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Introduction to Drug Repurposing in Pancreatic Cancer
Understanding Drug Repurposing
Drug repurposing, also known as drug repositioning, involves using existing FDA-approved medications originally designed for non-cancer conditions for new therapeutic applications in oncology. This innovative strategy aims to identify new uses for these drugs beyond their initial indications, capitalizing on their known safety profiles and established clinical data.
Advantages in Oncology
One of the main benefits of repurposing drugs in cancer treatment, including pancreatic cancer, is the significantly shorter development time and lower costs compared to developing novel drugs from scratch. Because these drugs have already undergone extensive safety testing, their path to clinical trials for cancer indications is faster. Additionally, repurposed drugs often exhibit multi-target effects, allowing modulation of various cancer hallmarks such as tumor metabolism, immune evasion, and cancer stem cell resistance.
Current Challenges and Clinical Impact
Despite its promise, drug repurposing faces hurdles such as dosage optimization, ensuring effective delivery to tumor sites, and regulatory or patent issues. Furthermore, translating preclinical successes into clinical efficacy remains challenging, especially for aggressive cancers like pancreatic ductal adenocarcinoma with complex tumor microenvironments. Nevertheless, ongoing clinical trials and bioinformatics analyses are uncovering promising repurposed candidates, offering hope for improved treatment options against this deadly disease.
Molecular Landscape and Bioinformatics in Identifying Repurposed Drug Candidates
What is drug repurposing in cancer treatment?
Drug repurposing in cancer treatment involves utilizing existing FDA-approved medications for new therapeutic indications. This strategy can accelerate drug development because these medications already have established safety profiles, shortening the time and cost associated with bringing new treatments to patients. It offers an affordable and effective option, with drugs such as statins, beta blockers, and antidiabetics being explored for cancer therapy enhancement. Clinical trials at leading institutions are investigating the combination of repurposed drugs with immunotherapies and targeted agents to improve cancer outcomes, including in pancreatic cancer.
Genetic mutations in pancreatic cancer (KRAS, TP53, CDKN2A, SMAD4)
Pancreatic cancer's molecular profile is characterized by frequent mutations in key genes that drive tumor growth and progression. Mutations in the KRAS gene occur in about 90% of cases, making it a central player in pancreatic tumorigenesis. Other common mutations include TP53, CDKN2A, and SMAD4, which contribute to cell cycle deregulation, impaired apoptosis, and metastasis. These genetic alterations also impact the tumor microenvironment and immune evasion, posing challenges for effective treatment.
Transcriptomic and network analyses to identify key molecular targets
Researchers analyze transcriptomic data from multiple repositories to identify genes that are upregulated in pancreatic cancer. Using datasets from GEO, CanProVar, PC-GDB, and HPCGD, scientists have identified over 300 such genes. Among these, matrix metalloproteinases (MMP3, MMP9, MMP2) and the epidermal growth factor receptor (EGFR) are prominent targets involved in tumor invasion and proliferation. Network analyses, including gene and pathway enrichment studies, help reveal the interactions and signaling cascades vital to pancreatic cancer progression.
Use of bioinformatics tools and databases in drug target discovery
Advanced bioinformatics tools like Cytoscape, GeneMANIA, and NetworkAnalyst facilitate visualizing and analyzing complex gene interactions and pathways. These platforms integrate transcriptomic and proteomic data, allowing researchers to pinpoint molecular hubs and critical pathways for therapeutic targeting. Connectivity Map (CMap) technology enables the identification of existing drugs that can modulate these molecular targets, accelerating the drug repurposing process.
Examples of promising drugs identified via docking studies (Dasatinib, Pioglitazone)
Computational docking studies have demonstrated strong binding affinities of certain repurposed drugs to key pancreatic cancer targets. Dasatinib, originally a tyrosine kinase inhibitor, shows significant binding to MMP3, MMP9, and EGFR, suggesting its potential to inhibit tumor invasion and growth pathways. Pioglitazone, a diabetes medication, exhibits strong affinity for MMP3, MMP2, and MMP9, highlighting its multitarget potential to interfere with tumor progression. These insights support further preclinical validation of these drugs as part of novel pancreatic cancer therapies.
