tbuckley/cabot-search huggingface dataset:
PSA response and cabazitaxel outcomes stratified by prior docetaxel PSA response in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Christopher Eing Wee, Amanda Nizam, Moshe Chaim Ornstein, Timothy D. Gilligan, Xiaoying Chen, Kimberly Maroli, Allison Martin, Amanda Bonham, Carolyn Pietro, Shilpa Gupta
Journal: Journal of Clinical Oncology (2024)

119 Background: In the TheraP trial, both cabazitaxel and lutetium Lu 177 vipivotide textraxetan demonstrated similar overall survival (OS) in patients with mCRPC previously treated with docetaxel. We seek to identify predictors for cabazitaxel benefit by evaluating patients’ cabazitaxel outcomes in the context of prior docetaxel outcomes. Methods: We identified patients who started cabazitaxel after January 2010 at our institution. Patients were included if they received docetaxel for mCRPC but excluded if they received docetaxel for hormone-sensitive disease, used taxane in combination with other agents (e.g. carboplatin), or received multiple courses of same taxane (e.g. “re-challenges”). For adequate assessment of PSA response, patients were only included if pre-chemo PSA was &gt; 20 ng/mL and had received at least two cycles of both taxanes. PSA response was defined as &gt;50% decrease from baseline sustained for at least 3 weeks (PSA50). OS was calculated from time of cabazitaxel start to death from any cause. Results: Eighty patients were identified with a median age of 70 years at cabazitaxel start. Forty (50%) patients had a PSA50 with docetaxel, while only 18.8% had a PSA50 with subsequent cabazitaxel. Patients who had a PSA50 to docetaxel had a significantly higher chance of PSA50 to cabazitaxel (OR 5.29, 95% CI: 1.36, 20.53, p = 0.0162); the PSA50 rates on cabazitaxel were 30% and 7.5% between those that did and did not have a PSA50 to docetaxel, respectively. There were no significant differences in cabazitaxel median OS based on prior docetaxel PSA50. Conclusions: Patients who had PSA50 to docetaxel had a significantly higher chance to have a PSA50 to cabazitaxel. Prior docetaxel PSA50 could be considered when deciding whether to use cabazitaxel or an alternative agent for subsequent treatment. [Table: see text]
Predictive analysis of breast cancer metastasis and identification of genetic markers using machine learning.
Authors: Kovuri Umadevi, Dola Sundeep
Journal: Journal of Clinical Oncology (2024)

4 Background: The study devises a framework integrating machine learning (ML) paradigms with explainable artificial intelligence (XAI) to prognosticate the metastatic trajectory of breast cancer (BC) and delineate critical genomic indicators pertinent to metastasis. Methods: An examination was conducted on 98 initial BC specimens, which included 34 instances evolving into distant metastasis within a quintennial monitoring phase and 44 instances evincing no recurrence for a minimum pentad post-diagnosis. Genomic datasets underwent rigorous biostatistical scrutiny, followed by the implementation of an elastic net algorithm for feature discernment, thereby constraining the scope to a salient subset of genomic markers implicated in BC metastasis. An ensemble of advanced predictive models encompassing Light Gradient Boosting Machine (LightGBM), Categorical Boosting (CatBoost), Extreme Gradient Boosting (XGBoost), Gradient Boosting Trees (GBT), and Adaptive Boosting (AdaBoost) was deployed. Model efficacy was gauged through metrics such as accuracy, F1 score, precision, recall, the Area Under the Receiver Operating Characteristic Curve (AUC), and the Brier score. To elucidate the reasoning behind the ML predictions and to navigate the opacity inherent in such models, a SHapley Additive exPlanations (SHAP) approach was invoked. Results: The predictive acumen of the LightGBM model was superior, evidenced by a striking accuracy of 96% and an AUC of 99.3%. Parallel to biostatistical assessments, SHAP analysis leveraging XAI illuminated that augmented expression levels of specific genes, namely TSPYL5, ATP5E, CA9, NUP210, SLC37A1, ARIH1, PSMD7, UBQLN1, PRAME, and UBE2T (with statistical significance p ≤ 0.05), correlated with an escalated risk of BC metastasis. Conversely, diminished expression of CACTIN, TGFB3, SCUBE2, ARL4D, OR1F1, ALDH4A1, PHF1, and CROCC (p ≤ 0.05) was similarly associated with heightened metastatic susceptibility in BC. Conclusions: The insights garnered from this investigation may catalyze preventative strategies against BC progression and metastatic dissemination, thereby enhancing therapeutic efficacy through personalized intervention modalities for BC patients.
