tbuckley/cabot-search huggingface dataset:
Bariatric intervention improves metabolic dysfunction-associated steatohepatitis in patients with obesity: A systematic review and meta-analysis
Authors: Juchul Hwang, Hyeyoung Hwang, Hyunjae Shin, Bo Hyun Kim, Seong Hee Kang, Jeong-Ju Yoo, Mi Young Choi, Dong eun Lee, Dae Won Jun, Yuri Cho
Journal: Clinical and Molecular Hepatology (2024)

Background/Aims: Bariatric intervention has been reported to be an effective way to improve metabolic dysfunction-associated steatotic liver disease (MASLD) in obese individuals. The current systemic review aimed to assess the changes in MRI-determined hepatic proton density fat fraction (MRI-PDFF) and nonalcoholic fatty liver disease activity score (NAS) after bariatric surgery or intragastric balloon/gastric banding in MASLD patients with obesity.Methods: We searched various databases including PubMed, OVID Medline, EMBASE, and Cochrane Library. Primary outcomes were the changes in intrahepatic fat on MRI-PDFF and histologic features of metabolic dysfunction-associated steatohepatitis (MASH).Results: Thirty studies with a total of 3,134 patients were selected for meta-analysis. Bariatric intervention significantly reduced BMI (ratio of means, 0.79) and showed 72% reduction of intrahepatic fat on MRI-PDFF at 6 months after bariatric intervention (ratio of means, 0.28). Eight studies revealed that NAS was reduced by 60% at 3–6 months compared to baseline, 40% at 12–24 months, and 50% at 36–60 months. Nineteen studies revealed that the proportion of patients with steatosis decreased by 44% at 3–6 months, 37% at 12–24 months, and 29% at 36–60 months; lobular inflammation by 36% at 12–24 months and 51% at 36–60 months; ballooning degeneration by 38% at 12–24 months; significant fibrosis (≥F2) by 18% at 12–24 months and by 17% at 36–60 months after intervention.Conclusions: Bariatric intervention significantly improved MRI-PDFF and histologic features of MASH in patients with obesity. Bariatric intervention might be the effective alternative treatment option for patients with MASLD who do not respond to lifestyle modification or medical treatment.
Mithramycin and its analogs: Molecular features and antitumor action
Authors: José Portugal
Journal: Pharmacology & Therapeutics (2024)

The antitumor antibiotic mithramycin A (MTA) binds to G/C-rich DNA sequences in the presence of dications. MTA inhibits transcription regulated by the Sp1 transcription factor, often enhanced during tumor development. It shows antitumor activity, but its clinical use was discontinued due to toxic side effects. However, recent observations have led to its use being reconsidered. The MTA biosynthetic pathways have been modified to produce mithramycin analogs (mithralogs) that encompass lower toxicity and improved pharmacological activity. Some mithralogs reduce gene expression in human ovarian and prostate tumors, among other types of cancer. They down-regulate gene expression in various cellular processes, including Sp1-responsive genes that control tumor development. Moreover, MTA and several mithralogs, such as EC-8042 (DIG-MSK) and EC-8105, effectively treat Ewing sarcoma by inhibiting transcription controlled by the oncogenic EWS-FLI1 transcription factor.
Plasma circulating tumor DNA in patients with cutaneous squamous cell carcinoma: Initial experience.
