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TPS760 Background: Local tumor progression is a cause of significant mortality and morbidity in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). Effective approaches to achieve durable local control are urgently needed. Metabolic reprogramming and enhanced mitochondrial function, both hallmarks of PDAC, are known contributors to chemo- and radio-resistance. CPI-613, a lipoic acid analog that selectively inhibits components of the Krebs cycle in tumors, showed promising preclinical synergy in combination with gemcitabine and radiation therapy (gem-RT). Methods: We describe a single-arm, single-center, open-label, phase I study designed to determine the maximum tolerated dose of CPI-613 when used concomitantly with gemcitabine and intensity modulated radiation therapy (IMRT) for local control of PDAC. CPI-613 will be administered once weekly by intravenous infusion over approximately 2 hours at a starting dose of 500 mg/m2 and dose-escalated/de-escalated using a Bayesian optimal interval design. Gemcitabine will be given once weekly at 400 mg/m2 dosage and IMRT as 54 Gray (Gy) in 30 fractions (1.8 Gy per fraction) with five fractions given per week. Up to 24 patients will be enrolled for the study after meeting the following main eligibility criteria, which include: pathologically confirmed PDAC; inoperable disease that by institutional pancreatic multidisciplinary tumor board or multidisciplinary review are considered to benefit from definitive local control of the primary tumor; ECOG of 0-2; and adequate organ and marrow function after completion of intended systemic chemotherapy. The secondary objectives are to determine the recommended phase II dose of CPI-613 when used with gem-RT, safety and tolerability of CPI-613-gem-RT, overall survival, local progression-free survival (PFS), overall PFS, patient-reported quality of life after treatment, and late gastrointestinal toxicities following treatment with CPI-613-gem-RT. Clinical trial information: NCT05325281 . Support: Cornerstone Pharmaceuticals. [Table: see text]

649 Background: The mTOR inhibitor, Everolimus (EVE), is FDA-approved for the treatment of advanced PNENs on the basis of delay of progression. The RADIANT-3 trial showed an increase in PFS from 4.6 to 11 months compared to placebo with an ORR of only 5%. Prior studies suggest that targeting the aberrant expression of mTOR regulators p21 activated kinase 4 (PAK4) and nicotinamide adenine dinucleotide biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT) in PNENs sensitizes these tumors to EVE. To further qualify these observations, we queried a large real-world dataset of PNENs, characterizing the molecular and immune landscapes, as well as the clinical outcomes associated with aberrant PAK4 and NAMPT expression. Methods: 294 cases of PNENs were analyzed using Next Generation Sequencing (NextSeq) and Whole Exome and Whole Transcriptome Sequencing (NovaSeq) at Caris Life Sciences (Phoenix, AZ). For our analyses, we stratified our study cohort into four groups based on the median expression of PAK4 and NAMPT: PAK4-low/NAMPT-low, PAK4-low/NAMPT-high, PAK4-high/NAMPT-low and PAK4-high/NAMPT-high. Significance was determined using chi-square, Fisher-Exact or Mann-Whitney U, and p-values were adjusted for multiple comparisons (q < 0.05). Results: High prevalence of mutations in PTEN (10.71% vs 1.18%; p < 0.05, q > 0.05), a tumor suppressor of the mTOR pathway and high expression of genes activated in response to mTOR activation such as SLC2A1 (3.07-fold), PFKP (3.32-fold), SCD (2.70-fold), MVK (2.92-fold) and G6PD (2.58-fold) were observed in PAK4-high/NAMPT-high compared to the PAK4-low/NAMPT-low tumors (all q < 0.05). A congruent enrichment of PI3K/AKT/mTOR and glycolysis pathways by single-sample gene set enrichment analysis was observed in these tumors (all q < 0.05). When querying the immune landscape, we observed enrichment in inflammatory response, IL6/JAK/STAT3, IL2/STAT5 signaling pathways and immune checkpoint genes such as PDCD1 (5.14-fold), CD274 (2.84-fold), PDCD1LG2 (2.44-fold), CD80 (3.00-fold), CD86 (2.82-fold), IDO1 (1.92-fold), LAG3 (3.09-fold), HAVCR2 (2.66-fold) and CTLA4 (4.49-fold) in the PAK4-high/NAMPT-high tumors (all q < 0.05). Immune cell infiltration estimates revealed an increase in Neutrophils, NK cells and Tregs in the PAK4-high/NAMPT-high tumors (p < 0.05, q > 0.05). Conclusions: Our study demonstrates that PAK4-high/NAMPT-high PNENs are associated with distinct molecular and immune profiles. While the dual blockade of PAK4 and NAMPT has been reported to enhance the efficacy of EVE in PNENs, whether such a blockade would enhance the efficacy of immunotherapeutics warrants further investigation.

