tbuckley/cabot-search huggingface dataset:
Abstract 1132: Quantifying selection intensity of driver genes in primary and metastatic thyroid cancer
Authors: Moein Rajaei, Andrew Ju, Jeffrey P. Townsend
Journal: Cancer Research (2025)

Abstract The mutational profiles of primary and metastatic thyroid cancer (THCA) have been identified by comparing genetic alterations between the two stages, using mutation prevalence and P values to identify significant differences. However, these metrics do not quantify the cancer effects of variants. In this study, we quantified somatic selection on variants and genes using exome and targeted sequencing data from 2, 145 primary and 1, 374 metastatic tumors, derived from previous studies as well as GENIE, and TCGA databases, utilizing cancereffectsizeR to measure the cancer effects of new mutations. Comparisons of trinucleotide mutation profile revealed a relatively similar mutational landscape between primary and metastatic THCA, with notable differences such as GTG → GAG, TTG → TCG, and ATG → ACG mutations, which were more prevalent in metastatic tissues. While it is shown that TERT genetic alterations are more frequent in metastatic papillary thyroid carcinomas (PTCs) compared to primary PTCs, our analysis showed that the strength of somatic selection on TERT coding mutations was lower during the span from primary to metastatic THCA than during the span from thyroid organogenesis to primary THCA. Conversely, RET mutations, which is also shown to be more prevalent in metastatic tumors, were highly selected during the progression from primary to metastatic THCA, in comparison from organogenesis to primary THCA, aligning with the broader spectrum of RET mutations observed in metastatic medullary thyroid carcinoma. Furthermore, the selection intensity for mutations in genes such as BRAF, NRAS, TP53, ATM, KMT2D, KMT2C, NF1, NF2, PTEN, and NKX2-1 was higher during the transition from organogenesis to primary THCA compared to the progression from primary to metastatic THCA. In conclusion, our application of cancer effect size analyses revealed that the strengths of selection on mutations vary dynamically across the trajectories from organogenesis to primary THCA and from primary to metastatic THCA. We identified key genes driving THCA initiation and progression, providing a quantitative understanding of the evolutionary trajectory of mutations in this disease. These insights shed light on the determinants of THCA pathogenesis and metastasis and hold potential to inform future precision treatment strategies. Citation Format: Moein Rajaei, Andrew Ju, Jeffrey P. Townsend. Quantifying selection intensity of driver genes in primary and metastatic thyroid 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 1132.
Abstract 224: Methyl-CpG-binding domain protein 2 (Mbd2) as a therapeutic target in breast cancer
Authors: Olivia Dumas, Niaz Mahmood, Ani Arakelian, Moshe Szyf, Shafaat Rabbani
Journal: Cancer Research (2025)

Abstract Abnormal DNA methylation is frequently observed in the cancer epigenome, rendering it a prime target for pharmacological manipulation. Methyl-CpG-binding domain protein 2 (Mbd2), a reader of DNA methylation, has been shown to be strongly linked to various malignancies, including breast cancer, establishing Mbd2 as a viable and effective therapeutic target. Our previous studies have demonstrated that genetic deletion of Mbd2 significantly reduces primary breast tumor growth and lung metastasis in a well-established transgenic mouse model of breast cancer. In the current study, we examined the effect of pharmacological inhibition of Mbd2 on breast cancer progression and metastasis to non skeletal and skeletal sites. Several small-molecule inhibitors for Mbd2 have been described, and among these, KCC-07 was shown to significantly reduce medulloblastoma in vitro and in vivo. Treatment of mouse luminal B breast cancer cell lines (PyMT-R221A, E0071) with KCC-07 resulted in a time- and dose-dependent decrease in tumor cell proliferation and reduced the invasiveness of the cells in vitro. These results were recapitulated in vivo, where PyMT-R221A cells inoculated via mammary fat pad (m.f.p) and intra-tibial (i.t) routes into female FVB mice and treated with vehicle alone or KCC-07 (100.0 mg/kg) 3QW via the intraperitoneal route for three weeks showed a decrease in tumor volume and skeletal metastasis. Further immunohistochemical analyses of the tumor tissues using markers of tumor proliferation (Ki67), angiogenesis (CD31), and bone resorption (TRAP), as well as any potential side effects on animal toxicity and global transcriptomic changes of the PyMT-R221A cells induced by treatment with KCC-07, will be presented and discussed. In other studies, PyMT-R221A cells were treated with the most effective dose of Mbd2 siRNA and KCC-07 (40µM) and cellular RNA from control and experimental groups was extracted and subjected to RNA-seq analysis, which is now being analyzed and validated in depth. Results from these analyses will identify key Mbd2-mediated signaling pathways and genes that play an important role in breast cancer. Taken together, the results of this study will provide mechanistic insights into the therapeutic potential of targeting Mbd2 with KCC-07 to block breast cancer growth and metastasis in a preclinical setting. These findings could be highly valuable for the future evaluation of selective inhibitors of Mbd2 to treat breast cancer patients. Citation Format: Olivia Dumas, Niaz Mahmood, Ani Arakelian, Moshe Szyf, Shafaat Rabbani. Methyl-CpG-binding domain protein 2 (Mbd2) as a therapeutic target in 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 224.
Abstract 1174: Examining antitumorigenic effects of <i>Ruminococcus gnavus</i>
Authors: Yue Zhang, Colin R. Laughlin, Amanda Lee, Catherine M. Phelps, Surya P. Pandey, Simran K. Randhawa, Alex C. McPherson, Jake H. Shapira, Reinhard Hinterleitner, Giorgio Trinchieri, Marlies Meisel
Journal: Cancer Research (2025)

