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Targeted Therapies for Pancreatic Cancer and Hurdles Ahead

Minela Aslan¹, Reza Shahbazi², Kezban Ulubayram^1,2,3

¹Bioengineering Division, Institute for Graduate Studies in Science and Engineering, Hacettepe University, Ankara, Turkey.

Anticancer Research

|December 4, 2018

Abstract:

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers with a median survival of 6 months after diagnosis. Intrinsic resistance to chemotherapeutics and lack of effective targeted therapies are the major factors contributing to dismal prognosis. Several important genetic alterations (i.e., mutations, deletions) have been identified to be involved in the initiation and progression of pancreatic cancer, including KRAS and inactivation of tumor suppressors, such as TP53, SMAD4 and CDKN2A. Unique tumor microenvironment with excessive stroma due to desmoplastic reaction is one of the major characteristics of PDAC, promoting tumor growth and leading to treatment failures. In addition, tumor stroma represents an important biological barrier for drug delivery and successful treatment of PDAC. Small interfering RNA (siRNA) has recently emerged as a potential and targeted therapeutic approach which is now evaluated in clinical trials. However, siRNA-based therapeutics face important challenges, including rapid serum degradation, poor tumor cell uptake and cellular uptake, leading to off-target effects. Therefore, there is a great need for the development of safe and effective nanoparticles for better tumor-specific delivery of anti-cancer therapeutics. In this article, the main challenges in the treatment of pancreatic cancer and recent advancements on nano delivery systems of chemotherapeutics and gene-targeted agents, used both in preclinical and clinical trials are reviewed.

Insights

Pancreatic cancer (PDAC) treatment faces challenges due to drug resistance and a dense tumor microenvironment. Nanoparticle delivery systems show promise for improving chemotherapy and gene therapy for PDAC.

Area of Science:

Oncology
Nanotechnology
Biomedical Engineering

Background:

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with poor prognosis due to treatment resistance and a unique, dense tumor microenvironment.
Key genetic alterations like KRAS mutations and tumor suppressor inactivation drive PDAC progression.
The desmoplastic stroma in PDAC hinders drug delivery and treatment efficacy.

Purpose of the Study:

To review the challenges in pancreatic cancer treatment.
To explore advancements in nanoparticle-based delivery systems for chemotherapeutics and gene-targeted agents in PDAC.
To highlight the potential of nanomedicine in overcoming PDAC treatment barriers.

Main Methods:

Review of preclinical and clinical trial data on nanoparticle delivery systems for PDAC.
Analysis of challenges associated with current PDAC therapies, including drug resistance and tumor stroma.
Evaluation of small interfering RNA (siRNA) therapeutics and their delivery challenges.

Main Results:

Nanoparticle delivery systems offer potential for improved tumor-specific delivery of anti-cancer agents.
Overcoming rapid serum degradation and poor cellular uptake are key challenges for siRNA therapeutics.
Nanomaterials can potentially enhance drug penetration through the tumor stroma.

Conclusions:

Developing safe and effective nanoparticles is crucial for targeted PDAC therapy.
Nanotechnology holds significant promise for improving the efficacy of chemotherapy and gene therapy in pancreatic cancer.
Further research into nanoparticle-drug conjugates and targeted delivery mechanisms is warranted for PDAC treatment.

Read full analysis

Keywords:

Pancreatic cancer RNA interference drug delivery gene regulation gene silencing gene therapy gene-knockdown liposomes microRNA nanoparticles ncRNA resistance review siRNA targeted therapy

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