tbuckley/cabot-search huggingface dataset:
Discovery of HDM2010, a highly potent PTPN2 inhibitor for immunotherapy.
Authors: Ke Li, Chen Min, Zhiping Zhang, Dongzhou Liu
Journal: Journal of Clinical Oncology (2024)

e15021 Background: Protein tyrosine phosphatase non-receptor type 2 (PTPN2), a negative regulator of JAK–STAT pathways that plays a crucial role in the immune system, has been identified as a promising target for immunotherapy. Genetic deletion of PTPN2 in either tumor cells or host immune cells promotes the anti-tumor immunity. In addition, PTPN2 inhibitors, alone or in combination with anti-PD1 therapy, significantly reduced tumor growth and enhanced survival in several subcutaneous tumour models. These findings demonstrate that PTPN2 inhibitors may have clinical benefits for immunotherapy-resistant tumors. Herein, the discovery of a series of novel PTPN2 inhibitors and their implications for immunotherapy are reported. Methods: We have successfully developed a series of small molecule inhibitors that specifically target PTPN2/N1. Molecular design was based on a novel backbone and incorporating both structure-based drug design (SBDD) and computational chemistry techniques. To evaluate the efficacy of our inhibitors, PTPN2 phosphatase activity was monitored using the small-molecule substrate DiFMUP in a fluorescence assay format in vitro. Tumor cells were treated with IFNγ and the cell viability was measured. Pharmacokinetic studies were conducted in mice, with serial blood samples analyzed by liquid chromatography−mass spectrometry (LC−MS)/MS. Pharmacokinetic parameters were calculated by noncompartmental analysis. Results: Based on the co-crystal structure of this target reported and multiple previous research projects, we have designed a multitude of novel compounds with the employment of computer-aided drug design (CADD) and scaffold hopping. Through a comprehensive evaluation of the in vitro and in vivo parameters, we have identified a series of compounds displaying potent PTPN2 inhibition (IC 50 &lt; 10 nM). Moreover, the compounds displayed remarkable efficacy in killing tumor cells to IFNγ treatment (IC 50 &lt; 100 nM). Artificial intelligence was utilized to conduct assessment and prediction of ADME properties, improving the drug-ability including permeability and physicochemical properties. Currently, a series of compounds demonstrating outstanding potency and good pharmacokinetic profiles, with lower hERG blockage (hERG IC 50 &gt; 30 µM), were synthesized and characterized. Among these hit compounds, a leading compound with PTPN2 IC 50 = 1.1 nM and tumor cells IC 50 = 79.5 nM was identified for further optimization and evaluation. Conclusions: We reported our work on discovering HDM2010, in which a series of potent PTPN2 inhibitors with prominent PK and safety profile were synthesized and characterized. Further optimization including in vivo experiments will lead to a preclinical candidate (PCC) selection.
Preliminary results from a first-in-human trial of AMT-116, a topoisomerase I inhibitor containing antibody-drug conjugate (ADC), in patients with advanced solid tumors.
