Hou, Xiaonan

Abstract Therapeutic resistance in ovarian cancer is frequently driven by persistent replication stress, yet the molecular mechanisms that convert replication stress into a therapeutically exploitable vulnerability remain incompletely understood. Here, we identify drug-induced nuclear cathepsin L (nCTSL) as a previously unrecognized regulator of replication stress and DNA repair. Clofarabine (CLF) combined with the ATR inhibitor AZD6738, or the CHK1 inhibitor prexasertib promoted nuclear accumulation of CTSL, where it remodeled the replication machinery through degradation of CCNE1, MCM3, MCM6, and geminin, accompanied by loss of RAD51 and 53BP1 and increased γH2AX and phospho-RPA2. DNA fiber analysis demonstrated marked inhibition of replication fork progression following CLF-based combinations, whereas CTSL depletion accelerated fork progression and abolished therapy-induced replication stress. Reconstitution with the nuclear M1F CTSL isoform restored replication restraint, confirming a direct role for nuclear CTSL in regulating replication dynamics. GFP-based DNA repair reporter assays further revealed that CLF-based combinations suppress DNA repair competence in a CTSL-dependent manner, indicating that nuclear CTSL couples replication stress amplification with functional inhibition of repair pathways. Functionally, CLF-based combinations selectively targeted transformed fallopian tube secretory epithelial cells while sparing non-transformed counterparts, demonstrated broad activity in patient-derived ovarian cancer ascites spheroids, and significantly inhibited tumor growth and prolonged survival in vivo . Collectively, our findings identify nuclear CTSL as a mechanistic driver of replication stress that remodels the replication machinery, impairs DNA repair, and creates a therapeutically exploitable vulnerability in ovarian cancer. We propose that nuclear CTSL promotes a transition from replication competence to replication catastrophe, thereby establishing a conceptual framework for biomarker-guided therapeutic strategies targeting CTSL-dependent replication stress.

Abstract Despite long-standing interest in combining topoisomerase I (TOP1) poisons with PARP inhibitors (PARPis), the mechanistic basis for the variable and often unpredictable response to this strategy remains unclear. Early preclinical studies suggested that PARP inhibition amplifies TOP1 poison-induced DNA damage, implying broad therapeutic potential; however, emerging translational and clinical data—particularly in ovarian cancer—indicate that synergy is context-dependent and governed by tumor-intrinsic features that have not been fully defined.Here we assessed determinants of response in five HR proficient ovarian cancer (OC) patient-derived xenografts (PDXs) previously treated with the SN-38 prodrug etirinotecan pegol (NKTR-102) in combination with the PARPi rucaparib (C. Nitschmann, Clin. Cancer Res. 22(2) Suppl. B50, 2016). Although all models were refractory to single-agent rucaparib, 50% exhibited enhancement of NKTR-102-induced tumor regression with the addition of rucaparib. Neither PARP1 abundance nor extent of rucaparib-mediated poly(ADP-ribose) suppression correlated with therapeutic benefit. Instead, sensitization was restricted to PDXs intrinsically responsive to NKTR-102 and was strongly associated with high levels of NKTR-102-induced TOP1-DNA covalent complexes. In further analysis, 2 of 3 resistant PDXs exhibited high levels of the ABC transporter ABCG2 despite lack of previous therapy, revealing a previously underappreciated mechanism of de novo resistance that limits effective TOP1 inhibitor activity independent of homologous recombination status. Notably, NKTR-102 response did not track with platinum/taxane sensitivity, highlighting the distinct molecular circuitry governing TOP1 poison susceptibility.Collectively, these findings demonstrate that rucaparib can potentiate NKTR-102-induced regression in tumors capable of forming abundant TOP1-DNA covalent complexes. This work identifies TOP1-DNA complex trapping and lack of ABCG2 expression