Bruton's tyrosine kinase inhibitor zanubrutinib-based regimens in relapsed/refractory primary diffuse large B-cell lymphoma of central nervous system.
Authors: Yali Wang, Feng Chen, Wenbin Li
Journal: Journal of Clinical Oncology (2024)

30 Background: Patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL) usually have a poor prognosis. Ibrutinib-based regimens revealed promising efficacy but showed off-target effects and drug resistance in some cases. Here, we conducted a retrospective study to evaluate the efficacy and safety of regimens based on second-generation bruton's tyrosine kinase (BTK) inhibitor zanubrutinib in R/R PCNSL. Methods: We respectively reviewed 23 patients with R/R PCNSL treated with zanubrutinib in our center from Apr. 2021 to Jan. 2024. The primary end points were overall response rate (ORR) and progression-free survival (PFS). Secondary end points included complete response rate (CRR), disease control rate (DCR), overall survival (OS) and adverse events (AEs). Response was assessed according to International Primary CNS Lymphoma Collaborative Group criteria. The severity of AEs was graded using the NCI Common Toxicity Criteria, version 5.0. Validated next-generation sequencing (NGS) panels were used to analyze the mutational status of the BCR pathway genes or other solid tumor-related genes. Results: The median follow-up at the cutoff date (15 Jan 2024) was 17.0 months (range, 2-33 months). The ORR, CRR and DCR were 78.3%, 39.1% and 91.3%. The median PFS was 31.0 months, but the median OS was not reached. Compared to germinal center B-cell like (GCB) group, non-GCB group showed a better ORR (76.9% vs 66.7%) and CRR (46.2% VS 33.3%). Multivariate analysis revealed that overall response (vs. no response, HR=0.20, P=0.027), long duration of zanubrutinib (≥6months vs. 2-5 months, HR=0.07, P=0.009) and refractory disease status (vs. relapse disease status, HR=0.12, P=0.014) were independent factors for longer PFS. The most commonly mutated genes are MYD88(15/17,88.2%), PIM1(9/17 52.9%), CD79B (8/17,47.1%), ETV6(7/17,41.2%), BTG1(5/17,29.4%) and GNA13(5/17,29.41%). The mutational status of MYD88/CD79B did not lead to any difference in PFS and OS. We obtained the Tumor Mutational Burden (TMB) information from 11 patients. The median TMB was 15.96 (range: 3.82-28.11) muts/Mb. Kaplan-Meier analysis demonstrated that PFS was significantly longer in patients with higher TMB (≥15.96 muts/Mb) after zanubrutinib-based treatment(P=0.005). Grade ≥3 and serious treatment-emergent AEs (TEAEs) were not found. The most commonly TEAEs were hematologic toxicity (8/23,34.8%) and skin rash (5/23,21.7%). Conclusions: Our study demonstrates that zanubrutinib-based therapy is effective and safe for the treatment of R/R PCNSL. We advocate for the prolonged administration of zanubrutinib to maintain treatment response. Patients with higher TMB derive greater benefits from zanubrutinib-based regimens.
Factors predicting long-term survival of hepatocellular carcinoma in developing country.
