tbuckley/cabot-search huggingface dataset:
Abstract LB455: SUMO1: induction contributes to the efficacy of fulvestrant and T6I-29 in breast cancer cells
Authors: Govinda Hancock, Kristen Young, Sean Fanning
Journal: Cancer Research (2025)

Abstract Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths in women worldwide. Estrogen receptor alpha (ERα), a ligand-dependent transcriptional regulator, is overexpressed in approximately 70% of breast cancer cases, driving tumor progression. Selective estrogen receptor modulators (SERMs) and downregulators or degraders (SERDs) are therapeutic agents that manipulate ERα conformation to treat and prevent metastatic disease. Despite their clinical efficacy, resistance to these competitive allosteric regulators develops in up to ∼40% of ERα-positive breast cancer patients, even as the tumor continues to depend on ERα signaling. In this study a novel SERM based on a tetrahydro-6-isoquinoline (T6I) scaffold and optimized utilizing structure-activity relationships is found to engage transcriptional programs similar to the clinically relevant SERD fulvestrant. Specifically, transcriptomic analysis via RNA sequencing shows that our lead compound, T6I-29, and fulvestrant both induce the expression of small ubiquitin-like modifier-1 (SUMO1), in contrast to the pathogenic hormone 17β-estradiol. SUMOylation, a post-translational modification (PTM), plays a significant role in various cellular processes, including protein-protein interactions, protein stability, nuclear transport, DNA damage response, apoptosis, and transcriptional regulation. Notably, high expression of SUMO1 correlates with a better prognosis in ERα-positive breast cancer patients. This induction of SUMO1 highlights its potential role in mediating the antiestrogenic effects of these compounds. The selective accumulation of ERα observed with T6I-29 further suggests that SUMOylation may be a key modulator of the therapeutic response in antiestrogen treatments. This effect is observed using a genetic knockdown of SUMO1, which attenuates anti-proliferative efficacy of the compounds in the T47D breast cancer cell line, while also modifying the mRNA levels of ERα target genes. On the other hand, overexpression of SUMO1 enhances the antiestrogens ability to control cell growth in these cells. Furthermore, a nanoBiT assay demonstrates the presence of fulvestrant increases interaction between ERα and the SUMOylation E2 conjugating enzyme UBC9. Together, these findings emphasize the need to deepen our understanding of SUMOylation in breast cancer, including its induction, structural mechanisms, and its potential as an exploitable therapeutic target for treating advanced breast cancer. Citation Format: Govinda Hancock, Kristen Young, Sean Fanning. SUMO1: induction contributes to the efficacy of fulvestrant and T6I-29 in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB455.
Abstract LB178: Neoplastic immune mimicry is a generalizable phenomenon in breast cancer and epithelial CD69 enables early tumor progression
Authors: Eric B. Berens, Sokchea Khou, Elaine Huang, Amber Hoffman, Briana Johnson, Nell Kirchberger, Sam Sivagnanam, Nicholas Calistri, Daniel Derrick, Tiera A. Liby, Ian C. McLean, Aryn A. Alanizi, E. Shelley Hwang, Pepper Schedin, Hugo Gonzalez, Zena Werb, Laura M. Heiser, Lisa M. Coussens
Journal: Cancer Research (2025)

Abstract Dedifferentiation programs are commonly enacted during breast cancer progression to enable novel cellular phenotypes. Increased cellular plasticity within the neoplastic compartment of tumors correlates with disease aggressiveness, often culminating in greater resistance to cytotoxic therapies or the augmented ability to metastasize to distant organs. Here we report that subpopulations of dedifferentiated neoplastic breast epithelial cells express canonical leukocyte cell surface receptor proteins and have named this unique cellular program ‘immune mimicry.” We have documented neoplastic cells engaging in immune mimicry within public human breast tumor single-cell RNA-seq datasets, histopathological breast tumor specimens, breast cancer cell lines, as well as in murine transgenic and cell line-derived mammary cancer models. Immune-mimicked neoplastic cells harbor hallmarks of dedifferentiation and appear enriched in treatment-resistant and high-grade breast tumors. We corroborated these observations in aggressive breast cancer cell lines where growth-arresting cytotoxic chemotherapies drove epithelial cells toward immune mimicry. Moreover, in subsequent proof-of-concept studies, we demonstrate that expression of the CD69 leukocyte activation marker by neoplastic cells confers a proliferative advantage that enhances early tumor growth. We conclude that neoplastic breast epithelial cells upregulating leukocyte surface receptors potentiate malignancy. Moving forward, neoplastic immune mimicry should be evaluated for prognostic utility in breast cancer to determine whether it stratifies patients with increased risks for tumor recurrence and metastasis. Citation Format: Eric B. Berens, Sokchea Khou, Elaine Huang, Amber Hoffman, Briana Johnson, Nell Kirchberger, Sam Sivagnanam, Nicholas Calistri, Daniel Derrick, Tiera A. Liby, Ian C. McLean, Aryn A. Alanizi, E. Shelley Hwang, Pepper Schedin, Hugo Gonzalez, Zena Werb, Laura M. Heiser, Lisa M. Coussens. Neoplastic immune mimicry is a generalizable phenomenon in breast cancer and epithelial CD69 enables early tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB178.
