bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular and clinical profiling of gastroenteropancreatic (GEP) neuroendocrine tumors (NETs): An analysis of the Oncology Research Information Exchange Network database.
Authors: Ueberroth Benjamin Edward , Robinson Hannah Ruth , Davis S. Lindsey , Lieu Christopher Hanyoung , Balmaceda Nicole Baranda , Hayden Alexander , Leal Alexis Diane , Kim Sunnie S. , Lentz Robert William , Messersmith Wells A. , Baiyee Toegel Emily
Published: January 2025

669

Background:
The incidence of neuroendocrine tumors (NETs) is approximately 7 per 100,000 persons and rising. By location, tumors in the gastroenteropancreatic (GEP) region, particularly midgut NETs, are most common. The Oncology Research Information Exchange Network (ORIEN) database contains complementary clinical, genomic, and transcriptomic profiling, providing opportunities to identify novel associations between molecular features and clinical outcomes in GEP-NETs.
Methods:
Survival analyses were performed using the log-rank testing, and clinical features were evaluated using Wilcoxon and chi-squared tests. Mutational analyses utilized sample-level enrichments from whole exome sequencing data, and statistical tests were performed using the one-sided Fisher Exact test. Transcriptomic analyses utilized a student’s t-test. We reviewed 240 samples from 226 patients, with 124 of pancreatic origin, 90 small bowel, 16 gastric, and 10 colorectal. All specimens were well-differentiated; further grading information was unavailable on the ORIEN platform. A p-value <0.05 was considered significant.
Results:
Patients with metastatic disease were significantly younger at diagnosis (58 vs. 61 years, p=0.0242) and had significantly higher tumor mutational burden (TMB) (0.48 vs. 0.32 mut/Mb, p=0.001). Among the 100 most common alterations across the entire cohort,
BPTF
(p=0.03) and
PRKCA
(p=0.007) mutations were more prevalent in pancreatic NETs than in other primary sites. The most frequently mutated genes identified included
TTN
(27.7%),
MUC16
(25.1%),
CCDC168
(22.1%),
KIR3DL1
(20%),
TGIF2LX
(20%),
MUC17
(19.1%).
TTN
mutation was significantly associated with higher TMB (p<0.0001). The most common copy number alteration was
MUC3a
amplification (7q22.1) in 61.5% of samples. This amplification was associated with more prolonged overall survival (OS) with a significance of p=0.0501. Patients with NETs harboring a mutation in
CSNK2A2
(p=0.0149),
WDR74
(p=0.0386), or
NCMAP
(p=0.0248) experienced significantly shorter OS compared to the cohort as a whole.
Conclusions:
We report the first clinical, genomic, and transcriptomic analysis of ORIEN GEP-NET cases. These findings create multiple avenues for further investigation and reinforce the value of multi-institutional consortia such as ORIEN in deepening our knowledge of well-differentiated NETs.

Most prevalent mutations in GEP-NETs from ORIEN database.

Mutation
Prevalence (Percentage of Samples)

TTN

27.7%

MUC16

25.1%

CCDC168

22.1%

KIR3DL1

20.0%

TGIF2LX

20.0%

MUC17

19.1%
Real-world clinical outcomes of locally advanced unresectable and de-novo metastatic pancreatic ductal adenocarcinoma: A multicenter retrospective study from Saudi Arabia.
Authors: Aseafan Mohamed , Alfakeeh Ali Hussain , Tashkandi Emad M , Mahrous Mervat , Alghamdi Mohamed , Alshamsan Bader , Al-hajeili Marwan R. , Bakhsh Safwan , Alshammari Kanan , Alqahtani Ali , Bazarbashi Shouki
Published: January 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.
Effect of ketorolac on serum GDF-15 and IL-8 in patients with pancreatic cancer with cachexia.
Authors: Levi Abrahm , Ebia Matthew , Geller Talya , Jorgensen Keith , Zhang Lingbing , Osipov Arsen , Gong Jun , Hendifar Andrew Eugene
Published: January 2025

