Cancer research最新文献

{"title":"Abstract 40: Organoid models of ovarian clear cell carcinoma for evaluating therapeutic sensitivity","authors":"Clare E. Padrick, Magdalena Zielinska, Minh Ha, Aisha L. Saldanha, Cam Anh Tran, Brendan Shay, Daohong Zhou, Kristopher A. Sarosiek, Cloud P. Paweletz, Ursula A. Matulonis, Joyce F. Liu, Elena V. Ivanova, Elizabeth H. Stover","doi":"10.1158/1538-7445.am2025-40","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-40","url":null,"abstract":"Ovarian clear cell carcinoma (OCCC) is a rare subtype of ovarian cancer, often resistant to platinum-based chemotherapy. OCCC is characterized by ARID1A mutations, PI3K and RAS/MAPK pathway alterations, and activation of the HIF signaling pathway. We and others showed that OCCC are sensitive to inhibition of BCL-XL, a pro-survival protein in the intrinsic pathway of apoptosis. Patient-derived models of OCCC could potentially accelerate pre-clinical testing of therapeutics in this difficult-to-treat cancer, but relatively few patient-derived organoid (PDO) or xenograft models of OCCC have been reported. We describe the establishment and propagation of two PDO models of OCCC. Patient 1 had recurrent OCCC with PIK3CA mutation and HER2 amplification. Patient 2 had recurrent OCCC with CDKN2A/B deletion. Both patients underwent secondary cytoreductive surgery for recurrent disease. Fresh tissue was collected under IRB-approved protocols and tumor cells were plated in Matrigel and formed PDOs. Patient 1 OCCC cells have been propagated for over 35 passages, and patient 2 cells for 9 passages to date. Immunohistochemistry to confirm fidelity to the original tumor is in progress. As a proof-of-concept for evaluating therapeutics in OCCC PDOs, we used a 3D microfluidic device (AIM Biotech) to evaluate drug responses in patient 1 PDO. PDO cells were seeded in the microfluidic device and expanded for one week, treated with drugs within the device, then stained at day 6 with fluorescence markers for live (TMRM, Thermo Fisher), apoptotic (CellEvent Caspase-3/7, Thermo Fisher), and dead (DRAQ7, CST) cells. Quantitative imaging was performed to determine the cell area positive for each marker. The OCCC PDO was treated with standard-of-care chemotherapies carboplatin and paclitaxel; BCL-XL inhibitor A1331852 (Selleckchem); a novel BCL-XL PROTAC degrader DT2216 (Dialectic Therapeutics); or combinations of the BCL-XL inhibitor/degrader with paclitaxel. Treatment with A1331852 or DT2216 induced apoptosis and death in the OCCC PDO cells compared to control. While paclitaxel alone also induced some cell death, the combination of DT2216 (1µM) and paclitaxel (500nM) was highly potent, resulting in elimination of almost all the OCCC cells (Bliss synergy score 0.28±0.08, p=0.013). These data suggest that BCL-XL inhibition/degradation combined with paclitaxel may be a promising treatment strategy for OCCC. Our study also demonstrates the successful establishment of OCCC PDOs and application of a microfluidic device for evaluating novel therapeutic strategies in ovarian cancer. Citation Format: Clare E. Padrick, Magdalena Zielinska, Minh Ha, Aisha L. Saldanha, Cam Anh Tran, Brendan Shay, Daohong Zhou, Kristopher A. Sarosiek, Cloud P. Paweletz, Ursula A. Matulonis, Joyce F. Liu, Elena V. Ivanova, Elizabeth H. Stover. Organoid models of ovarian clear cell carcinoma for evaluating therapeutic sensitivity [abstract]. In: Proceedings of the American Association for Cancer Researc","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"13 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 4221: Precision targeting of HDAC3 in ovarian cancer","authors":"Vijayalaxmi G. Gupta, Bisiayo Fashemi, Reni Akande, Preedia Babu, Yukihide Ota, Yufeng Xaio, Guangrong Zhang, Francisca Nathalia Vitorino, Benjamin Garcia, Mary Mullen, Dineo Khabele","doi":"10.1158/1538-7445.am2025-4221","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-4221","url":null,"abstract":"Introduction: Addressing chemo-resistant homologous recombination-proficient (HRP) ovarian cancers and CCNE1-amplified tumors, while minimizing treatment-related side effects, remains a significant clinical challenge. Our research demonstrated that HDAC inhibition suppresses tumors in PARP inhibitor (PARPi)-resistant ovarian cancers and enhances PARPi sensitivity in preclinical models. However, pan-HDAC