tbuckley/cabot-search huggingface dataset:
Abstract 4755: Preclinical mechanistic PK/PD-efficacy modeling for AZD9750, a novel oral androgen receptor degrader (PROTAC), to support dose selection during early clinical development
Authors: Pablo Morentin Gutierrez, Ana Quiroga Campano, Antonio Ramos Montoya, Claire Crafter, Chrysiis Michaloglou, Aaron Smith, Nuria Galeano Dalmau, Jamie Scott, Michael Niedbala
Journal: Cancer Research (2025)

Abstract Objectives: The androgen receptor (AR) is highly expressed in prostate cancers and is a clinically validated target in oncology. AZD9750 is a novel potent oral selective AR Proteolysis-targeting chimera (PROTAC) due to start clinical testing in 2025. We present here the preclinical PK/PD modeling work used to understand the required target modulation and concentration required to see anti-tumor efficacy and therefore help support the dose selection during the early clinical development of AZD9750. Methods: We developed a novel mechanistic mathematical model applied to in vivo preclinical mouse PDX models (MR041 and C901, primary prostatic adenocarcinoma, hormone sensitive and AR-wt) linking the compound pharmacokinetics with the magnitude of target modulation expressed as relative levels of AR measured by Western Blotting. These changes at the biomarker level were subsequently linked to inhibition of tumor cell proliferation resulting in macroscopic dynamic effects on tumor size. All model parameters were derived from internal studies; some were estimated using Non-Linear Mixed Effect modeling of individual longitudinal PK, PD biomarker and tumor size data taken from several studies. Results: The model described well the relationship between plasma concentration of AZD9750 and modulation of AR. In vivo AZD9750 concentration required to see 50% of the maximal target modulation in both animal models was on the region of 0.2-0.7 µM. Population tumor size patterns, for all treatment regimens ranging from 0 to tumour regressions across both tumor models were very well described with the model proposed. 55 - 80% reduction of AR levels was required to induce tumor regression in both models. Conclusions: This study provides quantitative mechanistic insights into the links between compound exposure, biomarker modulation (AR) and anti-tumor responses, supporting our understanding of the required target modulation needed for maximal anti-tumor effects in these two hormone sensitive patient-derived tumor models. This mechanistic understanding is valuable to contextualize compound-induced PD modulation in patients, for given doses and schedules. Citation Format: Pablo Morentin Gutierrez, Ana Quiroga Campano, Antonio Ramos Montoya, Claire Crafter, Chrysiis Michaloglou, Aaron Smith, Nuria Galeano Dalmau, Jamie Scott, Michael Niedbala. Preclinical mechanistic PK/PD-efficacy modeling for AZD9750, a novel oral androgen receptor degrader (PROTAC), to support dose selection during early clinical development [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 4755.
Abstract 6639: Optimized selection of tumor-informed MRD panels enhances sensitivity of ctDNA detection
Authors: Ashley Acevedo, Ravi Patel, Kyle Trettin, Nafei Xu, Genevieve Gould, Dale Muzzey
Journal: Cancer Research (2025)

Abstract Circulating tumor DNA (ctDNA) is a highly sensitive and specific biomarker for molecular residual disease (MRD) and can be by identified by the presence of tumor-specific somatic variants. We have developed a second-generation hybrid-capture-based tumor-informed MRD assay to detect the presence and quantity of ctDNA in plasma-derived cell-free DNA (cfDNA). Our assay surveys the whole tumor genome to identify the superset of high-confidence somatic variant targets that can be used to distinguish ctDNA from non-tumor cfDNA. Each panel consists of up to 1000 targets that are selected based on target-specific and tumor-specific features that impact the representation of tumor variants or the effective molecular depth of a panel, such as somatic call confidence, zygosity, copy number, background error rate and expected molecular depth following capture and sequencing. cfDNA captured using a patient-matched panel undergoes targeted sequencing and that sequence data is fit to a statistical model that evaluates the presence and fraction of ctDNA in the sample. Here, we evaluated the performance of our target-ranking algorithm using contrived mixtures of matched tumor and normal cell lines, with tumor DNA concentrations ranging from 5 to 10, 000 parts per million (ppm) and samples processed across multiple days, reagent lots, operators and instruments. Identical sets of contrived samples were analyzed using subsets of panel targets, including top-ranking and bottom-ranking target sets. We found the Limit of Detection with 95% sensitivity (LoD95) for top-ranking targets was 40% of the LoD95 for low-ranking targets, demonstrating the effectiveness of our ranking algorithm in stratifying high and low sensitivity targets. In conclusion, the constituents of tumor-informed MRD panels have a measurable impact on the sensitivity of ctDNA detection and, with optimization, can enhance the resolution of residual disease detection. Citation Format: Ashley Acevedo, Ravi Patel, Kyle Trettin, Nafei Xu, Genevieve Gould, Dale Muzzey. Optimized selection of tumor-informed MRD panels enhances sensitivity of ctDNA detection [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 6639.