713

Background:
Cancer cachexia deteriorates the quality of life, chemotherapy tolerance and survivability of pancreatic cancer (PC) patients. Although a prevalent condition affecting PC patients, there are no approved therapies for cachexia and its mechanism of action is poorly understood. Elevated growth differentiation factor 15 (GDF-15), a stress-induced cytokine, has been associated with the pathogenesis of cachexia. Similarly, prior studies have displayed positive correlations between the proinflammatory factor interleukin-8 (IL-8) and PC cachexia. This abstract focuses on the exploratory endpoints (serum GDF-15 and IL-8 levels) of a feasibility trial on ketorolac as a treatment for PC cachexia.
Methods:
Patients took ketorolac 10 mg PO QID for 5 consecutive days, with weights measured on Day 1 (D1) and Day 6 (D6). Serum cytokines were drawn on D1 and D6. IL-8 was measured using a HDF15 assay (Eve Technologies). GDF-15 was measured using a human R-plex GDF-15 assay. Activity (e.g., number of steps) was measured via Fitbit. Differences in weight, activity, GDF-15, and IL-8 were analyzed using two-sample paired t-tests.
Results:
Twenty-nine patients were enrolled, of which 19 were evaluable. Median age was 70, 47.4% (9/19) were female, and 94.7% (18/19) were adherent with ketorolac. Statistically significant increases in both weight per baseline BMI and activity were observed from D1 to D6 (0.0716±0.1079 kg/BMI, p=0.012; 1423±2477 steps, p=0.0221). Of the 19 evaluable patients, 16 patients provided complete D1 and D6 pairs of serum cytokines. From D1 to D6, the mean GDF-15 level decreased by 277.5 pg/mL (p=0.529) and mean IL-8 decreased by 65.13 pg/mL (p=0.103). In all patients who gained weight (n=14), a trend toward reduced IL-8 from D1 to D6 was observed (79.57±39.57 pg/mL, p=0.065). Similarly, for patients who gained ≥ 1-kg from D1 to D6 (n=10), a trend toward reduced GDF-15 was observed (951.2±482.3 pg/mL, p=0.080). Patients with increased activity from D1 to D6 (n=12) had mean reductions of 157.7 pg/mL (p=0.643) and 70.17 pg/mL (p=0.179) in GDF-15 and IL-8, respectively.
Conclusions:
Given the growing literature suggesting associations between inflammatory cytokines and cancer cachexia, it is critical to investigate treatments that may possibly alter cytokine levels. Although our findings suggest that ketorolac aids in weight gain and increased activity, larger sample sizes are needed to determine whether these differences are related to reductions of specific serum cytokines. However, given reductions that trended towards significance for both GDF-15 and IL-8 serum levels within subsets of patients that gained weight on ketorolac, further studies investigating these cytokines are warranted to hopefully provide insight on the mechanistic action of ketorolac in cachexia.
Clinical trial information: NCT05336266
.
Intra-arterial gemcitabine versus intravenous gemcitabine: Pharmacokinetic sub-study of the TIGeR-PaC phase 3 clinical trial.
Authors: Novelli Paula M. , Zureikat Amer H. , Pishvaian Michael J. , Meredith Kenneth Lee , Hatoum Hassan , Zervos Emmanuel E. , Nazemzadeh Reza , Laroia Sandeep , Agah Ramtin
Published: January 2025

719

Background:
Localized, dual balloon catheter-mediated, intra-arterial delivery of gemcitabine (IAG) targeted to tumors/tissue can provide higher local drug potency (1). Furthermore, IAG may result in a decreased systemic drug concentration and associated side effects. In patients with locally advanced pancreatic cancer (LAPC), this approach is currently being tested in the TIGeR-PaC Phase 3 clinical trial. Herein we report the results of a 19-patient pharmacokinetics (PK) sub-study analysis within TIGeR-PaC.
Methods:
PK analyses were performed for a total of 19 participants across 6 TIGeR-PaC study sites; 11 participants received IAG with the RenovoCath dual balloon catheter at 1000 mg/m
2
over 20 minutes and 8 participants received intravenous gemcitabine (IVG) (5 at 1000 mg/m
2
, 2 at 800 mg/m
2
, 1 at 500 mg/m
2
) over 30 minutes. IAG target treatment arteries were either the superior mesenteric artery (SMA) (n=5) or branches of the celiac axis (n=6). At T = -5, 10, 15, 20, 30, 40, 60, and 90 minutes from the onset of infusion, 2 mL of blood was collected in heparinized tubing containing 25 mcg/mL of tetrahydrouridine. Plasma from each sample was frozen and shipped to a reference lab for gemcitabine assays. Maximum plasma drug concentration (C
max
) and the area under the drug plasma concentration curve (AUC) based on the terminal phase were compared between the two groups; for these dose-dependent parameters, only participants who received 1000 mg/m
2
gemcitabine (IAG, N=11; IVG, N=5) were included in the comparison analysis.
Results:
As shown in the table, AUC was significantly lower with IAG (4.99) compared to IVG (9.97) (
P
= 0.019). Peak plasma gemcitabine concentrations were also lower with IAG (12.9 mcg/mL) vs. IVG (14.6 mcg/mL) despite a 50% higher drug concentration during IAG vs. IVG (1000 mg/m
2
infused over 20 minutes vs. 30 minutes, respectively). There was no difference in plasma levels between IAG treatment sites (SMA vs. celiac axis).
Conclusions:
In this analysis, localized, dual-balloon catheter-mediated IAG resulted in decreased systemic levels of gemcitabine compared to IVG. Thus, in addition to providing increased local potency, the IAG approach may also be beneficial in decreasing gemcitabine-related systemic side effects. 1. Farsad K, et al. 2024.
JVIR
35:1043-48 e3.
Clinical trial information: NCT03257033
.

Effects of treatment mode on mean pharmacokinetic parameters for gemcitabine.

PK parameter
IAG Group(N=11)
IVG Group(N=5)

C
max
(mcg/mL), Mean (SE)

12.9 (±2.4)
14.6 (±1.2)

AUC (hr ⋅ mcg/mL), Mean (SE)
4.99 (±0.96)
9.97 (±1.9)

AUC = area under the curve; C
max
= maximum serum concentration; IAG = intra-arterial gemcitabine; IVG = intravenous gemcitabine; PK = pharmacokinetic; SE = standard error.
Influence of time to first therapy (TTFT) variable on survival outcomes of neoadjuvant chemotherapy versus upfront surgery approach in resectable pancreatic ductal adenocarcinoma.
Authors: Almasad Qusai , Sousa Aryanna , Pena Paola , Kwon Steve ,   Roger Williams Cancer Outcomes Research and Equity (RWCORE) Center
Published: January 2025