Authors: Sunee Neesanun
Journal: Journal of Clinical Oncology (2024)

231 Background: Hepatocellular carcinoma (HCC) is a common cancer globally, especially in Asian Pacific countries with survival time limit. Previous data on long-term survival (LS) in HCC patients has been limited. This study aims identifying factors that predict LS for HCC patients treated in hospitals with restricted access to advanced therapies. Methods: This study utilized a retrospective cohort design, analyzing electronic medical records of patients diagnosed with HCC at Sawanpracharak Hospital from October 2018 to September 2022. LS for HCC was defined as survival for two years or more. Univariable and multivariable with stepwise backward regression analyses were employed to identify independent prognostic factors. Results: The analysis included 398 HCC patients, with 75 (18.84%) classified as long-term survivors (LS HCC). Stepwise backward regression identified that ALP levels &lt;172 U/L were associated with a significantly increased likelihood of LS (OR = 3.667, 95% CI 1.443-9.317, p=0.006). Additionally, curative surgery/RFA treatment (OR = 1.941, 95% CI 1.128-3.342, p=0.017) and Albumin &gt;3.5 g/dL (OR = 9.898, 95% CI 1.160- 84.438, p=0.036) were significant positive predictors. ECOG performance status (3-4 vs 2 vs 0-1) and AJCC stage (early vs locally vs advance) also emerged as significant factors, with better performance status (OR = 8.723, 95% CI 1.046-72.741, p=0.045) and AJCC stage 3 and 4 (OR 0.200 95% CI= 0.075-0.532, P= 0.001 and OR = 0.204, 95% CI 0.0547-0.760, p=0.018 respectively) associated with LS. Notably, alcohol consumption was associated with a decreased likelihood of LS (OR = 0.399, 95% CI 0.171-0.929, p=0.033). The model demonstrated good discriminative ability with an AUC of 0.912. Conclusions: Lower ALP levels, curative treatment, higher albumin levels, better ECOG performance status, earlier AJCC stage, and abstinence from alcohol consumption were all associated with a significantly increased likelihood of LS HCC. The high AUC of the model suggests its potential for predicting long-term survival in this patient population. [Table: see text]
Effect of ac4C acetyltransferase NAT10 on tumor progression via ATF4/ASNS mediated asparagine biosynthesis in osteosarcoma.
Authors: Yutong Zou, Xianbiao Xie
Journal: Journal of Clinical Oncology (2024)

234 Background: Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, characterized by high malignancy, high mortality, and high disability rates. Investigating the mechanism of osteosarcoma progression, identifying new targets, and developing effective therapy are of great significance for improving patient clinical outcomes. NAT10-mediated ac4C modification is widely present in mRNA and plays important roles in multiple biological processes of mRNA. NAT10 and ac4C modification also play a crucial role in the occurrence and development of malignant tumors such as bladder cancer, esophageal cancer, and breast cancer. Methods: Through RNA-seq and functional screening, NAT10 was identified as the potential therapeutic target. The biological functions of NAT10 and ac4C modification in osteosarcoma were explored in vivo and in vitro. Downstream target of NAT10 was identified through acRIP-seq combined with RNA-seq. The ac4C modification of downstream target gene were detected using RIP-qPCR and its regulatory effect on mRNA stability was explored using RNA half-life analysis. Drug screening was performed using FDA-approved drugs and a small molecule compound library to identify NAT10 inhibitors. The efficacy of inhibitors in osteosarcoma treatment is validated through in vivo, in vitro experiments and patient-derived tumor xenograft (PDX) models. Results: Functional screening targeting RNA modification regulatory factors demonstrated that inhibiting NAT10 significantly reduced the proliferation, migration and invasion of osteosarcoma cells. NAT10 knockout significantly inhibited the proliferation and metastasis of osteosarcoma cells, as well as the malignant progression in vivo. The acRIP-seq and RNA-seq revealed that ATF4 is a downstream target gene regulated by NAT10 in osteosarcoma. NAT10 promoted ac4C modification of ATF4 mRNA, enhanced the stability of ATF4 mRNA, and ATF4 promoted the transcription and expression of ASNS. ASNS catalyzes the synthesis of asparagine (Asn), thereby promoting the malignant progression of osteosarcoma. Drug screening identified Paliperidone and AG-401 as potential inhibitors of NAT10. Through cell functional experiments, orthotopic osteosarcoma models, organoids model, and PDX models, it was demonstrated that Paliperidone and AG-401 can inhibit the malignant progression of osteosarcoma. Conclusions: NAT10 was highly expressed in osteosarcoma and associated with patient prognosis. Through ac4C modification, NAT10 regulated the synthesis of asparagine mediated by ATF4/ASNS, providing materials for protein and nucleotide synthesis in tumor cells, thus promoting the malignant progression of osteosarcoma. Paliperidone and AG-401 were identified as potential NAT10 inhibitors and targeting NAT10 could be a promosing strategy in osteosarcoma treatment.
