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Overview: Drug Repurposing as a Vital Approach in Pancreatic Cancer Therapy
Understanding Drug Repurposing
Drug repurposing involves finding new therapeutic uses for existing FDA-approved drugs outside their original medical indications. This strategy accelerates clinical application since these drugs already have well-characterized safety profiles, dosage information, and known side effects.
Limitations in Current Pancreatic Cancer Treatments
Pancreatic cancer remains one of the deadliest cancers, with a five-year survival rate around 9–13%. Standard treatments like gemcitabine, FOLFIRINOX, and nab-paclitaxel are often limited by toxic side effects and only modest improvements in survival. Additionally, late-stage diagnosis and tumor resistance severely restrict treatment success.
Advantages of Repurposing for Pancreatic Cancer
Repurposed drugs present an attractive alternative due to faster development timelines—typically 3 to 12 years compared to 10 to 17 years for new drugs—and lower associated costs. Many agents originally approved for non-cancer uses, such as antibiotics, antipsychotics, and antivirals, have shown promising activity against pancreatic cancer by mechanisms like inducing apoptosis, inhibiting cancer stem cells, modulating the tumor microenvironment, and enhancing immune responses.
This approach could complement existing therapies or serve as effective alternatives, potentially reducing toxicity while improving efficacy. Several repurposed drugs are currently under clinical investigation, highlighting their growing role in expanding treatment options for pancreatic cancer patients.
Mechanisms of Repurposed Drugs Targeting Pancreatic Cancer Cells
What are some repurposed drugs and their mechanisms of action in pancreatic cancer?
Several repurposed drugs have been identified with promising activity against pancreatic cancer through distinct molecular mechanisms targeting cancer cells and the tumor microenvironment.
Auranofin in pancreatic cancer inhibits thioredoxin reductase 1 (TrxR1) and hypoxia-inducible factor-1α (HIF1α), resulting in reduced antioxidant defenses and increased reactive oxygen species (ROS). This leads to apoptosis especially under nutrient-deprived conditions and suppresses tumor growth and metastasis in preclinical models.
Haloperidol effects on pancreatic cancer and Penfluridol and gemcitabine synergy, antipsychotic drugs, induce endoplasmic reticulum (ER) stress, which promotes autophagy and apoptosis, inhibiting proliferation and migration of pancreatic cancer cells. Haloperidol also reduces tumor size and metastasis in vivo.
Disulfiram targeting pancreatic cancer stem cells functions as a proteasome inhibitor and downregulates NF-κB signaling. It effectively reduces proliferation and targets cancer stem cells (CSCs), which are implicated in therapy resistance and relapse.
Doxycycline reducing tumorsphere formation impairs mitochondrial protein synthesis, restricting tumorsphere formation and synergizing with chemotherapy (gemcitabine) to enhance anticancer activity.
Chloroquine and hydroxychloroquine in chemotherapy response inhibit autophagy, a survival mechanism exploited by pancreatic cancer cells. By blocking autophagy, these drugs improve chemotherapy and immunotherapy responses and decrease immunosuppressive factors in the tumor microenvironment.
Other noteworthy repurposed agents include Itraconazole anti-angiogenic effects in pancreatic cancer (induces apoptosis and inhibits angiogenesis), Losartan enhancing drug delivery in pancreatic cancer (modulates tumor stroma to enhance drug delivery and immune response), and Propranolol decreasing pancreatic tumor proliferation (reduces tumor proliferation and invasion by blocking stress-induced pathways).
These drugs demonstrate how Drug repurposing in pancreatic cancer can target critical pathways involved in pancreatic cancer cell survival, apoptosis induction, cancer stem cell depletion, and microenvironment modulation, addressing tumor resistance mechanisms and potentially improving treatment outcomes.