720

Background:
Evidence demonstrating overall survival (OS) benefit of neoadjuvant chemotherapy (NAC) followed by surgical resection over upfront surgical resection for resectable pancreatic ductal adenocarcinoma (PDAC) has been mixed. The time to first therapy (TTFT) variable has not been studied as a contributing factor.
Methods:
A nationwide retrospective analysis using the National Cancer Database to evaluate patients with clinical stage T1 and T2 PDACs from 2010 to 2020. Cox proportional hazards model was used to evaluate the impact of NAC followed by definitive surgery compared to upfront surgery on OS with and without TTFT.
Results:
Total of 43,196 patients were included – 9,880 patients with clinical stage T1 and 33,316 patients with T2 PDACs. There were increasing trends in the NAC approach from 2.9% in 2010 to over 25% by 2020 and decreasing trends in the upfront surgery approach from 69.35% in 2010 to 31.84% by 2020. There were significant differences in TTFT according to the treatment choice with upfront surgery group having a significantly shorter TTFT – proportion of those receiving first treatment within the 1
st
week was 24.32% in the upfront surgery compared to 4.22% in the NAC group. In the adjusted cox regression without the TTFT variable, there was a 25% higher rate of death in the upfront surgery compared to the NAC group (HR 1.25, 95% CI 1.19 – 1.30). When the adjusted regression was performed with addition of a TTFT interaction term, there was survival disadvantage of upfront surgery approach in patients whose TTFT occurred after 1 week, but not in those with TTFT occurring in less than 1 week (HR 1.01, 95% CI 0.86 - 1.17).
Conclusions:
Our study emphasizes the importance of incorporating TTFT variable when comparing NAC versus upfront surgery approach in PDAC. Future studies comparing NAC to upfront surgery in resectable PDAC should consider incorporating the TTFT variable.
AGITG ASCEND: Randomised, double-blind phase II study of certepetide or placebo added to gemcitabine plus nab-paclitaxel in patients with untreated metastatic pancreatic ductal adenocarcinoma: Initial results.
Authors: Dean Andrew Peter , Sjoquist Katrin , Gebski Val , Karapetis Christos Stelios , Lomma Chris , Burge Matthew E. , Steer Christopher B. , Tebbutt Niall C , Lee Belinda , Jackson Christopher G. C. A. , Day Fiona , Padinharakam Shamsudheen , Murray James , Yip Sonia , Mumford Jan , Siu Derrick HW , Lee Joanna , Gao Yan Ru , Harris Marion , Price Timothy Jay
Published: January 2025

728

Background:
Gemcitabine (GEM) plus nab-paclitaxel (NAB-PAC) is a standard first-line chemotherapy regimen for advanced/metastatic pancreatic ductal adenocarcinoma (PDAC), with median Progression Free Survival (mPFS) and Overall Survival (mOS) of 5.5 & 8.7 in the MPACT trial and 5.6 & 9.2 months (mo) in the NAPOLI 3 trial, respectively. Certepetide (formerly LSTA1 or CEND-1) is a novel cyclic peptide that improves targeted penetration of co-administered drugs into tumor and stroma, leading to potentially increased anti-neoplastic activity. ASCEND is a randomized phase II trial designed to investigate the impact of adding certepetide to GEM/NAB-PAC. (NCT05042128).
Methods:
Eligible participants (pts) with histologically confirmed advanced PDAC and ECOG 0-1 were randomized 2:1 to receive GEM/NAB-PAC plus certepetide (3.2 mg/kg) or placebo (PLA) on days 1, 8, & 15 of a 28-day cycle. Stratification was by age (<65/≥65 years), ECOG (0/1), presence of liver metastasis (Y/N) and trial site. The primary objective was to determine the effect of adding certepetide to GEM/NAB-PAC on PFS. Objective tumor response rate (OTRR), safety and OS were secondary objectives. This non-comparative phase II design targeted a PFS increase of 17% at 6 mo from 47% to 63%. A sample size of 65 patients in the certepetide arm was expected to have 80% power, with 95% confidence to exclude an uninteresting 6-mo PFS rate of 47%.
Results:
95 pts (66 certepetide, 29 PLA) were enrolled between May 2022 to December 2023. 6-mo PFS in the certepetide and PLA groups was 49.0% (95% CI 36.4%, 60.5%) and 40.8 (95% CI 22.6%, 58.3%) respectively, with mPFS of 5.5 mo in both groups. mOS was 12.42 mo for the certepetide and 9.72 mo for the PLA. An OTRR of 38.3% (certepetide) and 26.9% (PLA) was observed. Of note, 4 complete responses were observed in the certepetide group vs. 0 in PLA group. In subjects with ECOG 0, 6 mo PFS was 68.1% (95% CI 48.7%, 81.4%) in the certepetide compared to 36.4% (95% CI 11.2%, 62.7%) in the PLA. Grade ≥3 toxicities were similar in both groups at 16% (certepetide) and 15% (PLA).
Conclusions:
The addition of certepetide is safe and despite showing no improvement in 6-mo PFS, a possible signal of benefit in OS and OTRR, including the 4 complete responses was observed, warranting further investigation. A further cohort of the ASCEND study evaluating the addition of a second dose of certepetide is ongoing.
Clinical trial information: NCT05042128
.
Preliminary result of a phase Ib study: Efficacy and safety of FG-M108 plus gemcitabine/nab-paclitaxel as first-line (1L) treatment in patients with Claudin18.2-positive locally advanced unresectable or metastatic (LA/m) pancreatic cancer.
Authors: Liu Funan , Zhang Yanqiao , Zhang Shu , Gong Jifang , Zhang Miao , Liang Xinjun , Wang Junye , Li Yun , Jin Zhaoyu , Yang Yaping , Ding Guoliang , Tian Chen , Shen Lin
Published: January 2025

