHD1 reprograms cholesterol metabolism by modulating sterol regulatory element-binding protein 2 (SREBP2). The loss of CHD1 triggers increased cholesterol production, supporting intratumoral androgen biosynthesis and sustaining AR transcriptional activity in SPOP-mutated prostate tumors, leading to castration resistance. Moreover, our studies reveal that combining the androgen synthesis inhibitor abiraterone with cholesterol-lowering agents exerts synergistic and durable anti-tumor effects against CRPC with CHD1 loss and SPOP mutations in males. These findings advance our understanding of an emerging PCa subtype and mechanism of action, as well as provide novel strategies for biomarker-driven combination therapy for patients with CRPC. Citation Format: Feiyu Chen, Haoyan Li, Yin Wang, Ximing Tang, Kevin Lin, Qidong Li, Chenling Meng, Wei Shi, Javier Leo, Xin Liang, Jie Zhang, Vivien Van, Iqbal Mahmud, Bo Wei, Philip L. Lorenzi, Maria G. Raso, Ana Aparicio, Yue Lu, Daniel E. Frigo, Boyi Gan, Di Zhao. CHD1 loss hijacks SREBP2-mediated cholesterol biosynthesis to fuel SPOP-deficient prostate cancer and confers resistance to castration [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 6367.
Abstract 6897: Development of immunomodulatory nanoparticles targeting HER2 for breast cancer therapy
Authors: Mathilde Dacos, Lea Plantureux, Erwan Diroff, Sarah Giacometti, Joseph Ciccolini, Raphaelle Fanciullino
Journal: Cancer Research (2025)

Abstract Nanoparticles (NPs) are emerging as a promising strategy in oncology, offering optimised drug delivery and the potential to modulate immune responses. In this study, we developed an innovative nanoparticle encapsulating docetaxel and functionalised with trastuzumab for the precise targeting of HER2-positive tumours (called ANC for Antibody Nanoparticle Conjufate). Pharmacokinetic analyses were performed using C57BL/6 mice, which were administered free docetaxel (1.6 mg/kg) and trastuzumab (135 ng/kg) via intraperitoneal injection (n = 29), or ANC (nanoparticles at the same docetaxel and trastuzumab doses as the free drugs, n = 40). Blood samples were collected at 0.5, 1, 2, 3, 6, 8, 12, and 24 hours post-injection, and the frozen plasma was analysed using by HPLC-UV. For biodistribution studies, DiR-labelled nanoparticles were administered to C57BL/6 mice, and imaging was performed on a daily basis using an IVIS Spectrum imager. Immunomodulation study was assessed by flow cytometry. The AUC0-∞ for the ANC (4250.79 ng.mL/h) was four times higher than for free docetaxel (1050.3 ng.mL-1.h-1). In addition, the half-life of the liposomal docetaxel (22.14 hours) was significantly three times longer than that of the free docetaxel (7.15 hours). Biodistribution studies in mouse models showed that the nanoparticle remained stable and did not reach the liver until 30 hours after injection. Immunomodulation studies showed that ANC had a different effect on the distribution of lymphocyte subpopulations compared to free drug, with a notable decrease in regulatory T cells (Tregs) in the ANC-treated group, suggesting a potential immunostimulatory effect. The potential immunomodulatory effects of these nanoparticles on anti-tumour immune responses are currently being investigated. These preliminary results demonstrate the dual benefit of targeted drug delivery and immune system engagement offored by these nanoparticles, which could pave the way for novel breast cancer treatments. Citation Format: Mathilde Dacos, Lea Plantureux, Erwan Diroff, Sarah Giacometti, Joseph Ciccolini, Raphaelle Fanciullino. Development of immunomodulatory nanoparticles targeting HER2 for breast cancer 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 6897.
Abstract 6833: Influence of g<i>uthation S transferase</i> T1 and M1 polymorphisms on tamoxifen metabolism in malian women with breast cancer
Authors: Brehima Diakite, Yaya Kassogue, Mamoudou Maïga, Oumar Kassogue, Fousseyni Diarra, Kadidiatou Cisse, Aissata Coulibaly, Cheick B. Traore, Madani Ly, Jane L. Holl, Lifang Hou
Journal: Cancer Research (2025)