inhibitors (HDACis) have shown high toxicity in clinical trials. To overcome this, we focused on selectively targeting specific HDACs, particularly HDAC3 and HDAC8, which have unique structures and co-repressor complexes. HDAC3 is frequently upregulated in ovarian cancers, making it a promising therapeutic target. Here, we explore HDAC3 genetic depletion/knockout (KO) and precision targeting using HDAC-PROTACs in five cell lines. Methods: We employed siRNA-mediated depletion and CRISPR-Cas9 KO to study the impact of HDAC3 inhibition on CCNE1-amplified OVCAR3 cell proliferation, clonogenicity, and protein expression. Histone modifications were analyzed via mass spectrometry. The anti-proliferative efficacy of HDAC3 (XZ9002), HDAC8 (YL352), and dual HDAC3/8 (YX968) PROTACs was evaluated in OVCAR3, COV318, HRP and HRD mouse fallopian tube cells, and patient-derived primary cell lines. Results: HDAC3 siRNA treatment in OVCAR3 cells led to dose-dependent reductions in HDAC3 protein levels and PCNA expression. HDAC3-KO cells exhibited increased histone acetylation and decreased histone methylation. PROTACs showed differential efficacy across cell lines. In OVCAR3 cells, IC50 values were 1.82 µM for HDAC3-PROTAC, 1.98 µM for HDAC8-PROTAC, and ∼0.67 µM for HDAC3/8 dual PROTAC, indicating superior potency with dual targeting. In COV318 cells, the dual HDAC3/8 PROTAC exhibited an IC50 of 2.5 µM. HRD mouse fallopian tube cells were more sensitive to HDAC8 and HDAC3/8 PROTACs (IC50 ∼6 µM), while HRP cells were less sensitive (IC50: 8 µM for HDAC3/8 PROTAC, 10 µM for HDAC8 PROTAC, >10 µM for HDAC3 PROTAC). Patient-derived primary cell lines demonstrated the highest sensitivity to the dual HDAC3/8 PROTAC (IC50 ∼7 µM), with reduced response to single HDAC PROTACs. Pharmacodynamic analyses via Western blot and qPCR are ongoing. Conclusion: Selective targeting of HDAC3, HDAC8, and HDAC3/8 using PROTACs provides a promising therapeutic strategy to address toxicity limitations of conventional HDACis. These agents hold potential for low-dose applications in ovarian cancers and broader therapeutic use in other malignancies and diseases. Citation Format: Vijayalaxmi G. Gupta, Bisiayo Fashemi, Reni Akande, Preedia Babu, Yukihide Ota, Yufeng Xaio, Guangrong Zhang, Francisca Nathalia Vitorino, Benjamin Garcia, Mary Mullen, Dineo Khabele. Precision targeting of HDAC3 in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 20","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"11 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 1158: Preclinical characterization of AZD0516, a novel STEAP2 antibody-drug conjugate (ADC) for the treatment of prostate cancer","authors":"Darlene Monlish, Vanessa Muniz-Medina, Mel Ehudin, Dewald van Dyk, Claire Myers, Rachel Lawrence, Liang Zhang, Linda Irons, Chara Stavraka, Wardha Qureshi, Ruoyan Chen, Asurayya Worrede, Nicolas Giraldo, Miljenka Vuko, Melody Handali, Ali Saleh, Balakumar Vijayakrishnan, Maximillian Lee, Jeong Min Han, Crystal Cheung, Ariel Endlich-Frazier, Amber Lee, Mark Hutchinson, Andrew Dippel, Gilad Kaplan, Keith Rickert, Shraddha Kale, Ryan Fleming, Clare Hoover, Benedicte Recolin, Jan Zaucha, Sreedevi Kesavan, John` Meekin, Aida Mariani, Christian Eisen, John Bullen, Eric Gangl, Jay Harper, Andreas Maderna, Edward Rosfjord, Frank Comer, Elaine Hurt, Neil Gibson, Puja Sapra","doi":"10.1158/1538-7445.am2025-1158","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-1158","url":null,"abstract":"Metastatic castration-resistant prostate cancer (mCRPC) continues to pose a significant clinical challenge and is associated with poor survival rates in patients who failed previous lines of androgen receptor axis-targeted therapies and taxanes. Antibody drug conjugates (ADCs) provide a novel approach to traditional chemotherapy by targeting tumor-specific antigens to deliver cytotoxic payloads while sparing normal tissue and enhancing the therapeutic index. Herein, we describe the preclinical characterization of AZD0516, a first-in-class ADC directed against six-transmembrane epithelial antigen of the prostate-2 (STEAP2), a novel tumor associated antigen that is highly and homogenously expressed across all stages of prostate cancer. The anti-STEAP2 monoclonal antibody (mAb) is conjugated via interchain cysteines to a maleimide-reactive, β-glucuronidase-cleavable