Clinical Trials Advancing Repurposed Drug Use in Pancreatic Cancer
Ongoing and Completed Clinical Studies
Clinical trials investigating the use of repurposed drugs in pancreatic cancer are actively progressing to improve treatment outcomes, especially in advanced-stage disease. Among these, drugs such as chloroquine and hydroxychloroquine in chemotherapy response, disulfiram targeting pancreatic cancer stem cells, HIV inhibitors efavirenz and nelfinavir in pancreatic cancer, losartan enhancing drug delivery in pancreatic cancer, and propranolol decreasing pancreatic tumor proliferation are being tested for their antiviral, anti-inflammatory, and tumor microenvironment-modulating properties. These trials consider a combination of these agents with standard chemotherapy or radiation to enhance therapy efficacy and overcome chemoresistance.
Drugs Under Investigation
- Hydroxychloroquine: Targets autophagy inhibition, potentially increasing chemotherapy sensitivity and reducing tumor immunosuppression.
- Disulfiram: Functions as a proteasome inhibitor depleting cancer stem cells and altering inflammatory signaling.
- Nelfinavir: An HIV protease inhibitor that induces apoptosis and sensitizes pancreatic cancer cells to radiation.
- Losartan: Improves drug delivery by remodeling the tumor stroma and modulating immune effects.
- Propranolol: A beta-blocker that decreases tumor proliferation and reduces stress-induced tumor progression.
Trial Designs and Endpoints
Clinical studies range from phase I safety assessments to phase II/III efficacy evaluations. Designs include biomarker-driven approaches and combination regimens with existing chemotherapies like gemcitabine and FOLFIRINOX. Common endpoints include overall survival, progression-free survival, tumor response rates, and safety profiles. Some trials employ translational biomarkers to monitor immune response and tumor microenvironment changes.
Translational Implications for Patient Care
The ongoing trials embody the promise of repurposing FDA-approved non-oncology drugs for cancer to rapidly offer new treatment options for pancreatic cancer patients, including those with stage 4 disease. By leveraging known toxicity and pharmacokinetic profiles, these studies may accelerate clinical application. Enhanced understanding of tumor biology and microenvironment modulation could also improve personalized therapy strategies, potentially improving long-term survival and quality of life for patients facing this challenging cancer.
Integrating Targeted Therapies with Drug Repurposing in Pancreatic Cancer
What are the current targeted therapy options for pancreatic cancer?
Targeted therapy for pancreatic cancer focus on specific genetic alterations driving tumor growth. Approved agents include:
- BRAF V600E mutations: Treated with dabrafenib and trametinib, oral medications that inhibit aberrant signaling pathways.
- NTRK gene fusions: Larotrectinib and entrectinib, oral drugs, block oncogenic fusion proteins.
- KRAS G12C mutation: Adagrasib and sotorasib, newly approved pills, selectively inhibit this mutation found in a subset of cases.
- RET gene fusions: Selpercatinib targets these rare fusions effectively.
- BRCA mutations: PARP inhibitor olaparib improves progression-free survival in patients with germline BRCA1/2 mutations.
These therapies provide a precision oncology approach by specifically attacking oncogenic drivers, often with fewer systemic side effects than conventional chemotherapy.
How do mutation-specific drugs complement drug repurposing in treatment?
Combining targeted therapies with Drug repurposing in pancreatic cancer holds promise to improve outcomes. Repurposed agents—originally approved for non-oncologic uses—can modulate tumor microenvironment, overcome resistance, or sensitize tumors to targeted drugs. For example, drugs like Auranofin in pancreatic cancer induce apoptosis via redox disruption, while Losartan enhancing drug delivery in pancreatic cancer enhances drug delivery by remodeling tumor stroma.
Dual approaches may:
- Target multiple pathways simultaneously to prevent tumor escape.
- Reduce tumor bulk and disrupt supportive stroma, improving access for targeted agents.
- Modulate immune response, enhancing immunotherapy efficacy alongside targeted drugs.