Abstract LB204: Cis-delivery of a potency-reduced IL-12 via an anti-PD-1 single-chain antibody exhibits potent anti-tumor activity
Authors: Linda N. Liu
Journal: Cancer Research (2025)

Abstract Immune checkpoint blockade (ICB) works by alleviating immunosuppression on tumor-infiltrating lymphocytes (TILs) and has shown success in treating various cancer types. However, many patients with solid malignancies derive limited clinical benefit due to primary or acquired resistance. Interleukin-12 (IL-12), a proinflammatory cytokine produced by activated antigen-presenting cells, increases IFN-γ production and promotes Th1 cell differentiation, leading to enhanced T and NK cell proliferation and cytotoxicity. Numerous preclinical studies in mice have demonstrated that IL-12 can exert significant anti-tumor activity. However, its clinical application has been hindered by a narrow therapeutic index and severe adverse events associated with systemic IL-12 administration.ZL-1222 is a PD-1-targeted immunocytokine comprising an anti-PD-1 single-chain antibody (ScAb), a potency-reduced IL-12, and a non-effective Fc fragment with specific modifications to extend serum half-life. The potency-reduced IL-12 preferentially supports T cell function with reduced activity on NK cells due to differences in IL-12Rβ1 expression, thereby mitigating systemic toxicity in mice (Glassman et al. 2021). Since PD-1 is predominantly expressed on CD8+ and CD4+ TILs and is enriched in the tumor microenvironment (TME) compared to circulating T cell subsets, PD-1 targeting would further enhances IL-12-mediated T cell activity via a cis-effect within the TME while reducing systemic toxicity.In vitro, ZL-1222 effectively blocks PD-1/PD-L1 signaling in a co-culture/reporter cell assay and enhances mutant IL-12 activity in a PD-1-dependent manner in an IL-12 receptor reporter assay. In a SARS-CoV-2 Spike protein recall assay, ZL-1222 demonstrates significantly higher IFN-γ production in human PBMCs compared to the combination of potency-reduced IL-12 and the αPD-1 ScAb. Additionally, in a co-culture of human cancer cells and primary PBMCs, ZL-1222 demonstrates superior IFN-γ release and tumor killing compared to the combination treatment.In vivo, systemic administration of ZL-1222 mouse surrogates, m34 or m45, shows strong antitumor activity with reduced mouse body weight loss in the B16F10 syngeneic tumor model in human PD-1 knock-in C57Bl/6 mice and the B16F10.OVA syngeneic model in wild-type C57Bl/6 mice compared to treatment with wild type IL-12.These results position ZL-1222 as a promising next-generation IL-12 immunocytokine for cancer immunotherapy, potentially combining potent antitumor activity with improved systemic safety. Citation Format: Linda N Liu. Cis-delivery of a potency-reduced IL-12 via an anti-PD-1 single-chain antibody exhibits potent anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB204.