729

Background:
FG-M108, an ADCC-enhanced anti-CLDN18.2 monoclonal antibody, showed significant efficacy in 1L treatment of gastric cancer. Herein, we report the safety and efficacy results of FG-M108 in 1L treatment of pancreatic cancer (cohort C2&D2).
Methods:
In this open-label, multicenter phase I/II study patients received FG-M108 (cohort C2: 300mg/m
2
or cohort D2: 600mg/m
2
Q3W) plus gemcitabine (1000mg/m
2
, d1, d8, Q3W) and nab-paclitaxel (125mg/m
2
, d1, d8, Q3W). Eligible patients were those with CLDN18.2 positive (IHC 1+/2+/3+≥10%) previously untreated LA/m pancreatic cancer. The primary endpoint were the incidence of adverse events (AEs) and preliminary clinical efficacy (ORR, DCR, DOR, PFS, and OS).
Results:
As of Sep 5 2024, 50 patients were enrolled and received FG-M108+gemcitabine/nab-paclitaxel treatment (39 patients in cohort C2, 11 patients in cohort D2). The median age was 61 (range 30-72). 47 (94%) patients were with CLDN18.2 moderate-high expression (IHC 2+/3+≥40%). Out of 50 patients, 44 patients had at least one tumor assessment after baseline and included in the efficacy analysis set. The results of ORR and DCR in cohort C2 were 32.4% and 100.0%, while that in cohort D2 were 30.0% and 90.0%, respectively. In cohort C2, the median PFS and median DOR were 6.8 months and 9.8 months, respectively. In the subgroup patients with CLDN18.2 moderate-high expression, the median PFS and median DOR were 7.6 months and 9.8 months, respectively. The median OS has not been reached. FG-M108 related AEs were observed in all patients, with 39 patients (78%) having Grade 3/4 AEs and no FG-M108 related fatal AE was observed. The most common FG-M108 related AEs in cohort C2 & D2 were anemia (56.2% vs 63.6%), nausea (56.4% vs 36.4%), vomiting (48.7% vs 45.5%), and hypoalbuminemia (46.2% vs 54.5%).
Conclusions:
The combined therapy of FG-M108 plus chemotherapy as 1L treatment for patients with CLDN18.2 positive pancreatic cancer was well tolerated with encouraging survival especially in patients with CLDN18.2 moderate-high expression, deserving further investigation.
Clinical trial information: NCT04894825
.
GOBLET study: Results of the safety run-in for first-line metastatic pancreatic ductal adenocarcinoma (PDAC) patients treated with pelareorep + modified FOLFIRINOX +/- atezolizumab.
Authors: Seufferlein Thomas , Arnold Dirk , Burkhart Nina , Reinacher-Schick Anke C. , Ungerechts Guy , Martens Uwe Marc , Chater Jack , Goekkurt Eray , Coffey Matt , Li Ruimei , Heineman Thomas Charles
Published: January 2025

730

Background:
Immunotherapies are effective in only the small subset of metastatic PDAC patients with MSI-H or dMMR tumors. Pelareorep (pela) is a non-genetically modified, intravenously administered reovirus that selectively infects cancer cells. It stimulates the expansion of pre-existing tumor-infiltrating lymphocyte (TIL) clones, and it makes tumors visible to the immune system by upregulating interferon-induced gene expression including PD-L1, CXCL9, CXCL10, and CXCL11. PD-L1 upregulation also provides a basis for potential synergy between pela and immune checkpoint inhibitors. Pela combined with gemcitabine/nab-paclitaxel/atezolizumab showed promising tumor responses in mPDAC. Here, we are assessing the safety and preliminary efficacy of pela + mFOLFIRINOX +/- atezolizumab in a new cohort in the ongoing GOBLET study.
Methods:
GOBLET is a phase 1/2, open-label, Simon two-stage study in patients with advanced or metastatic GI cancers. In this new GOBLET cohort (Cohort 5), patients with newly diagnosed mPDAC are randomized to receive either pela + mFOLFIRINOX or pela + mFOLFIRINOX + atezolizumab. The primary endpoints are safety and objective response rate (ORR). In Stage 1, 15 evaluable patients will be enrolled in each arm. Both arms include a 3-6 patient safety run-in that must be successfully completed prior to opening the study to full enrollment. If pre-specified ORR success criteria are met, one or both arms may be advanced to Stage 2 during which 17 additional evaluable patients/per arm will be enrolled.
Results:
The 3-patient safety run-in for both arms of Cohorts 5 (6 patients total) have been enrolled, and all patients have completed the required 1-month evaluation period. Cohort 5 safety data have been reviewed by the independent Data Safety Monitoring Board (DSMB). The DSMB identified no safety signals attributable to the combination of pela and mFOLFIRINOX +/- atezolizumab and recommended that enrollment into these arms of Cohort 5 continue without modification. Reported adverse events are consistent with the known toxicities of the components of the treatment regimen. Tumor response results are pending.
Conclusions:
The results of the GOBLET Cohort 5 safety run-in indicate that pela can be given safely in combination with mFOLFIRINOX +/- atezolizumab to newly diagnosed mPDAC patients. Safety and efficacy of these combination therapies will continue to be monitored (Eudra-CT: 2020-003996-16).
Clinical trial information: 2020-003996-16
.
XPO1 inhibition as a clinically viable strategy to enhance durability of response to KRAS
G12D
inhibitor in pancreatic ductal adenocarcinoma.
Authors: Al Hallak Mohammed Najeeb , Khan Husain Yar , Aboukameel Amro , Bannoura Sahar , Choucair Khalil , Beal Eliza W. , Tobon Miguel , Beydoun Rafic , Shields Anthony F. , Mohammad Ramzi , Beebe-Dimmer Jennifer Lynn , Philip Philip Agop , Pasche Boris , Azmi Asfar S.
Published: January 2025

