tbuckley/cabot-search huggingface dataset:
Implication of the novel microtubule targeting agent, AUS_001, in pancreatic cancer cellular signaling.
Authors: Marina Koutsioumpa, Herman Lelie, Pony Yu-Ling Lee, Kun-Yuan Lin
Journal: Journal of Clinical Oncology (2025)

748 Background: Pancreatic cancer (PanCa) is considered a major therapeutic challenge due to its poor prognosis, high mortality rate and resistance to most therapies, underlining the need for new treatment approaches. Our previous investigations revealed that the prenylated hydroxy-stilbene, AUS_001, inhibits β-tubulin polymerization via its unique binding to the colchicine site of tubulin. A cell-based profiling platform identified sensitivity of 12 out of 13 PanCa lines to AUS_001 with a median concentration causing 50% growth inhibition of 0.227µM. The goal of the current study was to elucidate the signaling activity and cellular responses following treatment with AUS_001 and explore the prospect of the latter in PanCa treatment. Methods: A series of functional and biochemical assays were performed to delineate the effect of AUS_001 on the growth, colony formation ability, invasive capacity and oxidative status of PanCa cells. Tumor growth was evaluated in PANC-1 implanted CB.17 SCID mice and MIA PaCa-2 implanted nude mice upon intraperitoneal administration of AUS_001 once weekly. Metabolic profiling was carried out using the Seahorse XF Analyzer. RNA silencing and adenovirus-mediated overexpression of the Dominant-Negative Mutant of c-Jun were employed to explore the link of c-Jun activation and AUS_001-induced cytotoxicity. Results: The potential of AUS_001 to disrupt PanCa cell functions was established in vitro and in vivo . Viability and compromised membrane integrity were multiplexed and resulted in half maximal effective concentration agreement indicating drug-induced cytotoxicity. AUS_001-treated cells underwent apoptosis followed by secondary necrosis, exerted diminished anchorage-independent growth and metastatic potential in vitro . Importantly, tumor growth was significantly reduced in PanCa murine xenograft models by AUS_001 as a monotherapy. Pretreatment with N-acetyl-l-cysteine did not alter cellular sensitivity to AUS_001, suggesting that the time-dependent induction of reactive oxygen species upon AUS_001 exposure is not the primary cause of cytotoxicity. Notably, the oxygen consumption rate, extracellular acidification rate and function of all mitochondrial complexes (I-IV) of live MIA PaCa_2 cells were significantly impaired in both glucose- and galactose-containing media 48h after AUS_001 administration. Integration of transcriptomic and proteomic data originating from AUS_001-challenged cells uncovered the dramatic induction of c-Jun and FosB stress responders. Further studies demonstrated that c-Jun transcriptional activation acts as a partial mediator of AUS_001-induced cytotoxicity. Conclusions: Collectively, our findings provide critical insights into the molecular events triggered by AUS_001 in PanCa cells and serve as supporting data for future exploration of AUS_001 as a novel PanCa therapeutic agent.
Toxicology and clinical protocol development of DUO-207: An ultrasmall nanomedicine co-delivering gemcitabine and paclitaxel for the treatment of metastatic pancreatic cancer.
Authors: Katherine Eichinger, Sam Rothstein, Victoria G. Manax, Lindsay Berry
Journal: Journal of Clinical Oncology (2025)

749 Background: The long-term survival rates for metastatic pancreatic cancer have remained stubbornly low for decades. Most pancreatic cancers have dense, fibrous stroma tissue surrounding their tumors, which contributes to tumor growth and acts as a barrier to many therapies. Nanomedicines have been developed for use in oncology to reduce toxicity and improve efficacy, but a majority are too large (&gt; 100nm) to effectively penetrate dense stroma. DUO-207 is a novel ultrasmall nanomedicine (~ 20nm) composed of copolymer-conjugated gemcitabine that encapsulates paclitaxel. Numerous preclinical efficacy models have demonstrated DUO-207’s ability to penetrate and accumulate in tumor tissue. Here we describe results from toxicology studies performed in canines that assisted in the design of a phase 1b clinical trial using the continual reassessment method (CRM). Methods: A single cycle, bridging toxicology study of DUO-207 with a recovery period was performed in canines. Animal equivalent doses of nano-albumin-bound paclitaxel (nAb-PTX) and gemcitabine were administered as the standard of care (SoC) comparator. Blood was analyzed for hematological toxicity, biomarkers of major organ toxicity, and drug toxicokinetics. Toxicology results from DUO-207 were then used in a statistical model to explore plausible scenarios for clinical dose escalation. Results: DUO-207 treated canines demonstrated improved clinical observations compared to SoC. As expected, hematologic toxicities occurred in a dose dependent fashion in the DUO-207 group but no hepato- or nephrotoxicity was noted. Based on these data, a phase 1b CRM design has been developed with 90% power to detect the maximum tolerated dose in key scenarios with an average sample size of 11 patients per group. Conclusions: In summary, DUO-207 is a novel, ultrasmall nanomedicine that can co-deliver paclitaxel and gemcitabine in a single intravenous infusion to treat stroma-rich cancers. DUO-207 demonstrated dose dependent hematological toxicities but improved clinical observations compared to SoC and lacked signals of renal and hepatoxicity. Toxicokinetic data from canines was used in a statistical model to determine patient numbers for phase 1b dosing using the CRM. Duo Oncology will conduct its clinical trial in 2025.