Authors: Jim Coward, Ganessan Kichenadasse, John J. Park, Sagun Parakh, Gary Edward Richardson, Mark Voskoboynik, John D. Powderly, Zhengbo Song, Shutong Liu, Yaling Huang, Shu-Hui Liu, Xun Meng
Journal: Journal of Clinical Oncology (2024)

e15010 Background: CD44v9 is a tumor-associated antigen highly expressed in various solid tumor types including head and neck, lung, esophageal, pancreatic, colorectal, breast, bladder, hepatic, cervical, and gastric cancers. AMT-116 is a first-in-class antibody-drug conjugate (ADC) targeting CD44v9, by conjugating a novel topoisomerase I inhibitor, belotecan derivative named KL610023 (Sichuan Kelun-Biotech) to a humanized anti-CD44v9 immunoglobulin G1 (IgG1) antibody via a hydrolysable linker with an average drug-to-antibody ratio of 7-8. Methods: This is an ongoing first-in-human, non-randomized, open-label, multicenter, Phase 1 study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of AMT-116 in patients (pts) with advanced solid tumors, unselected for target expression. Pts received escalating doses of AMT-116 Q2W starting from 1.5 mg/kg guided by the Bayesian logistic regression model (BLRM) following escalation with overdose control (EWOC) principle. Results: As of Feb 1, 2024, eight pts (4 pts at 1.5 mg/kg, 3 pts at 3 mg/kg and 1 pt at 5 mg/kg) have been treated in Australia and pts at 1.5 mg/kg and 3 mg/kg completed the 28-day dose-limiting toxicity (DLT) evaluation period. No DLT events were observed, and the maximum tolerated dose (MTD) has not been reached. Treatment related adverse events (TRAEs) were reported in 5 pts out of 8. The most common TRAEs were fatigue (n=3) and nausea (n=3). Only one Grade 3 TRAE (leukopenia) was reported. There were no Grade 4 or 5 TRAEs or treatment-related SAEs. Seven pts have completed at least one post-treatment tumor assessment. At dose level 3 mg/kg, one pt with anal squamous cell carcinoma achieved unconfirmed PR with a 31% tumor shrinkage and one pt with hepatocellular carcinoma achieved SD with a 23% tumor shrinkage from baseline. Subject enrollment in 5 mg/kg is underway. Conclusions: These preliminary data indicate that AMT-116 is well tolerated at the first two dose levels in patients with heavily pretreated advanced solid tumors. Dose escalation is ongoing. Clinical trial information: NCT05725291 .
Advancing cancer MRD monitoring through tumor whole-genome informed, duplex ctDNA sequencing.
Authors: Won-Chul Lee, Jong-Yeon Shin, Chang Woo Kim, Minsuk Kwon, Sangmoon Lee, Erin Connolly-Strong, Brian Baek-Lok Oh, Young Seok Ju
Journal: Journal of Clinical Oncology (2024)

e15044 Background: Circulating tumor DNA (ctDNA), a cell-free DNA (cfDNA) present in the plasma of cancer patients, originates from cancer cells and serves as a crucial biomarker during cancer treatment. Despite its importance, the current limit of detection (LoD) of conventional ctDNA assays is suboptimal (0.01%; 10 -4 ) for detecting ctDNA from microscopic residual and recurrent cancer tissues. To address this, we integrated two cutting-edge techniques: whole-genome sequencing (WGS) of primary cancer tissue (a mutation capture step) and duplex DNA sequencing-based cfDNA sequencing (mutation recapture steps). Methods: Thirteen colorectal cancer patients participated in this study. Primary tumor tissues and matched normal blood tissues were collected for WGS in the mutation capture step, while plasma samples for cfDNA sequencing in the mutation recapture steps were obtained just prior to colorectal cancer surgery and 1-month post-surgery follow-up. Tumor DNA and germline DNA were analyzed using CancerVision, a CLIA-certified clinical-grade cancer WGS platform, in the mutation capture step. In the mutation recapture steps, somatically acquired mutations from the previous step were tracked in cfDNA samples using the Concatenating Original Duplex for Error Correction (CODEC) technique, a duplex DNA sequencing technique that examines both Watson and Crick strands of double-stranded DNA molecules to discern true mutations from sequencing noise. Results: The median WGS depth of tumor and germline tissues was 40x and 20x, respectively. The mean depth of cfDNA WGS with CODEC was 25x, with a median duplex sequencing rate of 70%. Overall, 4,828-301,434 somatic base substitutions (SBSs) per sample were discovered in the capture step. Four of the thirteen tumors exhibited hypermutator characteristics with microsatellite instability features. The CODEC technique demonstrated excellent capability in tracing cancer-specific mutations in cfDNA sequencing with a technical sequencing error rate of 4 x 10 -7 , defining the maximum technical LoD, which is 250-fold lower errors than conventional sequencing. In our sample cohort, tumor fractions in cfDNA sequencing were robustly estimated from 0.001% (10 -5 ), below the LoD of conventional MRD methods. Conclusions: Our integration of tumor-WGS-informed duplex cfDNA sequencing methods significantly enhances the sensitivity of sequencing-based MRD assays, achieving a technical LoD limit of 10 -7 for detecting ctDNA in cancer patients. These approaches represent a breakthrough in monitoring MRD in real-world cancer patients.