Abstract 6928: Combination treatment with cisplatin and PG3 for p53-mutated head &amp; neck cancers
Authors: Xiaobing Tian, Wafik S. El-Deiry
Journal: Cancer Research (2025)

Abstract More than 90% of head &amp; neck (H&amp;N) cancers are squamous cell carcinoma (HNSCC) that occur from the mucosal epithelial tissue of the oral cavity, oropharynx, and larynx. About 30∼40% of stage I or II HNC patients are curable and show improved survival rates after surgery or radiotherapy alone. However, over 60% of stage III or IV HNC patients require chemotherapy. Cisplatin is one of standard chemotherapy drugs for stage III and IV patients. In addition, the mutation frequency of the p53 gene in HNSCC is 65-85%. DNA damage following cisplatin treatment can activate apoptosis via p53 in p53 wild-type cancer cells. In p53-mutated/deleted cancer cells, DNA-damage drugs can lead to cell death through other mechanisms, such as integrated stress response (ISR). There multiple cisplatin-resistance mechanisms were reported. Nucleotide excision repair (NER) is known as the primary strategy for repair of cisplatin-induced DNA damage. Elevated ERCC1 and ERCC5 expression enhance NER and are associated with cisplatin resistance in HNSCC patients. It was reported that ATF4 downregulation promoted cisplatin resistance in p53 mutated and deleted gastric cancers. A small molecule PG3 treatment triggers ISR and leads to cell apoptosis through HRI/eIF2α/ATF4/PUMA pathway in p53-mutated and deleted colorectal cancer cell lines. We hypothesize that (1) combination treatment of PG3 with cisplatin can reduce side effects of cisplatin through reducing the dose of cisplatin, which can be achieved by enhanced induction of integrated stress response, (2) PG3 can sensitize cisplatin-resistant and p53-mutated H&amp;N cancer cells to cisplatin through enhanced induction of integrated stress response. The combination treatment shows synergistic effects in p53-mutated FaDu and Cal27 H&amp;N cancer cells. In combination therapy, use of PG3 allows use of a lower cisplatin dose to achieve a therapeutic benefit. The combined treatment enhances ISR induction, and the ISR contributes to cell apoptosis. We identified that cisplatin or the combination treatment activates the HRI/ATF4/NOXA pathway. NOXA mediates Mcl-1 degradation and is responsible for the combination treatment-induced apoptosis. Citation Format: Xiaobing Tian, Wafik S. El-Deiry. Combination treatment with cisplatin and PG3 for p53-mutated head &amp; neck cancers [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 6928.