| Topic | Details | Significance |
|---|---|---|
| Genetic Mutations | KRAS (~90%), TP53, CDKN2A, SMAD4 mutations | Drive tumorigenesis and influence resistance |
| Transcriptomic Analysis | Identification of 303 upregulated genes including MMPs and EGFR | Highlights potential therapeutic molecular targets |
| Bioinformatics Tools | Use of Cytoscape, GeneMANIA, NetworkAnalyst, CMap | Enables identification and visualization of drug targets and pathways |
| Docking Studies | Dasatinib targets MMP3, MMP9, EGFR; Pioglitazone targets MMP3, MMP2, MMP9 | Suggests repurposed drugs with promising molecular interactions for pancreatic cancer |
Clinical Trials and Novel Therapies Using Repurposed Drugs in Pancreatic Cancer
What new treatments are being explored for pancreatic cancer?
Recent therapeutic research for pancreatic cancer is driven by the urgent need to improve outcomes for a disease often diagnosed at an advanced and challenging stage. Emerging advances include genetic mutation-targeted drugs, especially those addressing the prevalent KRAS mutation in pancreatic cancer found in approximately 90% of pancreatic tumors. Pancreatic cancer vaccines represent a novel therapeutic class designed to activate the immune system early and potentially delay cancer recurrence. Strategies to enhance immunotherapy effectiveness include overcoming tumor microenvironment barriers that suppress immune cell infiltration.
What is the VESPA trial and how does it contribute to pancreatic cancer treatment?
The VESPA trial is an innovative clinical study investigating the repurposing of two well-known non-cancer drugs – valproic acid, an anti-epileptic agent, and simvastatin, a cholesterol-lowering statin – combined with standard chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC). This trial enrolls patients across centers in Italy and Spain, aiming to improve progression-free survival and reduce chemotherapy-associated toxicity. Thanks to promising preclinical results, this approach leverages safe and widely available medications, potentially offering a cost-effective enhancement to current chemotherapy regimens.
Which other repurposed drugs are under clinical investigation?
A variety of repurposed medications are being evaluated in clinical trials for their anticancer effects in pancreatic cancer. Drugs such as propranolol, a beta-blocker, metformin, widely used for diabetes management, and antipsychotic agents including haloperidol and penfluridol are notable. These drugs have shown preclinical effectiveness by targeting diverse pathways critical to cancer progression, including cancer stem cell survival, tumor metabolism, and immune modulation. Trials are often exploring these agents in combination with either chemotherapy or immunotherapy to improve therapeutic efficacy while aiming to minimize side effects.
How are combination therapies shaping pancreatic cancer treatment?
Combination therapies represent a promising strategy to overcome treatment resistance and augment efficacy in pancreatic cancer care. Studies are investigating combinations of repurposed drugs with standard chemotherapy, immunotherapies, and targeted agents. For instance, combining valproic acid with simvastatin and chemotherapy exemplifies efforts to increase effectiveness while reducing toxicity. Integration of multi-drug regimens attempts to attack pancreatic tumors through multiple mechanisms simultaneously, including disrupting tumor metabolism, modulating the immune microenvironment, and inhibiting critical molecular pathways as detailed in combination therapies in pancreatic cancer treatment.
What is the role of patient-centered approaches and biomarker identification?
Cutting-edge pancreatic cancer clinical trials like the VESPA study emphasize patient involvement and personalized medicine. Collaborative partnerships with patient advocacy organizations ensure that patient perspectives shape trial design and implementation. Moreover, biomarker identification within these studies aims to predict individual responses to repurposed therapies, enabling tailored treatments. This precision medicine approach seeks to maximize therapeutic benefits while minimizing unnecessary exposure to ineffective drugs, heralding a new era of more personalized and effective pancreatic cancer care.
Targeting the Tumor Microenvironment and Cancer Stem Cells with Repurposed Drugs
How do repurposed drugs impact the pancreatic tumor microenvironment, desmoplasia, and immune cells?
Pancreatic ductal adenocarcinoma (PDAC) features a dense, fibrotic tumor microenvironment known as desmoplasia that hinders drug delivery and promotes immune evasion. Repurposed drugs such as losartan and pirfenidone have shown promise in modulating this stroma. Losartan, an angiotensin receptor blocker, reduces tumor fibrosis by modulating extracellular matrix components, improving chemotherapy penetration. Pirfenidone, an anti-fibrotic agent, inhibits stromal activation and desmoplasia, thereby decreasing tumor growth and metastasis.