Authors: Cong Fan, Karina Brito, Jessica Lyn Geiger, Tamara A. Sussman, Shauna Campbell, Natalie L. Silver, Daniel McGrail, Jamie Ku, Eric Lamarre, Emrullah Yilmaz, Shlomo A. Koyfman
Journal: Journal of Clinical Oncology (2024)

e15034 Background: Circulating tumor DNA (ctDNA) has emerged as a potential noninvasive biomarker to assess tumor burden throughout cancer treatment and to aid in clinical decision-making. However, data on the use of ctDNA in cutaneous squamous cell carcinoma (cSCC) is currently lacking. In this study, we report our first experience with ctDNA in patients with cSCC. Methods: In this IRB-approved study at a tertiary care center, an initial cohort of patients with intermediate to high-risk cSCC had tissue and plasma sent for ctDNA analysis using Natera®’s proprietary bioinformatics pipeline. This cohort included 21 patients treated from 2023 to the present. Initial tissue samples were obtained through biopsy (i.e., excisional, punch, or shave), Mohs surgery, or surgical resection. Some patients had additional plasma sample(s) drawn later during or after the treatment course. Patients either received a “positive,” “positive below analytical range,” or “negative” result or had ‘insufficient sample’ to receive a result based on Natera®’s analysis. All patients were treated curatively with surgical resection with or without adjuvant radiation as per the standard of care. The assessment of gross disease was determined based on whether the patient had disease present on imaging or physical exam at the time of the plasma draw. A comparison of ctDNA results and the presence of gross disease was done using Fisher’s exact test. Results: Of the samples submitted for Natera® ctDNA analysis, 18/21 had sufficient tissue for analysis of tumor DNA. All 3 tumors with insufficient tissue were from biopsies (6/9 sufficient), while 12/12 of those from Mohs or surgical resection had sufficient tissue. The average tumor volume in these patients with insufficient samples for tumor analysis was relatively low (0.35 cm 3 ) compared to those that resulted (17-30 cm 3 ). 7/9 (78%) patients with gross disease had a positive ctDNA result, which was significantly greater than those with no gross disease (1/9 patients, 11%) (p = 0.004). Three patients in our cohort with an initially positive ctDNA result had multiple plasma draws, with all having a later draw demonstrating a negative ctDNA result after having surgery and/or radiation. Conclusions: Circulating tumor DNA is a reliable marker for patients with cSCC with a high tumor burden and is feasible in those with adequate tissue. However, in patients where it is only possible to obtain a small volume of tumor tissue and/or low tumor burden, ctDNA may be a less reliable biomarker. [Table: see text]
Disitamab vedotin combined with fruquintinib in patients with HER2-expressing or HER2 mutation/amplified metastatic colorectal cancer refractory to at least two standard regimens: A prospective, exploratory, single-arm study.
Authors: Hui Xu, Jin Peng, Han Wu, Lei Yang, Wenbo Wang, You Wang, Xin Long, Linli He, Fuxiang Zhou
Journal: Journal of Clinical Oncology (2024)

e15003 Background: Human epidermal receptor growth factor 2 (HER2) -expressing or amplified has been identified in 2-6% of patients with stage 3/4 colorectal cancer (CRC), and is associated with poor prognosis, however there are currently no approved HER2-targeted therapies for CRC in China. Herein, we aimed to study the antitumor activity and safety of Disitamab vedotin (RC48), a novel humanized anti-HER2 antibody conjugated to MMAE via a cleavable linker, combined with fruquintinib in patients with HER2-expressing or -amplified metastatic colorectal cancer. Methods: In this prospective, exploratory, single-arm study, patients diagnosed pathologically with mCRC, 18-75 years old harboring HER2 expression or HER2 mutation/amplification, and received at least two lines of treatment. HER2 expression was defined as a score of 1+, 2+ or 3+ on immunohistochemical [IHC] analysis, or mutation/amplification by NGS. Patients received RC48 2.5mg/kg intravenously every 2 weeks. Meanwhile, fruquintinib 3mg was administered orally once daily on days until disease progression, death, intolerable toxicity, withdrawal of consent. The primary endpoint was objective response rate (ORR) per RECIST v1.1; the secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: A total of 12 patients were enrolled from November 25, 2022 to June 6, 2023. The results of baseline molecular profiling revealed 4 with IHC 1+, 4 with IHC 2+, 2 with IHC 3+, and 2 with HER2 amplification. In the metastatic setting, patients had received a median of 4 (range, 3-6) lines of prior systemic therapy. In the per-protocol set, the investigator-assessed ORR was 18.2% (2/11) and DCR was 90.9% (10/11). Median PFS was 5.5 months (95% CI: 2.7-8.2) and the median OS was 12.3 months (95% CI: 5.3-19.3). During the study process, 11 (91.7%) patients experienced adverse events (AEs), among which, 4 (33.3%) experienced grade 3 treatment-related AEs (TRAEs). The most common grade 3 TRAEs were neutropenia (25%), leukopenia (16.7%), and hypertension (8.3%). Moreover, no grade 4 or 5 TRAEs were observed. In addition, 4 (33.3%) patients experienced a dose reduction. No patients experienced dose interruption or discontinuation due to TRAEs. Conclusions: RC48 combined with fruquintinib has shown promising efficacy and a manageable safety profile for HER2-expressing or -amplified mCRC patients refractory to at least two standard treatment failures. Clinical trial information: NCT05661357 .