e18688 Background:177Lu-Dotatate is FDA approved for advanced well differentiated (WD) midgut neuroendocrine tumors (NETs). However, questions remain about tolerability and efficacy in patients (pts) with higher grade disease, more than one prior line of treatment, and in non-ileal primaries. Methods: This is a retrospective analysis of pts with histologically proven WD metastatic GEP-NETs who received 177Lu-Dotatate at a single racially diverse urban cancer center. Patients had disease that progressed on systemic therapy that included somatostatin analog (SSA), and radiotracer uptake at disease sites using 68Gallium-Dotate PET/CT. ECOG performance score (PS) was 0 to 2. 177Lu-Dotatate was administered in 200 mCi doses every 8 weeks for a total of 4 cycles and a maximum of 800 mCi. Patients were followed with serial CT scan and/or abdominal MRI with best objective response per RECIST criteria. Results: Fifty-one pts were treated between December 2017 and August 2021. Thirty-eight pts completed a minimum 3-month follow-up imaging. Median age was 64 years, 59% were female, 66% identified as white, 26% as Black, 8% as other. Most frequent primary sites were small intestine (64%) and. All had metastatic disease involving the liver except for one pt. Median time from diagnosis to 177Lu-Dotatate was 51 months (3-201). CTCAE grade 3/4 hematologic toxicity was seen in 6 of 51 pts (12%). Grade 3/4 thrombocytopenia occurred in 3 pts, grade 3/4 leukopenia occurred in 2 pts and grade 3 anemia occurred in 1 pt. A single pt developed myelodysplastic syndrome 1 year after 177Lu-Dotatate. Non-white pts had significantly higher risk of grade 1 elevated creatinine at 38% vs 6% in those who identified as white (p = 0.015). Of the 37 pts who reached 3-month follow-up, 27% had partial response, 43% had a mixed/stable response, and 30% had progressive disease. Only gender demonstrated significant difference; with male gender associated with worse response categories (p = 0.001). Median OS was 3.09 years. Metastatic disease in the liver only was associated with significantly worse OS (p = 0.015) compared to liver and other tissues. The median PFS was 1.36 years. Metastatic disease in the liver only was associated with significantly worse PFS (p = 0.043). Higher tumor grade neared significant association with worse PFS (p = 0.053). There was no difference in PFS by race, primary tumor site (pancreatic vs small bowel), PS, prior treatment history or time to first 177Lu-Dotatate. Conclusions: Diverse patients with WD GEP-NETs treated at this single urban cancer center with 177Lu-Dotatate demonstrated acceptable toxicity. Median PFS and OS were inferior to reported outcomes in NETTER-1 probably because of differences in treatment timing and patient populations. Possible variables associated with difference in outcome include pattern of metastatic disease and tumor grade.

e21149 Background: P21-activated kinase 4 (PAK4) is a crucial effector of the Rho GTPases. It acts as a regulatory switch that controls a wide range of cellular functions and plays a pivotal role in cancer progression and metastasis. Very little is known about the expression and prognostic value of PAK4 in NSCLC. Methods: 17,689 NSCLC tumor samples were analyzed using next-generation sequencing (NextSeq, 592 Genes, or WES NovaSeq), immunohistochemistry (IHC), and whole transcriptome sequencing (NovaSeq) (Caris Life Sciences, Phoenix, AZ). PD-L1 expression was analyzed by IHC (Dako 22c3; PD-L1 positive: TPS >1%). TMB was measured by counting all somatic mutations found per tumor (TMB-high: >10 mutations/MB). Tumors with PAK4-high (H) and PAK4-low (L) expression were classified as those in top quartile and bottom 3 quartiles, respectively. Immune cell infiltrates were calculated by Quantiseq. Significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons (q-value < 0.05). Survival was extracted from insurance claims data and calculated from the time of tissue collection to the last contact using Kaplan-Meier estimates. Results: There was no difference in median age, gender, smoking status, and histologic distribution between PAK-H and PAK-L tumors. Compared to PAK4-L, the PAK4-H was associated with higher frequency of co-mutations in TP53 (76.3% vs 63.9%, p < 0.0001) and RB1 (13.6% vs 8.1%, p < 0.0001). PAK4-H tumors were associated with greater genomic loss of heterozygosity (24.1% vs 16.4%, p < 0.0001), and expression of immune checkpoint genes ( LAG3, PDCD1, PDCD1LG2, CD274, IDO1, CTLA4, CD80, HAVCR2; p < 0.05). KRAS (including KRAS G12C) , BRAF, STK11, and EGFR mutations, and ALK and ROS1 fusions were less frequent in PAK4-H tumors (p < 0.001). A greater proportion of PAK4-H tumors were TMB-H (40.3% vs 33.3%, p < 0.0001) and PD-L1 negative (48.2% vs 40.8%, p < 0.001). PAK4-H tumors had lower infiltration of B cells, M1/M2 macrophages, CD8+ T-cells, and Tregs (p < 0.001). Overall survival (OS) was inferior among patients with PAK4-H tumors (median, 14.9 vs 21.5 months, HR = 1.28, 95% CI, 1.21-1.36, p < 0.001), which was driven by adenocarcinoma histology. Survival with immunotherapy was also inferior in patients with PAK4-H adenocarcinoma (median, 23.6 vs 30.3 months, HR = 1.23, 95% CI, 1.02-1.48, p = 0.03), but not squamous cell carcinoma. A similar trend in survival was noted in patients who received EGFR- and ALK inhibitors. Conclusions: PAK4-H expression in NSCLC is associated with a higher frequency of alterations predisposing to genomic instability, differentially modulated immune phenotype, and a lower frequency of actionable genomic alterations. Patients with PAK4-H adenocarcinoma have inferior OS, and survival with immunotherapy and targeted therapy. PAK4-H expression defines a subgroup of patients with un unmet need for novel treatment strategies.

