e16484 Background: Pancreatic acinar cell carcinoma (PACC) is an ultra-rare (~1%) pancreatic malignancy. Management is often extrapolated from pancreatic ductal adenocarcinoma (PDAC) despite distinct molecular drivers. We characterize the clinicopathologic and genomic features of PACC at our center to identify precision oncology targets. Methods: A retrospective review of histologically confirmed PACC at a tertiary academic center was performed. Clinical, radiographic, pathologic, treatment, and outcome data were extracted. Standard of care next-generation sequencing (NGS) results were reviewed, with focus on potentially actionable alterations. Results: Seven patients were identified (median age 64, range 46–70; 57% male). Symptoms included abdominal pain and weight loss; notably, jaundice was absent. Pathologic evaluation demonstrated variable lymph node involvement, lymphovascular and perineural invasion, and occasional mixed acinar neuroendocrine differentiation. NGS was performed in a subset of patients and actionable alterations included 9p21.3 co-deletion (CDKN2A/B and MTAP loss), IZKF1 loss, SEC24D-BRAF fusion, and BAP1 mutation (Table 1). All were KRAS wild-type. Surgical resection was performed in three patients, and FOLFIRINOX chemotherapy was commonly used. Treatment responses varied. A swimmer plot analysis revealed that 2/7 patients had prolonged progression-free survival ( > 90months and > 200months), while the remaining patients had follow-up < 5 years. At the time of data reporting, four patients were alive without disease recurrence and under ongoing surveillance. Conclusions: Our cohort confirms PACC is molecularly distinct from PDAC, characterized by absence of KRAS mutation and high prevalence of targetable alterations. The identification of MTAP loss and BRAF alteration suggests that PACC patients should be prioritized for specific precision medicine trials (e.g., PRMT5 or MAPK inhibitors) rather than traditional PDAC regimens. Early NGS is mandatory to optimize precision treatment in this rare cancer. Patient Age Sex Presenting Symptoms Tumor Location Resection performed NGS Findings MSI Status TMB Potential Target 1 46 F Abdominal pain, nausea, bloating, fatigue Head Yes Not tested Not tested Not tested N/A 2 68 F Pruritis, abdominal pain, appetite loss, constipation/diarrhea Head Yes TP53 mutation; KRAS wild type; CDKN2A/B loss; MTAP loss; SEC24D-BRAF fusion MSS Intermediate BRAF/MEK/PRMT5 inhibitors 3 67 M Abdominal pain Head Attempted (aborted) Not tested Not tested Not tested N/A 4 70 M Flank pain and hematuria Head No Not tested Not tested Not tested N/A 5 86 F Asymptomatic (incidental lab finding) Head No BAP1 mutation MSS 6.6 EZH2 inhibitors 6 55 M Abdominal pain Tail No CDKN2 A/B loss; IKZF1 loss; MTAP loss; KRAS wild type MSS 6.8 PRMT5 inhibitors 7 57 M Asymptomatic (incidental imaging finding) Head Yes Not tested Not tested Not tested N/A

BACKGROUND:Globally, pancreatic cancer is one of the leading causes of cancer-related mortality. Although FDA-approved chemotherapy regimens are available, rapid deterioration is often observed after first-line treatment. The PARP inhibitor niraparib may offer a therapeutic benefit in patients with advanced pancreatic cancer, necessitating thorough investigation. PATIENTS AND METHODS:This was an open-label, single-arm, phase II trial involving 37 patients with metastatic or unresectable pancreatic cancer with DNA damage repair (DDR) gene alterations. Patients were administered niraparib (300 or 200 mg daily, based on weight and platelet count) in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal. Efficacy was assessed using the 6-month progression-free survival (PFS) rate as the primary endpoint. RESULTS:Of the 37 patients, 29 were evaluated for efficacy. The 6-month PFS rate was 41.38% (12/29 patients; 95% CI, 4.70%-100%), the median PFS was 4.4 months (95% CI, 3.6-6.5 months), and the median OS was 10.3 months (95% CI, 7.6-15.9 months). Further subgroup analysis revealed that the BRCA1/2 germline mutation-positive patient group (n = 14) reported a 6-month PFS rate of 50% and a median overall survival (mOS) of 12.1 months, while the non-BRCA group (n = 15) showed a 6-month PFS rate of 33.33% and a mOS of 10.3 months. Adverse events occurred in 78% of patients, the most common being anemia (27%), and no treatment-related deaths were observed. CONCLUSIONS:These data demonstrate clinical activity of niraparib in patients with metastatic or unresectable pancreatic cancers harboring DDR gene defects. Future studies are warranted to establish their roles in diverse genetic patient subpopulations. CLINICALTRIALS.GOV IDENTIFIER:NCT03553004.