The incidence and risk of cardiovascular events among gastroesophageal cancer patients receiving immune-checkpoint inhibitors.
Authors: Furkan Bahar, Betul Ibis, Sena Cakir Colak, Akshat Banga, Junmin Song, Kuan-Yu Chi, Yu Chang, Cho Han Chiang
Journal: Journal of Clinical Oncology (2025)

374 Background: Immune checkpoint inhibitors (ICIs) have been associated with an increased risk of cardiovascular events. However, these data were mostly derived from patients with lung cancer or melanoma. To date, there is limited data describing the incidence and risk of cardiovascular adverse events associated with the use of ICIs among patients with gastroesophageal cancers. Methods: We performed a propensity score-matched cohort study using the TriNetX Analytics Network database, which comprises de-identified data from over 120 participating institutions and 101 million individuals. We defined the ICI cohort as patients who received any of the ICIs and chemotherapy. We defined the control cohort as patients who received only chemotherapy but not an ICI. We matched 2 cohorts based on predetermined variables including age, race, gastroesophageal cancer-directed therapy, cardiovascular agents, underlying comorbidities, and surgical history. The outcomes were myocarditis, pericarditis, myocardial infarction, heart failure, cerebral ischemia/infarction, atrial fibrillation, conduction disorders, and venous thromboembolism (VTE). All outcomes were captured within 1-year of the start of ICI therapy and identified using the International Classification of Diseases (ICD)-10 codes. Results: We identified 2005 patients who received ICI and chemotherapy (ICI cohort) and 14048 patients who received chemotherapy only (control cohort). We matched 952 patients in 2 cohorts. The mean age was 62.8 ± 12.7 and 62.8 ± 12.3 for the ICI and chemotherapy cohorts, respectively. We observed a significant increase in cardiovascular events in the ICI cohort compared to the chemotherapy cohort. In particular, the risk of myocarditis (4 cases in the ICI cohort and no cases in the chemotherapy cohort), pericarditis (Hazard ratio (HR), 2.53 [95% CI: 1.52-4.19]), conduction disorders (HR, 1.64 [95% CI: 1.04-2.59]), and VTE (HR, 1.56 [95% CI: 1.17-2.10]) were higher in the ICI cohort than the chemotherapy cohort. Conclusions: The use of ICI was associated with an increased risk of cardiovascular events, particularly myocarditis, pericarditis, conduction disorders, and VTE among patients with gastroesophageal cancer. Further studies are needed to identify strategies to stratify patients at high risk of developing ICI-associated cardiovascular events. Outcomes ICI + Chemotherapy(ICI cohort) Chemotherapy only(Control cohort) Hazard ratio(95% CI) Cases At risk patients Cases At risk patients Myocarditis 4 952 0 952 - Pericarditis 52 952 21 952 2.53 (1.52-4.19) Myocardial infarction 18 952 12 952 1.49 (0.72-3.11) Cerebral Ischemia/Infarction 22 952 17 952 1.30 (0.69-2.44) Atrial fibrillation 56 952 48 952 1.16 (0.79-1.71) Conduction disorder 49 952 30 952 1.64 (1.04-2.59) Venous thromboembolism 112 952 73 952 1.56 (1.16-2.10) Heart Failure 118 952 114 952 1.04 (0.80-1.34)
Retrospective analysis of HAIP therapy in metastatic colorectal cancer: Efficacy, safety, and prognostic factors.
