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Global Translational Medicine Small RNA therapy for pancreatic cancer

Table 1. Categories, principles, and side effects of existing chemotherapy drugs for PC
Drug name Category Mechanisms of action Side effects
Gemcitabine Cytosine nucleoside Its main metabolites penetrate DNA inside cells, interfering with Leukopenia, thrombocytopenia,
derivative DNA synthesis and inhibiting ribonucleotide reductase. anemia, and gastrointestinal reactions.
Nab-paclitaxel Paclitaxel nanodrug-targeted Paclitaxel is a natural anticancer agent that inhibits DNA Bone marrow suppression.
formulation unwinding, thereby suppressing tumor cell proliferation and
metastasis.
5-FU Antimetabolic drug Inhibits thymidylate synthase, suppressing DNA synthesis. Bone marrow suppression, leading
to reduced white blood cells and
platelets.
Leucovorin Antidote to folic acid Enhances the antitumor effect of 5-FU Gastrointestinal discomfort at high
antagonists doses.
Irinotecan DNA topoisomerase I Blocks DNA replication and inhibits RNA synthesis, specifically Gastrointestinal discomfort at high
inhibitor during the S-phase. doses.
Oxaliplatin DNA crosslinker Platinum atoms form crosslinks with DNA, disrupting replication Neurotoxicity.
and transcription.
Abbreviations: PC: Pancreatic cancer; 5-FU: 5-Fluorouracil.

paclitaxel. The results showed that patients receiving the repeat domain containing 7. The KRAS protein functions
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combination therapy demonstrated superior outcomes, as a molecular switch, which is activated in response to
leading to the Food and Drug Administration (FDA) upstream epidermal growth factor receptor and regulated
approval of nab-paclitaxel for PC in 2014. downstream mitogen-activated protein kinase 1 (MAPK)
and PI3K/mTOR pathways, ultimately controlling cell
In general, there are no established universal guidelines proliferation, differentiation, and survival. KRAS gene
for second-line treatments and beyond for PC. The choice mutations are particularly common in solid tumors and
of therapy typically depends on factors such as the patient’s have long been a focus of precision therapy. In addition,
performance status, the presence of “actionable” targets, the classic targets with abnormal mutations associated
and the availability of suitable clinical trials. with the invasiveness and metastasis of PC also include
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3. Genetic factors involved in PC matrix metallopeptidase 2 (MMP2), Ras-responsive
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element binding protein 1 (RREB1), nuclear factor-
development kappa B (NF-κB), ribonucleotide reductase regulatory
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3.1. Proteins involved in the development of PC subunit M2, and signal transducer and activator of
transcription 3 (STAT3). In addition to known classical
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Seventeen protein targets for PC are shown in Table 2. mutations, a recent study found that ubiquitin-specific
These targets can be categorized into three major groups peptidase 15 (USP15) acts in a haplodeficient manner,
according to their mechanisms of action. where the loss of USP15 or SR-related CTD-associated
The first group focuses on inhibiting tumor factor 1 leads to reduced inflammatory tumor necrosis
invasiveness and metastasis. PC develops due to the factor-alpha, transforming growth factor beta, and
accumulation of multiple genetic alterations, including interleukin-6 responses and increased sensitivity to poly-
mutations in tumor suppressor genes, oncogenes, and ADP ribose polymerase inhibitors and gemcitabine. All
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chromosomal abnormalities. These changes may arise these abnormal mutated genes represent potential targets
gradually through a multistep process or suddenly for small RNA drug development (Table 2).
in a single catastrophic event. 19,20 As a result of these The second group of genetic factors is related to
mutational processes, tumors acquire numerous random enhancing the sensitivity of PC cells to chemotherapy
bystander mutations that contribute to tumor initiation, drugs. Another challenge in the development of new drugs
progression, metastasis, and resistance to therapy. Whole- for PC is their resistance to chemotherapy. The transport,
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exome sequencing studies have revealed several recurrent activation, and metabolism of gemcitabine are regulated
mutations that impact the function of critical oncogenes by a wide range of enzymes, meaning that drug resistance
and tumor suppressors, including Kirsten rat sarcoma can arise through various mechanisms, as almost all
viral oncogene homolog (KRAS), tumor protein p53, metabolic processes involving gemcitabine contribute to
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cyclin-dependent kinase inhibitor 2A, SMAD family resistance. The intracellular transport of gemcitabine
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member 4, ring finger protein 43, and F-box and WD is mainly mediated by human equilibrative nucleoside
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Volume 4 Issue 2 (2025) 14 doi: 10.36922/gtm.8247