e20533 Background: Nuclear protein transport is essential in guiding the organized traffic of important proteins and RNAs between the nucleus and cytoplasm of the cell. Export of proteins from the nucleus is exclusively regulated by Exportin 1(XPO1). In cancer, XPO1 is universally hyperactive and can promote the export of important tumor suppressors to the cytoplasm, leading to their functional inactivation. XPO1 is aberrantly over expressed in NSCLC and this over expression has been linked to poor overall survival. The underlying mechanisms of XPO1 over expression are not known. Currently there are no studies evaluating the impact of XPO1 mutations on NSCLC incidence and therapy resistance. Additionally, there are no studies that examined the XPO1 related pathways in NSCLC harboring co-alterations with other driver mutations such as EGFR or ALK. Methods: Tumor samples were analyzed using next-generation sequencing (NextSeq, 592 Genes), IHC, and whole transcriptome sequencing (WTS ,NovaSeq) (Caris Life Sciences, Phoenix, AZ). PD-L1 expression was tested by IHC using 22c3 (Dako) and TPS scores were reported (cutoff > 1%). TMB was measured by totaling somatic mutations (TMB-high cut-off ³ 10 mutations per Megabase). Gene fusions were detected by RNA sequencing using either the Archer FusionPlex panel or WTS. Survival was extracted from insurance claims data and calculated from time of tissue collection to last contact using Kaplan-Meier estimate. Statistical significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons. Results: Among 18,218 NSCLC tumors sequenced, 26 harbored XPO1 mutations. XPO1 mutant tumors were more likely to be TMB High(79% vs. 52%, p = 0.007) and less likely to have high PDL1(32% vs. 68%, p = 0.03). KRAS mutations were seen in 19%(n = 5), EGFR mutation were rare (n = 2), and no targetable fusions were seen. Among the 17,449 NSCLC tumors with clinical data, there were 24 XPO1 mutant tumors with no histology imbalance observed in mutant vs. wild-type(WT). Comparison of survival in the NSCLC group between XPO1 mutant and WT showed a negative association with a hazard ratio(HR) of 1.932 (95% CI: 1.144- 3.264 p = 0.012). Comparing the survival within the subgroup with confirmed adenocarcinoma histology (9973 XPO1 WT and 14 XPO1 mutant) showed a similar negative correlation in survival with a HR of 2.156 (95% CI: 1.027- 4.525 P = 0.037). Conclusions: Presence of XPO1 pathogenic mutations was associated with a poor survival in both the entire NSCLC cohort and the adenocarcinoma subgroup. Further studies of this negative association at the molecular level along with effect of other co-existing mutations can result in development of novel treatment strategies.

e15652Background: Hispanic populations in the United States are historically underserved with less access to health care as well as lower quality of the provided medical care. With the Colorectal C...

e16141Background: Due to lymphoid tissue in the liver parenchyma, non-Hodgkin lymphomas (NHL) in the liver has been well studied. However, studies regarding development of second primary Hepatocell...