Abstract Melanoma is one of the most commonly occurring cancers in the world, with increasing occurrence over the past several decades. Common treatment regimens for melanoma include immune checkpoint inhibitor (ICI) therapy, which enhances interferon-γ production in CD8 T cells (Tc1). Despite showing efficacy in some patients, a majority of melanoma patients are resistant to ICI therapy. Prior studies have demonstrated the ability of the gut microbiota to impact Tc1 antitumor responses and ICI therapy efficacy. In analyzing top gut bacteria enriched in ICI-responders, Ruminococcus gnavus (R. gnavus) is a commonly identified species. Along with being ICI-responder associated, R. gnavus has been shown to catabolize dietary tryptophan into aryl hydrocarbon receptor (AHR) ligands.Here we demonstrate the tumor retraining properties of R. gnavus in subcutaneous, spontaneous, and metastatic cancer models. Further, gnotobiotic monocolonization experiments demonstrate the ability for this bacterium to restrain tumor growth independent of a complex microbiome. Analyzing the mechanism behind how R. gnavus causes melanoma growth suppression in our model, we have demonstrated requirements of bacterial viability and AHR activation. Colonization with R. gnavus at early, middle, and late-stage tumor timepoints was able to induce a significant Tc1 response locally in the tumor and systemically in tumor-draning lymph nodes and spleen. Finally, we found R. gnavus colonization to facilitate ICI efficacy in our model. This study uncovers a potential mechanism of how a common ICI-reponse associated bacterium enhances ICI efficacy in melanoma. Citation Format: Yue Zhang, Colin R. Laughlin, Amanda Lee, Catherine M. Phelps, Surya P. Pandey, Simran K. Randhawa, Alex C. McPherson, Jake H. Shapira, Reinhard Hinterleitner, Giorgio Trinchieri, Marlies Meisel. Examining antitumorigenic effects of Ruminococcus gnavus [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 1174.
Abstract 650: Enhancing antitumor immunity by inducing PANoptosis using a new generation of vesicular stomatitis virus
Authors: Fanghui Chen, Liwei Lang, Sijia Tang, Fan Yang, Nabil F. Saba, Ming Luo, Yong Teng
Journal: Cancer Research (2025)

Abstract Despite significant advances, the limited therapeutic efficacy of virotherapy remains a major hurdle in the use of oncolytic viruses (OVs) for cancer treatment. To overcome this challenge, we integrated the SMAC/DIABLO gene into the genome of vesicular stomatitis virus (VSV) to create a new generation of VSV, termed VSV-S. In this study, we infected head and neck squamous cell carcinoma (HNSCC) cells and tumors with VSV-S to evaluate its therapeutic efficacy and underlying mechanisms. VSV-S exhibited significantly enhanced antitumor activity in HNSCC cells compared to the parental virus. It not only promoted cancer cell apoptosis through the overexpression of SMAC during VSV infection, but also induced PANoptosis (a combination of pyroptosis, apoptosis, and necroptosis) through the activation of caspase 3, gasdermin D and gasdermin E, and MLKL signaling pathways, which led to enhanced recruitment of CD8+ T cells to the tumor and eventually potentiated T cell-mediated antitumor immunity. In addition, VSV-S reduced PD-L1 levels in HNSCC cells and, when combined with anti-PD-1 antibody, produced a more potent antitumor effect than either treatment alone. These results provide valuable preclinical evidence to support the development of VSV-S-based antitumor therapies that could improve outcomes for patients with HNSCC. Citation Format: Fanghui Chen, Liwei Lang, Sijia Tang, Fan Yang, Nabil F. Saba, Ming Luo, Yong Teng. Enhancing antitumor immunity by inducing PANoptosis using a new generation of vesicular stomatitis virus [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 650.
Abstract 639: Targeting TET3 potentiates an effective anti-tumor immune response after irradiation
Authors: Sera Averbek, Stephen J. Kron
Journal: Cancer Research (2025)