Authors: Matthew Sawyer, Nilesh Verma, Amy Little Jones, Anna Moscowitz, Timothy J. Brown, Radhika Kainthla, Salwan Al Matar, Syed Mohammad Ali Kazmi
Journal: Journal of Clinical Oncology (2025)

126 Background: HAIP (hepatic arterial infusion pump) therapy is a promising intervention for metastatic colorectal cancer (mCRC) with liver metastases, addressing significant challenges in management and prognosis. It offers targeted treatment to maximize efficacy while minimizing systemic toxicity. We present a retrospective analysis of patients with metastatic colorectal adenocarcinoma treated with HAIP therapy at an academic center and safety net hospital. Methods: Patients with mCRC and hepatic metastasis who received at least one HAIP floxuridine (FUDR) cycle from 2013 to 2023 were included. Baseline data, including demographics, tumor characteristics, and treatment history, were collected pre-HAIP. The main outcome was overall survival (OS) post-pump placement, with secondary outcomes being real-world progression-free survival (rwPFS) and HAIP-related complications. Results: In total, 88 patients were evaluated for inclusion, of whom 63 met inclusion criteria and were included for analysis. The median age of included patients was 46 years (interquartile range (IQR) 41-57) and 54% were male. Prior to HAIP, 38 (60%) of patients received one line of systemic therapy, while 18 (29%) had two. The median OS from HAIP placement was 28.0 months (95% CI 21.9-NR) and median rwPFS was 11.2 months (95% CI 7.1-16.1). Baseline bilirubin, KRAS mutant status, and CEA were associated with OS in the multivariate cox model. The most common complication from HAIP placement was hematoma (n=4, 6.3%), followed by pump infection (n=2, 3.2%). Grade 3 toxicities from FUDR infusion were infrequent, involving alkaline phosphatase (n=6), AST or ALT elevation (n=3), bilirubin increase (n=2), and platelet count decrease (n=1). Conclusions: HAIP treatment is associated with durable responses and few complications, making it well-tolerated by patients. For individuals with colorectal cancer and hepatic metastases, HAIP chemotherapy using FUDR presents a viable and effective treatment option, potentially improving overall outcomes and quality of life. Further prospective and randomized work may establish the role for HAIP in mCRC with liver metastases.
Real-world assessment of MDM2 amplification and survival among patients with advanced or metastatic biliary tract cancer in the United States.
Authors: Renuka Iyer, Kathryn Evans, Alyssa B Klein, Divya Shridharmuthy, Stephen Stanhope, Beth Nordstrom, Vaibhav Sahai
Journal: Journal of Clinical Oncology (2025)

544 Background: There are few real-world studies on biliary tract cancer (BTC), especially those related to biomarkers for potential novel targeted therapies. The aim of this study was to provide additional information of the prevalence of biomarkers, treatment patterns, and clinical outcomes of patients with BTC in the US, with a focus on patients with mouse double minute 2 homolog ( MDM2 ) amplified, tumor protein 53 wild type (TP53 WT) BTC. Methods: This was an observational cohort study using deidentified data from the Flatiron Health-Foundation Medicine BTC Clinico-Genomic Database, which included patients with advanced or metastatic BTC who underwent genomic analysis and received antineoplastic therapy in the US between January 1, 2013 and June 30, 2023. Three cohorts were created: 1) 1L+ cohort that included all patients that initiated 1 st line (1L) therapy during the study period, 2) 2L+ cohort that included all patients that initiated 2 nd line (2L) therapy during the study period, and 3) MDM2 amp + TP53 WT cohort that included patients in the 1L+ cohort that had MDM2 amplified (≥ 8 copies), TP53 WT. The prevalence of select biomarkers was assessed, as well as treatment patterns, and clinical outcomes including time to next therapy (TTNT) and overall survival (OS). Results: A total of 1,548 patients met the selection criteria for the 1L+ cohort, of whom, 875 initiated 2L therapy (2L+ cohort), and 55 had MDM2 amplified, TP53 WT BTC ( MDM2 amp + TP53 WT cohort). In the 1L+ cohort, 66 (4.3%) had MDM2 amplification and 872 (56.3%) had TP53 WT. The most common treatment regimens were cisplatin/gemcitabine (44.5%, 50.7%, 41.8% of patients in the 1L+, 2L+, and MDM2 amp + TP53 WT cohorts, respectively) at 1L and FOLFOX (12.9%, 22.9%, 16.4% of patients, respectively) at 2L. The median (95% CI) OS from start of 1L was 10.7 (10.0 – 11.3) months for the 1L+ cohort and 11.9 (10.4 – 17.7) months for the MDM2 amp + TP53 WT cohort. The median OS from the start of 2L was 8.0 (7.2 – 8.8) months for 2L+ cohort. Furthermore, the median TTNT was similar between 1L+ cohort and MDM2 amp + TP53 WT cohort, 5.3 (5.0 – 5.7) and 4.8 (4.0 – 7.6) months, respectively. The median TTNT from the start of 2L in the 2L+ cohort was 4.3 (3.8 – 4.6) months. We will present co-mutation data in MDM2 amp + TP53 WT cohort. Conclusions: The MDM2 amplification and TP53 WT status does not appear to be a prognostic biomarker in advanced/metastatic BTC with similar median TTNT and OS in the 1L+ and MDM2 amp + TP53 WT cohorts. Targeted treatments may help improve OS among these patients and thus further research into these treatments and how they impact survival is warranted.