linker bearing the topoisomerase 1 inhibitor (TOP1i) payload, exatecan. The STEAP2 antibody binds specifically to the extracellular domains of human, cynomolgus monkey, mouse, and rat STEAP2, but exhibits no detectable binding to other STEAP family members. The fragment crystallizable (Fc) domain of the antibody binder portion carries three amino acid point mutations designed to reduce Fc-mediated immune effector functions. In vitro characterization of the STEAP2 mAb in prostate cancer cells demonstrated specific binding, rapid internalization, and efficient lysosomal trafficking. In vitro cytotoxicity assays with AZD0516 revealed IC50 values in the low nM range and the ADC induced both single- and double-strand DNA breaks, characteristic of the proposed primary mechanism of action (MoA) of the TOP1i payload, namely, DNA damage and apoptotic cell death. Exatecan-driven bystander cell killing from intracellular release of payload was demonstrated in co-culture systems involving STEAP2-positive and negative cell lines. Murine plasma pharmacokinetic data suggest minimal impact of linker-payload conjugation on antibody clearance, while maintaining high plasma stability. The mechanistic and pharmacodynamic effects of AZD0516 were observed in a prostate cancer cell line-derived xenograft (CDX) model via a dose-dependent increase in positive staining for γH2AX foci, indicative of DNA damage. AZD0516 monotherapy administration in prostate cancer CDX and patient-derived xenograft models led to sustained tumor responses. AZD0516 was well-tolerated in both rats and cynomolgus monkeys with no unexpected toxicities observed. Safety findings included hematological and gastrointestinal effects, consistent with the MoA and known effects of TOP1i payloads. Together, these data support exploring AZD0516 clinically for patients with mCRPC. Citation Format: Darlene Monlish, Vanessa Muniz-Medina, Mel Ehudin, Dewald van Dyk, Claire Myers, Rachel Lawrence, Liang Zhang, Linda Irons, Chara Stavraka, Wardha Qureshi, Ruoyan Chen, Asurayya Worrede, Nicolas Giraldo, Miljenka Vuko, Melody Handali, Ali Saleh, Balakuma","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"71 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 5352: Identification of novel potentially pathogenic SNPs and associated genes in esophageal cancer: Insights from whole exome sequencing","authors":"Waqas A. Abbasi, Sajida Qureshi, Muhammad A. Qureshi, Mohammed S. Quraishy","doi":"10.1158/1538-7445.am2025-5352","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-5352","url":null,"abstract":"Esophageal carcinoma (EC) is a prevalent malignancy and a leading cause of mortality, yet limited biomarkers exist to aid in prognosis and guide therapy. In this study, to pinpoint critical markers that could improve prognostic accuracy and reveal potential therapeutic targets, we employed whole exome sequencing (WES), to identify novel and potentially pathogenic single nucleotide polymorphisms (SNPs) and their associated genes in a cohort of EC patients (n=10). WES and subsequent data analysis were conducted as a commercial service at Macrogen. Genomic DNA was sequenced on the Illumina NovaSeq 6000 platform, and sequences were mapped to the human genome (hg38) using BWA. PCR duplicates were removed with Picard's Mark Duplicates, followed by recalibration and variant calling using GATK. Variants were filtered and annotated with SnpEff, dbSNP, ClinVar, ESP6500, and the 1000 Genomes Project. SNP pathogenicity was assessed using in-silico tools (SIFT, LRT, Mutation Taster, FATHMM, and PROVEAN). Genes associated with variants were prioritized/listed based on their frequency across the cohort. STRING analysis was conducted to examine protein interactions and enriched biological processes associated with key genes harboring multiple variants. We identified a total of 912, 214 SNPs in our cohort, of which 703 were classified as potentially pathogenic, including 331 novel SNPs that have not been reported in any population to date. Genes along-with associated variants were prioritized based on their highest frequency of occurrence across the cohort, including those with ≥2 distinct or repeated variants (Genes: RPS4X, PSMC1, HOMER2, PPAT, TPM3, RANBP9, NALCN, PTPN11, ARIH2, BMPR1B, HOXA13, PRKAA2, SCN8A, HDAC1, LRP2, HNRNPA3, FECH, PSMC5, MTMR2, ABCB1, RPL23, ITPR1, COL5A2, TBL1XR1, ITGB1, ZFAND1, PBX2, TCP1, HNRNPD, CALM2, PEX5, PCBD2, CACNA1E, FOXO1, GPD2, KARS, ABCC2, AFG3L2, CHCHD2, HNRNPA1). STRING analysis further highlighted crucial protein-protein interactions and biological processes in which these genes are involved, including (GO:0010604: Positive regulation of macromolecule metabolic process) , (GO:0048522: Positive regulation of cellular process), (GO:0051173: Positive regulation of nitrogen compound metabolic process), (GO:0045935: Positive regulation of nucleobase-containing compound metabolic process), (GO:0048518 Positive regulation of biological process), (GO:0009987 Cellular process), and (GO:0010557 Positive regulation of macromolecule biosynthetic process). These findings highlight potentially actionable genetic alterations in our cohort that could be developed as biomarkers for EC. Future studies are warranted to validate these variants in larger cohorts and investigate their mechanistic roles in EC progression through a range of in-silico and in-vitro validations. Citation Format: Waqas A. Abbasi, Sajida Qureshi, Muhammad A. Qureshi, Mohammed S. Quraishy. Identification of novel potentially pathogenic SNPs and associated genes in eso","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"5 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 6377: TEAD-targeting small molecules induce a cofactor switch to regulate the Hippo pathway","authors":"Alissa D. Guarnaccia, Thijs J. Hagenbeek, Wendy Lee, Noelyn Kljavin, Meena Choi, Gözde Ulas, Vasumathi Kameswaran, Daniel Le, Sayantanee Paul, Samir Vaidya, Jason R. Zbieg, James J. Crawford, Bence Daniel, Anwesha Dey, Jennie R. Lill","doi":"10.1158/1538-7445.am2025-6377","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-6377","url":null,"abstract":"The Hippo signaling pathway is a major regulator of cellular growth and is frequently deregulated in cancer. TEAD proteins are the main transcriptional effectors of the Hippo pathway and a pharmacological target in oncology. Most TEAD-targeting small molecules act by binding to the conserved lipid binding pocket of TEAD and allosterically disrupting interaction between TEAD and the oncogenic transcriptional activators YAP and TAZ. However, the molecular details of how TEAD-binding small molecules function beyond YAP and TAZ is not fully understood. Using unbiased, mass spectrometry-based proteomic profiling we find an alternative mechanism for TEAD lipid pocket-binding molecules whereby certain sulfonamide-containing compounds act as molecular glues to induce the TEAD interaction with the transcriptional repressor VGLL4. The chemically induced VGLL4-TEAD interaction occurs in a variety of cell types and can be biochemically recapitulated in vitro. Additionally, small molecule activation of VGLL4-TEAD complexes counteracts YAP activity at chromatin to repress pro-growth gene networks, including genes involved in cellular proliferation and mechanosignaling. Thus, enhanced interaction between TEAD and VGLL4 stimulates a small molecule-mediated cofactor switch from YAP to VGLL4. Cells that do not express VGLL4 are not sensitive to this class of compounds, but become sensitive upon exogenous overexpression of VGLL4. Additionally, genetic deletion of VGLL4 causes resistance to these molecules in cells and in in vivo tumors. These results demonstrate that VGLL4 is the required factor that mediates an anti-proliferative response to these sulfonamide-containing TEAD lipid pocket-binding compounds. Our data reveal a suite of molecules that act as molecular glues toward the repressive VGLL4-TEAD interaction and open up new understandings for curbing the oncogenic activity of Hippo pathway deregulation. Citation Format: Alissa D. Guarnaccia, Thijs J. Hagenbeek, Wendy Lee, Noelyn Kljavin, Meena Choi, Gözde Ulas, Vasumathi Kameswaran, Daniel Le, Sayantanee Paul, Samir Vaidya, Jason R. Zbieg, James J. Crawford, Bence Daniel, Anwesha Dey, Jennie R. Lill. TEAD-targeting small molecules induce a cofactor switch to regulate the Hippo pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1): nr 6377.