Abstract The benefits of radiotherapy (RT) have long been appreciated as limited by formation and repair of DNA double-strand breaks (DSBs) in tumor cells, but recent understanding has identified a key role for RT and DNA damage in promoting inflammation that drives anti-tumor immune response. While chromosomal DSBs indeed directly limit cancer cell survival and proliferation, RT-induced damage leads to cytosolic DNA that activates cGAS/STING/IRF3 signaling and drives IFNα/β expression, recruiting cytotoxic T and NK cells to shrink tumors. In turn, along with DSB repair, another determinant of RT resistance is rebound immunosuppression. Here, IFNγ released by the infiltrating lymphocytes activates JAK/STAT to induce interferon-stimulated genes (ISGs) including PD-L1 that can reduce tumor inflammation and restore growth. Though combining PD-1/PD-L1 blockade with RT is sufficient to block this adaptive response in mice, the lack of benefit to patients suggests the need to more broadly target immunosuppressive ISG expression. Targeting IFNγ signaling by blocking JAK/STAT may limit immunosuppressive ISG expression but will impair T and NK cytotoxicity. Looking downstream, blocking JAK/STAT-dependent ISG promoter CpG demethylation by Ten Eleven Translocation (TET) dioxygenase enzymes may prevent PD-L1 expression without affecting cytotoxicity. In this study, we disrupted TET activity with small-molecule inhibitors and CRISPR RNP knockouts (KO) to evaluate effects on radiation response in vitro and in tumors. As predicted, TET inhibitors blocked PD-L1 induction in irradiated CT26 murine colon carcinoma cells. Assaying TET1, 2 and/or 3 KO CT26 cells for PD-L1 induction identified TET3 as the critical mediator. TET3 KO cells also exhibited slower DSB repair after irradiation, associated with markedly increased ssDNA resection and cytosolic DNA. The irradiated TET3 KO cells also displayed enhanced IFNα/β expression, suggesting intact cGAS/STING/IRF3 signaling. While TET3 KO CT26 cells formed tumors in syngeneic BALB/c mice much like CT26 controls, RT produced greater NK cell infiltrates by one week and increased tumor elimination by two weeks. TET3 KO 4T1 mammary carcinoma cells formed orthotopic tumors in BALB/c mice but produced fewer lung metastases compared to controls. In conclusion, TET3 may offer an attractive, druggable target for radiosensitization by slowing DSB repair, enhancing tumor inflammation, and blocking immunosuppressive ISG expression. Citation Format: Sera Averbek, Stephen J. Kron. Targeting TET3 potentiates an effective anti-tumor immune response after irradiation [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 639.
Abstract 638: Discovery of HX016-7, a novel PD-L1 x VEGF BsAb, as a new candidate treatment of solid tumors
Authors: Hang Ke, Tao Yang, Feiyu Peng, Jialing Li, Cen Chen, Stephen Xiong, Lei Zhang, Faming Zhang, Henry Qixiang Li
Journal: Cancer Research (2025)