730 Background: Nectin-4, a type I transmembrane protein, is critical for adherens junction formation and maintenance. Aberrant overexpression of Nectin-4 has been observed in pancreatic ductal adenocarcinoma (PDAC) and is associated with tumor proliferation and metastasis/ Enfortumab vedotin (EV), an antibody–drug conjugate targeting Nectin-4, delivers the microtubule-disrupting agent monomethyl auristatin E to Nectin-4–expressing cells. EV is approved in urothelial carcinoma, supporting its evaluation in other tumors. Methods: This open-label, single-arm, phase II trial evaluated EV in previously treated locally advanced, recurrent, or metastatic PDAC. Pts received EV 1.25 mg/kg IV on days 1, 8, and 15 of each 28-day cycle until progression or unacceptable toxicity. Imaging was performed every 8 weeks. Mandatory biopsies were obtained pre-treatment and on-treatment (C1, D15–21). Eligible patients had ECOG PS 0–1 and ≥1 prior line of therapy. The primary endpoint was ORR. Secondary endpoints included safety, DOR, DCR, PFS and OS. Exploratory endpoints included correlation of Nectin-4 expression and tumor mutational profile with ORR. A Simon’s two-stage design required ≥3 responses among 28 evaluable patients to reject the null hypothesis. Results: As of January 2025, 43 patients were enrolled (16 female, 27 male; mean age 64.7 y), with 28 evaluable for efficacy. ORR was 10.7% (3/28; 95% CI, 2.3–28.2%), with 1 confirmed PR. Two PRs progressed at confirmatory scans (day 50–55). Prior therapies among PRs included FOLFIRINOX (n=1), FOLFIRINOX→gemcitabine based (n=1), and FOLFIRINOX→gemcitabine/nab-paclitaxel (n=1). DCR for best response was 53.6% (95% CI, 33.9–72.5%); 16-week, 24-week, and 32-week DCRs were 28.6%, 21.4%, and 17.9%. At baseline, 24/28 (85.7%) had elevated CA19-9; 13/24 achieved PR/SD. Mean CA19-9 change from baseline to week 8 was +11,701 (PD group) vs +1,400 (PR/SD group); 6/13 in PR/SD group had ≥50% decrease. Similarly, 24/28 (85.7%) had elevated CEA; 12/24 achieved PR/SD. Mean CEA change was +179 (PD) vs +13 (PR/SD); 4/12 PR/SD patients had ≥30% decrease. Among 38 pts evaluable for safety, TRAE occurred in 79.0% (30/38), and Grade 3/4 TRAE occurred in 47.4% (18/38). The most common TRAE were fatigue (40.0%, 12/30), peripheral neuropathy (26.7%, 8/30), rash maculo-papular (23.3%, 7/30), anorexia (20.0%, 6/30), and neutropenia (20.0%, 6/30). Serious TRAE were reported in 10.5%% (4/38). Only deaths were Grade 5 Pneumonitis possibly related to EV in a pt with diffuse lung mets and death due to disease progression not related to study drug. Conclusions: In this phase II study, EV showed modest antitumor activity with ORR >10% and durable disease control in a heavily pretreated PDAC. Safety was consistent with prior reports. Survival outcomes and nectin 4 biomarker analyses will be reported during the presentation. Clinical trial information: NCT05915351 .

Certepetide (aka CEND-1, LSTA1) is a tumor-penetrating peptide that binds integrin αvβ3 on tumor endothelium and neuropilin-1, triggering transcytosis to enhance intratumoral drug delivery and modulate the tumor microenvironment (TME). We report findings from resectable and borderline resectable PDAC of the CENDIFOX trial evaluating Certepetide plus mFOLFIRINOX as neoadjuvant therapy. Eligible patients with resectable and borderline resectable PDAC received neoadjuvant mFOLFIRINOX for 3 cycles followed by addition of Certepetide (3.2 mg/kg IV on Day 1) to mFOLFIRINOX every 2 weeks from cycles 4 onward for at least 6 cycles, followed by evaluation for resection. The primary objective was safety; secondary endpoints included resection rate, pathologic response, PFS, OS, and immune profiling. Correlative biopsies were obtained pre-treatment and at end of therapy. 35 patients were enrolled. No dose-limiting toxicities were observed. Common Grade ≥3 AEs included neutropenia, mucositis, fatigue, anorexia, and gastrointestinal events. Toxicities were manageable with dose reductions or delays. Most AEs were attributed to mFOLFIRINOX; no serious AEs were attributed to Certepetide. Of the 35 patients enrolled, 10 underwent pancreatic cancer resection following treatment regimen. Among these evaluable cases, the pathologic partial response rate (Tumor Regression Grade 2) was 70%, and the R0 resection rate was 50%. At limited follow-up, the 2-year OS rate was 60% (95% CI, 26%–100%), and median DFS was 12 months (95% CI, 10–NA). Immunofluorescence staining of PDAC tissue demonstrated increased post-treatment expression of CD68 (tumor-associated macrophages, TAMs) and immune checkpoints PD-1/PD-L1. Mean log-transformed CD68 intensity increased from 13.96 to 15.20; PD-1 from 12.94 to 13.57; and PD-L1 from 13.33 to 13.54, suggesting enhanced immune infiltration. Certepetide combined with mFOLFIRINOX is safe and feasible in resectable PDAC. Encouraging early OS and PFS data, high pathologic partial response rates, and correlative immune findings support further evaluation in randomized trials. Enhancement of TAMs and PD-1/PD-L1 in the tumor microenvironment supports the potential to convert PDAC from an immune-cold to an immune-hot tumor, possibly sensitizing it to immunotherapy. NCT05121038 Anup Kasi, Raed Al-Rajabi, Anwaar Saeed, Jianzheng Wu, Milind Phadnis, Shannon Bradbury, Stacey Krepel, Subhrajit Saha, Grace Li Haug, Prasad Dandawate, Rashna Madan, Mojtaba Olyaee, Amit Rastogi, Timothy Schmitt, Sean Kumer, Weijing Sun, Joaquina Baranda. CENDIFOX: Phase I/II Trial of CEND-1 (LSTA1, certepetide) with Neoadjuvant mFOLFIRINOX in Resectable and Borderline Resectable PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A070.