736

Background:
The OFF State (GDP bound) KRASG
12D
inhibitor MRTX1133 is currently being evaluated in pancreatic ductal adenocarcinoma (PDAC) patients. Nevertheless, as with other OFF state KRAS
G12C
inhibitors sotorasib and adagrasib, the KRAS
G12D
inhibitor may yield only a modest increase in disease-free survival due to emergence of drug resistance. This underscores the need to identify strategies that can enhance the efficacy of KRAS inhibitors in PDAC. Nuclear protein transport plays an important role in several pro-tumorigenic pathways and has been shown to be a therapeutic vulnerability in KRAS mutant cancers. XPO1 is the major nuclear exporter and plays a pivotal role in shuttling various critical tumor suppressors, genome surveillance proteins, and transcription factors out of the nucleus and is frequently overexpressed in various cancers, including PDAC. In this study, we employed a KRAS
G12D
inhibitor resistant model and evaluated its sensitivity to nuclear exporter protein inhibitor.
Methods:
We examined the cytotoxic and molecular effects of KRAS
G12D
inhibitor MRTX1133 in combination with nuclear transport inhibitor eltanexor in KRAS
G12D
inhibitor resistant models. The preclinical antitumor efficacy of the combination was evaluated in KRAS
G12D
mutant PDAC cell derived xenograft (CDX) subcutaneous and orthotopic models.
Results:
Eltanexor treatment reversed MRTX1133 resistance
in vitro
yielding suppressed proliferation of KRAS
G12D
mutant 2D and 3D cultures of PDAC cell lines and patient derived primary tumors cells. High throughput P-kinome analysis showed suppression of a larger repertoire of MAPK substrates in combination treatment compared to single agent group. Eltanexor and MRTX1133 combination led to reduction in protein expression of KRAS downstream effectors and cell cycle markers. Furthermore, a combined administration of eltanexor and MRTX1133 at sub-optimal doses resulted in remarkable tumor growth inhibition in multiple subcutaneous and orthotopic KRAS
G12D
mutant mice models. Moreover, eltanexor as a maintenance therapy also prevented tumor relapse indicating durability of response in PDAC.
Conclusions:
This is the first study demonstrating that nuclear transport inhibitors can overcome KRAS
G12D
inhibitor MRTX1133 resistance in PDAC cells. This study provides a rationale for combining MRTX1133 with eltanexor for the treatment of PDAC patients with KRAS
G12D
mutant tumors.
Predictive factors for the efficacy of nal-IRI + 5FU/LV therapy in patients previously treated with conventional irinotecan.
Authors: Asai Yasutsugu , Kobayashi Satoshi , Shiraishi Kazumasa , Enomoto Masato , Hamaguchi Tomomi , Tozuka Yuichiro , Fukushima Taito , Tezuka Shun , Ueno Makoto , Furuse Junji
Published: January 2025

737

Background:
There were some reports that nal-IRI + 5FU/LV (NAPOLI) therapy was effective for patients with unresectable pancreatic cancer who had a history of treatment containing conventional irinotecan (IRI) though the others did not. We aimed to investigate the factors that contribute to the effectiveness of NAPOLI therapy for patients who have already received IRI-containing treatment.
Methods:
We retrospectively enrolled the consecutive patients who had previously treated with IRI-containing treatment and started NAPOLI therapy at our hospital between June 2020 and December 2022. We compared the patient backgrounds of patients who achieved CR, PR, or SD according to RECISTv1.1 (effective group) and those who did not (ineffective group). Continuous variables were divided into two groups by the median of the entire population, and factors contributing to the effectiveness of NAPOLI therapy were determined by logistic regression analysis.
Results:
The subjective were 52 patients. The reason for discontinuation of IRI-containing treatment was refractory and intolerant in 45 and 7 patients, respectively. The median age was 65 years. Twenty-three patients (44%) had ECOG PS of 0, and 41 patients (79%) had metastatic disease. The median albumin, CRP, CEA and CA 19-9 was 3.8 g/dL, 0.3 mg/dL, 8.5 ng/mL and 2082 U/mL, respectively. Twenty-one patients (40%) showed SD and they were allocated in the effective group whereas 31 patients were in the ineffective group. Of the 21 patients in the Effective Group, 16 patients(76%) were refractory, while of the 31 patients in the Ineffective Group, 29 patients (94%) were refractory. The factors contributing to disease control were PS of 0 (odds ratio, 5.79; 95% confidence interval, 1.34–25.0), CA 19-9 <1000 U/mL (odds ratio, 5.53; 95% confidence interval, 1.26–24.3), and Alb >3.8 g/dL (odds ratio, 5.19; 95% confidence interval, 1.14–23.7). Age, sex, disease stage, serum level of CRP, and CEA did not affect the effectiveness of NAPOLI therapy.
Conclusions:
Even in patients who have already received IRI treatment, the NAPOLI regimen is expected to be effective in patients with PS of 0, Alb >3.8 g/dL, and CA 19-9 <1000 U/mL.
Galeterone monotherapy in advanced pancreatic ductal adenocarcinoma: Results from a phase two trial.
Authors: Ciner Aaron , Jiang Yixing , Njar Vincent , Weber David J , Carder Margaret
Published: January 2025