Abstract 4766: Characterization of XON9, an effective glyco-humanized polyclonal antibody against hepatocarcinoma
Authors: Pierre-Joseph Royer, Carine Ciron, Ophelie Dauphouy, George Graur, Odile Devaux, Firas Bassissi
Journal: Cancer Research (2025)

Context: Hepatocarcinoma is the second leading cause of cancer-related death, and its incidence is increasing. Multikinase inhibitors (Sorafenib or Lenvatinib) are the conventional first line treatment for unresectable HCC, with limited response rates and serious side effects. Although immune base therapies such as checkpoint inhibitors have recently showed promising results, they remain applicable to a small fraction of patients. Thus, new treatment and strategies are desperately needed to improve the management of hepatocarcinoma. We evaluate here the in vitro and in vivo efficacy and safety of XON9, first-in-class glyco-humanized polyclonal antibody (GH-pAb) against hepatocarcinoma. Material and methods: Cytotoxic activity of XON9 against HUH7, HepG2 and Hep3B cell lines was investigated and compared to the activity of standards of care Sorafenib and Lenvatinib. Primary hepatocytes were used as control. Mechanisms of apoptosis were further explored. Activity of caspases 8 and 9, level of reactive oxygen species (ROS) and mitochondrial membrane potential was investigated after treatment with XON9. The in vivo efficacy of XON9 was then assessed in NMRI nude engrafted with HUH7 cancer cells while pharmacokinetics and safety parameters were evaluated in a non-human primate after once weekly dosing at 50mg/kg over 2 weeks. Results: XON9 shows a potent complement dependent cytotoxicity (CDC) against HUH7, HepG2 and Hep3B cells (EC50&amp;lt;10µg/ml). By contrast, primary hepatocytes were relatively spared by XON9 (EC50&amp;gt;50µg/ml). Moreover, XON9 treatment induced apoptosis of the three cell lines tested with activation of caspases 8 and 9, increase of ROS levels and drop of mitochondrial membrane potential. Overall, in vitro lytic activity of XON9 towards HUH7, HepG2 and Hep3B was superior to that of Sorafenib and Lenvatinib, the current standards of care for hepatocarcinoma. In vivo, XON9 significantly reduced tumour progression in a mouse xenograft model (40% reduction at day 25). No toxicity was observed after repeated injections of 50mg/kg of XON9 in a non-human primate. Conclusion: Although recent immunotherapy advances have been made, hepatocarcinoma remains an incurable disease with a real need for innovative therapies. XON9 represents a promising and selective immunotherapy against refractory hepatocarcinoma. Citation Format: Pierre-Joseph Royer, Carine Ciron, Ophelie Dauphouy, George Graur, Odile Devaux, Firas Bassissi. Characterization of XON9, an effective glyco-humanized polyclonal antibody against hepatocarcinoma [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 4766.
Abstract 6944: Transient pan-RAF inhibitor treatment for melanoma prevention
Authors: Rachel E. Lew, Harsha S. Sanaka, Venkat R. Chirasani, Sharon L. Campbell, Christin E. Burd
Journal: Cancer Research (2025)

Abstract Therapeutic options are currently limited for the 15-25% of cutaneous melanomas driven by an oncogenic NRAS mutation. Our previous findings showed that melanoma-associated NRAS substitutions stabilize conformations optimal for BRAF binding, thereby promoting RAF dimerization, proliferative signaling, and ultimately melanomagenesis. Building on these discoveries, we hypothesized that NRAS-mutant melanoma precursors would exhibit substitution-specific sensitivity to pan-RAF inhibition, and that a temporary blockade of RAF signaling would eliminate NRAS mutant-melanocytes in the skin. BRET and NanoBiT complementation assays revealed that pan-RAF inhibitors promote RAS-RAF and RAF-RAF interactions at lower doses in human melanoma cell lines with a weakly melanomagenic NRAS substitution (Q61H) compared to those with a stronger melanomagenic NRAS substitution (Q61R). Surprisingly, these drug-induced RAF complexes were associated with decreased MAPK&amp;gt;ERK signaling and higher drug sensitivity, suggesting that fully inhibited, drug-bound protomers drive increases in NRAS-RAF interactions. To test the mutation-specific sensitivity of NRAS-mutant melanoma precursors in vivo, mouse models of spontaneous NRAS Q61R- or Q61H-driven melanoma were prophylactically treated with a pan-RAF inhibitor for three days and then followed for tumor formation. Consistent with our in vitro data, short-term pan-RAF inhibitor treatment delayed melanoma onset in NRAS Q61H, but not Q61R mice. These findings highlight the critical role of RAF signaling in NRAS-mutant melanoma formation, suggesting that short-term use of effective, targeted therapies could prevent melanoma formation. Citation Format: Rachel E. Lew, Harsha S. Sanaka, Venkat R. Chirasani, Sharon L. Campbell, Christin E. Burd. Transient pan-RAF inhibitor treatment for melanoma prevention [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 6944.