Abstract A first-in-class PD-L1xVEGF bispecific antibody (BsAb), BNT327/PM8002, has demonstrated promising efficacy in treating TNBC and NSCLC cancers in advance stage of clinical development, which prompted us to engineer a novel and potentially best-in-class (BIC) PD-L1xVEGF BsAb by using a validated anti-PD-L1 and a novel anti-VEGF (HX006, a novel VEGF mAb with more favor activity over Avastin) mAb sequences. HX016-7 has 2+2 IgG1 symmetric structure constructed by grafting the PD-L1 binding domain of PD-L1 mAb onto the N-terminus of HX006. HX016-7 binds with similarly affinity to PD-L1 recombinant protein with EC50 of 0.27nM (vs. 0.36nM by BNT327/PM8002) and to VEGF recombinant protein with EC50 of 0.094nM (vs. 0.063 by BNT327) in ELISA assay. It also binds similarly to the PD-L1 positive cell line as BNT327/PM8002 with comparable affinity. Reporter-based bioassay for PD1/PD-L1 blockade function demonstrated that HX016-7 has EC50 of 4.85 nM (vs. 5.13nM for BNT327/PM8002), while reporter-based bioassay for VEGF function demonstrated that HX016-7 has EC50 of 11.7nM (vs. 15.8nM for BNT327/PM8002). In a MC38-hPD-L1-hVEGF colorectal cancer syngeneic model implanted in hPD-1 humanized mice, HX016-7 was shown to have comparable anti-tumor activity as BNT327/PM8002, but stronger activity over HX006, which can be attributed to both PD-L1- and VEGF-targeting. In a subcutaneous A549 non-small-cell lung cancer (NSCLC) cell-derived xenograft model in immunocompromised mice, HX016-7 also showed slightly stronger anti-tumor activity over BNT327/PM8002, which can be attributed to anti-VEGF function. We believe these preclinical data warrants the candidacy of HX016-7 to be further developed for the treatment of solid tumors. Citation Format: Hang Ke, Tao Yang, Feiyu Peng, Jialing Li, Cen Chen, Stephen Xiong, Lei Zhang, Faming Zhang, Henry Qixiang Li. Discovery of HX016-7, a novel PD-L1 x VEGF BsAb, as a new candidate treatment of 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 638.
Abstract 1190: Discovery of novel compounds selectively targeting LIN28 to modulate let-7 expression and exhibit anticancer activity in LIN28 positive tumors
Authors: Myongjae Lee, Minkyung Kim, Jong Ha Kim, Sung Wook Kwon, Won Sik Lee
Journal: Cancer Research (2025)

Abstract The discovery of the highly conserved microRNA (miRNA) lethal-7 (let-7) has increased interest in miRNAs as gene expression regulators. Let-7 suppresses tumor proliferation and survival by downregulating oncogenes and key regulators of the cell cycle, differentiation, and apoptosis. Let-7 is regulated by the RNA-binding protein LIN28, which has an oncofetal expression pattern. Let-7 family members are efficiently uridylated and suppressed in cancer cells via LIN28 reactivation. Therefore, LIN28 is a promising molecular target for directed inhibition, potentially benefiting a diverse group of aggressive malignancies. Despite various efforts to modulate let-7 expression through LIN28 inhibition, selectively targeting LIN28 has been challenging. Using computational analysis and structure-based drug design, we identified a novel class of candidate compounds that exhibited selective anticancer effects in LIN28-expressing tumors. In cell viability assays using the JAR choriocarcinoma and PA-1 teratocarcinoma cells expressing LIN28, the candidates showed nanomolar IC50 values. However, they had negligible effects on LIN28-negative MCF7 breast cancer cells and WI-38 normal fibroblast cells. Pharmacodynamic assays revealed that these compounds selectively modulated the let-7 subclasses, let-7b, let-7d, let-7g, let-7l, and miR-98, demonstrating excellent selectivity in targeting LIN28. Western blot analysis further demonstrated effective suppression of cancer stem cell markers, including OCT4, SOX2, and MYC. In vivo studies using LIN28-positive IGROV-1 ovarian cancer xenograft model indicated strong inhibition of tumor growth following intratumoral administration. Pharmacokinetic studies revealed rapid absorption, with &amp;gt;30% bioavailability and a 3-hour half-life with oral administration. However, limited tumor distribution is expected owing to the low volume of distribution in the intravenous pharmacokinetic results, indicating the need for future optimization of the distribution profile. This study highlights promising lead compounds that selectively inhibit LIN28, enhance let-7 expression, thereby reducing cancer hallmarks and exerting anticancer effects. Future efforts should focus on optimizing the pharmacokinetic profile to develop an orally bioavailable LIN28 inhibitor for effective cancer treatment. Citation Format: Myongjae Lee, Minkyung Kim, Jong Ha Kim, Sung Wook Kwon, Won Sik Lee. Discovery of novel compounds selectively targeting LIN28 to modulate let-7 expression and exhibit anticancer activity in LIN28 positive 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 1190.
Abstract 1067: The ISB Cancer Gateway in the Cloud (ISB-CGC): access, explore and analyze large-scale cancer data through the Google Cloud
Authors: Fabian Seidl, Lauren Hagen, Jacob Wilson, Boris Aguilar, Deena Bleich, Lauren Wolfe, Poojitha Gundluru, Suzanne Paquette, Elaine Lee, Danna Huffman, William Longabaugh, David Pot
Journal: Cancer Research (2025)