BC3195, a novel ADC targeting CDH3: Preliminary results of a first-in-human phase I study in patients with advanced solid malignancies.
Authors: Hua-Jun Chen, Sheng Wang, Rong Su, Xu-Feng Li, En-Tzu Tang, Yi-Wei Wang, Yong-Jiang Hei, Yi-Long Wu
Journal: Journal of Clinical Oncology (2024)

e15008 Background: Cadherin-3 (CDH3), a calcium-dependent cell-cell adhesion glycoprotein, is overexpressed on lung, breast, ovarian, colorectal, pancreatic, head and neck and other malignancies, but with negligible expression on nonmalignant tissues, and associated with cancer aggressiveness, invasiveness, and poor prognosis. BC3195 is known as the only antibody drug conjugate (ADC) in clinical stage, targeting CDH3 with payload of monomethyl auristatin E (MMAE). Methods: A phase I, open-label, first in human study to evaluate the safety, tolerability, PK, and preliminary antitumor activity of BC3195 is being performed in subjects with advanced solid malignancies. Disease assessments are performed every 6 weeks using RECIST v1.1. BC3195 is administered as 1 hour (h) IV infusion every 3 weeks. An evaluation of seven dose levels is planned: 0.3, 0.6, 1.2, 2.4, 3.0 and 3.6 mg/kg with a BOIN design guiding dose escalation. Results: Up to January 1 st , 2024, nine patients (median age, 59; male, 56%) have been enrolled and treated with BC3195, with 3 patients each in the 0.3, 0.6 and 1.2 mg/kg dose cohorts. No DLT was observed across all the 3 dose cohorts. Treatment emergent adverse events (TEAEs) occurring in ≥3 patients included: aspartate aminotransferase increased (5/9, 55.6%), conjugated bilirubin increased (5/9, 55.6%), triglycerides increased (4/9, 44%), uric acid increased (3/9, 33.3%), heart rate increased (3/9, 33%), and hypoalbuminemia (5/9, 55.6%), cough (4/9, 44.4%), hyponatraemia (4/9, 44.4%), anemia (4/9, 44.4%), asthenia (3/9, 33.3%), rash (3/9, 33.3%), vomiting (3/9, 33.3%) and back pain (3/9, 33.3%). Two subjects experienced ≥ Grade 3 TEAEs unrelated to study drug. Six subjects were evaluable for tumor assessment, and 3 subjects (3/6, 50%) show stable disease (SD) as the best response (2 subjects with target lesion reduction). PK results demonstrated that exposure for the ADC and total antibody (TA) increased with dose, the relationship between AUC 0-last and dose was greater than dose-proportional, while C max was linear. Free MMAE was highest at the 1.2 mg/kg dose level. Median T max values for ADC and TA were 1 h (end of infusion), and median T max for free MMAE was 25-169 h. In addition, elimination t 1/2 values averaged 27-48 h, 31-68 h and 63-76 h for the ADC, TA, and MMAE, respectively. Conclusions: BC3195 exhibited favorable safety profile and PK characteristics up to 1.2mg/kg. Given BC31095’s safety and PK behavior, as well as preliminary activity at the 0.6 mg/kg dose level, patient enrollment at higher dose levels is ongoing. Clinical trial information: NCT05957471 .
