Targeting KRAS and MYC has been a tremendous challenge in cancer drug development. Genetic studies in mouse models have validated the efficacy of silencing expression of both KRAS and MYC in mutant KRAS driven tumors. We investigated the therapeutic potential of a new oligonucleotide-mediated gene silencing technology (U1 Adaptor) targeting KRAS and MYC in pancreatic cancer. Nanoparticles in complex with anti-KRAS U1 Adaptors (U1-KRAS) showed remarkable inhibition of KRAS in different human pancreatic cancer cell lines in vitro and in vivo. As a nanoparticle-free approach is far easier to develop into a drug, we refined the formulation of U1 Adaptors by conjugating them to tumor targeting peptides (iRGD and cRGD). Peptides coupled to fluorescently tagged U1 Adaptors showed selective tumor localization in vivo. Efficacy experiments in pancreatic cancer xenograft models showed highly potent (>90%) anti-tumor activity of both iRGD and (cRGD)2-KRAS Adaptors. U1 Adaptors targeting MYC inhibited pancreatic cancer cell proliferation caused apoptosis in vitro (40–70%) and tumor regressions in vivo. Comparison of iRGD conjugated U1 KRAS and U1 MYC Adaptors in vivo revealed a significantly greater degree of cleaved caspase-3 staining and decreased Ki67 staining as compared with controls. There was no significant difference in efficacy between the U1 KRAS and U1 MYC Adaptor groups. Our results validate the value in targeting both KRAS and MYC in pancreatic cancer therapeutics and provide evidence that the U1 Adaptor technology can be successfully translated using a nanoparticle free delivery system to target two undruggable genes in cancer.

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Objectives-The survival of patients with metastatic colorectal cancer (CRC) has been increasing over recent decades due to improvements in chemotherapy and surgery. There is a need to refine prognostic information to more accurately predict survival as patients survive for any given length of time to assist multidisciplinary cancer management teams in treatment decisions. Methods-We performed a single center retrospective analysis of patients treated with metastatic CRC (unresectable and resectable) who survived >24 months between 2005 and 2015 (N = 155). Patient tumor and treatment related variables were collected. Overall survival (OS) estimates conditional on surviving >24 months were compared with actuarial survival estimates of a cohort of patients (33,104 resected, 39,382 unresected) from the National Cancer Database (NCDB). Results-With a median follow up of 44.2 months, the median OS of resected patients (n=86) was not reached. The median OS of unresected patients was 75.9 months. The conditional survival probabilities of living 1, 2 or 3 years longer after 24 months of survival are 92%, 72% and 52% respectively in unresectable patients and 98%, 92% and 89% in patients who were resected. The corresponding NCDB 1,2 and 3 year actuarial survival was 38%, 20%, and 11% for unresected patients and 68%, 46%, and 32% for resected. *

e15587 Background: For resected stage II MSI-high (MSI-H) colorectal cancer (CRC) without high-risk features (HRF), standard of care recommendation per NCCN guidelines is observation. For tumors with HRF, the prognostic significance and impact of adjuvant therapy remains uncertain. The NCDB was queried to assess outcomes. Methods: Adult patients with stage II MSI-H CRC, surgically resected between 2010 and 2017, were identified in the NCDB. Univariate and multivariate Cox proportional hazards models and Kaplan Meier survival curves were generated to assess impact of HRF, clinical and demographic variables, and chemotherapy use on overall survival (OS). Results: 9634 patients with stage II MSI-H CRC who met criteria were identified. In multivariate analysis T4 tumor status, < 12 lymph nodes (LN) examined, perineural invasion (PNI) and positive margins were associated with worse OS, as were older age and increased comorbidity index (CDCC). Poor differentiation and lymphovascular invasion (LVI) were not associated with OS. No OS difference was observed between T4a vs T4b tumors or based upon tumor sidedness, tumor size, or sex. Excluding poor differentiation (33%) and LVI (17%), HRFs were present in 26% of cases: 21% (n = 2033) had 1 HRF and 5% (n = 505) had > 1 HRF. HRFs were associated with decreased 5-year OS. For 1 HRF OS was 66% (HR 1.48, p < 0.0001) and for > 1 HRF OS was 54% (HR 2.31, p < .0001), compared to 77% with 0 HRFs. HRF presence was associated with increased chemotherapy use: 46% for > 1 HRF, 26% for 1 HRF, and 8% with 0 HRFs. pT4 tumors (T4b > T4a) and younger age were also associated with increased chemotherapy use. By age group, chemotherapy was utilized in 31% of those < 50, 27% of those 51-60, 17% of those 61-70 and 6% of those > 70 years old. In the overall population, chemotherapy administration was associated with improved OS on multivariate analysis compared with no treatment (N = 1344; HR 0.76, p < 0.0001). 69% of patients received multi-agent chemotherapy. However, survival was similar between those receiving single-agent vs multi-agent chemotherapy (HR 1.2, p = 0.2016). In patients < 60 years old, chemotherapy use was associated with decreased OS (HR 1.4, p = 0.0156). Conclusions: In this retrospective, uncontrolled large database survey, HRFs are associated with decreased OS in stage II MSI-H CRC. This data indicates that poor differentiation and LVI do not independently worsen outcomes, but that the presence of multiple HRFs bears relevance. Though chemotherapy was associated with improved OS, the association is reversed in the < 60 year old population; this analysis cannot fully control for extent of disease and PS, among other factors. Chemotherapy should be judiciously administered in Stage II MSI-H CRC with HRFs. Immunotherapy trials are justified.[Table: see text]