TPS4229 Background: Pancreatic cancer is a highly lethal disease. Despite research and drug development efforts focused on KRAS, no effective RAS inhibitors have been approved for the treatment of pancreatic cancer with KRAS mutation. PLK1 inhibition is a potential target in KRAS-mutated pancreatic cancer and may provide a new first-line treatment option. Onvansertib (also known as PCM-075 and NMS-1286937) is the first PLK1-specific adenosine triphosphate competitive inhibitor administered by oral route to enter clinical trials with proven antitumor activity in different preclinical models. Methods: This is a phase 1b/II, non-randomized, open label single arm study being conducted at the University of Kansas Cancer Center and its affiliated sites. The study is open for enrollment. Eligibility: Key inclusion includes pts with locally advanced, unresectable, or metastatic pancreatic adenocarcinoma who are treatment naïve, have adequate archival tissue for biomarker evaluation or are willing to undergo a biopsy, and have an ECOG of 0-1. Key Exclusion: Planned concomitant use of medications known to prolong the QT/QTc interval, use of strong CYP3A4 or CYP2C19 inhibitors or strong CYP3A4 inducers. Treatment Plan: The phase 1b (safety lead-in) will follow a dose de-escalation phase in which up to 2 different Onvansertib dose levels will be tested in combination with standard NALIRIFOX. Onvansertib starting dose level is 30mg orally once daily. The Phase II portion of the study will be a single-arm open-label enrollment with dosing based on the starting dose determination in the Phase Ib portion of the study (30mg or 20mg). NALIRIFOX (Nano-liposomal Irinotecan 50 mg/m2, Oxaliplatin 60 mg/m2, Leucovorin 400 mg/m2, 5-FU 2400 mg/m2) will be administered intravenously on D1 of the 14-day cycle. Onvansertib will be dosed orally on D1-5 of each 14-day cycle. Imaging will be performed at baseline and after every 4 cycles. Objectives: The primary objective of this study is to determine anti-tumor activity by measuring Overall Response Rate (ORR). The secondary objectives are to determine treatment safety based on toxicities in participants who have received at least one dose of onvansertib, to determine anti-tumor activity by Progression Free Survival (PFS), to determine anti-tumor activity by Disease Control Rate (DCR), to determine Overall Survival (OS). Statistical Plan: Simon's two-stage Optimum design will be used. The null hypothesis that the true response rate is 41% will be tested against a one-sided alternative that the true response rate is 65%. In the first stage, 10 evaluable pts will be enrolled. If there are 4 or fewer responses in these 10 pts, the study will be stopped. Otherwise, 11 additional evaluable pts will be accrued for a total of 21 evaluable pts. The null hypothesis will be rejected if 12 or more responses are observed in 21 evaluable pts. Clinical trial information: NCT06736717 .

ImportanceA new liver allocation policy was implemented by United Network for Organ Sharing (UNOS) in February 2020 with the stated intent of improving access to liver transplant (LT). There are growing concerns nationally regarding the implications this new system may have on LT costs, as well as access to a chance for LT, which have not been captured at a multicenter level.ObjectiveTo characterize LT volume and cost changes across the US and within specific center groups and demographics after the policy implementation.Design, Setting, and ParticipantsThis cross-sectional study collected and reviewed LT volume from multiple centers across the US and cost data with attention to 8 specific center demographics. Two separate 12-month eras were compared, before and after the new UNOS allocation policy: March 4, 2019, to March 4, 2020, and March 5, 2020, to March 5, 2021. Data analysis was performed from May to December 2022.Main Outcomes and MeasuresCenter volume, changes in cost.ResultsA total of 22 of 68 centers responded comparing 1948 LTs before the policy change and 1837 LTs postpolicy, resulting in a 6% volume decrease. Transplants using local donations after brain death decreased 54% (P < .001) while imported donations after brain death increased 133% (P = .003). Imported fly-outs and dry runs increased 163% (median, 19; range, 1-75, vs 50, range, 2-91; P = .009) and 33% (median, 3; range, 0-16, vs 7, range, 0-24; P = .02). Overall hospital costs increased 10.9% to a total of $46 360 176 (P = .94) for participating centers. There was a 77% fly-out cost increase postpolicy ($10 600 234; P = .03). On subanalysis, centers with decreased LT volume postpolicy observed higher overall hospital costs ($41 720 365; P = .048), and specifically, a 122% cost increase for liver imports ($6 508 480; P = .002). Transplant centers from low-income states showed a significant increase in hospital (12%) and import (94%) costs. Centers serving populations with larger proportions of racial and ethnic minority candidates and specifically Black candidates significantly increased costs by more than 90% for imported livers, fly-outs, and dry runs despite lower LT volume. Similarly, costs increased significantly (>100%) for fly-outs and dry runs in centers from worse-performing health systems.Conclusions and RelevanceBased on this large multicenter effort and contrary to current assumptions, the new liver distribution system appears to place a disproportionate burden on populations of the current LT community who already experience disparities in health care. The continuous allocation policies being promoted by UNOS could make the situation even worse.