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"17 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 4517: Comprehensive intraoperative imaging of surgical margins with AI-driven open-top light-sheet microscopy","authors":"David Brenes, Qinghua Han, Rui Wang, Rauf Kareem, Michael C. Topf, Eben L. Rosenthal, Emily Marchiano, Emily Palmquist, Faisal Mahmood, Sara H. Javid, Suzanne M. Dintzis, Jonathan T. Liu","doi":"10.1158/1538-7445.am2025-4517","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-4517","url":null,"abstract":"Surgeons rely on subjective visual and tactile feedback to differentiate tumors from adjacent normal tissue, which lacks accuracy and may make complete resection challenging. Over 20% of breast and 40% of head & neck cancer surgeries yield positive margins—cancerous cells at the edge of the resected specimen—requiring costly additional treatments with inferior outcomes. When pathologists assess margins, they quantify the tumor's proximity to the margin surface, where a margin of several millimeters is often desired. This is done by viewing formalin-fixed, paraffin-embedded (FFPE) tissue sections oriented perpendicularly to the specimen surface. FFPE sections are typically ∼5 µm thick and are obtained at 3 - 5 mm intervals, meaning that < 0.1% of the specimen surface is evaluated. We propose that for solid continuous tumors, comprehensive surface microscopy — though unable to measure the tumor’s proximity to the specimen surface — could more accurately identify positive margins and could be performed rapidly in the operating room to maintain specimen orientation. We are developing an intraoperative open-top light-sheet (OTLS) microscopy system that comprehensively assesses fresh specimen surfaces through an artificial intelligence (AI)-driven, time-efficient, multi-resolution workflow. The system resembles a flatbed scanner and images the bottom face of a specimen placed on a glass plate. Fresh specimens are rapidly stained (< 1 min) with a fluorescent agent for nuclear and stromal contrast. A profilometer quickly (< 1 min) obtains a height map of the specimen’s bottom surface to guide the OTLS microscope as it captures a thin volume (50 – 100 µm in depth) encompassing the specimen’s surface. The OTLS microscope operates at two resolution modes: low (∼5 × 5 × 5 µm xyz) and high (∼1 × 1 × 3 µm xyz). First, a comprehensive low-resolution scan is acquired rapidly (< 3 min per 10 x 10 cm area). An AI model then identifies high-risk regions to re-scan at high resolution for diagnosis. Our 3D AI-driven imaging strategy mimics the time-efficient workflow of pathologists, who first examine FFPE slides at low magnification before zooming into localized regions at high magnification. The ability to acquire a shallow amount of volumetric data (up to ∼ 100 microns deep) can improve positive margin detection over a single 2D surface due to the greater amount of cellular information and the ability to avoid artifacts from surgical damage (e.g. cautery). To develop our 3D AI algorithm, we are building a dataset from freshly excised breast and head & neck specimens, with ground-truth diagnostic labels provided by pathologists. The model will be weakly supervised, using pre-trained models for 3D feature extraction.In summary, AI-guided multi-resolution OTLS microscopy has the potential to enable rapid, comprehensive intraoperative margin assessment, reducing positive margin rates and improving patient outcomes. Citation Format: ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"138 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 1132: Quantifying selection intensity of driver genes in primary and metastatic thyroid cancer","authors":"Moein Rajaei, Andrew Ju, Jeffrey P. Townsend","doi":"10.1158/1538-7445.am2025-1132","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-1132","url":null,"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 s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1): nr 1132.