Effect of DeltaRex-G ± DeltaRex-G Plus (an FDA-approved drug) on advanced chemoresistant pancreatic cancer, sarcoma, and breast cancer.
Authors: Neal Shiv Chawla, Samantha Jeffrey, Nadezhda Omelchenko, Rheanna Carter, Anmol Dia Agarwal, Ishrat Buhyian, William H. Isacoff, Michael Morse, William Swaney, Sant P. Chawla, Frederick L. Hall, Erlinda Maria Gordon
Journal: Journal of Clinical Oncology (2024)

e15086 Background: Expanded access for DeltaRex-G, a tumor targeted retrovector encoding a CCNG1 inhibitor, is being studied for advanced cancers. Methods: 137 archived tumor specimens were analyzed with AI RNA sequencing to identify CCNG1 expression levels, reported as: Low = 17%, Medium-low = 17%-49%, Medium-high = 50%-83%, High = 83%. Nine patients with advanced solid malignancies, whose CCNG1 levels were identified, received DeltaRex-G (2-3 x 10e11 cfu/dose one to three times a week), either without an FDA-approved drug, or with an FDA-approved drug (“DeltaRex-G Plus”). Overall survival, duration of treatment, and responses were evaluated. Results: All analyzed tumors showed enhanced CCNG1 expression. Thirty (22%) tumors exhibited High CCNG1 expression, 48 (35%) showed Medium-High CCNG1 expression, 53 (39%) displayed Medium-Low CCNG1 expression, and six (4%) had Low CCNG1 expression. One hundred (73%) patients had metastatic disease, and 37 (27%) had localized disease. There was no correlation between CCNG1 expression and disease stage. Four patients with advanced pancreatic cancer (n = 1), Stage 1 HR+Her2+ invasive breast cancer (n = 1), Stage 1 triple negative breast cancer (n = 1), and squamous cell carcinoma of skin (n = 1), received DeltaRex-G alone or DeltaRex-G Plus between 2008 and 2021 and are alive 15, 3, 2.5, and 2.5 years since treatment initiation, respectively. Retrospective analysis of their respective tumors showed CCNG1 expression levels of 24%, 23%, 74%, and 40%. Three of the patients are in sustained remission and the patient with squamous cell carcinoma had a partial response. Of the five patients currently being treated with DeltaRex-G Plus: one patient with advanced breast cancer had a partial response (n = 1), one patient with advanced pancreatic cancer (n = 1) and three patients with soft tissue sarcoma (n = 3) had stable disease. Four of five patients had previously progressed with standard doses of chemotherapy. All patients are alive from 11 to 22 weeks since treatment initiation. No serious treatment-related adverse events have been reported. Conclusions: Taken together, the data shows that (1) 100% of 137 tumors tested have enhanced CCNG1 expression, further reinforcing the 2021 FDA-CBER authorization for use of DeltaRex-Plus, and (2) DeltaRex-G Plus is a promising therapy for advanced pancreatic cancer, sarcoma, and breast cancer. Randomized Phase 2/3 studies are warranted to confirm the efficacy and safety of DeltaRex-G Plus. Clinical trial information: NCT04091295 .
YB-800, a monoclonal antibody targeting the human neuronal pentraxin receptor (NPTXR), as a potential candidate for the design of a first in class antibody drug conjugate (ADC) as novel therapeutic intervention in gastro-intestinal cancers.