4156 Background: Targeting a molecular subset of pancreatic cancer (PC) may identify alternatives to perpetual chemotherapy and chemo-resistance/toxicity. Poly (ADP ribose) polymerase inhibitors (PARPi) have shown efficacy in germline BRCA mutation via synthetic lethality. Preclinical evidence suggests PARPi may target DNA repair defects beyond BRCA. We conducted a Niraparib phase II study in PC patients with germline/somatic DNA repair defects. Methods: This is an open-label, phase 2 trial in pts with locally advanced or metastatic PC with germline or somatic mutations , known or tested after consent to pre-screening tumor tissue analysis in DNA repair genes (BRCA1/2, PALB2, ATM, NBN, ATR, BRIP1, IDH1/2, RAD51, RAD51B/C/D, RAD54L, CDK12, BARD1, FAM175A, BAP1, CHEK1/2, GEN1, MRE11A, XRCC2, SHFM1, FANCD2, FANCA, FANCC, FANCG, RPA1, ARID1A), who have progressed on or intolerant of at least one line of therapy, no prior PARPi, with evaluable disease, and ECOG PS 0-1. Eligible pts were treated with Niraparib 300mg or 200mg PO daily for 28 days (1 cycle = 28 days) (200mg dose for baseline weight is < 77 kg or baseline platelet count is < 150,000 µL) until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death. The primary objective was 6-month PFS rate. The secondary objectives were OS, DCR and safety. Pts were evaluable for safety if they had received > 1 dose of Niraparib and for efficacy if they had also received > 1 follow-up imaging study. Results: As of Feb 2023, 36 (13 female, 23 male) pts were enrolled, with a mean age of 62.9 (median 64, IQR 51-73, min 41, max 83, SD 11.25), of whom 27 (8 female, 19 male) were evaluable for efficacy. After a median follow-up of 9.0 months (IQR 6.0-15.1 m), the 6-month PFS rate was 40.7% (11/27 pts; 95% CI 4.7%- 100 %). The median PFS is 4.4 m (CI 2.3 - 6.5 m), and median OS is 9.1 m (7.5 -15.1 m). The disease control rate at 8 weeks was 70.4% (19 of 27 pts; 95% CI 49.8%-86.3%). Of the 27 evaluable pts- BRCA2 mutation was seen in 10 pts, ATM (5), CHEK2 (5), BRCA1 (2), NBN (2), ARID1A (1), FANCA (1), FAM175 A (1), RAD51B (1), IDH1 (1), IDH2 (1). Among 36 pts evaluable for safety, treatment-related adverse events occurred in 75% (27/36), and Grade 3 and grade 4 treatment-related adverse events occurred in 31% (11/36). The most common treatment-related AEs were anemia (25%, 9/36), nausea (22%, 8/36), thrombocytopenia (19%, 7/36), vomiting (19%, 7/36), and fatigue (17%, 6/36). Serious treatment-emergent adverse events were reported in 11% (4/36). There were no treatment-related deaths. Conclusions: In previously treated pts with locally advanced and metastatic PC harboring DNA repair defects, niraparib monotherapy yielded a 6-month PFS rate of 40%, median PFS of 4.4 months, and median OS of 9.1 months. Clinical trial information: NCT03553004 . [Table: see text]

TPS4205 Background: MRD detected by presence of circulating tumor DNA (ctDNA) after intended curative treatment is associated with high risk of relapse in pancreatic cancer. Early treatment of patients with presence of ctDNA after completion of surgery +/- adjuvant therapy may offer an opportunity to clear ctDNA and improve outcomes. TG01 is a RAS-neoantigen peptide vaccine adjuvanted by QS-21 (Stimulon) targeting the seven most frequent codon 12-13 RAS mutations. TG01 has previously demonstrated ability to activate mutant RAS specific CD4+ and CD8+ T-cell responses in vaccinated patients and repeated TG01 dosing in resected pancreatic cancer was found to be well tolerated and associated with a median OS of 33.4 months (95% CI 24.0, 45.8) 1,2 . Checkpoint inhibitors as single agents have not shown anti-tumor activity in pancreatic cancer, suggesting that a priming agent inducing tumor-specific T-cells may be required to support efficacy. Balstilimab is a human monoclonal antibody targeting programmed cell death protein 1 (PD-1) which is intended to reverse the immunosuppressive effects of this signaling pathway in the context of tumor immuno-surveillance by T-cells. Methods: Design: A two-arm, open-label, phase II randomized trial of TG01/QS-21 vaccine or TG01/QS-21 vaccine plus balstilimab (n=12 per arm, N=24) with surgically resected Stage 1-3 RAS mutant PDAC who are MRD+ following completion of standard adjuvant chemotherapy. Assay: MRD is detected by a commercially available ctDNA assay (Signatera, Natera). Somatic variants are identified by whole–exome sequencing of the primary tumor and the matched normal (whole blood) sample and a bespoke assay of up to 16 clonal, somatic variants are generated for each patient. This “tumor signature” will be monitored in plasma throughout the study. Treatment schedule: A priming phase of six vaccine administrations once every two weeks followed by a maintenance phase of administrations once every 8 weeks for up to 51 weeks. Balstilimab will be administered every 2 weeks for up to 51 weeks beginning at week 3. Imaging assessment will be done every 12 weeks. Eligibility: Surgically resected pancreatic adenocarcinoma with pathogenic RAS mutation, and no evidence of recurrent disease on baseline imaging. Inclusion criteria also include ECOG PS 0-1, and positive Signatera ctDNA MRD. Objectives: The primary objective is to assess the 6-month molecular disease control rate as defined by ctDNA stable, decreased or cleared. Secondary objectives include safety of TG01/QS-21 with or without balstilimab, 6 and 12-month DFS rate in each cohort, as well as correlation between the depth of molecular response and DFS. Exploratory: changes in clonality of RAS mutations and assess immune response. Enrollment is ongoing. 1) Gjertsen MK et al. Int J Cancer 1997, 72(5) 784-90. 2) Palmer DH et al. Br J Cancer 2020 122:971-77. Clinical trial information: NCT05638698 .