744

Background:
Advanced pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with limited treatment options. Dysregulated MAPK and PI3K signaling in PDAC activates the eukaryotic translational initiation complex, promoting cell growth, chemoresistance and metastatic spread (PMID 25593033). Galeterone, a novel steroidal anti-androgen, downregulates critical mediators of this complex including Mnk1/2 and phosphorylated eIF4E, thereby blocking epithelial-to-mesenchymal transition and NF-kB activity. In-vitro, galeterone exhibits anti-tumor activity both alone and in combination with gemcitabine and slows tumor growth in a MiaPaCa-2 xenograft murine model (PMID 28881737). We present results of the monotherapy arm from an ongoing phase two trial evaluating galeterone +/- gemcitabine for patients with advanced PDAC.
Methods:
Patients with locally advanced or metastatic PDAC, an ECOG performance status of 0-2 and adequate organ function, who progressed on two prior lines of systemic therapy were eligible. Galeterone was administered orally at 2550mg daily and gemcitabine intravenously at 1000mg/m
2
weekly for three weeks on 28-day cycle. The primary endpoint was radiographic response rate per RECIST v1.1 and secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. We used a Simon’s optimal two-stage design with a null hypothesis of p
0
=0.05 and one-sided alternative of p
1
=0.20 with an early stopping rule for futility in each arm. Due to poor accrual and no signal of activity, the galeterone alone arm closed after enrollment of four patients.
Results:
Four patients were evaluable for the primary endpoint. Ages ranged from 43 to 68. Two patients were male and two were female. Two patients were white and two were black; one patient was Hispanic/Latino. All patients had ECOG PS of 1. No patients had a radiographic response; the best response was progressive disease (PD). PFS from cycle 1 day 1 ranged from 0.9 – 1.7 months and overall survival between 1.8 – 3.6 months. The only treatment-related adverse events (TRAEs) were grade 1 dizziness and grade 3 fatigue in one patient each. There were no treatment-related serious adverse events. No patients required dose modification or discontinued due to TRAEs.
Conclusions:
Galeterone showed no clinical activity, but with a favorable safety profile, as a single-agent in heavily pre-treated patients with advanced PDAC. Activation of the Mnk-eIF4E axis mediates chemoresistance in PDAC and galeterone may prove more efficacious with gemcitabine. This combination arm is currently open to enrollment.
Clinical trial information: NCT04098081
.

Clinical outcomes with galeterone monotherapy in PDAC.

Pt #
Age
Prior lines of Therapy
Time on Treatment (days)
Best Response
PFS (months)
OS(months)

1
68
4
46
PD
1.5
3.6

2
59
2
54
PD
1.7
3.8

3
55
2
47
PD
1.4
2

4
43
2
35
PD
0.9
1.8
Immunotherapy engagement in pancreatic adenocarcinoma: Provisional results of iLSTA study— Durvalumab, LSTA1 (certepetide), gemcitabine, and nab-paclitaxel for locally advanced pancreatic ductal adenocarcinoma.
Authors: Dean Andrew Peter , Johansson Mikael , Yusoff Ian , Rao Samarth , Sparrow Susan , Kumarasinghe Priyanthi , Navadgi Suresh , Watanabe Yuki , Webber Laurence , Grew Jenny , Fitzgerald Shane , Comito Olivia Rose
Published: January 2025

746

Background:
Pancreatic ductal adenocarcinoma (PDAC) is characterised by a dense, extracellular matrix-rich stroma, which creates a physical barrier against drug penetration. Evidence suggests that the iRGD peptide, LSTA-1, can increase the penetration of anti-cancer drugs to tumours through selective targeting of tumour endothelial cell receptors. Additionally, LSTA-1 administration promotes CD8+ immune cell tumour infiltration, potentially enabling immunotherapy as a treatment modality. iLSTA examined safety, tolerability and effect of the combination.
Methods:
Participants diagnosed with locally advanced PDAC were divided into 3 cohorts in a 1:1:4 ratio. Cohort 1 (n=5) received gemcitabine (1000mg/m
2
), nab-paclitaxel (125mg/m
2
), placebo LSTA-1 (3.2mg/kg) and placebo durvalumab (750mg). Cohort 2 (n=5) received gemcitabine, nab-paclitaxel, active and placebo LSTA-1, and placebo durvalumab. Cohort 3 (n=20) received gemcitabine, nab-paclitaxel, LSTA-1 and durvalumab. Tissue biopsies via endoscopic ultrasound were obtained pre-treatment and between weeks 12 and 16 for analysis of tumour infiltrating lymphocytes (TILs). Patient tumour sizes were assessed every 8 weeks using radiological imaging according to RECIST v1.1, and serum CA19-9 levels were analysed monthly.
Results:
6/17 patients showed significant RECIST partial response after 2 cycles of treatment (5 patients in cohort 3), with the remaining 11 patients exhibiting stable disease. After 4 cycles of treatment, 10/17 patients demonstrated partial response (9 patients in cohort 3). Of the remaining 7 patients, 6 demonstrated stable disease, and 1 patient (cohort 2) exhibited a RECIST complete response. 13/17 patients who completed 4 treatment cycles showed a decrease in CA19-9 levels. 6 patients demonstrated >90% reduction in CA19-9 (5 in cohort 3), with the remaining 7 patients showing a >50% reduction in CA19-9 levels (5 in cohort 3). 12 patients underwent repeat biopsies 12-16 weeks post-treatment to assess TILs. 10 patients showed immune cell infiltration (5% to 50% stroma infiltration), 2 had no tumour found (Cohort 3). The combination was safe with no unexpected toxicities.
Conclusions:
The preliminary results of this study suggest that the combination of gemcitabine and nab-paclitaxel with LSTA-1 and durvalumab is safe and potentially induces tumour infiltrating lymphocytes and RECIST response in locally advanced pancreatic adenocarcinomas.
Clinical trial information: ACTRN12623000223639
.
Toxicology and clinical protocol development of DUO-207: An ultrasmall nanomedicine co-delivering gemcitabine and paclitaxel for the treatment of metastatic pancreatic cancer.
Authors: Eichinger Katherine , Rothstein Sam , Manax Victoria G. , Berry Lindsay
Published: January 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 (> 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.
Clinical and genomic features of the morphological subtypes in advanced pancreatic cancer.
Authors: Flores-Figueroa Eugenia , Fang Yuanchang , Monajemzadeh Maryam , Elqaderi Ayah , Ouellette Tom , Zhang Amy , Jang Gun Ho , Ng Karen , Gallucci Milena , Liu Zhen-Mei , Radulovich Nikolina , Pham Nhu An , Dodd Anna , Wilson Julie , Tsang Erica S , Gallinger Steven , Knox Jennifer J. , O'Kane Grainne M. , Notta Faiyaz , Grant Robert C
Published: January 2025