What roles do chloroquine and beta blockers play in modulating the stroma and immune response?
Chloroquine and hydroxychloroquine inhibit autophagy, sensitizing pancreatic cancer cells to chemotherapy and immune system attack. Beta blockers like propranolol enhance immune response and reduce tumor invasion, with ongoing trials investigating their perioperative benefits. These drugs alter the tumor’s immune-suppressive environment, potentially overcoming inherent pancreatic cancer therapy resistance.
How can repurposed drugs target cancer stem cells and overcome therapy resistance?
Cancer stem cells (CSCs) contribute significantly to pancreatic cancer progression and relapse by resisting conventional therapies. Repurposed agents such as metformin and doxycycline have demonstrated the ability to inhibit CSCs by interfering with mitochondrial function and metabolic pathways. This targeting may reduce recurrence and improve long-term outcomes.
What are the benefits of combination therapies involving repurposed drugs in pancreatic cancer?
Combining repurposed drugs with standard chemotherapy or immunotherapy can produce synergistic effects, enhancing overall treatment efficacy. For example, valproic acid and simvastatin combined with chemotherapy improved outcomes in preclinical models. Similarly, integrating immune modulators and stroma-targeting drugs addresses multiple resistance mechanisms simultaneously, presenting a comprehensive strategy against PDAC.
This multipronged approach leveraging repurposed drugs reprograms the tumor microenvironment, inhibits CSCs, and potentiates immune response, offering new hope in managing pancreatic cancer's complexity and resistance.
Technological Advances Facilitating Drug Repurposing and Targeted Delivery
How are computational tools, molecular docking, and AI used to identify drug candidates?
Computational technologies have revolutionized drug repurposing for cancer therapy by enabling the rapid screening and identification of potential therapeutic agents. Molecular docking simulations predict how drugs bind to target proteins implicated in pancreatic cancer, allowing researchers to prioritize candidates with strong binding affinities. Artificial intelligence and machine learning algorithms analyze vast datasets to uncover novel drug-target interactions and predict efficacy, shortening the discovery timeline.
What role do nanotechnology-based delivery systems play in pancreatic cancer treatment?
Nanotechnology enhances the targeted delivery of repurposed drugs, improving treatment efficacy and reducing systemic toxicity. Nanocarriers such as liposomes, polymeric nanoparticles, and mesoporous silica facilitate precise drug delivery to tumor sites, overcoming biological barriers and sparing healthy tissues. This targeted approach can increase the bioavailability of anticancer agents and minimize side effects commonly seen with conventional chemotherapy.
How are organoids and tumoroids utilized in preclinical screening?
Patient-derived organoids and tumoroids model the heterogeneity and complexity of pancreatic tumors more accurately than traditional cell cultures. These 3D models serve as platforms for screening repurposed drugs, enabling personalized medicine by assessing drug responses specific to an individual’s tumor. This preclinical testing helps tailor treatment strategies and improves the likelihood of clinical success.
What are some examples of innovative delivery systems enhancing therapy?
New approaches like targeted nasal delivery and specialized oral formulations aim to optimize drug bioavailability and minimize toxicity. For example, nasoduodenal delivery systems for radioprotective agents allow increased radiation dosing while protecting healthy tissue. Additionally, integration with nanomedicine techniques supports synergistic effects with existing chemotherapies and immunotherapies.
What are the advantages, challenges, and impact of drug repurposing for cancer treatment?
Drug repurposing in cancer therapy accelerates therapy availability due to known safety profiles and existing approvals, reducing costs and development time. Nevertheless, challenges include limited knowledge of oncologic mechanisms, off-label safety concerns, and the need for rigorous clinical validation. Despite these, repurposing offers a promising avenue to expand treatment options, especially for difficult cancers like pancreatic disease, potentially improving survival and quality of life for patients.
| Technology/Strategy | Role/Benefit | Example/Application |
|---|---|---|
| Computational Docking | Predicts drug-target binding to prioritize candidates | Dasatinib binding to MMPs and EGFR in pancreatic cancer |
| Artificial Intelligence | Identifies novel targets and drug interactions | Machine learning analysis of transcriptomic data in pancreatic cancer |
| Nanotechnology | Enhances targeted delivery, reduces side effects | Liposomal and polymeric nanoparticles for drug delivery (Drug repurposing in cancer therapy) |
| Organoids/Tumoroids | Personalized preclinical drug screening | Patient-derived tumoroids guide individualized therapies |
| Innovative Delivery | Improves bioavailability and tissue protection | Nasal delivery of radioprotective amifostine (Radiation treatment breakthrough in pancreatic cancer) |
Notable Repurposed Drugs and Their Mechanisms Against Pancreatic Cancer
Which repurposed drugs show promising anticancer effects in pancreatic cancer?