Type III collagen pro-peptides (PRO-C3) as a proposed prognostic biomarker of risk of survival outcomes in clinical trials of patients with solid tumors.
Authors: Nicholas Willumsen, Neel Ingemann Nissen, Morten Asser Karsdal
Journal: Journal of Clinical Oncology (2024)

e15050 Background: Tumor fibrosis is essential for defining outcome of patients with various solid tumors. The major pathological signature of tumor fibrosis is a fibrous connective tissue formed by proliferation and activation of fibroblasts and increased synthesis and deposition of fibrillar collagens (type III collagen) leading to immune exclusion and high interstitial pressure in the tumor microenvironment. Recently, the USA FDA issued a Letter of Support to encourage the further study and use of the biomarker PRO-C3 (type III collagen pro-peptides) as a proposed prognostic biomarker of risk of survival outcomes in clinical trials of patients with solid tumors ( https://www.fda.gov/media/169332/download ). Here we summarize the published data that supports the use of PRO-C3 as a prognostic biomarker that reflects fibrotic activity in the TME. Methods: A PubMed search was used to find studies with PRO-C3, cancer and survival outcome. The hazard ratios (HR) with 95% confidence intervals (95%CI) calculated from univariate cox regression analyses for overall survival (OS) outcomes were collected for where patients were dichotomized based on their pre-treatment PRO-C3 levels and results summarized across indications including breast cancer, pancreas cancer, colorectal cancer, hepatocellular carcinoma, biliary tract cancer and malignant melanoma. Results: Nine studies were retrieved. Table 1 shows the studies with HR and 95%CI for OS after dividing patients into high and low PRO-C3. Various cutoffs were used in the different indications. In all studies, high levels of PRO-C3 were predictive of poor OS with an increased risk of dying ranging 48%-337%. Conclusions: Type III Collagen pro-peptides (PRO-C3) are prognostic for poor OS across indications. These data suggest that quantifying tumor fibrosis is important for prognostication of patients with cancer and that this can be assessed non-invasively in serum or plasma across indications. [Table: see text]
Increased risk of hyperglycemia in patients with advanced urothelial cancer treated with enfortumab vedotin: A systematic review and meta-analysis.
Authors: Ryan Cheng, Montek Boparai, Shenhong Wu
Journal: Journal of Clinical Oncology (2024)

e15001 Background: Enfortumab vedotin (EV), an antibody-drug conjugate targeting anti-nectin-4, which is highly expressed in urothelial cancers, has emerged as an effective therapy in the management of previously treated advanced urothelial cancer. urothelial cancer. Severe hyperglycemia has been recognized as an unexpectedly adverse effect, and can lead to discontinuation of EV or fatal event. To assess the overall risk of hyperglycemia associated with the use of EV, a systematic review and meta-analysis of published clinical trials was performed. Methods: A comprehensive review through 2023 of PubMed and American Society of Clinical Oncology conferences was performed to identify relevant clinical trials and abstracts. Eligible studies were clinical trials of patients with urothelial cancer receiving EV at the standard dose with data on hyperglycemia available. Incidence rates, relative risks, and 95% confidence intervals were calculated using random-effects or fixed-effects models. Results: Our search culminated in the inclusion of 1,150 patients from four trials, with 859 of them receiving EV. The summary incidences for all-grade and high-grade hyperglycemia were 9.9% (95% CI: 7.8-12.5%) and 6.0% (95% CI: 4.6-7.8%) respectively. Patients treated with EV had an increased risk of developing hyperglycemia in comparison with chemotherapy with an RR of 19.66 (95% CI: 2.66-145.55, P=0.004) for all-grade and 26.54 (95% CI: 1.59-444.48, P=0.023). In comparison with single-agent EV, its combination with pembrolizumab did not significantly increase the risk of all-grade hyperglycemia (P=0.148). Conclusions: EV is associated with a significantly increased risk of all-grade and high-grade hyperglycemia.