Abstract Background: The metabolism of tamoxifen, used in breast cancer treatment, is influenced by the GSTT1 and GSTM1 genes. Women were classified as poor (inactivated genes), intermediate (reduced enzyme activity), or rapid (functional genes) metabolizers. This classification helped to understand how genetic variations affected treatment efficacy and side effect risk, promoting a personalized therapeutic approach. This study aimed to analyze the impact of GSTT1 and GSTM1 genetic variations on tamoxifen metabolism in Malian women with breast cancer. Methods: A cohort study was conducted involving 109 Malian women (ages 18-50) diagnosed with ER/PR (+) breast cancer and eligible for tamoxifen treatment. GSTM1 and GSTT1 genotypes were determined using multiplex PCR. Results: A significant correlation was observed between the GSTM1 gene and family history of breast cancer (p = 0.026) as well as tumor size (p = 0.031). The genotypic frequencies were 75.2% for functional GSTM1 and 24.8% for inactive; for GSTT1, 56.9% were functional and 43.1% inactive. The categories of metabolizers were distributed as follows: 42.2% (rapid), 14% (intermediate), and 11% (poor), with a significant difference (p &amp;lt; 0.0001). Conclusion: This study highlights the correlation between the GSTM1 and GSTT1 genes and factors related to breast cancer. Genotypic variations affect tamoxifen metabolism, emphasizing the importance of genetic factors in optimizing treatment. Citation Format: Brehima Diakite, Yaya Kassogue, Mamoudou Maïga, Oumar Kassogue, Fousseyni Diarra, Kadidiatou Cisse, Aissata Coulibaly, Cheick B. Traore, Madani Ly, Jane L. Holl, Lifang Hou. Influence of guthation S transferase T1 and M1 polymorphisms on tamoxifen metabolism in malian women with 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 6833.
Abstract 6828: Therapeutic potential of novel polyisoprenylated phosphonyl ester inhibitors in triple-negative breast cancer
Authors: Joshua K. Ablordeppey, Amarender Burra, Kweku Ofosu-Asante, Jahnissi Odoom, Nazarius S. Lamango
Journal: Cancer Research (2025)

Abstract Hyperactive monomeric G-proteins such as RAS are dominant “drivers” in cancer. In triple negative breast cancer (TNBC), RAS hyperactivity is due to low levels of the RAS-GTPase activating protein, RASA1, a tumor suppressor. KRAS is polyisoprenylated and methylated to become functional. Polyisoprenylated methylated protein methyl esterase (PMPMEase) is overexpressed in various cancers and its specific inhibition causes cancer cell death. Polyisoprenylated phosphonyl ester inhibitors of PMPMEase (PPEIs) were designed to suppress hyperactive RAS-promoted cancers through PMPMEase inhibition. Here, we evaluated the anti-proliferative properties of the PPEIs against two TNBC cell lines, MDA-MB-468 and MDA-MB-231. The PPEIs, NSL-AB-01, NSL-AB-02 and NSL-AB-03 inhibited TNBC cells with EC50 values of 3.3 µM, 4.0 µM and 3.6 µM for MDA-MB-468 and 4.1 µM, 5.6 µM and 5.6 µM for MDA-MB-231, respectively. Following 48 h exposure to 1 µM NSL-AB-01, the proliferation of MDA-MB-231 and MDA-MB-468 cells was inhibited by 48% and 8%, respectively. At 2 to 3 µM concentrations, the proliferation of both cell lines was completely blocked. In addition, NSL-AB-01 inhibited the migration of MDA-MB-231 and MDA-MB-468 cells by 95% at 5 µM and 73% at 3 µM, respectively, thereby suggesting potential antimetastatic effects of the PPEIs. Further investigations are in progress to ascertain the molecular mechanisms underlying these effects. Overall, these findings suggest the therapeutic potential of PPEIs as novel agents for TNBC and other cancers with activated G-protein signaling. Citation Format: Joshua K. Ablordeppey, Amarender Burra, Kweku Ofosu-Asante, Jahnissi Odoom, Nazarius S. Lamango. Therapeutic potential of novel polyisoprenylated phosphonyl ester inhibitors 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 6828.
Abstract 4727: Exploring glycosylation as a barrier to drug therapy in lymphoma: unlocking new therapeutic potential
Authors: Shayan Mosaffa, Thao Nguyen, Nasr Issa, Robert B. Campbell
Journal: Cancer Research (2025)