Integrating pharmacogenetic testing in the management of gastrointestinal cancers.
Authors: Darshana Patil, Navin Srivastava, Atreyee Saha, Stefan Schuster, Sachin Apurwa, Dadasaheb B Akolkar, Vineet Datta, Rajan Datar
Journal: Journal of Clinical Oncology (2025)

113 Background: Gastrointestinal cancers are among the most prevalent malignancies, often treated with chemotherapeutic agents whose efficacy and toxicity can be influenced by genetic variations. Pharmacogenetic testing for key metabolic genes, including DPYD, UGT1A1, and G6PD, can guide personalized treatment approaches. Methods: We analyzed samples from 3,519 individuals for genotyping using semiconductor-based Next-Generation Sequencing (NGS) technology. High-quality genomic DNA was extracted and subjected to target enrichment via high multiplex PCR amplification using an NGS panel targeting variants of key metabolic genes, including DPYD, G6PD, and UGT1A1. Results: For the DPYD gene, 96% of patients were normal metabolizers. However, 4% intermediate and 0.17% individuals had poor metabolizer status. Poor metabolizers possess homozygous non-functional alleles, leading to complete dihydropyrimidine dehydrogenase (DPD) deficiency and increased toxicity risk with fluoropyrimidine drugs like 5-fluorouracil (5-FU), Capecitabine, and Tegafur. Patients with certain homozygous or compound heterozygous variants in the DPYD gene are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions due to fluorouracil. 5-FU is not recommended for use in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete absence of DPD activity. Intermediate metabolizers exhibit approximately 50% reduced DPD activity, necessitating a 50% reduction in starting doses followed by careful titration based on toxicity. UGT1A1 analysis revealed 46% normal, 42% intermediate, and 12% poor metabolizers, affecting Irinotecan metabolism and toxicity risks. Poor metabolizers show decreased UGT1A1 activity, resulting in reduced clearance of Irinotecan and increased risk of dose-limiting toxicities. These patients are also at higher risk for neutropenia, diarrhea, and asthenia, requiring starting dose adjustments. Additionally, they may experience elevated hyperbilirubinemia with treatments like Regorafenib. Recognizing G6PD deficiency in GI cancers can prevent serious complications and ensure safer treatment options. G6PD testing indicated that 98% were homozygous wildtype, 2% heterozygous, and 0.31% homozygous/hemizygous deficient. Patients with homozygous/hemizygous deficient genotype may be at increased risk for drug-induced hemolysis, particularly when treated with Dabrafenib. Conclusions: These findings highlight the therapeutic significance of incorporating genetic testing into clinical practice to tailor treatments, enhance drug efficacy, and minimize side effects in GI cancer management. By integrating pharmacogenetic insights, the safety and effectiveness of therapies can be significantly improved, ultimately leading to better patient care in GI oncology.
Real-world clinical outcomes of locally advanced unresectable and de-novo metastatic pancreatic ductal adenocarcinoma: A multicenter retrospective study from Saudi Arabia.