The role of folate receptor-positive circulating tumor cells in the prognosis analysis of esophageal squamous cell carcinomas.
Authors: Qiang Zhou, Qiao He, Yongtao Han, Dongsheng Wang, Xuefeng Leng
Journal: Journal of Clinical Oncology (2024)

e15026 Background: Patients with ESCC always be discovered at an advanced stage and have a poor prognosis. The Circulating Tumor Cells (CTCs) were investigated for use as a biomarker for diagnosis and assessing the effectiveness of treatment. This study aims to investigate the predictive value of the baseline level of folate receptor-positive circulating tumor cells (FR+CTCs) for disease-free survival (DFS) and overall survival (OS) in patients with esophageal squamous cell carcinomas (ESCC). Methods: A retrospective observational study was conducted from January 2018 to February 2021 and followed up to June 2022 with ESCC patients in Sichuan Cancer Hospital &amp; Institute Esophageal Cancer Case Management Database (SCCH-ECCM Database). Three ml of peripheral blood were obtained from each patient, and FR+CTCs were quantified using ligand-targeted polymerase chain reaction (LT-PCR). Traditional techniques were employed to measure other serum markers. Clinicopathological features were collected from the hospital medical record system, and survival data (DFS and OS) were obtained by outpatient follow-up or phone calls. The correlation between clinicopathological characteristics, survival data, and FR + CTCs was analyzed. Cox regression analysis was used to assess risk factors that might have an impact on DFS and OS. Results: Analysis was conducted on 123 ESCC patients. Of them, 86% were men, and their average age was 62.0. FR+CTCs did not significantly correlate with patient age, sex, albumin, pre-albumin, C-reactive protein (CRP), ferritin, tumor size, grade of differentiation, metastasis of lymph nodes, perineural invasion/vessel invasion, or tumor size (all P&gt;0.05). But for DFS (HR 3.29; 95% CI 1.52-7.15, P=0.003) and OS (HR 3.85; 95% CI 1.53-9.72, P=0.004), preoperative FR+CTCs were an independent prognostic factor. Patients with post-operative FR+CTCs ≥17.42 FU/3ml had a substantially shorter DFS than patients with FR+CTCs &lt; 17.42 FU/3ml (P=0.0012). Patients with FR+CTCs ≥17.42 FU/3ml had a shorter OS than patients with FR+CTCs &lt;17.42 FU/3ml, although the difference was not statistically significant (P=0.51). Conclusions: Patients with ESCC who have elevated FR+CTCs typically have a poorer prognosis. We anticipate that FR+CTCs will be able to guide clinical treatment, assess patient prognosis, and monitor cancer recurrence and metastasis in real-time.
HER2 expression-independent antitumor effect of trastuzumab deruxtecan (T-DXd) on pediatric solid tumors.