765

Background:
In resected pancreatic cancer (PDA), morphology from routine histopathology slides provides a rapid inexpensive biomarker that predicts overall survival and correlates with transcriptomic subtypes. In this study, we evaluated clinical and genomic associations of morphological subtypes in resected and advanced disease and validated the consistency of subtypes in patient-derived organoids (PDO) and mouse xenografts (PDXs) during
in vitro
and
in vivo
modeling.
Methods:
Our cohort included PDA tumor tissues from 152 resectable (stage I/II) and 228 advanced cases (Stage III/IV). Hematoxylin and eosin-stained slides were blindly reviewed by two pathologists and classified into subtypes based on Kalimuthu (1). Morphological subtypes were correlated with clinical and genomic data from whole-genome and transcriptome sequencing. Histological preparations from PDOs and PDXs obtained from pancreatic resections and metastases were reviewed using the same criteria.
Results:
Morphological subtypes were significantly associated with clinical patterns. Locally advanced PDA exhibited the highest proportion of glandular tumors. Metastatic tumors were enriched for non-glandular morphologies. The non-glandular morphologies were significantly associated with lower survival rates in both resected and advanced tumors. Furthermore, morphological subtypes were significantly associated with unique genomic alterations. Compared to glandular tumors, non-glandular tumors were associated with increased
KRAS
copy number,
KRAS
imbalances, and polyploid genomes. In advanced settings, glandular and non-glandular tumors mostly exhibited classical and basal-like transcriptional subtypes, respectively. Squamous tumors had the highest mutation burden and the highest proportion of Basal A signature (2). Using differential gene expression, we identified transcriptional signatures of the morphological subtypes. PDOs and PDXs maintained the morphological subtypes, although non-glandular tumors had a lower success rate for PDO establishment.
Conclusions:
Morphological subtypes have distinct clinical and genomic associations across all stages of pancreatic cancer, which can be consistently modeled both
in vitro
and
in vivo
. These results demonstrate that morphological subtyping offers a rapid and biologically-relevant classification of PDA that could be used for drug development and stratification to predict therapy selection. 1. Gut; 69:317-328 (2020). 2. Nat Gen; 52:231-240 (2020).
Analysis of lipogenic and metabolic subtypes and survival outcome in patients with pancreatic adenocarcinoma.
Authors: Kundranda Madappa N. , Mahaveer Chand Nischal , Barrett J. Carl , Moser James , Grund Eric M. , Tekumalla Poornima K. , Miller Gregory M. , Narain Niven R. , Modur Vijay , Kiebish Michael A. , Ramanathan Ramesh K.
Published: January 2025

775

Background:
Delayed diagnosis and rapid progression are major drivers of poor survival outcomes for Pancreatic Ductal Adenocarcinoma (PDAC). In previous studies, molecular profiling in tumor tissue has identified Cholesterogenic, Classical, or Exocrine-Like pathological subtypes associated with improved prognosis. Herein, in a clinical trial called Project Survival, we molecularly and clinically characterized a prospective PDAC biomarker cohort. This multicenter (n=6) clinical trial (NCT 02781012) of PDAC combined with high-fidelity longitudinal phenotypic characterization and multi-omic profiling was utilized to identify biomarkers with diagnostic and therapeutic utility. The study included assessment of plasma, serum, buffy coat, urine, saliva, and tumor tissue samples and followed 269 PDAC subjects for up to 7 years (Median survival was 700 days, with IQR of 822 days).
Methods:
We assessed plasma samples to identify circulating biomarkers using proteomics, metabolomics, and lipidomics profiling. Multi-omic comparison of patients with Overall Survival (OS) above the 75th percentile (improved survival) against those with OS below the 25th percentile (poor survival) was performed.
Results:
We identified distinct panels of proteins, metabolites, and lipids that were associated with patient survival outcomes. Protein biomarkers that were increased in improved survival outcomes were associated with cholesterol metabolism (7/14, p-value = 0.00085) and glycolysis/gluconeogenesis (5/12, p-value = 0.00089), however, protein markers associated with immune surveillance and inflammation were associated with poorer survival. For metabolite biomarkers, 19 metabolites were increased in poorer survivors of which 13/19 were carnitine metabolites, and 42 metabolites were increased in patients with improved survival. Interestingly, only two lipid molecular species of the diacylglyceride family were increased in patients with poorer survival.
Conclusions:
Project Survival, a prospective biomarker-driven clinical trial identified distinct metabolic and molecular subtypes of patients which characterize survival outcome in PDAC. These subtypes go beyond tumor genomic characterization and align with distinct cholesterogenic and glucogenic phenotypes associated with survival outcomes, which can potentially be leveraged for therapeutic intervention strategies.
The effect of cachexia and anti-cancer therapies on GDF-15 levels in patients with pancreatic adenocarcinoma.
Authors: Geller Talya , Levi Abrahm , Osipov Arsen , Gong Jun , Hendifar Andrew Eugene
Published: January 2025