Abstract LB173: Growth kinetics of Fanconi anemia derived head and neck cancer cells <i>in vitro</i> and <i>in vivo</i>
Authors: Nathan DeMichaelis, Sanjana Arji, Haley Ring, Beverly Wuertz, Frank G. Ondrey
Journal: Cancer Research (2025)

Abstract Introduction: Treatment of head and neck cancer in Fanconi anemia (FA) patients is highly challenging because all conventional chemo radiotherapy exacerbates DNA damage which is deleterious in these patients. We have been working with Wee kinase cell cycle inhibitors in vitro to potentially treat these cancers and avoid DNA damage. In the current study we sought to establish growth kinetics of Fanconi anemia and non FA squamous cancer cells to compare with human head and neck cancer growth rates. We hypothesized that if we observed preclinical experimental cellular growth rates to actual human head and neck cancer growth, a more accurate cancer treatment model would be achieved. Methods: We first examined the growth kinetics of several FA/ non FA cell lines in MTT assays and nude mice xenografts. We next compared these pre clinical growth kinetics to the human head and neck cancer tumor literature and clinical data. P&amp;lt;0.05 was significant. Results: For the FA tumor cell lines we found growth rates ranging from 4-220% /day on MTT Assays. For non FA tumor cell lines we found growth rates ranging from 31.2 -53.0 %/day on MTT assays. For the FA tumor cell lines we found growth rates ranging from 0.7- 23.2%/day in mouse xenografts. For HeLa cells (a non FA tumor squamous cell line) we found growth rates ranging from 10.7 - 24.5%/day in mouse xenografts. In the human tumor literature and rapid growing clinical specimens we found growth rates from 0.1%- 15.1% / day. We found a wide variety of growth kinetics in head neck cancer cell lines of FA and non FA patients that were not significantly different from each other in standard MTT experiments. Some experimental conditions in setting up mouse xenograft experiments with FA cell lines, (but not HeLa xenografts) more closely resembled published human tumor growth rates (0.1-4.2%/day). In general, growth rates were all more rapid in cell line and animal xenograft experiments than human head and neck cancer clinical tumors. Conclusions: We discovered effects of cell cycle disruptors like Wee kinase inhibitors are likely to show significantly amplified effects in preclinical experiments compared to actual human squamous tumor treatment. Therefore, there might be improved utility in carefully designing preclinical experiments with cell cycle disrupting therapy (like WEE kinase inhibitors) to resemble human tumor kinetics. Citation Format: Nathan DeMichaelis, Sanjana Arji, Haley Ring, Beverly Wuertz, Frank G. Ondrey. Growth kinetics of Fanconi anemia derived head and neck cancer cells in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB173.
Abstract LB217: RAGE inhibition improves vemurafenib effect in melanoma cells
Authors: Estelle Leclerc, Yousuf Alam, Md. Zahidul Hasan, Stefan W. Vetter
Journal: Cancer Research (2025)

Abstract Background: The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor that participates to many aspects of tumorigenesis including cancer cell proliferation, migration, invasion. RAGE also contributes to resistance to chemotherapeutic agents. We have previously shown that RAGE inhibition, with the small molecule RAGE inhibitor (FPS-ZM1), increased the efficacy of the chemotherapeutic agent dacarbazine, in a mouse model of melanoma. We later showed that RAGE inhibition also enhances the efficacy of the cytotoxic agent gemcitabine in an orthotopic mouse model of pancreatic cancer, suggesting that RAGE inhibition could enhance the efficacy of different chemotherapeutic agents in different types of cancer. Objective of the study: The goal of our study was to determine if RAGE inhibition increases the efficacy of the BRAF V600E mutant inhibitor vemurafenib in melanoma cells.Methodology:We assessed the synergistic or antagonistic effect of the small molecule RAGE inhibitor, FPS-ZM1, combined with the current standard of care vemurafenib. We compared the viability of human melanoma WM115 cells after treatment with different concentrations of vemurafenib and FPS-ZM1. The data were analyzed for the presence of synergistic effect using a dedicated software. Results and conclusion: As anticipated, treatment of WM115 cells with FPS-ZM1 alone did not affect the viability of the melanoma cells. However, when combined with vemurafenib, FPS-ZM1 enhanced the apparent IC50 of vemurafenib by 2 to 3-fold, suggesting that RAGE inhibition enhances the efficacy of vemurafenib in WM115 cells and possibly in other melanoma cells. We will next investigate if RAGE inhibition also enhances the efficacy of vemurafenib in a mouse model of melanoma. Citation Format: Estelle Leclerc, Yousuf Alam, Md. Zahidul Hasan, Stefan W. Vetter. RAGE inhibition improves vemurafenib effect in melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB217.