The mechanisms connecting obesity with type 2 diabetes, insulin resistance, nonalcoholic fatty liver disease, and cardiovascular diseases remain incompletely understood. The function of MAPK phosphatase-2 (MKP-2), a type 1 dual-specific phosphatase (DUSP) in whole-body metabolism, and how this contributes to the development of diet-induced obesity, type 2 diabetes (T2D), and insulin resistance is largely unknown. We investigated the physiological contribution of MKP-2 in whole-body metabolism and whether MKP-2 is altered in obesity and human fatty liver disease using MKP-2 knockout mice models and human liver tissue derived from fatty liver disease patients. We demonstrate that, for the first time, MKP-2 expression was upregulated in liver tissue in humans with obesity and fatty liver disease and in insulin-responsive tissues in mice with obesity. MKP-2-deficient mice have enhanced p38 MAPK, JNK, and ERK activities in insulin-responsive tissues compared with wild-type mice. MKP-2 deficiency in mice protects against diet-induced obesity and hepatic steatosis and was accompanied by improved glucose homeostasis and insulin sensitivity. Mkp-2−/− mice are resistant to diet-induced obesity owing to reduced food intake and associated lower respiratory exchange ratio. This was associated with enhanced circulating insulin-like growth factor-1 (IGF-1) and stromal cell-derived factor 1 (SDF-1) levels in Mkp-2−/− mice. PTEN, a negative regulator of Akt, was downregulated in livers of Mkp-2−/− mice, resulting in enhanced Akt activity consistent with increased insulin sensitivity. These studies identify a novel role for MKP-2 in the regulation of systemic metabolism and pathophysiology of obesity-induced insulin resistance and fatty liver disease.

e16254 Background: Neo-adjuvant therapy (NAT) and associated pathologic complete response (pCR) rates have correlated with improved survival in resected pancreatic ductal adenocarcinoma (PDAC). In this study, we explored the relationship between pathologic response, peri-operative therapy, and survival, especially the impact of change in adjuvant therapy in patients with no/poor path response to NAT. Methods: Retrospectively reviewed 66 PDAC patients who received NAT ± radiation and underwent resection at KU Cancer Center between 2011-2022. We compared DFS and OS between Path Responders vs Non-Responders based on standard Tumor Regression Scores from pathology reports. A subanalysis was performed in path non-responders based on switch in adjuvant therapy (AT) versus not. Results: Patient characteristics are summarized in the table. Among 66 PDAC patients, 50 (75.8%) achieved a path response (G0-G2), 16 (24.2%) experienced no/poor path response (G3). Of the 50 pts who achieved a path response, 4 (8.0%) had a complete path response (pCR; G0), 5 (10%) marked response (G1), 41 (82%) moderate response (G2). Median DFS (mDFS) was 17.3 months (95% CI: 12.7-22.4) in Path Responders vs 15.9m (95% CI: 9.6-35.8) in Non-Responders [p=0.59]. Median OS (mOS) was 32.9m (95% CI: 23.4-41.5) vs 27.7m (95% CI: 15.2-38.2), respectively [p=0.39). A sub-analysis in the Non-Responders (n=16) based on switch in AT (n=8) vs not (n=3), revealed mDFS 16.4m (95% CI: 9.6-41.8) when AT was switched vs mDFS 11.3m (95% CI: 5.9-16.6) when AT was not switched [p=0.24]; and mOS 30.6m (95% CI: 15.7-60.3) vs 17.2 months (95% CI: 6.7-27.7), respectively [p=0.18]. Conclusions: Our study found no statistical difference in DFS and OS between Pathologic Responders and Non-Responders to neo-adjuvant therapy. However, a sub-analysis within Pathologic Non-Responders revealed a longer DFS and OS after switching adjuvant therapy without reaching statistical significance, likely due to small sample size. Our findings warrant validation in a larger cohort as switch in adjuvant therapy could potentially change the treatment landscape for Pathologic Non-Responders.[Table: see text]

The surgical management of metastatic colorectal cancer (CRC) has evolved over time. Most often, the management of asymptomatic primary CRC with simultaneous liver metastases (LM) proceeds with neoadjuvant chemotherapy followed by surgical resection. Although the timing of surgical resection has remained controversial, the ability to achieve R0 resection and the importance of patient selection remain widely accepted. Preoperative novel modalities such as portal vein ligation (PVL) or portal vein embolization (PVE) have allowed for improved surgical outcomes and decreased post-surgical morbidity. Combination or hybrid management has also seen increased utility by associating ablation therapies with surgical resection. Finally, patients with significant comorbidities and surgically unresectable disease have benefited greatly from locoregional salvage therapies such as percutaneous ablation and radioembolization. Here we will review pertinent literature associated with surgical management for resectable disease and explore newly developed locoregional salvage therapies for unresectable disease.