Abstract Rapid growth of cancer data in recent decades has made data discovery and wrangling difficult for the average cancer research lab. Our mission at the ISB Cancer Gateway in the Cloud (ISB-CGC), part of the NCI’s Cancer Research Data Commons ecosystem, is to democratize access to large cancer datasets. Funded by the NCI, we have performed ETL processes on data from GDC and PDC projects such as TCGA, TARGET, and CPTAC. We generated hundreds of publicly available BigQuery tables containing data such as mutations, gene expression, and protein abundance, which enable data analysis in the cloud via SQL. BigQuery analyses are inexpensive and rapid even when scaled to petabyte sized inputs, for example in one analysis 6.6 billion correlations were computed in 2.5 hours with a total cost of about one dollar. These data can also be accessed affordably from Google Cloud VMs where researchers can develop analysis pipelines in Python, R, and workflow languages. We will also highlight recently improved accessibility to the Mitelman Database, added and expanded HTAN single cell data and notebook selections, and updates to our BigQuery Table Search tool. Citation Format: Fabian Seidl, Lauren Hagen, Jacob Wilson, Boris Aguilar, Deena Bleich, Lauren Wolfe, Poojitha Gundluru, Suzanne Paquette, Elaine Lee, Danna Huffman, William Longabaugh, David Pot. The ISB Cancer Gateway in the Cloud (ISB-CGC): access, explore and analyze large-scale cancer data through the Google Cloud [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 1067.
Abstract 328: A novel human-like asparaginase - indication expansion made possible
Authors: Amanda M. Schalk, Maaike Van Trimpont, Ying Su, Ashley De Loera, Alyssa Garcia, Tim Lammens, Steven Goossens, Arnon Lavie
Journal: Cancer Research (2025)

Abstract L-asparaginase (ASNase) has been a cornerstone of pediatric acute lymphoblastic leukemia (ALL) treatment since the 1970s, leveraging a unique mechanism that exploits the metabolic vulnerability of leukemic cells. Cancer cells deficient in asparagine synthetase (ASNS), which rely on blood asparagine, are starved when ASNase depletes asparagine in the bloodstream. While this approach is effective in ALL, preclinical studies suggest that ASNase could also target other ASNS-deficient (ASNSlow) cancers, including acute myeloid leukemia (AML) and subsets of solid tumors like liver and colorectal cancers. However, the severe toxicity of existing ASNase formulations, largely due to off-target glutaminase activity and immunogenicity, has limited its broader clinical application. To overcome these barriers, we developed a novel human-like mammalian ASNase designed to minimize immunogenicity and eliminate glutaminase-driven toxicity while maintaining high specificity for asparagine. This engineered ASNase demonstrated robust in vitro and in vivo efficacy against both T-cell and B-cell ALL. Notably, it also showed potent activity as a monotherapy in AML, eradicating tumor cells in blood and bone marrow. Beyond blood cancers, this ASNase displayed significant anti-tumor effects against a CRISPR/CAS-9-engineered melanoma model with genetic loss of ASNS and a hepatocellular carcinoma model with low endogenous ASNS expression, achieving durable tumor suppression. This demonstrates that for ASNSlow tumors the glutaminase activity is not required for efficacy. Crucially, the novel ASNase was well tolerated in animal studies, enabling prolonged asparagine depletion—an essential factor for its striking anti-cancer effects. With its enhanced safety profile and specificity, this humanized ASNase represents a transformative advancement, extending the benefits of metabolic tumor starvation to a broader range of cancers. Its predictable mechanism of action, guided by biomarkers of ASNSlow status, positions it as a promising therapeutic breakthrough for targeting diverse malignancies. The authors used GPT-4.o in order to rephrase certain sentences. After using this tool or service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication. Citation Format: Amanda M. Schalk, Maaike Van Trimpont, Ying Su, Ashley De Loera, Alyssa Garcia, Tim Lammens, Steven Goossens, Arnon Lavie. A novel human-like asparaginase - indication expansion made possible [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 328.