Therapeutically targeting the CALR/CD47 pathway in MPN to reactivate natural immunosurveillance mechanisms within the body to enhance treatment outcomes.
Authors: Ciro Roberto Rinaldi, Matthew Simmonds, Claire Walker, Niloofar Amirian, Moradalden Musleh, Anya Megan Squires
Journal: Journal of Clinical Oncology (2024)

170 Background: MPNs are a group of related myeloid malignancies characterized by alterations in mature blood cell production/bone marrow environment and have a tendency to evolve into acute myeloid leukaemia. We demonstrated that CD47 blockade in combination with ruxolitinib, increased CALR expression enhancing cytotoxicity in vitro, promoting enhanced neoplastic clone clearance. With this study we describe a potential methodology for assessing effect of new compounds or combinations and the impact of modulating the immunoresponse upon myeloid malignant clones. Methods: Utilising HEL 92.1.7 and SET-2 cells (JAK2 mutated), Marimo cells (CALR mutated) and K562 cell line models; we will incubate with routine therapies (hydroxyurea, anagrelide, ruxolitinib) in combination with a range of anti-CD47 compounds (Anti-CD47 monocloncal antibodies, BET-1 inhibitors, SIRa inhibitor) and will determine the impact upon CD47 and CALR cell surface expression via flow cytometry. Monocyte derived macrophage (MDM) will be produced through Phorbol 12-myristate 13-acetate (PMA) differentiation of a monocytic Thp-1 cell line. Expression of macrophage cell surface markers (CD11b, CD14), as well as intracellular markers (CD68), will be detected by flow cytometry. MDM will then be polarized to either a pro-inflammatory M1, or anti-inflammatory M2 phenotype, with lipopolysaccharide/interferon gamma or interleukins 4 and 13, respectively. Co-culture experiments will then be undertaken to determine how different anti-CD47 therapy combination impact macrophage polarization and destruction of MPN cell lines. Results: We predict that CALR/CD47 levels on each cell line subtype will respond differently highlighting heterogeneity within MPNs and demonstrating the clear need for a more personalised immunotherapy approach. Alterations in JAK/STAT pathway and BET inhibition may hinder macrophage polarisation to the anti-tumorigenic M1 macrophage phenotype. We theorise that indirect co-culture of M1 macrophage with MPN suspension cells under different treatment modalities will enhance MPN cell death and decrease CD47 expression to a greater level than that which we expect to see in M2 polarised macrophage. We also anticipate that the M2 polarised macrophage, which dominate in the tumour microenvironment as MPN progresses, will fail to phagocytose MPN cells and may not be rescued by novel immunotherapeutics. Conclusions: Our group demonstrated the role of CD47 and CALR expression as a key mechanism and a potential target to enhance presentation of the cancer cell to the immune system, and we believe that understanding the interaction of CD47/CALR – macrophages, will drive new therapeutical approaches able to modulate the immune response and improve patients outcomes, potentially leading to complete MPN clone eradiation and cure.
Use of a novel proteomimetic nanoplatform for simultaneous delivery of antigens with adjuvants to impact tumor growth in multiple tumor models.