TPS4195 Background: The efficacy of chemotherapy is often compromised due to poor penetration of drugs in solid tumors. The tumor microenvironment, which is characterized by dense extracellular matrix‐rich stroma that creates a physical barrier to penetration of anti‐cancer drugs, is especially pronounced in Pancreatic Ductal Adenocarcinoma (PDAC) and in peritoneal metastases from Colorectal/Appendiceal Adenocarcinoma. CEND‐1 is a tumor‐penetrating peptide (scientifically also known as iRGD) that has preclinically demonstrated to enhance the tumor penetration of chemotherapy agents through binding and activation of alphav-integrins and neuropilin‐1 (NRP-1). The 2-step mechanism leads to a higher delivery and concentration of chemotherapeutics selectively in the tumor, while sparing normal tissue. Hence CEND-1 therapy has the potential to improve the efficacy of anti‐cancer therapies and reduce side effects through increased tumor access, specificity, and sensitivity. We hypothesize that CEND‐1 may become a powerful adjuvant that safely enhances standard anti‐neoplastic therapy in the neoadjuvant setting for the above populations. Methods: A safety lead-in 6-9 patients (Phase Ib) will be followed by an open label, single arm, parallel (3 cohorts) Phase IIa study. A total of 50 patients (20 PDAC, 15 colorectal/appendiceal with peritoneal metastases, 15 oligometastatic colorectal) will be enrolled. A starting CEND-1 dose of 3.2 mg/kg in combination with the standard doses of FOLFIRINOX (+/- Panitumumab if RAS/RAF wild type) will be used for the safety lead-in. CEND-1 dose will be lowered for Phase IIa if > 1/6 patients experienced DLTs. Participants enrolled will receive standard doses of FOLFIRINOX q2w +/- Panitumumab q2w 6mg/kg IV q2w (14-day cycles) for Cycles 1-3. After a subsequent research biopsy, the CEND-1 + chemotherapy combo will be continued at RP2D q2w for cycles 4-6, followed by CEND-1 +/- Panitumumab ̃72h prior to resection. Assessment of tumor response using RECIST v1.1 will be done every 3 cycles. Up to 10 patients may receive Panitumumab. Eligible Pts are untreated, newly diagnosed, resectable/borderline resectable PDAC or colorectal/appendiceal adenocarcinoma with peritoneal metastases or oligometastases eligible for cytoreductive surgery, as determined by multidisciplinary evaluation. Inclusion criteria also include ECOG PS 0-1, adequate organ function, measurable or evaluable disease. Primary objectives are safety and biological activity of CEND‐1. Secondary objectives include ORR, R0 resection rate, DFS, OS. Exploratory objectives include pathologic response, tissue immune response, EGFR expression, tumor tissue-to-plasma concentration of Panitumumab pre and post CEND-1 treatment. Enrollment to the CENDIFOX trial is currently ongoing. Clinical trial information: NCT05121038.

The function of MAPK phosphatase-2 (MKP-2), a type 1 dual-specific phosphatase (DUSP) in metabolic regulation is largely unknown. Here we demonstrate that MKP-2 expression was upregulated in liver tissue in humans with obesity and fatty liver disease, and in insulin-responsive tissues in mice with obesity. MKP-2 deficient mice have enhanced p38 MAPK, JNK and ERK activities in insulin-responsive tissues compared with wild type mice. MKP-2 deficiency in mouse protects against diet-induced obesity and hepatic steatosis and was accompanied with improved glucose homeostasis and insulin sensitivity. This was associated with enhanced circulating insulin-like growth factor-1 (IGF-1) and stromal cell-derived factor 1 (SDF-1) levels in Mkp-2 mice. PTEN, a negative regulator of Akt, was upregulated in livers of Mkp-2 mice, resulting in enhanced Akt activity consistent with increased insulin sensitivity. Pancreatic islet analysis demonstrated that MKP-2 deficiency altered islet composition and this has the potential to regulate in b-cell physiology. These studies demonstrate for the first time that MKP-2 is essential in the regulation of metabolic homeostasis and pathophysiology of obesity-induced insulin resistance and fatty liver disease.