Abstract 4768: Development of fully human TCR-mimic antibodies targeting intracellular tumor antigens using humanized RenTCR-mimic transgenic mice
Authors: Han Zhang, Wanbo Tang, Jun Du, Yue Zhang, Limin Zhao, Xin Jiao, Baihong Liu, Yi Yang
Journal: Cancer Research (2025)

Abstract T cell receptors (TCRs), a promising therapeutic strategy for targeting intracellular antigens, can specifically recognize antigen peptide presented by human lymphocyte antigen (HLA) and mediate T cell responses to eliminate tumor cells. However, the low affinity of TCRs presents a great challenge to their broader clinical application. TCR-mimic (TCRm) antibodies, with similar antigen recognition capabilities as TCRs but higher affinity, offer a solution to these limitations, enabling the targeting of previously undruggable cancer antigens. Neverthelss, specificity remains a major challenge to ensure therapeutic accuracy and patient safety, as TCRm antibodies need to precisely target a single tumor-specific peptide antigen presented by HLA rather than other similar peptides. Using RenTCR-mimic transgenic mice, we describe the generation and preclinical evaluation of fully human TCRm antibodies by fusing them with a humanized anti-CD3 scFv to form T cell engager or assembled on T cell surface to build TCRm-T cells, further to specifically redirect T cells to lysis tumors by our proprietary RenTCR-mimic platform. We determine cross-reactive peptide sequences predicted by in silico or known off-target sequences. We further confirm the specificity and safety of TCRm antibodies. Despite low density antigen copies, TCRm antibodies elicited antibody-mediated T-cell recognition and cytotoxicity against antigen peptide-HLA complexes-restricted cell lines. Based on these methods, we perform screens to validate TCRm antibodies specificity. These experiments led us to discriminate between the target peptide and the potential off-target peptides presented by HLA and highlight the therapeutics potential of TCRm antibodies in tumor immunotherapy, offering a novel approach to expanding the repertoire of druggable cancer targets. Citation Format: Han Zhang, Wanbo Tang, Jun Du, Yue Zhang, Limin Zhao, Xin Jiao, Baihong Liu, Yi Yang. Development of fully human TCR-mimic antibodies targeting intracellular tumor antigens using humanized RenTCR-mimic transgenic mice [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 4768.
Abstract 5781: Comparing prognostic association of manual vs. artificial intelligence derived quantifications from baseline computed tomography scans in MYSTIC, a global phase 3 trial for treatment of metastatic non-small cell lung cancer
Authors: Harish RaviPrakash, Qin Li, Kedar Patwardhan, John Riskas, Shahid Haider, Oleksandra Samodorova, Jay Hennessy, Vignesh Sivan, Felix Baldauf-Lenschen, Omar Khan
Journal: Cancer Research (2025)

Abstract Background: Sum of longest diameters (SLD) of target lesions per response evaluation criteria in solid tumors (RECIST) 1.1 is the standard measure of baseline (BL) disease burden, which plays an important prognostic role. Fully automated, artificial intelligence (AI) derived measures from BL computed tomography (CT) scans like imaging-based prognostication (IPRO) and lung volumetric tumor burden (VTB), generated by AI models trained on real-world imaging data, have shown promising association with overall survival (OS). Methods: BL CT scans acquired in MYSTIC (NCT02453282) were combined across trial arms and retrospectively analyzed. Patients with consent were included in this study. We compared the prognostic association of manually derived SLD with AI derived IPRO and lung VTB using concordance index (c-index), Kaplan-Meier methods, time-dependent area under the curve (TD-AUC), and standardized hazard ratios (HRs) from Cox proportional hazards models. Results: BL CT scans of 672 patients