Authors: Michel Janicot, Gunther Wennemuth, Mykola Lyndin, Janine Moyer, Peter Schiemann
Journal: Journal of Clinical Oncology (2024)

e15022 Background: The human neuronal pentraxin receptor (NPTXR) gene encodes a type II transmembrane protein that functions as a trans-synaptic organizer and anchors neuronal pentraxin complexes to plasma membranes. Beside a subset of neuronal cells (Hippocampus and Cerebral Cortex), expression of NPTXR is not detected in all other tissues [ The Human Protein Atlas database]. In recent studies [Kanda et al. (2020) Mol. Cancer. doi: 10.1186/s12943-020-01251-0], transcriptome and bioinformatics analysis of gastric cancer (GC) tissues from patients with or without metastasis have revealed that NPTXR expression was associated with disease progression. NPTXR expression was also correlated negatively with survival in GC patients. It appears that NPTXR does not have a major physiological function; e.g., NPTXR −/− mice showed no abnormalities in reproduction, development, metabolism, or motor function. NPTXR is expressed in a number of GI cancers, i.e., gastric, esophageal, colorectal, pancreatic, bladder, liver, as well as breast and thyroid cancer. YB-800 is a fully humanized monoclonal antibody against NPTXR (identified by in silico analysis). Methods: The present studies were conducted to provide a rationale for the design of a YB-800-based antibody drug conjugate (ADC) for therapeutic intervention in oncology. Hence, YB-800 binding to and internalization in selected tumor cells, as well as immunohistochemistry (IHC) in tumor biopsies, were evaluated. Results: Taken together experimental data confirm that: (i) YB-800 binds to a new target (NPTXR) on selected tumor cells; confirmed by FACS analysis; (ii) IHC analysis in tumor samples demonstrates specific immunoreaction in bladder, gastric, prostate, hepatocellular carcinoma, colorectal cancer and cervical cancer, but not in adjacent healthy tissues; and (iii) once YB-800 binds to NPTXR, the conjugate is internalized in selected tumor cells in a time-dependent manner. Conclusions: In conclusion, YB-800 represents a first in class ADC candidate that could be used as novel treatment for gastro-intestinal cancers. Hence, as initial proof of concept, tesirine (DNA intercalating agent) and deruxtecan (topoisomerase I inhibitor) containing protease-sensitive linkers were coupled to YB-800 by stochastic maleimide conjugations to interchain cysteines. Initial results with YB-800-based ADCs will be discussed.
Use of integrated multi-omics analysis to determine antitumor efficacy of donafenib in combination with FADS2 inhibition in hepatocellular carcinoma.
Authors: Hui Li, Di Wu, Yafeng Dai, Song Gao, Jianhai Guo, Pengjun Zhang, Fuxin Kou, Shaoxing Liu, Aiwei Feng, Baojiang Liu, Xu Zhu
Journal: Journal of Clinical Oncology (2024)

e15083 Background: Pharmacotherapy remains a pivotal treatment strategy for patients with advanced hepatocellular carcinoma (HCC). Donafenib, globally the first targeted therapy proven to offer superior survival benefits and safety over sorafenib in a large-scale phase III clinical trial with head-to-head comparison, has been adopted for first-line treatment of advanced HCC. Given the limited basic research on Donafenib both domestically and internationally, and its constrained clinical efficacy, this study aims to explore combination drug therapy for HCC in an attempt to achieve further breakthroughs and enhance the anticancer activity of Donafenib. Methods: A xenograft tumor model in nude mice was established to observe the in vivo antitumor effects of Donafenib. Transcriptomics and proteomics were employed to characterize the gene expression changes in HCC cell lines after Donafenib intervention and to screen for key molecules. A series of assays, including the Cell Counting Kit-8 (CCK8), flow cytometry, scratch assays, Transwell assays, Western blotting, and in vivo tumorigenicity in nude mice, were conducted to determine the impact of the hub gene on the malignant behavior of HCC and to evaluate the combined antitumor effects of the molecular inhibition and Donafenib treatment in HCC. Results: Treatment with Donafenib significantly slowed tumor growth in a nude mouse xenograft model, resulting in a marked reduction in final tumor volumes compared to control subjects. Proteomic analyses post-Donafenib treatment identified FADS2 as the protein with the highest absolute log2 fold change among all differentially expressed proteins in HCC cells. This finding was corroborated by transcriptomic data, which indicated a concurrent downregulation of FADS2 at the mRNA level. Subsequent in vitro and in vivo assays validated the inhibitory effect of FADS2 blockade on the malignant biological behaviors of HCC cells. Importantly, the concomitant administration of Donafenib and the FADS2 inhibitor SC-26196 exhibited a synergistic antitumor action, significantly enhancing therapeutic efficacy in both HCC cell lines and xenografted tumors in nude mice. Conclusions: Combination therapy, a prevalent approach in clinical oncology, has the potential to augment treatment efficacy while simultaneously diminishing toxicity. This study employed an extensive multi-omics approach complemented by a range of both in vitro and in vivo experiments. It revealed that the synergistic use of Donafenib and SC-26196 markedly enhances Donafenib-induced the inhibition of cancer cell growth and metastasis, demonstrating a significant synergistic antitumor effect. These findings from our preclinical investigations may offer a promising new combinational drug regimen for the therapeutic management of HCC patients.