Pancreatic intraepithelial neoplasms (PanINs) and intraductal papillary mucinous neoplasms (IPMNs) are common pancreatic adenocarcinoma precursor lesions. However, data regarding their respective associations with survival rate and prognosis are lacking. We retrospectively evaluated 72 pancreatic adenocarcinoma tumor resection patients at the University of Kansas Hospital between August 2009 and March 2019. Patients were divided into one of two groups, PanIN or IPMN, based on the results of the surgical pathology report. We compared baseline characteristics, overall survival (OS), and progression free survival (PFS) between the two groups, as well as OS and PFS based on local or distant tumor recurrence for both groups combined. 52 patients had PanINs and 20 patients had IPMNs. Patients who had an IPMN precursor lesion had better median PFS and OS when compared to patients with PanIN precursor lesions. However, the location of tumor recurrence (local or distant) did not show a statistically significant difference in OS.

TPS4168 Background: Attempts to improve therapy for patients with pancreatic adenocarcinoma with traditional chemotherapy have largely failed to meaningfully improve survival. Therefore, there is a critical need for identification of specific molecular changes that define prognosis and potentially guide therapy decisions. Defective DNA damage response pathways in pancreatic cancer represent a targeted opportunity for treatment. PARP inhibitors exert activity in tumor cells that may not be effectively able to repair initially single-stranded and cumulatively double-stranded DNA breaks and can have a heightened susceptibility in tumor cells over normal tissue. This concept is referred to as synthetic lethality. Niraparib is an orally available, potent, highly selective PARP-1 and -2 inhibitor. We are studying the efficacy of Niraparib in pancreatic cancer patients that harbor DNA repair defects. Methods: This study is funded by a research grant from TESARO. Pre-screening of patients to find biomarker positive patients is funded by KU Cancer Center. This is a phase II open label single arm trial in metastatic pancreatic cancer patients with germline or somatic mutations, either already known, or tested after consent to pre-screening tumor tissue analysis in BRCA1/2, PALB2, ATM, NBN, ATR, BRIP1, IDH1/2, RAD51, RAD51B/C/D, RAD54L, CDK12, BARD1, FAM175A, BAP1, CHEK1/2, GEN1, MRE11A, XRCC2, SHFM1, FANCD2, FANCA, FANCC, FANCG, RPA1, ARID1A. Patients are being treated with Niraparib 300mg or 200mg by mouth daily for 28 days (1 cycle = 28 days) (200mg dose is for participants whose baseline weight is < 77 kg [169.756 lbs] or baseline platelet count is < 150,000 µL). The primary objective is to assess antitumor efficacy of niraparib using Objective Response Rate per RECIST 1.1. Secondary objectives include PFS, OS, DCR, DOR, and safety. Eligible patients received > 1 line of therapy, no prior PARP inhibitor(s), have measurable disease, and ECOG PS 0-1. Accrual target enrollment of 18 patients over a period of 24 months with a study duration of 30 months. Correlative studies include assessment of pharmacokinetics, circulating tumor cells and storing samples for future research. The trial is currently enrolling. Clinical trial information: NCT03553004.

Introduction . Ampullary cancers represent a subset of periampullary cancers, comprising only 0.2% all gastrointestinal cancers. Localized disease is primarily managed by a surgical intervention, called pancreaticoduodenectomy (PD), followed in many cases by the administration of adjuvant chemotherapy (CT) or chemoradiation therapy (CRT). However, there are no clear evidence-based guidelines to aid in selecting both the modality and regimen of adjuvant therapy for resected Ampullary carcinoma. Methods . We retrospectively analyzed 54 patients at KU Cancer Center, who had undergone endoscopic resection or pancreaticoduodenectomy (PD) for Ampullary cancer from June 2006 to July 2016. We obtained patients’ baseline characteristics, clinical presentation, pathology, treatment modality, recurrence pattern, and survival outcomes. The time-to-events data were compared using Kaplan-Meier methods. A univariate and multivariate Cox proportional hazards regression was performed to evaluate factors associated with overall survival (OS) and generate hazard ratios (HR). Results . The mean age of the 54 patients was 68 (37-90). 38 (70%) were males and 16 (30%) were females. Most of the patients were Caucasian (76%). Approximately half of all patients had a history of smoking, 20% had alcohol abuse, and 13% had pancreatitis. Among the 54 patients with localized cancers, 9 (16%) were treated definitively with nonoperative therapies, usually due to a prohibitive comorbidity profile, performance status, or unresectable tumor. 45 out of 54 patients (83%) underwent surgery. Of the 45 patients who underwent surgery, 18 patients (40% of the study cohort) received adjuvant therapy due to concerns for advanced disease as determined by the treating physician. 13 patients (24%) received adjuvant CT and 5 patients (9.2%) received CRT. The remaining 27 patients (50%) underwent surgery alone. The median OS for the entire study cohort was 30 months. When compared to surgery alone, adjuvant therapy with either CT or CRT had no statistically significant difference in terms of progression-free survival ( p =0.56) or overall survival ( p =0.80). In univariate Cox proportional hazards regression analysis, high-risk features like peripancreatic extension (16%) and perineural invasion (26%) were found to be associated with poor OS. Lymph node metastasis (29%) did not significantly affect OS (HR 1.42, 95% CI [0.73-1.86]; p =0.84). Lymphovascular invasion (29%) was not associated with poor OS (HR 1.22, 95% CI [0.52, 2.96]; p =0.76). In multivariate Cox regression analysis, only age group>70 years was significantly associated with OS , while other factors, including the receipt of adjuvant therapy, lymph nodes, positive margin, and lymphovascular, perineural, and peripancreatic involvement, were not significantly associated with OS. These results are likely due to small sample size. Conclusions . Despite numerous advances in both cancer care and research, efforts in rare malignancies such as Ampullary cancer remain very challenging with a clear lack of an evidence-based standard of care treatment paradigm. Although adding adjuvant therapies such as chemotherapy or chemoradiotherapy is likely to improve survival in high-risk disease, there is no standardized regimen for the treatment of Ampullary cancer. More research is required to elucidate whether statistically and clinically relevant differences exist that may warrant a change in the current adjuvant treatment strategies.

