Tracey Pu

Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) are a rare subset of cancers with increasing incidence. Due to their slow growth and lack of targetable mutations, the identification of effective treatments remains limited. One reason behind this stagnation is the lack of applicable, accurate study models. One solution is patient tumor organoids (PTOs) that maintain tumor characteristics and can scale for high throughput assays. In this study, PTOs were generated from 35 tumors of pancreatic, small intestinal, and gastric origin, obtained from 17 patients. Important subtypes including hormone functional and MEN1 / VHL mutant GEP-NETs are represented, with each demonstrating growth in culture while maintaining GEP-NET immunohistochemistry and genomic characteristics. Half of G2/G3 tumors (10 of 20) could be cultured past passage 6, whereas G1 tumors ( n = 15) were capable of growth until passage 4. Therapeutic targeting of the PTOs displayed both tissue-origin and grade-based response to standard of care and investigational therapies while maintaining patient tumor sensitivity and resistance. Last, a successful PTO xenograft model was developed from one PTO line. This study describes GEP-NET organoid development that demonstrates feasibility for expansion, enabling their use for translational investigations.

PURPOSE: Smoking cessation after a cancer diagnosis improves survival, but widespread adoption of evidence-based cessation assistance has not been demonstrated. American College of Surgeons' accredited cancer programs participated in the nationwide Beyond ASK quality improvement (QI) initiative to increase the proportion of currently smoking patients with cancer offered cessation assistance as part of cancer care delivery. METHODS: A national QI project was employed between January 2023 and January 2024 following the Plan-Do-Study-Act methodology, and five longitudinal surveys were administered. Participating programs received educational webinars, an online practice change package that contained information about evidence-based smoking assessment and cessation assistance tools, training opportunities, and electronic health record guidance. Primary outcomes included identification of current smoking among patients with newly diagnosed cancer and rate of providing cessation assistance among currently smoking patients. RESULTS: A total of 324 programs (164 [50.8%] community programs) enrolled in Beyond ASK. Participation rates were high with 300 (92.6%) programs completing all five surveys. Among 446,015 reported patients newly diagnosed with cancer, 52,794 (11.8%) were identified as currently smoking of which 33,638 (63.7%) received cessation assistance. The mean assist rate increased from 48.0% (95% CI, 43.7 to 52.2) at baseline to 67.5% (95% CI, 63.6 to 71.3) at final. Full adoption was reported by 65.4% of programs. Delivery of cessation assistance increased over time for in-office brief counseling (33.9%-65.8%, P = .0002), in-office behavioral counseling (7.1%-18.5%, P = .02), referral to in-house program (14.5%-27.3%, P = .02), referral to community program (12.1%-29.5%, P = .002), and referral to web-based programs (12.2%-33.9%, P = .0002). CONCLUSION: Scaled improvement in smoking cessation assistance across accredited cancer programs is feasible and achievable relatively quickly. Findings provide a framework to guide national adoption for smoking cessation assistance as standard care for all patients with newly diagnosed cancer.

PURPOSE: Most patients with metastatic colorectal cancer (CRC) have microsatellite stable or mismatch repair-proficient tumors, which are resistant to immunotherapy especially in cases of liver metastases. We sought to determine whether tumor-targeted interleukin-12 (PDS01ADC) can improve outcomes for patients with CRC liver metastases managed with hepatic artery infusion pump (HAIP) chemotherapy. MATERIALS AND METHODS: NCT05286814 is a phase II nonrandomized trial evaluating subcutaneous PDS01ADC in combination with HAIP floxuridine and systemic chemotherapy (leucovorin, 5-fluorouracil, and oxaliplatin or leucovorin, 5-fluorouracil, and irinotecan) in patients with unresectable microsatellite stable or mismatch repair-proficient colorectal liver metastases previously treated with at least one line of systemic chemotherapy. The primary end points for the planned interim analysis were overall response rate and safety. RESULTS: Nine patients were included in this planned interim analysis. Seventy-eight percent (7/9) of patients receiving PDS01ADC with HAIP therapy had partial or complete responses at 6 months. The median hepatic progression-free survival for patients receiving PDS01ADC + HAIP therapy was 12.7 months with a minimum follow-up of 13.1 months. Grade ≥3 toxicities occurred in 78% but were manageable and did not limit HAIP therapy. No patients developed a biliary stricture within 6 months of initiating treatment. Clinical responders to PDS01ADC demonstrated enhanced peripheral immune activation, including elevated levels of circulating T-cell subsets with stem-like features, and increased CD8 ⁺ T-cell:T regulatory cell ratio in tissue biopsies. CONCLUSION: Addition of PDS01ADC is not detrimental to HAIP therapy and is associated with both systemic and intratumoral immune modulation. Initial results warrant continuation to full enrollment for further evaluation of clinical and scientific end points.

Targeting tumors with proteosome inhibitors has demonstrated antitumor activity and has been successfully translated to the clinic for patients with multiple myeloma. However, in patients with solid tumors, treatment with proteosome inhibitors as single agents has consistently failed to yield meaningful responses. In our study, we investigate the potential of hepatic artery infusion pump delivery of carfilzomib, to continuously direct a large dose to the tumor with least hepatic toxicity.

TRANSITE prediction of RNA binding proteins whose motifs are overrepresented in the 3’-UTR transcriptomes of GCN1 KD (SH1 and SH2) KLM1 cells.

Figure S4. IMPACT abrogates GCN1-mediated immune cell evasion

List of all hits identified in the cDNA screen and categorized by function. cDNAs highlighted in red were identified in the 3 KB library fraction. The number of tumor lesions identifying the cDNA is given.

Figure S2. GCN1 drives metastatic growth through activation of ATF4

Figure S7. Expression of IMPACT is lost through genomic deletion and epigenetic silencing

GCN1 cDNA sequence in 4964-POP and 4964-HOP cells.