as mechanistic predictors of benefit, providing an updated framework for selecting patients most likely to respond to TOP1 poison/PARPi combinations and challenging the long-standing assumption that PARP inhibition can universally resensitize tumors to TOP1 poisons. Citation Format: Annapoorna Venkatachalam, Caroline C. Nitschmann, Karen S. Flatten, Rachel Hurley, Xiaonan Hou, Cristina Correia, Paula A. Schenider, Krista Goergen, Matthew Maurer, Ethan P. Heinzen, Ann L. Oberg, S John Weroha, Paul Haluska, Scott H. Kaufmann, Elizabeth M. Swisher. TOP1-DNA protein complex as a predictive biomarker for NKTR-102/Rucaparib combination therapy in PARP-inhibitor resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB364.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are an important therapy for high-grade serous ovarian cancer (HGSOC). However, PARPi resistance frequently emerges, necessitating previously unrecognized approaches to improve HGSOC responses. Here, we showed that the anaplastic lymphoma kinase (ALK) inhibitor brigatinib enhances PARPi activity in HGSOC cells by disrupting an adaptive survival mechanism orchestrated by Fos-related antigen 1 (FRA1) in response to PARPi. This effect of brigatinib occurred through an ALK-independent pathway, wherein brigatinib induced a dual blockade of focal adhesion kinase (FAK) and EPH receptor A2 (EPHA2) tyrosine kinases, leading to the suppression of protein kinase B (Akt) and extracellular-regulated kinase (ERK) signaling accompanied by disruption of a phosphorylation event crucial for FRA1 protein stability. Moreover, in HGSOC patient-derived xenograft (PDX) models, brigatinib and PARPi combination therapy induced tumor regression and improved overall survival compared with PARPi alone, particularly in models with high FAK and EPHA2. These findings support dual targeting of FAK and EPHA2 as a strategy to achieve effective and durable PARPi responses and identify a promising biomarker-based combinatorial approach using brigatinib and PARPi for HGSOC, particularly the subset characterized by high FAK and EPHA2.

Abstract Cancer can recur when a subset of tumor cells, termed persister cells, survive therapy and re-enter the cell cycle. The cellular lineages that give rise to persister cells and the mechanisms that confer the persister state remain poorly understood. Through single-cell multiomic profiling (snRNA-seq and snATAC-seq) on a cohort of (1) non-malignant fallopian tube, (2) treatment-naïve, and (3) neoadjuvant chemotherapy (NACT)-treated high-grade serous ovarian cancer (HGSOC) patient samples, we identified an epigenetic signature that defines the chemotherapy-tolerant persister state. The changes in chromatin accessibility characterizing the signature were identified in residual NACT tumors but are also present in treatment-naive samples from patients who later developed resistance. Furthermore, this epigenetic signature independently predicted chemotherapy response in patient-derived xenograft models of HGSOC and in a separate patient cohort. Cells enriched in the persister state arose from multiple lineages and displayed activation of oncogenic pathways, including altered stress responses, epithelial to mesenchymal transition, and changes to the cell cycle promoting quiescence. Finally, we identified a subset of genes that are epigenetically primed for expression before treatment and are upregulated after treatment. These findings suggest that an intrinsic epigenetic program primes tumor cells towards chemotherapy tolerance and reveal new vulnerabilities that could be exploited to delay or prevent cancer recurrence. Citation Format: Mihai G. Dumbrava, Wazim M. Ismail, Leticia Sandoval, Amelia Mazzone, Syed Mohammed Musheer Aalam, Megan L. Ritting, Xiaonan Hou, Yiwen Xie, Shariska Harrington, Scott H. Kaufmann, Nagarajan Kannan, S. John Weroha, Alexandre Gaspar-Maia. Single cell multiomic analysis of high-grade serous ovarian carcinoma reveals an intrinsic epigenetic program that primes chemotherapy tolerance in persister cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr PR008.