Authors: Nao Takasugi, Takao Deguchi, Motohiro Kato
Journal: Journal of Clinical Oncology (2024)

e15016 Background: Treatment of pediatric solid tumors shows limited improvement even with intensification of conventional chemotherapy, suggesting novel approaches such as targeted therapies are needed. Trastuzumab Deruxtecan (T-DXd), a HER2-targeting antibody–drug conjugate, exhibits significant anti-cancer activity in breast cancers with a broad range of HER2 expression. T-DXd might be a promising agent for refractory or relapsed pediatric solid tumors, but its efficacy in pediatric tumors needs to be studied. Methods: Anti-cancer efficacy of T-DXd and its payload DXd were assessed in vitro by utilizing our in-house cancer cell line models. Cytotoxicity assays were performed for 60 pediatric cancer cell lines, including Neuroblastoma (NB) = 25, Ewing sarcoma / Ewing sarcoma family of tumors (EWS / EWSFT) = 17, Rhabdomyosarcoma (RMS) = 10, Others (Osteosarcoma, Brain tumor, Wilms tumor, Hepatoblastoma, and Malignant rhabdoid tumor (MRT) = 8, and 2 breast cancer cell lines expressing HER2 high or low (IHC score 2+ or 0) as positive or low control, respectively. We analyzed HER2 expression on the cell surface by flow cytometry and evaluated relative mean fluorescence intensity (MFI) values. Results: In the flow cytometric assessment, pediatric cancer cell lines showed smaller median MFI of 1.40 (0.67 - 2.71) compared with breast cancer control with HER2 high expression (33.77). The median MFI of each cell lines were 0.94 in NB, 1.76 in EWS / EWSFT, 1.42 in RMS, 1.52 in other pediatric cancers. Although low or no expression of HER2, certain inhibitory activities to the cell growth were observed for T-DXd against a part of NB, EWS, RMS and MRT cell lines, with the minimum IC 50 values of 14.5 nM, 6.5 nM, 10.2 nM, 8.1 nM, respectively. In NB, EWS and RMS, a wide range of sensitivity to T-DXd were seen among different cell lines in the same disease. Most of cell lines showed high sensitivity to DXd (Median IC 50 value: 0.90 nM [0.08 - 6.46 nM]), but, among them, cell lines with lower sensitivity to DXd tend to show less sensitivity to T-DXd. There was no clear correlation between sensitivity to T-DXd and HER2 expression among pediatric cancer cell lines, indicating that other mechanism such as intrinsic sensitivity to payload might affect antitumor activity of T-DXd. Conclusions: T-DXd exhibited antitumor efficacy against pediatric solid tumors in vitro irrespective of HER2 expression. Our results suggest that T-DXd might be an alternative therapy for pediatric solid tumor cases for whom conventional chemotherapies and other targeting therapies are ineffective. This study supports further investigation for T-DXd in this population.
Thioredoxin 1 in blood as a monitoring biomarker for patients with breast cancer post-treatment.
Authors: Young Kim, Hye Mi Ko, Ye Ri Lee, Kyoung Hoon Suh, Je Ryong Kim, Jin Sun Lee
Journal: Journal of Clinical Oncology (2024)

e15041 Background: The spatial and temporal heterogeneity of tumors in breast cancer pose challenges in precision oncology. Although breast imaging during screening has increased tumor detection and reduced mortality rates, it is limited in tracking minimal residual disease after surgery. Consequently, there is a need for liquid biopsy with easy longitudinal sampling to track real-time changes in tumor characteristics during treatment. Existing biomarkers (CA15-3 and CEA) for post-treatment monitoring are unsatisfactory. This study explores the clinical validity and stability of thioredoxin1 (Trx1) in a 54-month longitudinal study, reflecting tumor characteristics during treatment. Methods: Approved by IRB from Chungnam National University Hospital (IRB: 2021-02-003). Fourteen out of the initial 20 BC patients were finally enrolled because pre-surgery samples for the 6 patients excluded were missing. A total of 116 sera were collected before and after surgery at intervals from 6 to 54 months. After isolating the serum, an immunoassay was performed to measure the level of serum Trx1 using the DxMe® BC kit (E&amp;S Healthcare). CA15-3 and CEA levels were measured in paired samples and collected from medical records. The results were retrospectively analyzed along with clinical information, and the profile of Trx1 level change was analyzed for each individual. Results: The blood Trx1 levels in pre-operation BC patients were 20.68±4.44 U/ml (±SD). From 6 months’ post-operation to the 54th month, blood Trx1 levels in patients were consistently low, averaging 5.43±3.34 U/ml (p &lt; 0.0001 compared to pre-op). In contrast, levels of CEA and CA15-3 did not change significantly before and after surgery. The pre-op and post-op AUC for Trx1, CA15-3, and CEA were 0.998 (95% CI: 0.941 to 1.000), 0.599 (95% CI: 0.482 to 0.709), and 0.550 (95% CI: 0.433 to 0.663), respectively. There was no significant difference in the decreasing profile of Trx1 levels over 54 months between different treatment methods. While existing a microscopic difference according to BC characteristics, all post-op values were already below the cut-off value. Regardless of treatment, Trx1 levels decreased to those of normal healthy women after surgery. There were no recurring cases to compare over 54 months. Conclusions: The results of this 54-month post-operation tracking observation revealed a rapid decrease in Trx1 levels in the blood after surgery, which remained consistently downregulated without a statistical association with pathological findings. This suggests that Trx1 is related to the presence of tumor masses rather than the pathological characteristics of the tumor. It is likely that if any treatment causes the removal and suppression of BC, the level of Trx1 is kept low. Besides its already reported ability to detect BC in blood, Trx1 levels have the potential to serve as a monitoring biomarker in the management of BC patients after treatment.