Abstract LB186: Development of simvastatin nanoformulations using various polymers for the management of colorectal cancer
Authors: Mohammed Riaz Hasan Chowdhury, Hunter Payne, Leslie Kuang, Sunil Prabhu, Preshita Desai
Journal: Cancer Research (2025)

Abstract Colorectal Cancer (CRC) is one of the leading causes of cancer-related deaths globally, which highlights the need for efficient preventive measures. Simvastatin (SIM) is a drug with a repurposing potential for CRC chemoprevention. Previous studies from our lab have shown promising chemopreventive efficacy of SIM. In this study, we developed and compared the CRC chemopreventive action of 3 SIM nanoformulations: simvastatin lignin nanoparticles in combination with ferulic acid (SIM-LNPs-FA), SIM self-micro emulsifying drug delivery system nanoformulation (SIM-SMEDDS) and SIM- SMEDDS in combination with Chondroitin Sulfate (CHS) nanoformulation (SIM-SMEDDS-CHS). Specifically, SIM-LNPs-FA were prepared by dissolving the polymer and drug in a water-miscible solvent, which was added to an aqueous solution containing PVA. Formulations were optimized by varying the concentration of lignin (10 - 20 mg/mL), antisolvent PVA (1 - 2 %), polymer: antisolvent ratio, and polymer: drug ratio. SIM-SMEDDS formulations were prepared with a 1:1-1:3 w/w ratio of Smix (CapmulC8: Tween80-Transcutol HP) and loaded with different concentrations of SIM (3 - 7%). SIM-SMEDDS-CHS formulations were prepared in a 1:3 w/w ratio of SIM and CHS. All formulations were further characterized by particle size, polydispersity index (PDI), zeta potential, and encapsulation efficiency, and the data for optimized formulations is depicted in Table 1 (Some studies are underway). In vitro assessments using CRC cell lines (HT 29 and HCT 116) evaluate the nanoformulation's cytotoxicity, cellular uptake, and modulation of signaling pathways. The CRC cell line inhibitory studies using MTS assay revealed that the IC50 value of SIM decreased almost 2.6-fold when combined with FA, indicating synergistic activity. SIM-LNPs showed an IC50 of 28.8 µM in HT29 cells and 27.5 µM in HCT116 cells, compared to free SIM (64.5 µM and 40.5 µM, respectively) with p &amp;lt; 0.05, indicating statistical significance. Preliminary MTS studies for SIM-SMEDDS showed a 10-fold decrease in IC50 compared to free SIM. SIM-SMEDDS (6%) and SIM-SMEDDS-CHS (6%) demonstrated significant chemopreventive efficacy. This study highlights the potential of SIM nanoformulations for CRC chemoprevention. Citation Format: Mohammed Riaz Hasan Chowdhury, Hunter Payne, Leslie Kuang, Sunil Prabhu, Preshita Desai. Development of simvastatin nanoformulations using various polymers for the management of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB186.