Impaired macroautophagy/autophagy has been implicated in experimental and human pancreatitis. However, the transcriptional control governing the autophagy-lysosomal process in pancreatitis is largely unknown. We investigated the role and mechanisms of TFEB (transcription factor EB), a master regulator of lysosomal biogenesis, in the pathogenesis of experimental pancreatitis. We analyzed autophagic flux, TFEB nuclear translocation, lysosomal biogenesis, inflammation and fibrosis in GFP-LC3 transgenic mice, acinar cell-specific tfeb knockout (KO) and tfeb and tfe3 double-knockout (DKO) mice as well as human pancreatitis samples. We found that cerulein activated MTOR (mechanistic target of rapamycin kinase) and increased the levels of phosphorylated TFEB as well as pancreatic proteasome activities that led to rapid TFEB degradation. As a result, cerulein decreased the number of lysosomes resulting in insufficient autophagy in mouse pancreas. Pharmacological inhibition of MTOR or proteasome partially rescued cerulein-induced TFEB degradation and pancreatic damage. Furthermore, genetic deletion of tfeb specifically in mouse pancreatic acinar cells increased pancreatic edema, necrotic cell death, infiltration of inflammatory cells and fibrosis in pancreas after cerulein treatment. tfeb and tfe3 DKO mice also developed spontaneous pancreatitis with increased pancreatic trypsin activities, edema and infiltration of inflammatory cells. Finally, decreased TFEB nuclear staining was associated with human pancreatitis. In conclusion, our results indicate a critical role of impaired TFEB-mediated lysosomal biogenesis in promoting the pathogenesis of pancreatitis. Abbreviations: AC: acinar cell; AMY: amylase; ATP6V1A: ATPase, H+ transporting, lysosomal V1 subunit A; ATP6V1B2: ATPase, H+ transporting, lysosomal V1 subunit B2; ATP6V1D: ATPase, H+ transporting, lysosomal V1 subunit D; ATP6V1H: ATPase, H+ transporting, lysosomal V1 subunit H; AV: autophagic vacuole; CDE: choline-deficient, ethionine-supplemented; CLEAR: coordinated lysosomal expression and regulation; CQ: chloroquine; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; EM: electron microscopy; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; H & E: hematoxylin and eosin; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK1/ERK2: mitogen-activated protein kinase 1; MTORC1: mechanistic target of rapamycin kinase complex 1; ND: normal donor; NEU: neutrophil; PPARGC1A/PGC1α: peroxisome proliferator-activated receptor, gamma, coactivator 1 alpha; RIPA: radio-immunoprecipitation; RPS6: ribosomal protein S6; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TM: tamoxifen; WT: wild-type; ZG: zymogen granule.

Alcohol is a well‐established risk factor for hepatocellular carcinoma (HCC), but the mechanisms by which it promotes liver cancer are not well understood. Several studies have shown that cellular protein arginine methylation is inhibited by alcohol. Arginine methylation is controlled by the reciprocal activity of protein arginine methyltransferases, primarily protein arginine methyl transferase 1 (PRMT1), and a demethylase Jumonji C domain‐containing protein 6 (JMJD6). The aim of this study was to explore the role of arginine methylation changes in alcohol pathogenesis. We found that PRMT1 activity is inhibited in livers of mice fed with alcohol compared to pair‐fed mice. Using hepatocyte‐specific PRMT1 knockout mice, we identified that loss of PRMT1 results in enhanced hepatocyte proliferation and a 33% increase in liver size. This increased hepatocyte proliferation was associated with reduced expression of hepatocyte nuclear factor 4 alpha (Hnf4α), an important regulator of liver tumorigenesis. We found that PRMT1 regulates Hnf4α expression directly through arginine methylation at the (Hnf4α) promoter. In the absence of PRMT1, JMJD6 can demethylate the Hnf4α promoter and suppress its expression. We were able to restore Hnf4α expression and abolish the increase in hepatocyte proliferation by knockdown of JMJD6 in PRMT1 knockout mice. Knockdown of JMJD6 in alcohol‐fed mice similarly increased Hnf4α expression. We then examined whether loss of arginine methylation might play a role in alcohol‐associated liver cancers. We examined 25 human HCC specimens and found a strong correlation (R = 0.8; P < 0.01) between arginine methylation levels and Hnf4α expression in these specimens, suggesting that the above mechanism is relevant in patients. Conclusion: Taken together, these data suggest that PRMT1 inhibition, such as induced by alcohol, may result in epigenetic changes leading to loss of Hnf4α. This effect may contribute to alcohol's ability to promote liver tumors. (H epatology 2018;67:1109–1126)