Lais Haddad

Background:  Pancreatic ductal adenocarcinoma (PDAC) remains an elusive challenge for oncology, with a 5-year survival rate <10.8% and a projection of becoming the 2^nd leading cause of cancer deaths by 2030.^1,2 One of the primary factors contributing to PDAC’s poor prognosis is late diagnosis, as 90% of cases are late-stage diagnoses, and more than 50% of diagnoses are already systemically metastatic at the time of discovery, severely limiting viable therapeutic approaches for treatment.^3,4 Furthermore, PDAC’s poor prognosis is also attributable to the excessive proliferation of pancreatic hyaluronan-collagen-dense extracellular matrix (ECM), which physically compresses nearby vasculature and consequently limits therapeutic drug penetration.^5,6 Consequently, current research into PDAC treatment largely focuses on improving diagnostic latency and therapeutic efficacy.

Methods:  An initial literature search was conducted on Google Scholar using the keywords “pancreatic ductal adenocarcinoma” and “PDAC epidemiology.” Afterwards, targeted searches were conducted using keywords like “PDAC therapy,” “PDAC treatment,” and “PDAC collagen matrix.”

Results:  Dr. Kang et al.’s ⁴ retrospective study on PDAC patients (n = 257) revealed that 25.7% of patients had imaging exams with missed findings, which led to significantly delayed diagnoses in most cases. When reviewing the imaging exams of patients with missed findings (n = 107 exams), at least 88% showed secondary signs of PDAC.⁴ The most missed PDAC sign was vascular encasement, which was present in 36.4% of missed cases but remained unreported in 90% of these cases.⁴ The study also identified technical limitations in imaging protocols that could have contributed to these missed findings, including the lack of pancreas-focused imaging, insufficient contrast dosing, suboptimal slice thickness, and the lack of diffusion-weighted imaging.⁴ Regarding the challenge of PDAC’s dense ECM, Dr. Zinger et al.⁵ developed 100nm collagozomes (collagenase-loaded liposomes) and tested their efficacy in targeting human PDAC ECM implanted into mouse models. The collagozomes significantly reduced PDAC ECM by 5.6 ± 0.8% after 24h of treatment. Furthermore, when followed by administration of paclitaxel micelles, the collagozomes resulted in 87% smaller tumors compared to those first treated with empty liposomes.⁵

Conclusions:  Increasing awareness of PDAC’s secondary signs and addressing the technical limitations of imaging protocols has the potential to significantly improve PDAC prognosis by reducing diagnostic delay. Furthermore, the development of human-tested, ECM-targeting agents could usher in a new generation of potent combination therapies that have the potential to improve outcomes for PDAC patients.

Work Cited

1. Mukund A, Afridi MA, Karolak A, Park MA, Permuth JB, Rasool G. Pancreatic Ductal Adenocarcinoma (PDAC): A Review of Recent Advancements Enabled by Artificial Intelligence. Cancers. 2024;16(12):2240. doi:https://doi.org/10.3390/cancers16122240
2. Principe DR, Underwood PW, Korc M, Trevino JG, Munshi HG, Rana A. The Current Treatment Paradigm for Pancreatic Ductal Adenocarcinoma and Barriers to Therapeutic Efficacy. Frontiers in Oncology. 2021;11. doi:https://doi.org/10.3389/fonc.2021.688377
3. Wood LD, Canto MI, Jaffee EM, Simeone DM. Pancreatic Cancer: Pathogenesis, Screening, Diagnosis and Treatment. Gastroenterology. 2022;163(2). doi:https://doi.org/10.1053/j.gastro.2022.03.056
4. Kang JD, Clarke SE, Costa AF. Factors associated with missed and misinterpreted cases of pancreatic ductal adenocarcinoma. European Radiology. 2020;31(4):2422-2432. doi:https://doi.org/10.1007/s00330-020-07307-5
5. Zinger A, Koren L, Adir O, et al. Collagenase Nanoparticles Enhance the Penetration of Drugs into Pancreatic Tumors. ACS nano. 2019;13(10):11008-11021. doi:https://doi.org/10.1021/acsnano.9b02395
6. Storz P, Crawford HC. Carcinogenesis of Pancreatic Ductal Adenocarcinoma. Gastroenterology. 2020;158(8). doi:https://doi.org/10.1053/j.gastro.2020.02.059