Background: Lymphoma, a cancer more common in younger males, poses challenges in developing treatments with precise target selectivity. Mucin, a glycosylated protein overexpressed in tumor cells, forms a barrier shown elsewhere to impede drug effects. For example, we previously demonstrated in pancreatic cancer models that the inhibition of mucin glycosylation improved treatment outcomes in vitro and in vivo. This approach remains unexplored in lymphoma. This study examines the extent to which mucin glycosylation impacts the intracellular uptake and effectiveness of lymphoma therapeutics in vitro. We hypothesize that glycosylation functions as a cellular barrier limiting cellular access to model agents and subsequent drug effects. Methods: The U-937 human lymphoma cell line (ATCC CRL-1593.2) was cultured in RPMI-1640 medium supplemented with 5% fetal bovine serum (FBS). Cells were seeded in 24-well plates and exposed to a glycosylation inhibitor (benzyl-α-GalNAc). After a required incubation period, the cells were exposed to a fluorescently tagged anti-MUC1 antibody (used to probe the degree of cell access to molecular entities in the presence and absence of the glycation mesh). Antibody uptake was analyzed using a fluorescent microplate reader. The functional drug effects of pre-exposing U-937 cells to the glycosylation inhibitor were initially assessed through cell viability experiments (using Quadcount™), with follow-up studies using a fluorometric assay. Results: At 1 hour, cells that were pre-exposed to the glycosylation inhibitor demonstrated significantly higher uptake of the anti-MUC1 antibody compared to untreated cells (p = 0.0266), suggesting enhanced drug delivery in the early stages. Future studies will investigate whether the uptake is time-dependent, favoring prolonged cellular exposure to the antibody. Preliminary data shows that the pre-exposure of U-937 cells to benzyl-α-GalNAc enhanced the effect of imatinib significantly when compared to imatinib alone (P= 0.0240). The impact of cellular glycosylation on the effect of additional therapeutic agents is currently under investigation. Conclusions: Targeting mucin glycosylation with benzyl-α-GalNAc enhanced anti-MUC1 antibody uptake. The improved cell kill observed with the inhibitor-imatinib combination further underscores the promise of this strategy in overcoming drug resistance in lymphoma. Citation Format: Shayan Mosaffa, Thao Nguyen, Nasr Issa, Robert B. Campbell. Exploring glycosylation as a barrier to drug therapy in lymphoma: unlocking new therapeutic potential [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 4727.
Abstract 4744: State-gating cancer to prevent chemotherapy-resistance
Authors: Christine Louise Chaffer, Heloisa H. Milioli, Beatriz P. San Juan, Rachel F. Dear, Jia (Jenny) Liu
Journal: Cancer Research (2025)

Abstract New approaches are urgently required to treat advanced-stage cancers that are therapy resistant and incurable. Furthermore, salvage treatment protocols rely on cytotoxic chemotherapies that actively induce cancer cells to transition into therapy-resistant states via non-genetic mechanisms. We show in large clinical cohorts of triple-negative breast cancer (TNBC) that chemotherapy-induced cell state changes are mediated by androgen receptor (AR) signaling and are associated with poor patient outcome. AR inhibition blocks canonical and non-canonical AR signaling to lock cancer cells in therapy-sensitive states, and synergizes with a broad spectrum of cytotoxic chemotherapies to improve survival in pre clinical TNBC models. Seviteronel, a dual CYP17 lyase and AR inhibitor, faithfully mimics genetic AR ablation and is the most effective AR inhibitor in combination with chemotherapy. A Phase 1 clinical trial (NCT04947189) confirmed the safety of combining seviteronel with taxane chemotherapies in metastatic breast cancer. Early signs of clinical efficacy in patients with advanced disease led to a Phase 2 expansion study for AR-positive TNBC. These data provide proof-of-concept for AR inhibition as a ‘state-gating’ strategy to lock cancer cells in therapy-sensitive states and prevent the emergence of chemotherapy-resistance in TNBC. This paradigm may be widely applicable to other cancers. Citation Format: Christine Louise Chaffer, Heloisa H. Milioli, Beatriz P. San Juan, Rachel F. Dear, Jia (Jenny) Liu. State-gating cancer to prevent chemotherapy-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 4744.