Abstract LB235: HP-001: A highly potent IKZF1/3 degrader that demonstrates superior safety profile
Authors: Dihuang Wang, Jinhua Wu, Zheng Xu, Ting Peng, Kefeng Zhang, Liwen Zhao
Journal: Cancer Research (2025)

Abstract Introduction: Ikaros family zinc finger protein 1 and 3 (IKZF1/3) are essential transcription factors (TF) for the differentiation of B and T lymphocytes. IMiDs (e.g. pomalidomide, CC-220, CC-92480. etc) degrade IKZF1/3 via interaction with the cereblon (CRBN) E3 ligase and have shown promise in Multiple Myeloma (MM) and B-NHL. Enhanced IKZF 1/3 degradation would generally lead to improvement on both efficacy and toxicity. Here we presented HP-001, a highly potent IKZF1/3 degrader with improved efficacy and favorable safety profiles both in vitro and in vivo. Results: HP-001 demonstrated 5-fold improvement in CRBN binding and 10-fold improvement in IKZF1 degradation compared to CC-92480 in HTRF and K562-HiBiT-IKZF1 assays, respectively. The high IKZF1/3 degradation shown with HP-001 enabled potent antiproliferative activity across a panel of cancer cells (FL. MM, MCL, DLBCL, IC50 ranged from 0.01∼0.09 nM). In REC-1 and Mino MCL cells, after 24 h co-incubation, HP-001 (100 nM) demonstrated no degradation on other neo-substrates, e.g. SALL4, GSPT1, and CK1α, compared to &amp;gt;80% CK1α degradation in CC-92480 (100 nM) treatment. Additionally, HP-001 demonstrated 1000∼8000-fold optimized PBMC toxicity compared to CC-92480. In the H929 tumor xenograft model, administration of HP-001 (0.03 mpk, QD) promoted tumor regression (98% tumor growth inhibition by 15 days). On Day 21, the protein level of IKZF1/3 was measured by WB, indicating ∼80% and ∼70% degradation for HP-001 treatment group (0.03 mpk, QD) respectively, compared to ∼35% and ∼16% in CC-92480 group (0.03 mpk, QD). In mice bearing RPMI-8226 xenograft tumors, the combination of HP-001 (0.01 mpk, QD) and dexamethasone (5 mpk, QW) enabled complete tumor regression.Conclusions: HP-001 is a highly potent, catalytic degrader of IKZF1/3, with marked antitumor activity as a single agent and in combination with dexamethasone. HP-001 is currently in phase 1 clinical trial (CDE registration number: CTR20242943), a first-in-human, open-label, multicenter study to evaluate it as monotherapy in patients with r/r MM or NHL. Citation Format: Dihuang Wang, Jinhua Wu, Zheng Xu, Ting Peng, Kefeng Zhang, Liwen Zhao. HP-001: A highly potent IKZF1/3 degrader that demonstrates superior safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB235.
Abstract LB312: FOXA1 mutations co-opt nascent transcription factor networks in partnership with androgen receptor to enhance prostate tumorigenicity
Authors: Erik Ladewig, Abbas Nazir, Tyler Park, Vinson B. Fan, Robert Tijian, Christina Leslie, Charles Sawyers
Journal: Cancer Research (2025)

Abstract Gain of function mutations in the pioneer transcription factor FOXA1 are found in 10-40% of human prostate cancers. These mutations rewire global chromatin accessibility, driving prostate cell growth, yet the underlying molecular details behind this transformation remain elusive. To investigate this further, we leveraged single nucleus multiome sequencing of primary mouse organoids following inducible expression of FOXA1 alleles with clinically relevant missense, in/del or truncating mutations in the Wing2 region of the forkhead binding domain. While each FOXA1 mutant induces distinct transcriptomic and DNA accessibility features, all shared one compelling feature, aberrant epithelial lineage gene expression, with a marked shift toward a secretory luminal fate (L1), mirroring what is seen in FOXA1-mutant human prostate cancers. A standout mutation was a truncation of FOXA1 downstream of the Wing2 domain (G275X) that caused an 11-fold surge in the frequency of L1 cells, coupled with enrichment of a composite androgen receptor-FOXA1 hybrid motif and cooperativity with the Oct family transcription factor POU2F1. G275X triggered this L1 state transition within 24 hours, a dramatic acceleration compared to the 5-day timeline of wildtype FOXA1 while exhibiting a shorter chromatin residence time in single molecule tracking assays.In vivo studies revealed that these Foxa1 mutants enhance prostate tumorigenicity when combined with Trp53/Pten loss, producing tumors with secretory luminal cell histology. Thus, Wing2 domain mutations in FOXA1 confer gain of function pioneering activity, resulting in co-option of AR to establish transcription factor networks (Pou2f1/Oct1) that collectively enhance tumorigenicity. These findings illuminate FOXA1 as a master regulator in prostate cancer and opens new avenues for targeted therapeutic interventions. Citation Format: Erik Ladewig, Abbas Nazir, Tyler Park, Vinson B. Fan, Robert Tijian, Christina Leslie, Charles Sawyers. FOXA1 mutations co-opt nascent transcription factor networks in partnership with androgen receptor to enhance prostate tumorigenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB312.