Target-Specific Nanoparticle Polyplex Down-Regulates Mutant Kras to Prevent Pancreatic Carcinogenesis and Halt Tumor
Jill P Smith1, Wenqiang Chen1, Narayan Shivapurkar1
1Department of Medicine, Georgetown University, Washington, DC 20007, USA.
Abstract:
Survival from pancreatic cancer is poor because most cancers are diagnosed in the late stages and there are no therapies to prevent the progression of precancerous pancreatic intraepithelial neoplasms (PanINs). Inhibiting mutant KRASG12D, the primary driver mutation in most human pancreatic cancers, has been challenging. The cholecystokinin-B receptor (CCK-BR) is absent in the normal pancreas but becomes expressed in high grade PanIN lesions and is over-expressed in pancreatic cancer making it a prime target for therapy. We developed a biodegradable nanoparticle polyplex (NP) that binds selectively to the CCK-BR on PanINs and pancreatic cancer to deliver gene therapy. PanIN progression was halted and the pancreas extracellular matrix rendered less carcinogenic in P48-Cre/LSL-Kras mice treated with the CCK-BR targeted NP loaded with siRNA to mutant Kras. The targeted NP also slowed proliferation, decreased metastases and improved survival in mice bearing large orthotopic pancreatic tumors. Safety and toxicity studies were performed in immune competent mice after short or long-term exposure and showed no off-target toxicity by histological or biochemical evaluation. Precision therapy with target-specific NPs provides a novel approach to slow progression of advanced pancreatic cancer and also prevents the development of pancreatic cancer in high-risk subjects without toxicity to other tissues.
Insights
Targeted nanoparticles deliver gene therapy to halt pancreatic intraepithelial neoplasm (PanIN) progression and treat pancreatic cancer by inhibiting mutant KRAS. This precision therapy shows promise for preventing and treating pancreatic cancer with no observed toxicity.
Area of Science:
- Oncology
- Nanomedicine
- Molecular Biology
Background:
- Pancreatic cancer has a poor survival rate due to late-stage diagnosis and lack of therapies for precancerous lesions.
- Targeting the mutant KRASG12D driver mutation, common in pancreatic cancer, remains a therapeutic challenge.
- Cholecystokinin-B receptor (CCK-BR) is over-expressed in pancreatic cancer and high-grade PanINs, making it a viable therapeutic target.
Purpose of the Study:
- To develop and evaluate a novel biodegradable nanoparticle polyplex (NP) for targeted gene therapy delivery to CCK-BR-expressing pancreatic tumors.
- To assess the efficacy of CCK-BR targeted NPs delivering siRNA to mutant KRAS in halting PanIN progression and treating pancreatic cancer in a mouse model.
- To evaluate the safety and toxicity profile of the targeted NP system in vivo.
Main Methods:
- Development of CCK-BR targeted biodegradable nanoparticle polyplexes (NPs) loaded with siRNA against mutant KRAS.
- Administration of targeted NPs to P48-Cre/LSL-Kras mice with PanINs and orthotopic pancreatic tumors.
- Evaluation of PanIN progression, tumor proliferation, metastasis, survival rates, and safety/toxicity through histological and biochemical analyses.
Main Results:
- CCK-BR targeted NPs successfully halted PanIN progression and reduced the carcinogenic nature of the pancreatic extracellular matrix.
- Treatment with targeted NPs significantly slowed tumor proliferation, decreased metastasis, and improved survival in mice with advanced pancreatic tumors.
- Extensive safety and toxicity studies in immune-competent mice demonstrated no off-target toxicity after short or long-term exposure.
Conclusions:
- Precision therapy utilizing target-specific NPs offers a novel strategy to slow the progression of advanced pancreatic cancer.
- This approach can potentially prevent the development of pancreatic cancer in high-risk individuals without causing toxicity to healthy tissues.
- CCK-BR targeted nanoparticle-mediated gene therapy represents a promising therapeutic avenue for pancreatic cancer.