778

Background:
Growth differentiation factor 15 (GDF15) is a novel biomarker in the setting of pancreatic adenocarcinoma (PDAC). Preliminary studies have found that downstream effects of GDF-15 promote the progression of pancreatic cancer. PDAC has a high prevalence of cachexia which is commonly treated with enzyme supplementation and nutritional support. Platinum-based therapies often used to treat PDAC increase the likelihood of patients experiencing cachexia. The purpose of this study was to observe the GDF-15 levels in respect to weight change of PDAC patients being treated with cachexia and anti-cancer therapies.
Methods:
Serum and Plasma samples were collected from locally advanced and advanced PDAC patients on 5 IRB approved studies from 2014-2024. Samples were analyzed using the R-PLEX Human GDF-15 Antibody Set. The study objective was compared using two-sample paired t-tests and Pearson correlation matrices. Elevated GDF-15 was determined as >1500 pg/mL.
Results:
Samples from 73 patients were utilized for this study (63% female; median age: 69; BMI: 23.31±4.96 kg/m
2
). At baseline 71.8% (46/64) had elevated GDF-15, at Cycle 3 76% (25/33), and at Cycle 5 86% (25/29). In the total sample set, there was a slight negative correlation in the change of weight (-1.75 kg, p = 0.013) and GDF-15 (577.5 pg/mL, p = 0.278) from C1 to C3 (r = -0.185, p = 0.366). There was a slight negative correlation (r = -0.44, p = 0.076) in the difference of weight and GDF-15 from C1 to C3 in patients receiving chemotherapy. A strong negative correlation was observed in the change of GDF15 and weight from C1D1 to C1D8 in patients treated with platinum-based therapy (r = -0.530, p = 0.212) and a weak negative correlation (r = -0.421, p = 0.065) for patients with non-platinum-based therapy. There was a strong positive association (r = 0.993, p < 0.01) between the change in weight and GDF-15 from C1 to C5 in patients not receiving chemotherapy. There was no significant decrease in GDF-15 levels across the patients at all time points.
Conclusions:
Despite cachexia and anti-cancer treatment, the GDF-15 levels of PDAC patients continue to remain elevated in consecutive blood draws. Further research in GDF-15 kinetics is warranted.

Clinical trial information:
NCT02400398

,

NCT03207724

,

NCT04098237

,

NCT05336266

,

NCT04634539

.

Weight and GDF-15 levels across different chemotherapy regimens.

Baseline
Cycle 1
Cycle 3
Cycle 5

BMI (kg/m2)
Weight (kg)
GDF15 (pg/mL)
Weight (kg)
GDF15 (pg/mL)
Weight (kg)
GDF15 (pg/mL)

Chemotherapy
23.21
63.83
3243.25
63.44
3498.76
60.14
3201.33

No Chemotherapy
23.77
65.85
3113.73
62.32
2949.56
71.05
2944.54

Platinum Based
20.88
59.89
6527.78
51.7
3600.87
58.1
5152.50

Non-platinum-based chemotherapy
23.86
64.89
2442.14
64.67
3487.41
60.39
2957.43
Comparative efficacy of TAS-102 and chemotherapy rechallenge in the third-line setting and beyond in patients with advanced colorectal cancer: A retrospective study.
Authors: Alshammari Kanan , Alanazi Rakan , Alotaibi Khalid , Ali Murtada Mohamed , Abushara Ahmed , Albahrani Zainab , Alsehali Afrah , Almesfir Reem , Alsubaie Razan , Alkaiyat Mohammad , Shehata Husam , Sabatin Fouad , Algarni Mohammed Ahmed
Published: January 2025

78

Background:
The optimal approach to third line therapy for patients with metastatic colorectal cancer remains a subject of debate. Options include Trifluridine/Tipiracil (TAS-102), TAS-102 with bevacizumab, regorafenib, chemotherapy rechallenge with or without an anti-EGFR agent, or fruquintinib. This study aims to evaluate the efficacy of standard of care TAS-102, TAS-102 with bevacizumab, or regorafenib versus chemotherapy rechallenge in patients with metastatic colorectal cancer in the third line setting and beyond.
Methods:
We conducted a retrospective analysis of patients with metastatic colorectal cancer who received either TAS-102 with or without bevacizumab, regorafenib or chemotherapy rechallenge with or without an anti-EGFR agent between 2018 and 2023, at the Ministry of National Guard for Health Affairs in Riyadh, Saudi Arabia. Patients received such agents in the third line setting and beyond.
Results:
A total of 75 patients were included in this study, with 39 patients receiving TAS-102 with or without bevacizumab, or regorafenib, and 36 receiving chemotherapy rechallenge. The median patient age was 58 years (range 28-81), with the majority being males at 55%. Among the chemotherapy rechallenge group, 31% were treated with cetuximab and 6% had panitumumab rechallenge, some of which were guided by cell free DNA liquid biopsy testing. In the other group, 66% received regorafenib, 26% TAS-102 alone, and 8% TAS-102 with bevacizumab. At the time of analysis, 56% of patients had passed away. Median overall survival for patients who received TAS-102 with our without bevacizumab, and regorafenib in the third line setting was found to be 13.1 months. Whereas for patients who received chemotherapy rechallenge, their median overall survival was 19.5 months.
Conclusions:
Patients with metastatic colorectal cancer who received chemotherapy rechallenge in the third line setting survived longer compared with patients who received TAS-102 with or without bevacizumab, or regorafenib.