Efficacy and safety of surufatinib combined with EP regimen and serplulimab in first-line treatment of NEC.
Authors: Tao Zhang, Zhenyu Lin, Lei Zhao, Hong Ma, Dejun Zhang, Dandan Yu, Min Jin, Jing Wang, Hongli Liu
Journal: Journal of Clinical Oncology (2024)

e15123 Background: Neuroendocrine carcinomas (NEC) are more challenging than neuroendocrine tumors (NET) due to poor differentiation, aggressive invasion, and early diagnosis difficulties, often marked by local and distant metastasis at diagnosis, leading to poor outcomes. The ORR for NEC as first-line treatment with EP or EC regimens is approximately 30%, highlighting a substantial treatment gap. Surufatinib, a targeted small molecule kinase inhibitor, acts on vascular endothelial growth factor receptors (VEGFR-1/2/3), fibroblast growth factor receptor (FGFR-1), and colony-stimulating factor-1 receptor (CSF-1R). Its efficacy focuses on anti-angiogenesis and vascular normalization, alongside its role in modulating tumor-associated macrophages (TAMs) and boosting the effectiveness of immunotherapy. Methods: This single-arm, open-label, multicenter clinical study comprised a safety run-in (SR) phase and a dose-expansion (DE) phase. In the SR phase, six patients (pts) were planned to be enrolled to receive treatment with surufatinib (250 mg, QD, PO, Q3W) combined with the EP regimen (etoposide injection: 100mg/m 2 , d1-3, IV, Q3W; cisplatin: 25mg/m 2 , d1-3, IV, Q3W) and serplulimab (300mg, d1, IV, Q3W) for a maximum of six cycles, followed by a maintenance phase of surufatinib plus serplulimab until disease progression or other criteria as specified in the protocol. The dose of surufatinib in the DE phase was based on results from the SR phase. The primary endpoints were recommended Phase 2 dose (RP2D) and PFS, while secondary endpoints included ORR, DCR, OS, and safety. Results: As of December 27, 2023, this reports results from the SR phase. Six pts, median age 61.5 years (range 38-70), 66.7% male, all with ECOG performance status 1, were enrolled and completed their first treatment cycle. A majority (83.3%) had gastrointestinal-origin tumors with a median Ki-67% index of 70% (range 30%-90%). During the SR phase, one patient experienced Grade 4 hematologic toxicity (neutropenia and leukopenia) as a dose-limiting toxicity (DLT). Consequently, RP2D of surufatinib was established at 250mg for further research in the DE phase. The most common adverse events were neutropenia (50%), decreased white blood cell count (33.3%), fatigue (33.3%), and diarrhea (33.3%). Among those enrolled in the SR phase, 5 pts underwent at least one assessment of efficacy, yielding an objective response rate (ORR) of 60% and a disease control rate (DCR) of 100%, with the median progression-free survival (mPFS) not yet mature. Conclusions: Surufatinib combined with the EP regimen and serplulimab for NEC as first-line treatment showed notable efficacy and safety. The study established a phase II recommended surufatinib dose of 250mg, alongside immunotherapy and chemotherapy. Clinical trial information: NCT05747729 .