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"50 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 4261: Synthetic lethality of targeting thymine DNA glycosylase (TDG) in p53-deficient lung cancer","authors":"Jiaxin Zhou, Zhenyu Shao, Jiannan Guo, Yiqin Wang, Qing Xu, Yarui Du, Haiping Wu, Guoliang Xu","doi":"10.1158/1538-7445.am2025-4261","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-4261","url":null,"abstract":"TP53 stands as the most frequently mutated gene in human cancers, with a strong correlation to poor prognosis across various cancer types. This makes it a critical target, representing the largest patient population and a substantial tumor drug market, with a pressing unmet medical need. Directly targeting p53 remains highly challenging, leaving a significant therapeutic gap. However, synthetic lethality presents a promising approach for developing treatments targeting tumors with TP53 mutations. Thymine DNA glycosylase (TDG) is a multifaceted enzyme involved in DNA base excision repair (BER), transcriptional regulation, and DNA demethylation, playing critical roles in both embryonic development and tumor progression. In this study, we identified TDG as a synthetic essential effector in p53-deficient cancers. This identification was facilitated through an in vitro CRISPR-Cas9 screening assay conducted in Trp53 knockout cells. Our finding reveals that knocking out Tdg selectively kills p53-deficient cells while sparing wild-type cells. Conversely, knocking out Trp53 selectively kills Tdg-deficient cells. Furthermore, elevated TDG expression was observed to correlate with p53-deficiency in human cancers. TDG knockout significantly reduced the viability of the p53-deficient lung cancer cell line NCI-H1299, an effect was rescued by ectopic expression of wild-type p53, but did not affect the viability of p53 wide-type cell line A549. Using a genetically engineered mouse model of lung adenocarcinoma (LUAD), we further demonstrated that genetic inactivation of Tdg specifically suppressed tumor growth in the context of p53-deficiency. Mechanistically, TDG and p53 cooperate to regulate the transcription of the RNA helicase DHX9, which facilitates the resolution of double-strand RNA (dsRNA). Inhibition of TDG in p53-deficient cancer cells downregulated DHX9, leading to aberrant accumulation of dsRNA derived from SINEs (short interspersed nuclear elements). This accumulation triggered an anti-viral response via the RIG-I/MDA5-MAVS axis, resulting in tumor growth inhibition and an enhanced anti-tumor immune response. Notably, the dsRNA-mediated antiviral response induced by Tdg depletion facilitated the recruitment of tumor-infiltrating lymphocytes (TILs), enhancing response to immune checkpoint blockade (ICB) treatment. These findings reveal a novel therapeutic vulnerability in p53-deficient lung cancer and suggest that targeting TDG could synergize with immunotherapies to improve patient outcomes. Our study highlights the function of TDG in transcriptional regulation, extending beyond its proposed roles in active DNA demethylation and mismatch repair, and unveils TDG as a promising therapeutic target for p53-deficient lung cancer. Citation Format: Jiaxin Zhou, Zhenyu Shao, Jiannan Guo, Yiqin Wang, Qing Xu, Yarui Du, Haiping Wu, Guoliang Xu. Synthetic lethality of targeting thymine DNA glycosylase (TDG) in p53-deficient lung cancer [abstract]. In: Proceedin","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"219 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 5583: Small molecule mediated restoration of PAX3 inhibits malignant features in neuroblastoma cells","authors":"Abinayaselvi Murugan, Sowndharyalatha Balasubramanian, Narenkumar Muralidharan, Ann Mary Alappat Sanjive, Prabhuraj Andiperumal Raj, Mathivanan Jothi","doi":"10.1158/1538-7445.am2025-5583","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-5583","url":null,"abstract":"Neuroblastoma is the most common extracranial childhood tumor diagnosed in the first year of life. A complete molecular understanding of neuroblastoma is necessary to identify novel therapeutic targets for their management, particularly for high-risk groups. Many transcription factors play an essential role during development, and their expression is restricted to specific cells/tissues after development is completed. PAX3 belongs to the paired box family of transcription factors involved in various cellular processes like cellular proliferation, migration, lineage specificity, and differentiation. Reexpression of PAX3 is reported in various childhood tumors, including neuroblastoma; however, its role in tumor development is contradicting. Here, we investigated the contribution of PAX3 in neuroblastoma in a panel of neuroblastoma cell lines and identified a PAX3-targeted small molecule activator that can alter tumorigenic phenotypes. Specifically, we have analyzed the PAX3 mRNA, protein, subcellular localization, and