Abstract Pancreatic ductal adenocarcinoma (PC) is the fourth most common cancer-related cause of death in Western countries. It is projected that PC will become the second most prevalent cause of cancer-related mortality by the year 2030. Although chemotherapy may offer certain advantages to those who have been diagnosed with pancreatic cancer, its effectiveness is notably constrained by the emergence of chemoresistance and excessive toxicity. In recent studies, it has been established that circulating tumor DNA (ctDNA) serves as a mechanism for cell-specific genetic transfer. We discovered that transposon sequences (known as Zip Codes, ZC) were responsible for ctDNA cell targeting. Therefore, we investigated the possibility of hijacking these ZC to deliver drugs specifically. We began by determining whether PDCA ZC synthesized chemically could target PDCA cells selectively. To achieve this, ZC sequences were labeled with CY5 for high-throughput microscopy. Results show that numerous PDCA-ZC were specific and efficient at targeting PC cell lines while sparing other cancer cell lines. The AluSc8 (PCZC) sequence was chosen for further investigation. The specificity of PCZC for targeting cells was validated using pancreatic islet cells. Based on these findings, we developed a technique for conjugating PCZC with SN38 via a CL2A linker. The results indicated that PCZC-SN38 was a very effective agent at killing PC cells (IC50: 1 μg), but not other cancer cell lines. The therapeutic efficacy of PCZC-N38 was evaluated in vivo using PDX (patient-derived xenografts, Garcia et al Plos One 2013). Maximum tolerated dose testing (MTD) (dosing from 1 to 21 mg of PCZC-SN38/Kg) failed to reach an MTD. Subsequently, we evaluated the efficacy signal of PCZC-SN38 by administering PCZC-SN38 to animals three times per week for three weeks at concentrations of 3 and 30 mg/kg of DNA (equivalent to 0.05 and 0.5 SN38 mg/kg). We used animals treated with vehicle, PCZC alone, and irinotecan (either once per week (50 mg/kg) or three times per week (0.5 mg/Kg) as a comparison. PCZC-SN38 decreased tumor growth by 41% and 70%, respectively, when compared to the vehicle or PCZC alone. The observed efficacy did not result in a change in body weight. In contrast, every animal administered irinotecan at a dosage of 50 mg/kg died within a week. On the contrary, animals that were given irinotecan at a dosage of 0.5 mg/kg demonstrated a growth inhibition of 60% and exhibited remarkable tolerability. Currently, research is being undertaken to determine the therapeutic efficacy of PCZC-SN38 at higher doses. The results outlined in this study illustrate the preliminary application of PC targeted drug delivery using a PC zip code drug conjugate. The results of our study demonstrate an innovative methodology for targeting PC cells specifically with therapeutic cargo material and supports further preclinical development of PCZC-SN38 for PC. Citation Format: Munnever Cinar, Purnachandra Ganji, Andrey Pisarev, Lourdes Martinez-Medina, Dhana S. Bandi, Pavan K. Puvvula, Steven Chang, Daniel Maneval, Bassel El-Rayes, Leon Bernal-Mizrachi. Development of first in class zip code drug conjugate in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3211.
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Oct 1, 2024
Hyunsik Kim + 2
Open Access