Several FDA-approved non-oncology drugs for PC have demonstrated potential against pancreatic cancer. These include auranofin for oxidative stress in PC, disulfiram proteasome inhibition, doxycycline mitochondrial function in PC, itraconazole anti-tumor activity, metformin effects on pancreatic cancer, and propranolol in pancreatic cancer treatment. Their diverse mechanisms target cancer cell survival, metabolism, and the tumor microenvironment, making them promising candidates for drug repurposing in pancreatic cancer strategies.
How do these drugs act mechanistically against pancreatic cancer?
- Auranofin: Used for rheumatoid arthritis, it induces apoptosis by inhibiting thioredoxin reductase and HIF1α, causing mitochondrial reactive oxygen species (ROS) accumulation (auranofin for oxidative stress in PC).
- Disulfiram: An anti-alcoholism drug that downregulates the NF-kB pathway, reduces cancer stem cells, and inhibits proteasome activity, thereby suppressing tumor growth (disulfiram proteasome inhibition.
- Doxycycline: Primarily an antibiotic, it inhibits mitochondrial protein synthesis, targets cancer stem cells, and enhances the effects of gemcitabine chemotherapy (doxycycline mitochondrial function in PC.
- Itraconazole: An antifungal agent causing ROS-induced apoptosis and exerting anti-angiogenic effects (itraconazole anti-tumor activity.
- Metformin: A diabetes drug that activates AMPK, inhibits mitochondrial Complex-1, reduces insulin levels, and may suppress cancer stem cell phenotypes (metformin effects on pancreatic cancer.
- Propranolol: A non-selective beta-blocker that inhibits tumor growth and invasion, modulates the immune response, and enhances treatment sensitivity (propranolol in pancreatic cancer treatment.
(More details on the mechanisms and multifaceted approaches can be found in Drug repurposing in pancreatic cancer.)
What evidence supports their use in pancreatic cancer treatment?
Preclinical studies have shown these drugs reduce proliferation, invasion, and tumor growth in pancreatic cancer models. Some, such as metformin and propranolol, have progressed to clinical trials, either alone or in combination with chemotherapy or immunotherapy. For example, propranolol is being clinically investigated for perioperative use to improve outcomes. However, clinical data remain preliminary, and larger trials are needed to confirm efficacy. Further insights are discussed in the review on drug repurposing in pancreatic cancer.
Why is combination therapy important, and how does molecular targeting enhance outcomes?
Combining repurposed drugs with standard chemotherapy or immunotherapy can address multiple tumor survival pathways simultaneously. This approach helps overcome drug resistance common in pancreatic cancer. Molecular targeting of key pathways such as key gene mutations in pancreatic cancer, cancer stemness, apoptosis regulation, and the tumor microenvironment enhances therapeutic precision and efficacy, which is crucial given pancreatic cancer's complexity and heterogeneity.
Is it still worth pursuing metformin as a cancer therapeutic?
While early epidemiological and preclinical data suggested anticancer potential for metformin, recent large-scale randomized trials have not demonstrated significant benefits as a standalone cancer treatment. Its mechanisms include mitochondrial Complex-1 inhibition and tumor suppressor activation, but the evidence does not support routine use for cancer therapy currently. Ongoing research into genetic markers and tumor microenvironment effects may define specific contexts where metformin could be beneficial, yet at present, its widespread use for pancreatic cancer treatment is not justified (see detailed discussion in drug repurposing studies.
| Drug | Primary Original Use | Mechanism of Action | Status in Pancreatic Cancer |
|---|---|---|---|
| Auranofin | Rheumatoid arthritis | Induces apoptosis via ROS and enzyme inhibition | Preclinical evidence; promising |
| Disulfiram | Anti-alcoholism | Proteasome inhibition and NF-kB pathway downregulation | Preclinical; targeting cancer stem cells |
| Doxycycline | Antibiotic | Inhibits mitochondrial protein synthesis | Preclinical synergy with chemotherapy |
| Itraconazole | Antifungal | ROS induction and anti-angiogenic effects | Preclinical anti-tumor activity |
| Metformin | Diabetes mellitus | AMPK activation, metabolic pathway modulation | Mixed clinical trial results; still under study |
| Propranolol | Beta-blocker for cardiovascular diseases | Immune modulation and inhibition of invasion | Ongoing clinical trials for enhanced treatment outcomes |
Advances in Early Detection and Complementary Supportive Care in Pancreatic Cancer
What are the recent breakthroughs in pancreatic cancer treatment as of 2025?
