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Global Translational Medicine Small RNA therapy for pancreatic cancer

drugs lies in their ability to target sites that traditional prevents effective drug delivery. All these factors contribute
drugs cannot reach, with higher specificity and fewer to an overall 5-year survival rate of <7% for PC patients.
side effects. Despite their enormous potential, applying
small RNAs in clinical settings remains challenging. Small 2.2. The main treatment methods for PC
RNA molecules are highly susceptible to degradation by The current treatment of PC primarily includes surgical
nucleases in the body, and they struggle to penetrate cell treatment, radiation therapy, chemotherapy, interventional
membranes effectively due to their relatively large size. therapy, and best supportive care. Chemotherapy remains
Although the development of RNA drugs is confronted the main treatment option for metastatic PC patients.
with unprecedented challenges, numerous strategies have Here, the categories, principles, and side effects of six
been developed to enhance RNA metabolic stability and existing PC drugs are summarized, including gemcitabine,
intracellular delivery, including nanoparticle carriers, nab-paclitaxel, 5-fluorouracil (5-FU), leucovorin,
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liposomes, and viral vectors. With continued advancements irinotecan, and oxaliplatin (Table 1). Among these six
in these technologies, small RNA drugs hold promise as a drugs, gemcitabine is the most studied chemotherapy for
new and effective treatment for PC and other malignant PC. Gemcitabine is a cytosine nucleoside analog that
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tumors. can be incorporated into replicative DNA to inhibit DNA
This article provides a brief overview of the current synthesis. After entering the body, gemcitabine is converted
state of PC treatment and the development of small RNA by deoxycytidine kinase into gemcitabine diphosphate and
drugs, including 17 approved small RNA drugs and 43 triphosphate, which are active drug metabolites that have
small RNA drugs currently in clinical trials. Subsequently, multiple inhibitory effects on DNA synthesis. 15
the genetic factors involved in the progression of PC are For a long time, single-agent gemcitabine treatment
explored, summarizing 17 protein-coding genes and 15 was the standard treatment regimen for advanced PC.
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miRNA genes that could serve as targets for small RNA However, gemcitabine had significant limitations as a
drugs. Finally, six strategies for the development of small monotherapy for advanced PC, with the biggest drawback
RNA drugs are discussed. being its short half-life. A higher dosage was required to
2. PC maintain an effective concentration. However, high-dose
administration inevitably causes severe side effects in
2.1. PC introduction patients, such as leukopenia, thrombocytopenia, anemia,
PC is a malignant tumor that originates from the pancreatic and gastrointestinal reactions. Given these limitations in
ductal epithelium and acinar cells, often referred to as monotherapies, the clinical communities have increasingly
the “king of cancers” in the medical community. The turned their attention to combination therapy. In the past
exact cause of its onset is not yet fully understood, but decade, two new combination therapies have emerged as
studies suggest that factors such as long-term smoking, first-line treatment options for patients with advanced
poor dietary habits, high body mass index, and chronic PC. The first was a combination of 5-FU, leucovorin,
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pancreatic damage may increase the risk of developing PC. irinotecan, and oxaliplatin, known as FOLFIRINOX.
In recent years, the incidence of PC has risen significantly, PRODIGE 4/ACCORD 11 was a clinical trial involving 342
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more than two-fold over the past 30 years. Even more French patients, in which FOLFIRINOX was administered
concerning, projections indicate that by 2040, PC will fortnightly to previously untreated, functionally intact
surpass colorectal cancer to become the second leading metastatic PC patients (Eastern Tumor Cooperative group
cause of cancer-related deaths, behind only lung cancer. 11 performance status 0 – 1) and compared with gemcitabine
monotherapy. This study highlighted the superior
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PC is notorious for its difficult prognosis, which is
driven by several factors. First, PC is difficult to detect in efficacy of FOLFIRINOX across all clinically significant
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parameters. Consequently, FOLFIRINOX has become
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its early stages due to its tendency to grow around nerves the preferred first-line treatment for patients; however, its
and blood vessels. In addition, it often metastasizes to severe side effects require that patients be in good physical
distant sites early, which makes radical surgical resection condition.
unsuccessful in most patients. Second, patients with
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advanced PC exhibit significant resistance to most The second combination therapy combined gemcitabine
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conventional treatment methods, including chemotherapy, with nab-paclitaxel, a 130-nm paclitaxel formulation
radiation, and molecularly targeted therapy. Finally, PC bound to albumin particles. An international phase III
displays multiple genetic and epigenetic alterations and study involving 861 patients with metastatic PC was
has a complex, dense tumor microenvironment, which not conducted, in which participants were randomly assigned
only makes it difficult to develop specific drugs but also to receive either gemcitabine alone or gemcitabine + nab-

Volume 4 Issue 2 (2025) 13 doi: 10.36922/gtm.8247