Authors: Mohamed Aseafan, Ali Hussain Alfakeeh, Emad M Tashkandi, Mervat Mahrous, Mohamed Alghamdi, Bader Alshamsan, Marwan R. Al-hajeili, Safwan Bakhsh, Kanan Alshammari, Ali Alqahtani, Shouki Bazarbashi
Journal: Journal of Clinical Oncology (2025)

691 Background: Pancreatic ductal adenocarcinoma (PDAC) has dismal clinical outcomes, even with existing treatment regimens. This study evaluates the clinical characteristics and outcomes of patients with locally advanced unresectable or de-novo metastatic PDAC in Saudi Arabia to provide real-world data that can be compared to international benchmarks. Methods: This is a retrospective, multicenter study. Patients diagnosed with unresectable locally advanced or de-novo metastatic PDAC between January 2015 and November 2023 were included. Data were collected from 10 oncology centers across Saudi Arabia. Patient characteristics, treatment regimens, and clinical outcomes, including progression-free survival (PFS) and overall survival (OS), were analyzed using univariate and multivariate analyses. Results: A total of 350 patients were identified, with a median age of 60 years at time of diagnosis, 63% of patients presenting with multiple metastatic sites, primarily in the liver (66.3%). Among patients tested, 7.1% had deficient mismatch repair (d-MMR), and 5.8% harbored BRCA mutations. FOLFIRINOX was the most common first-line treatment (55.1%), followed by gemcitabine plus nab-paclitaxel (15.1%). The median PFS for first-line treatment was 5.3 months, with FOLFIRINOX achieving the longest PFS (6.5 months). The median OS was 10.34 months for the entire cohort, with better survival outcomes observed in patients receiving FOLFIRINOX (12.3 months). Independent prognostic factors for PFS and OS included performance status, type of first-line regimen, and neutrophil-lymphocyte ratio (NLR). Conclusions: This real-world study confirms that clinical outcomes for locally advanced unresectable and metastatic PDAC in Saudi Arabia are consistent with international data, with trend of FOLFIRINOX showing superior outcomes over gemcitabine-based regimens. However, both treatments reflect the persistent poor prognosis of PDAC, underscoring the need for novel therapeutic strategies. Further research is warranted to optimize treatment selection and improve survival outcomes in this population.
Incidence trends, demographic disparities, and survival outcomes of gastrointestinal malignancies in young adults: A focus on stomach and pancreatic cancers.
Authors: Shivani Modi, Claudia M Dourado, Malay Rathod
Journal: Journal of Clinical Oncology (2025)

339 Background: The incidence of gastrointestinal (GI) cancers has been rising among younger populations. While prior research has highlighted the increasing incidence of colorectal cancer (CRC) in adolescents and young adults (AYA), defined as individuals aged 15-39, there is less focus on non-CRC GI malignancies, such as stomach and pancreatic cancers, within this age group. This study aims to further elucidate the incidence, mortality, and demographic disparities in the AYA population for stomach and pancreatic cancers compared to older populations (&gt;50 years old). Methods: Data was extracted from the SEER database spanning from 2000 to 2020. Demographic, clinical, and secondary cancer characteristics were summarized across the sample, stratified by cancer type. Overall survival (OS) and disease-specific survival (DSS) were analyzed using the Kaplan-Meier method, with comparisons performed via the log-rank test. Univariate and multivariate analyses were conducted to identify predictors of survival outcomes. Results: We identified 19,983 AYA patients diagnosed with non-CRC GI malignancies (including esophageal, stomach, small intestine, anal, hepatobiliary, and pancreatic cancers) between 2000 and 2020. Among these patients, the majority were male (58%), White (47%), and resided in metropolitan areas (90%). The median age at diagnosis was 38 years. Pancreatic cancer was 20% more common in the AYA group compared to those over 50 years old (12%), while stomach cancer was also more prevalent in the AYA group (27% vs. 17%). Survival outcomes were significantly better in the AYA group, with a median OS of 24 months compared to 9 months in the older population, and a median DSS of 52 months versus 13 months (p&lt;0.001). Predictors of worse OS and DSS included male sex, African American race, income below $45,000/year, lack of surgical intervention, and delayed initiation of treatment. Conclusions: The incidence of stomach and pancreatic cancers is notably higher in the AYA population compared to older adults, with AYA patients demonstrating better overall and disease-specific survival outcomes. However, certain demographic factors, such as male sex, African American race, and lower income, are associated with worse survival, underscoring the need for targeted interventions to address these disparities. Early diagnosis and timely treatment are critical to improving outcomes in this younger population.