Authors: Max Mu Wang
Journal: Journal of Clinical Oncology (2024)

40 Background: Patient-specific cancer vaccines derived from tumor antigen have been explored as a promising therapeutic strategy, however, challenges delivering vaccine components in a coordinated fashion to elicit antitumor responses remain. To overcome these, we utilize a novel nanoplatform called the Protein-Like Polymer (PLP), which allows for sustained and targeted delivery of tumor antigens in conjunction with adjuvants. Methods: PLPs containing peptide antigens were synthesized via ROMP and characterized. A library of compounds with different sidechain linkage chemistries, degrees of polymerization (DP), and inclusion/exclusion of Oligo-ethylene glycol (OEG) were made to determine design rules for immune activation. Cell uptake and functional assays using payload-specific T Cells were conducted. Immunization in three independent tumor models was done to show generalizability. Ability of PLPs to co-deliver adjuvants was tested by electrostatically coupling small molecule STING agonist, 2’3’ cGAMP. Results: Conjugating antigens to the polymer via a cleavable disulfide linkage, which reduces intracellularly in APCs, resulted in increased endosomal localization, higher levels of induced T cell proliferation, cytokine production, and expression of activation markers in CTLs and APCs. Incorporating a diluent amount of OEG side chains reduced enzymatic degradation while increasing immunogenicity and uptake. Additionally, increasing the DP, and therefore the density of antigen side chains, further improved vaccine efficacy and resistance to proteolysis. Antigen-PLP conjugates enhanced dendritic cell activation and T-cell response only when paired with cells from their cognate system, with no activity in immune cells not expressing receptors for the payload demonstrating antigen-specificity. Mice bearing established B16F10, MC38, or TC-1 tumors treated with PLPs containing gp100, adpgk, or E7 respectively all showed increased survival times, reduced tumor burden with corresponding changes in immune cell profiles, and immunological memory upon rechallenge. Impressively, mice treated with STING-PLP complexes had significantly smaller tumors vs control at day 14 (0.038g vs 0.76g; p &lt; 0.0001) and allowed for subcutaneous administration of 2’3’ cGAMP, which traditionally requires intratumoral injection. Studies on the effects of vaccinating with pools of neoantigens multiplexed onto one PLP are ongoing. Conclusions: This work validates the ability of PLPs to overcome major limitations in cancer vaccine development. The modularity of the platform allows for complex nano-architectures including systems capable of delivering challenging compounds, ie small molecule STING agonists, subcutaneously through electrostatic coupling, highlighting its potential to revolutionize cancer vaccinology.
Effect of TTYH3 on cholangiocarcinoma invasion, metastasis and lymph node metastasis through Wnt/β-catenin pathway.
Authors: Yuwei Xie, Shengze Wu, Fangqian Du, Ruiqian Gao, Tingting Wu, Chen Jin, Jingyu Cao, Chengzhan Zhu
Journal: Journal of Clinical Oncology (2024)

57 Background: Cholangiocarcinoma is a malignant tumor originating from the bile duct epithelium. Metastasis is an important factor affecting the prognosis of cholangiocarcinoma. To explore the role and mechanism of calcium-activated chloride channel protein Tweety homolog 3 (TTYH3) in cholangiocarcinoma metastasis. Methods: TTYH3 was overexpressed and knocked down in cholangiocarcinoma cells, and in vitro experiments were performed to clarify the biological function of TTYH3 in cholangiocarcinoma. Experiments on xenograft tumor mice model have shown that TTYH3 promotes tumorigenesis of cholangiocarcinoma cells. Analysis of the relationship between TTYH3 expression and patient prognosis and lymph node metastasis in cholangiocarcinoma tissue specimens. Exosomes were extracted from bile of patients with cholangiocarcinoma and bile duct stones, and the expression of TTYH3 in exosomes was compared. TTYH3 overexpressed exosomes were used to treat endothelial cells, and their function and mechanism in promoting lymphangiogenesis were analyzed. Results: In vitro experiments confirmed that TTYH3 promoted the migration and invasion of cholangiocarcinoma cell line QBC939. In vivo experiments confirmed that TTYH3 promotes the tumorigenesis of cholangiocarcinoma cells. TTYH3 promotes epithelial-to-mesenchymal transition of cholangiocarcinoma cells through the Wnt/β-catenin signaling pathway. TTYH3 promotes cholangiocarcinoma cell self-expression through positive feedback. TTYH3 is highly expressed in cholangiocarcinoma tissues. Patients with high TTYH3 expression have poor prognosis and a high incidence of lymph node metastasis. The TTYH3 protein content of bile exosomes in patients with cholangiocarcinoma is increased, which promotes the invasion and metastasis of cholangiocarcinoma cells, while also promoting lymphangiogenesis and increased permeability. TTYH3 promotes the uptake of exosomes by lymphatic cells and promotes lymphangiogenesis by regulating the influx of calcium ions and chloride ions in lymphatic cells. Conclusions: TTYH3 promotes the invasion and metastasis of cholangiocarcinoma cells through the Wnt/β-catenin signaling pathway, and exosome TTYH3 promotes lymphangiogenesis and lymph node metastasis.