Recent advances in pancreatic cancer research focus heavily on improving early detection and developing complementary treatments that enhance patient outcomes.
A landmark initiative is the Pancreatic Cancer Action Network’s (PanCAN) Early Detection Initiative, which enrolled more than 8,800 participants to identify high-risk individuals. Tools like the ENDPAC risk score have demonstrated that glycemically-defined new-onset diabetes (GNOD) can serve as an early warning, especially within non-Hispanic white populations. This highlights the urgency of tailored, equitable screening programs.
Emerging diagnostic modalities such as liquid biopsies, microRNA blood tests with up to 91% accuracy, and artificial intelligence algorithms are at the forefront of experimental detection research. Although these technologies are not yet standard practice, they represent promising avenues toward diagnosing pancreatic cancer much earlier when treatment may be more effective.
Beyond detection, breakthroughs include targeting the historically “KRAS mutation in pancreatic cancer” with novel inhibitors in trials like RASOLUTE 302. These efforts aim to improve systemic therapies and extend survival.
What is Acoustic Cluster Therapy (ACT) and its role in pancreatic cancer treatment?
Acoustic Cluster Therapy (ACT) is an innovative, non-invasive technique under investigation to improve chemotherapy delivery. It uses ultrasound waves to activate clusters carrying drugs directly to pancreatic tumors, enhancing drug concentration at the tumor site while reducing side effects.
Currently, clinical trials are exploring ACT combined with chemotherapy regimens such as modified FOLFIRINOX, especially for patients with locally advanced pancreatic cancer. This targeted drug delivery addresses major treatment hurdles like poor tumor penetration and resistance mechanisms.
How do pancreatic cancer vaccines and immunotherapy contribute?
New-generation pancreatic cancer vaccines are designed to stimulate the immune system early to recognize and attack cancer cells, with clinical trials showing encouraging results in survival extension. Trials such as TEDOPAM, evaluating cancer vaccines like OSE2101 (Tedopi®), demonstrated a significant improvement in one-year survival rates (50%) and low toxicity.
Immunotherapy advances also include immune checkpoint inhibitors and combination strategies tailored to tumor subtypes, although their success in pancreatic cancer is limited due to the tumor’s immunosuppressive microenvironment. Ongoing research focuses on combination therapies for pancreatic cancer to overcome these barriers.
What role does nutritional support and dietary choices play?
Proper nutritional support is crucial as pancreatic cancer and its therapies often compromise patient health and wellbeing. While research is ongoing, some dietary components like bananas are noted for their beneficial nutrients, including vitamins and antioxidants, which may support general health and provide energy.
What complementary supportive treatments are emerging?
Tumour-Treating Fields (TTFields) represent another novel supportive therapy, utilizing electric fields to interfere with cancer cell division. The Phase III PANOVA-3 trial demonstrated that combining TTFields with gemcitabine and nab-paclitaxel improved overall survival by two months in patients with locally advanced pancreatic cancer without increasing toxicity.
These advances collectively offer hope for earlier diagnosis, more effective targeted therapies, and supportive care options to improve quality of life and outcomes for pancreatic cancer patients.
Conclusion: The Promising Horizon of Drug Repurposing in Pancreatic Cancer Therapy
Drug repurposing offers a rapid, cost-effective path to new pancreatic cancer treatments by utilizing existing drugs with known safety profiles.
This approach addresses challenges such as late diagnosis, treatment resistance, and limited efficacy of current therapies. Despite promising preclinical and early clinical results with drugs like Dasatinib, valproic acid, and simvastatin, hurdles remain including dosing optimization and regulatory approvals.
Continued research and well-designed clinical trials are essential to validate these therapies and personalize treatment. Drug repurposing holds potential to transform pancreatic cancer care, improving survival and quality of life for patients facing this aggressive disease.
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