Abstract Despite therapeutic advances, ovarian cancer (OC) recurrence remains common and outcomes for advanced disease are poor, highlighting the need for novel therapeutic targets. To this end, we identified CTPS1 as a highly expressed and essential gene for the survival of many OC cell lines, including models resistant to chemotherapy and PARP inhibitors. CTPS1 is one of two enzymes, alongside CTPS2, responsible for the de novo synthesis of cytidine triphosphate (CTP), a critical nucleotide required for DNA and phospholipid biosynthesis. We discovered that CTPS1 is the predominant isoform expressed in OC cells, with significantly higher levels of expression in advanced and resistant disease compared to normal tissue, benign lesions and treatment naïve cancers. Intriguingly, 25% of all OC samples were found to completely lack CTPS2 protein expression suggesting their near complete reliance on CTPS1 for survival. Using CTPS1 siRNAs and genetically engineered OC cells with a degradation tag (dTAG) fused to the C-terminus of endogenous CTPS1 alleles, we showed that CTPS1 knockdown or proteasomal degradation induces an S-phase cell cycle arrest followed by apoptosis. Leveraging a first-in-class, highly selective, and orally bioavailable CTPS1 inhibitor (STP938) developed by Step Pharma, we identified nanomolar-range IC50 values across a panel of over 20 OC cell lines and validated its anti-neoplastic activity in ex vivo patient-derived xenograft (PDX) models. STP938 synergized with standard-of-care chemotherapy and PARP inhibitors, even in resistant models, further supporting its clinical potential. To elucidate STP938’s mechanism of action, we performed multi-omic profiling (bulk RNAseq, phospho- and total proteomics) on sensitive and isogenic resistant OC lines, as well as single-cell RNAseq of an OC PDX tumor following in vivo treatment with vehicle or STP938, revealed dysregulation of DNA replication, cell cycle, and metabolic pathways. As expected, STP938 rapidly depleted CTP levels, which remain suppressed for 72 hours, suggesting insufficient salvage pathway compensation which ultimately compromised cancer cell viability. As CTP is also a direct precursor for activated intermediates in phospholipid biosynthesis. Mass-spectrometry based lipidomics and metabolomics were employed to interrogate the impact of STP938 in these processes where numerous changes were found. To uncover mechanisms of resistance to STP938 and reveal therapeutic vulnerabilities, we conducted genome-wide CRISPR knockout screens in multiple treatment naïve and STP938 resistant models and analysis of results are ongoing. In collaboration with Step Pharma, a Phase 1a/b clinical trial of STP938 is currently enrolling patients with advanced solid tumors, including an expansion cohort for CTPS2 null OC patients (NCT06297525). These laboratory discoveries and ongoing clinical efforts aim to enable broader uptake of this novel therapeutic approach to improve long-term outcomes in patients with CTPS1-dependent disease. Citation Format: Xiyin Wang, Michael J. Emch, Lauren A. Voll, Rebecca Epp, Esther P. Rodman, Noa Odell, Nicole A. Pearson, Xiaonan Hou, Matthew P. Goetz, Scott H. Kaufmann, S. John Weroha, Philip Beer, John R. Hawse. Exploiting CTPS1 dependency for the treatment of ovarian cancerPR005: Exploiting CTPS1 dependency for the treatment of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr PR005.