its isoform expression in various neuroblastoma cell lines and correlated the results with their tumorigenic potential. Our results showed that most of the PAX3 expressed in these cells are PAX3a/b isoforms that lack PAX3’s transactivation domain. Further, we have observed the depletion of PAX3a/b isoforms could not alter the malignant properties of neuroblastoma cells. Interestingly, the ectopic PAX3 expression in the absence of PAX3a/b isoform in these cells inhibited malignant phenotypes including growth, colony formation and migration potentials. Furthermore, we have identified potential small molecule PAX3 activators from our previous small molecule screening. PAX3 activators effectively inhibited in vitro malignant properties of neuroblastoma cell lines. Our results revealed that tumor inhibitory properties of transcriptionally active PAX3 and its reactivation using small molecules have great potential in inhibiting neuroblastoma development. Citation Format: Abinayaselvi Murugan, Sowndharyalatha Balasubramanian, Narenkumar Muralidharan, Ann Mary Alappat Sanjive, Prabhuraj Andiperumal Raj, Mathivanan Jothi. Small molecule mediated restoration of PAX3 inhibits malignant features in neuroblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1): nr 5583.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"16 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 4553: Evaluation of cfDNA release profiles in colorectal cancer patients during surgery","authors":"Mailson Alves Lopes, Maria Elvira Ribeiro Cordeiro, Flávio de Alencar Teles Barreto, Lara de Souza Moreno, André Araújo Silva, Mayra Veloso Soares, Mariana Braccialli de Loyola, Joao Batista de Sousa, Fabio Pittella-Silva","doi":"10.1158/1538-7445.am2025-4553","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-4553","url":null,"abstract":"Surgical intervention is one of the most employed treatments for colorectal cancer, especially in patients with localized disease. However, the dynamics of circulating cell-free DNA (cfDNA) release during surgical procedures remain poorly understood. This lack of understanding underscores a significant gap regarding the biological processes underlying tumor response to surgery. Here we examined surgical cfDNA release from 30 colorectal cancer patients. cfDNA was extracted from plasma samples at three key points: preoperative (just before surgery), intraoperative (during surgery), and postoperative (at the end of surgery). Automated electrophoresis was used to analyze cfDNA concentrations and fragment sizes, which were then correlated with different clinical variables. Our findings show a significant increase in cfDNA release during and after surgery in comparison to preoperative time (2.8- and 2.2-fold higher, respectively). cfDNA fragments of <400 bp were predominant at all surgical stages, with no significant release of genomic DNA detected in any stage. We found that cfDNA concentrations increase on an average of 2 to 3-folds during and after surgery in patients over 60 years old, in patients with comorbidities and in patients with CEA levels > 5 ng/mL. Importantly, cfDNA release during surgery was significantly higher in patients with adverse clinical characteristics. Patients with locally advanced tumors or metastasis had a 3.1-fold increase in cfDNA release intraoperatively and a 2.4-fold increase postoperatively (p < 0.01). cfDNA concentrations also increase intraoperatively in patients with high tumor bud scores (2.6-fold higher, p < 0.02), perineural invasion (3.4-fold higher, p < 0.02), and lymphovascular invasion (3.1-fold higher, p < 0.05). Overall, our findings indicate that factors such as advanced physiological age, existing comorbidities, adverse clinical characteristics, and extensive surgical manipulation may contribute to increased tissue damage and enhanced cfDNA release. Citation Format: Mailson Alves Lopes, Maria Elvira Ribeiro Cordeiro, Flávio de Alencar Teles Barreto, Lara de Souza Moreno, André Araújo Silva, Mayra Veloso Soares, Mariana Braccialli de Loyola, Joao Batista de Sousa, Fabio Pittella-Silva. Evaluation of cfDNA release profiles in colorectal cancer patients during surgery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1): nr 4553.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"108 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}