233 Background: Pancreatic cancer (PC) is a deadly disease in urgent need of novel molecularly targeted drugs. Gene copy number amplification studies in PC patient cohorts has shown amplification of the p21-activated kinase (PAK) family member PAK4. PAK4 acts as a key effector of the Rho family GTPases downstream of Ras signaling. Moreover, PAK4 protein is over-expressed in PC cell lines but not in normal human pancreatic ductal epithelial (HPDE) cells. Most importantly, RNA interference of PAK4 has been shown to suppress PC cell proliferation. These studies clearly make PAK4 an attractive therapeutic target especially because direct targeting of Kras has been a failure. Methods: We have identified a new class of PAK4 allosteric modulators that show anti-proliferative activity against several PC cell lines (IC50s 50s5 fold higher). Results: Cell growth inhibition is concurrent with apoptosis induction and suppression of colony formation in the PC cell lines (and not in HPDE cells). Our small molecule PAK4 allosteric modulator, KPT-7189, suppresses PAK4 protein expression and caused reversal of anti-apoptotic signaling. PAK4 RNA interference enhances KPT-7189 activity, and co-immunoprecipitation experiments showed disruption of PAK4 binding partners. KPT-7189 also inhibited spheroid forming ability of highly resistant PC cells carrying markers of cancer stem cells (CSCs;triple positive for CD33+CD44+EpCAM+) consistent with epithelial-to-mesenchymal (EMT) phenotype. Molecular analyses of KPT-7189 treated CD33+CD44+EpCAM+ spheroids showed suppression of EMT and CSC markers with re-expression of epithelial phenotype markers. Another potent PAK allosteric modulator in the same series, KPT-7651 showing good oral bioavailability (%F = 95%) was well tolerated by mice with a maximum tolerated dose of 60 mg/kg following oral administration. Pre-clinical animal efficacy trial in sub-cutaneous, orthotopic and LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre transgenic mice model is currently under investigation. Conclusions: This is the first proof of concept study demonstrating the development of a PAK4-targeted drug for the treatment of PC, and thus further pre-clinical and clinical investigations are warranted.

245 Background: Pancreatic (PC) and Colon (CC) cancer remain deadly diseases despite the advent of novel targeted and cytotoxic therapies. Therefore, identification of new targets and development of novel agents against these targets are urgently needed. CRM-1 is a nuclear export protein encoded by the XPO1 (exportin 1) gene that mediates leucine-rich nuclear export signal ( NES )-dependent protein export. Elevated CRM-1 expression has been correlated with poor prognosis in PC and CC making it an attractive therapeutic target. Methods: Using structure based drug design, we have identified novel, irreversible small molecule inhibitors of CRM-1 that lock target proteins, including TSP, in the nucleus. Normal cells undergo cell cycle arrest, but most cancer cells initiate apoptosis. Thus, the drugs selectively kill cancer cells with minimal toxicity to normal tissue and possess clinically acceptable pharmacokinetic parameters. In this report, using multiple molecular biological techniques, we have evaluated the role of CRM-1 inhibition on nuclear localization and apoptosis by PAR-4. Results: The most potent small molecule CRM-1 inhibitor (KPT-185) induced growth inhibition and apoptosis in a panel of PC and CC cell lines with IC50’s Conclusions: This is the first report demonstrating CRM-1 as a potential therapeutic target in both PC and CC, perhaps by enhancing PAR-4 function. The drugs KPT-185 and related CRM1-inhibitors warrant further clinical investigations for this deadly malignancy.

e13613 Background: p53 mutation (mut-p53) has been reported in over 50% of pancreatic adenocarcinoma (PC). MDM2 inhibitors disrupt the MDM2-p53 interaction and restore p53 function in wild type (wt...

19541 Background: VTD is a highly active combination in pts with relapsed/refractory multiple myeloma (RRMM). ATO alone has modest activity but AA may enhance the cytotoxic effects of ATO. V, T, and ATO inhibit NF-κB, but it is unknown if combining these agents results in increased NF-κB inhibition. This study was undertaken to generate preliminary data on the combination of ATO, AA, and VTD for the treatment of RRMM. Methods: Five male pts (ages 49–77 yrs old) were enrolled in this IRB approved study between Sept 2005 and Aug 2006. The mean number of prior treatments was 3 (range 1–7; autologous transplant in 3 pts). Pts received D 40 mg po/IV and V 0.7 mg/m2 IV on days 1, 4, 8, and 11 of a 21-day cycle and T 50 mg daily po. Starting with cycle 2, ATO (given at an initial dose of 0.10 mg/kg IV) and AA (1000 mg IV) were added on days 1, 4, 8, and 11. Blood samples were drawn prior to and 1 hour after the administration of V on day 1 of cycle 1, and 1 hour after administration of therapy (V + ATO/AA) on da...