Abstract Introduction: Despite treatment advances, ovarian cancer (OC) remains the deadliest gynecological cancer, with a ∼70% mortality rate. OCs initially respond to platinum chemotherapy but often develop resistance. While PARP inhibitors improve relapse-free survival in responsive cases, they do not extend overall survival. This underscores the need for effective combination therapies beyond BRCA status. The lysosomal protein cathepsin L (CTSL) can traffic to the nucleus, where it can regulate DNA repair and serve as a chromatin modifier. We found that nucleoside analog clofarabine (CLF) induces CTSL nuclear trafficking in OC cells. Here we tested the hypothesis that accumulation nuclear CTSL (nCTSL) is a biomarker of sensitivity to DNA damaging therapy in OCs for improved therapeutic options. Methods: To determine the role of CLF induced nuclear CTSL in DNA damage and its synergy with PARP and CRM1 inhibitors in PARP inhibitor–sensitive and –resistant ovarian cancer (OC) cell lines, ex vivo cultures of ascites-derived patient OC cells (OVA-3D spheroids), primary ovarian tumors, and patient-derived xenograft (PDX) models and validated by colony formation assays. Nuclear CTSL localization was determined in subcellular fractionated lysates by western blots and immunofluorescence cytometry (IFC). Tumor regression was determined in vivo using ex vivo cultures of PDX derived cells. Results: In ovarian cancer (OC) cell lines, CLF monotherapy induced nuclear CTSL (nCTSL) in a subset of models classified as CLF-responsive (CLF-r), sensitizing them to the PARP inhibitors olaparib and rucaparib. In CLF-non-responsive (CLF-nr) models, nCTSL induction and therapeutic synergy were observed only with the CLF+olaparib combination. Synergy was detected in 47% of CLF-r and 24% of CLF-nr patient-derived ascites samples (OVA). Mechanistically, CLF induced nuclear import of CTSL via KPNB1 in CLF-r cells, while this import was triggered by the CLF+olaparib combination in CLF-nr cells. CLF also downregulated the nuclear export protein CRM1 (XPO1) in both groups. Knockdown of CTSL in either CLF-r or CLF-nr cells abrogated sensitivity to the combination. Notably, in 29% of OVA samples classified as CLF-resistant (CLF-Res), CLF failed to suppress CRM1 expression. In these cases, CRM1 inhibition with KPT8602 restored CLF+PARP inhibitor synergy. In vivo, CLF-r and CLF-nr PDX models treated with the combination exhibited increased DNA damage, reduced tumor burden, and extended survival. Conclusion: These findings identify nuclear CTSL (nCTSL) induction as a potential biomarker of response to DNA-damaging therapies. The combination of CLF and olaparib represents a promising strategy to overcome drug resistance in ovarian cancer by promoting CTSL nuclear localization and enhancing DNA damage. Citation Format: Prabhu Thirusangu, Ling Jin, Upasana Ray, Anya Zhao, Julie Staub, Xinyan Wu, Xiaonan Hou, Jamison L. VanBlaricom, Syed Mohamed Musheer Aalam, Sun-Hee Lee, Ann Oberg, Nagarajan Kannan, John Weroha, Jeremy Chien, Scott H. Kaufmann, Jamie N. Bakkum-Gamez, Viji Shridhar. Role of drug induced nuclear CTSL (nCTSL) in DNA damage response in cancer- therapeutic implications [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A050.

Abstract PARP inhibitors (PARPis) are now a standard of care for high-grade serous ovarian cancer (HGSOC), but resistance to these drugs poses a significant concern, necessitating the exploration of novel treatment strategies. Here we investigated the mechanism underlying enhanced PARPi activity in HGSOC cells following treatment with brigatinib—a second-generation anaplastic lymphoma kinase (ALK) inhibitor approved for treating lung cancer. Our previous work has shown that brigatinib is a dual inhibitor of tyrosine kinases FAK and EPHA2 with subsequent additive reduction in downstream PI3K/AKT and MAPK/ERK cell survival signaling. Suppression of these pathways conferred PARPi sensitivity to HGSOC cell lines and patient-derived xenograft (PDX) models, particularly in those with high FAK and EPHA2. To dissect the mechanism linking the FAK/EPHA2 – AKT/ERK pathway to PARPi synergy, we focused on proteomics approaches which revealed that FRA1—an Activator Protein 1 (AP-1) transcription factor known to be downstream of AKT/ERK—and its targets were decreased by brigatinib treatment. In subsequent phosphoproteomics approaches and cell-based confirmatory studies, a phosphorylation crucial for FRA1 stability was found to be disrupted, leading to reduction in total FRA1 protein levels and synergy with PARPis. To explore how FRA1 mediates response to PARPis, immunoblotting analysis revealed that PARPis increased the abundance of FRA1 in HGSOC cells at early timepoints, indicating potential involvement in an adaptive survival response. Follow-up pharmacologic and gene silencing techniques demonstrated that brigatinib still reduces FRA1 in PARPi-treated cells, and FRA1 depletion induces apoptosis when combined with PARPi to levels comparable to brigatinib treatment. Overall, our studies unveil a beneficial ALK-independent effect of brigatinib that may offer new avenues for considering its repurposing as a HGSOC therapy through disruption of a PARPi-induced adaptive survival mechanism. Citation Format: Julie R. Duffield, Xiaonan Hou, Benjamin W. Wilson, Anjali Prasad, Iman K. McKeon-Makki, Amelia M. Huehls, Xinyan Wu, Cristina Correia, Melissa C. Larson, Fergus J. Couch, Ann L. Oberg, Scott H. Kaufmann, Larry M. Karnitz, Arun Kanakkanthara. A PARP-inhibitor-induced early adaptive survival response is tackled through depletion of FRA1 by brigatinib in high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A024.