Enhancing liquid biopsy potential: The impact of the R<sup>3</sup>CE 3D culture platform.
Authors: Yi-Chun Wu, Mark D. Pegram, Wen-Hung Kuo, Hsu-Huan Chou, Yen-Jang Huang, Jia-Yang Chen, Hao-Wei Han, Yu Zong, Chia-Chun Chen, Ying-Chih Chang
Journal: Journal of Clinical Oncology (2024)

e15032 Background: The ability to expand and preserve tumor cells ex vivo has been an important aspect of cancer research, offering insights into tumor biology and the advancement of personalized therapies. However, expanding rare tumor cells, such as circulating tumor cells (CTCs) and needle biopsies, remains challenging. Methods: We present the R 3 CE (Reproducible, Rapid, Rare Cell Expansion) 3D culture platform, a novel system that enhances the conventional tissue culture plate with a coating of polyelectrolyte multilayer. This approach can reliably cultivate various tumor specimens, including CTCs, needle biopsies, and surgical tissues, into tumor spheroids. Results: Our platform achieved over a 90% success rate (n = 305) in producing tumor spheroids with uniform size and preserved mutational profiles across diverse cancer types such as breast, lung, and colorectal cancers. In comparison to traditional tissue biopsies, liquid biopsies are less invasive and contain CTCs that offer a more comprehensive representation of heterogeneous tumor cell populations. We show that the proliferative capacity of cultured CTCs, rather than the initial CTC counts, have a strong correlation with lung adenocarcinoma prognosis (n = 124), highlighting the clinical potential of the R 3 CE platform (1). Furthermore, we have successfully employed cultured CTCs for drug screening for various cancers (breast cancer, cholangiocarcinoma, colon cancer, EMPD, gastric cancer, hepatoma, lung cancer, mucosal melanoma, pancreatic cancer, and urinary bladder cancer, n = 80), resulting in measurement of ex vivo response to chemotherapy and targeted drugs. For instance, R 3 CE-cultured CTCs have been used in predicting response to neoadjuvant chemotherapeutic drugs in breast cancer, as evidenced by an ROC curve analysis with an AUC of 0.963, 100% sensitivity, 87.5% specificity, P=0.02. Also in an exploratory analysis of immunotherapy efficacy, involving co-culture of R 3 CE-cultured CTCs (n = 6) and tumor tissue-derived organoids (n = 6) with immune cells such as CAR-T and autologous NK cells, has shown promising outcomes for selected cancers. Conclusions: The R 3 CE 3D culture platform represents a potentially transformative tool above and beyond CTC enumeration, significantly enhancing 1) the expansion of tumor cells ex vivo and, more importantly, informing phenotypic and genotypic characterization of CTCs, thereby holding promise for advancing cancer care and treatment efficacy. 1. Che et al., Lung Cancer, 2023; 178:198-205.