had available quantifications for comparative analysis. Median OS (mOS) was 12.2 months, 194 patients (29%) were female, 106 (16%) were non-smokers, 193 (29%) had squamous cell carcinoma and 201 (30%) had PD-L1 &amp;gt; 50%. SLD, IPRO, and lung VTB, yielded c-indexes of 0.56 (95% CI: 0.54-0.59), 0.61 (0.59-0.64), and 0.57 (0.54-0.60), respectively. Results are shown in Table 1. Conclusions: BL IPRO has greater association with OS than SLD, and VTB shows similar prognostic association as SLD. AI derived quantifications offer enhanced stratification and may provide an efficient way to analyze treatment effects.‬‬‬‬‬‬‬‬‬ Citation Format: Harish RaviPrakash, Qin Li, Kedar Patwardhan, John Riskas, Shahid Haider, Oleksandra Samodorova, Jay Hennessy, Vignesh Sivan, Felix Baldauf-Lenschen, Omar Khan Comparing prognostic association of manual vs. artificial intelligence derived quantifications from baseline computed tomography scans in MYSTIC, a global phase 3 trial for treatment of metastatic non-small cell lung 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 5781.
Abstract 6570: Characterization of diverse extracellular nanoparticles and tumorigenic relevance in hepatocellular carcinoma
Authors: Jiaqi Lai, Cherlie Lot Yeung, Cui Le, Lavisha Korani, Tung Him Ng, Xiaoxin Zhang, Zhixian Chen, Ruiqi Ma, Chi Ming Che, Judy Wai Yam
Journal: Cancer Research (2025)

Abstract Introduction: Tumor-derived extracellular nanoparticles termed exomeres (EM), distinct to small extracellular vesicles (sEV), act as critical mediators of the tumor microenvironment (TME) formation and are associated with tumor progression and therapy resistance in hepatocellular carcinoma (HCC). Methods: sEV and EM were isolated from various normal and cancer cell lines using serial ultracentrifugation. The physical and biomedical characterization of EM versus sEV was conducted through transmission electron microscopy (TEM) and mass spectrometry (MS) analysis. Potential molecular EM markers were identified based on the distinct proteomic profiles between sEV and EM. The tumorigenic potentials of HCC-EM were evaluated using in vitro functional assays and in vivo mice models. Relevant oncogenic mechanisms were studied according to the differential cargo contents of HCC- and normal-EM, as well as differential gene expression of the recipient cells by RNA sequencing. The effects of EM on cell cycle progression and metabolic dysregulation were investigated by flow cytometry and analytical metabolomic/lipidomic approaches. Results: The TEM and MS analysis demonstrated distinct morphological and protein differences between sEV and EM. GALNS and MAN2B1 were two proteins identified as potential EM markers, showing exclusive or significantly higher expression. Functionally, EM released from HCC cells, instead of normal hepatocytes, stimulated cell growth, motility and tumor development. The EM originated from human HCC cells exhibited increased WNT5A, LRP5, and LRP6 levels, activating the PI3K/AKT/mTOR pathway in recipient cells. In addition, EM derived from murine HCC cells were shown to accelerate cell cycle progression by shifting cells through the checkpoint into the G1 phase, and reconstitute the lipid pattern to be enriched with a very-long chained saturated fatty acid, which triggers the metabolic reprogramming. Conclusions: Collectively, our findings underscore the unique characteristics of EM as a nanoparticle subpopulation that differs from sEV, and that EM derived from HCC can play a significant role in tumorigenesis and metastasis. Citation Format: Jiaqi Lai, Cherlie Lot Yeung, Cui Le, Lavisha Korani, Tung Him Ng, Xiaoxin Zhang, Zhixian Chen, Ruiqi Ma, Chi Ming Che, Judy Wai Yam. Characterization of diverse extracellular nanoparticles and tumorigenic relevance in hepatocellular carcinoma [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 6570.