e15125 Background: Endometrial cancer (EC) is the most common gynecologic malignancy, with endometrioid being the most prevalent histology. Approximately 75% of high-grade endometrioid tumors are TP53 wild-type. During studies testing a novel combination of the PARP inhibitor rucaparib and TOP1 poison SN38 in high-risk primary patient serous and serous-like ECs, a subset of non-serous ECs with normal p53 expression showed unexpected synergy. This suggests broad efficacy in EC, warranting in vivo studies to assess tolerability and efficacy. Given potential overlapping toxicity, a novel formulation, pegylated SN38 (PLX038A), was tested. Methods: Primary patient tumors (n=4) were treated with rucaparib (0µM-25 µM) and SN38 (0µM-0.5 µM) in 3D cell culture experiments. RealTime Glo assessed viability after 3-5 days of drug exposure. Combination indices were determined using the Chou-Talalay method. Tolerability and efficacy were assessed in female SCID-beige mice (n=45) injected with intraperitoneal EC PDX tumors. Mice were randomized to controls, PLX038A (15 mmol/µmol IP, every 14 days), rucaparib (150 mg/kg daily gavage), or combination (same dose and schedule) for 8 weeks. Tolerability was assessed by daily animal weight and total condition score (TCS) from 1 (emaciated, non-ambulatory) to 13 (obese). Weight change more than -20% or TCS < 5 defined moribund criteria. Weekly ultrasound measurements assessed tumor response. Results: All four primary patient tumors exhibited synergy, with a combination index less than 1. Moribund criteria were not met in any mice across all cohorts. The average percent weight change and lowest TCS across cohorts were: rucaparib (-8.51%, min/max -19 to +14%; TCS 6.25, range 5-8, n=8), PLX038A (-3.97%, min/max -19 to +5%; TCS 6.8, range 6-9, n=10), the combination (-5.52%, min/max -15 to +1.8%; TCS 7.18, range 6-8, n=11), and control (+1.61%, range -6 to +8%; TCS 6.5, range 6-7, n=4). Scores were similar between groups, but the slightly lower TCS in the rucaparib cohort was associated with higher tumor burden from ineffective therapy. Tumors in the rucaparib monotherapy group grew similarly to controls. In contrast, the combination therapy cohort exhibited significant regression below baseline during treatment. Conclusions: These findings suggest that the combination of rucaparib and SN38 (PLX038A) is effective in EC primary patient tumor organoids and PDXs with wild-type TP53. No significant negative physiological effects on animal TCS and weight change were observed. No drug-related toxicity was observed in mice receiving combination treatment. Mice receiving combination treatment displayed significant tumor regression below baseline compared to both single agents and control. These data support future exploration of this combination therapy in ECs.

Abstract Cancer can recur when a subset of tumor cells, denoted here as persister cells, are able to survive therapy and re-enter the cell cycle. The precise mechanisms that confer the persister state and whether it is characteristic of a subgroup of cells or arises from multiple cellular lineages remain poorly understood. We hypothesize that an epigenetic signature underlies the drug-tolerant persister state, characterized by transcriptional and chromatin accessibility changes that promote survival of residual cancer following chemotherapy. To identify clinically relevant features of persister cells in untreated tumors and residual disease, we performed single-cell multiomic profiling (snRNA+snATAC) on a cohort of non-malignant fallopian tube, treatment-naïve, and neoadjuvant chemotherapy (NACT)-treated high-grade serous ovarian cancer (HGSOC) samples. We identified differences in gene expression and open chromatin between naïve and residual patient tumors following chemotherapy. Although only a small proportion of the differentially expressed genes enriched in residual HGSOC overlapped with established gene sets for chemo-response and patient prognosis, the epigenomic analysis revealed activity of several DNA-binding factors that are both enriched upon chemotherapy and also high in resistant tumors prior to treatment. From this analysis, we identified an epigenetic signature that precedes expression and defines the persister state. This epigenetic signature also correlated with chemotherapy sensitivity and resistance using patient-derived xenograft models of HGSOC. Gene regulatory networks driven by the persister signature are involved in the activation of oncogenic pathways, including changes to the cell cycle promoting quiescence and stress response. Further study of the persister cells identified by this epigenetic signature may increase understanding of the mechanisms underlying persister cell survival and reveal new vulnerabilities that could be exploited to delay or prevent cancer recurrence.

Abstract Background: Epithelial ovarian cancer (EOC), commonly known as ovarian cancer (OvCa), is the deadliest gynecological malignancy. High tumor expression of either NR3C1 mRNA (encoding the glucocorticoid receptor or GR) or GR protein (IHC) are associated with poor overall survival (OS) in patients (pts) with advanced stage OvCa. We hypothesized that high GR expression and associated GR transcriptional activity favor OvCa cell survival and chemotherapy resistance, thereby reducing OS. Here we investigated whether a GR transcriptome-based gene signature (GR-sig) would be a better prognosticator than tumor NR3C1 mRNA expression alone. Methods: mRNAs up- or downregulated &gt;1.5 fold after glucocorticoid treatment (Dex) in one or both cultured OvCa cell lines (OVSAHO and HEYA8) were defined as differentially expressed genes (DEGs). DEGs were then identified in n=1247 unique OvCa microarrays from 15 publicly available Gene Expression Omnibus (GEO) datasets with matched pt OS (training set). We then used the OS data to train a Cox proportional hazards model. The “best subset selection” (BeSS) algorithm and bootstrap sampling identified those GR-regulated DEGs whose tumor mRNA expression correlated most significantly with pt OS, creating a GR-sig “risk score.” Subsequently, all n=522 microarray and n=374 RNA-seq publicly available samples from the OvCa TCGA were used as two independent validation sets. Microarray and RNA-seq data were normalized using the MAS5 and FPKM-UQ algorithms respectively. The two validation sets were independently stratified relative to the median training set risk score into low- and high-risk score groups. To examine the prognostic ability of NR3C1 mRNA expression alone, the median training set NR3C1 expression value was used to stratify validation set pts into low- and high-expression groups. In all cases, OS was estimated by the Kaplan-Meier method. Results: We identified n=2288 protein-coding DEGs in one or both cell lines. Of these genes, n=1251 were expressed in each GEO microarray sample (training set). A 10-gene GR-signature (GR-Sig) was then identified using the BeSS algorithm and bootstrap sampling, yielding a median training set risk score of 1.02. In both the microarray and RNA-seq validation datasets, the 10-gene GR-sig risk score was associated with significant OS differences between low- and high-risk score groups (microarray p = 0.018; RNA-seq p = 0.00049). In contrast, the OS difference between low- and high- NR3C1 mRNA expression groups did not reach significance (microarray p = 0.12; RNA-seq p = 0.28). Conclusion: In this retrospective analysis, a 10-gene GR-sig derived from OvCa GR-regulated DEGs performed better as a prognosticator than NR3C1 mRNA expression alone. Prospective application of the GR-sig may be useful in stratifying patients for treatment response with novel agents in OvCa clinical trials. Citation Format: Ananth V. Panchamukhi, Lei Huang, Eleanore P. Gray, Yuanhang Liu, Manisha Taya, Jennifer T. Veneris, Xiaonan Hou, S John Weroha, Balázs Győrffy, Gini F. Fleming, Chen Wang, Suzanne D. Conzen. Development of a prognostic ovarian cancer gene signature based on glucocorticoid receptor transcriptional activity [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 4739.