Benefits of combining targeted therapies with repurposed agents
| Benefit | Explanation | Examples |
|---|---|---|
| Enhanced efficacy | Synergistic therapeutic effects on cancer cells | Penfluridol and gemcitabine synergy |
| Overcome resistance | Target compensatory survival mechanisms | Losartan enhancing drug delivery in pancreatic cancer |
| Improved tolerability | Lower doses of chemotherapy/targeted therapy possible | Doxycycline reducing tumorsphere formation |
| Modulate tumor microenvironment | Disrupt desmoplasia and immunosuppression | Losartan enhancing drug delivery in pancreatic cancer, Pirfenidone reducing fibrosis in pancreatic cancer |
Integrating FDA-approved targeted therapies with repurposed drugs represents a cutting-edge, multi-faceted approach under active clinical investigation. This strategy offers hope to improve survival in pancreatic cancer, traditionally a treatment-refractory disease.
Emerging Research on Novel Drug Candidates and Bioinformatics Approaches
Discovery of New Repurposed Drug Candidates Like Dasatinib and Pioglitazone
Recent bioinformatics and molecular docking analyses for drug repurposing have identified promising existing drugs that could be repurposed for pancreatic cancer treatment. Notably, Dasatinib shows strong binding affinity to proteins MMP3, MMP9, and EGFR, which play critical roles in tumor invasion, metastasis, and cell proliferation. Similarly, Pioglitazone targets MMP2, MMP3, and MMP9, suggesting potential to interfere with tumor progression pathways. These findings illustrate how approved drugs for other indications might be redirected effectively against pancreatic cancer.
Use of Computational and Bioinformatic Analyses to Identify Drug Targets
Advanced computational techniques, including transcriptomic data analysis, gene network mapping, and docking simulations, have become invaluable for identifying overexpressed genes and molecular targets in pancreatic cancer. By integrating data from multiple databases, researchers have pinpointed clusters of upregulated genes linked to aggressive disease features. Such in silico methods expedite drug discovery by predicting interactions between repurposed drugs and critical cancer-related proteins, paving the way for more targeted preclinical and clinical evaluation.
Innovative Mechanisms Such As PRLX-93936 for Protein Degradation
Innovative drug repurposing strategies have uncovered unique mechanisms of action, such as that of PRLX-93936. Originally designed to induce toxic iron accumulation, this compound acts as a molecular glue promoting protein–protein interactions that trigger targeted degradation of the nuclear pore complex via the TRIM21 protein. By disrupting nuclear transport processes essential for cancer cell survival, PRLX-93936 effectively inhibits pancreatic cancer growth in model systems. This approach highlights the potential of repurposed drugs to exploit novel cellular vulnerabilities.
Overall, bioinformatics-driven identification of drug candidates and mechanisms reveals an expanding arsenal of repurposed therapies for pancreatic cancer. These advances promise efficient translation to the clinic and contribute to personalized treatment strategies against this challenging disease.
Combining Immunotherapy and Drug Repurposing to Overcome Tumor Resistance
What is immunotherapy for pancreatic cancer?
Immunotherapy for pancreatic cancer aims to activate the patient’s immune system to detect and eradicate cancer cells. However, pancreatic tumors create an immunosuppressive microenvironment that resists immune attack, making treatment challenging.
Immunotherapy challenges and strategies in pancreatic cancer
The dense stroma and immunosuppressive cells within pancreatic tumors limit immune cell infiltration and reduce immunotherapy effectiveness. To combat this, researchers focus on modifying the tumor microenvironment and employing combination therapies for pancreatic cancer to boost immune response.
Repurposed drugs modulating immune responses and autophagy
Certain repurposed drugs modulating immune response in pancreatic cancer enhance immunotherapy by targeting mechanisms in pancreatic cancer cells and their environment. For instance, chloroquine and hydroxychloroquine in chemotherapy response inhibit autophagy—a process cancer cells use for survival—thereby enhancing chemotherapy and immunotherapy. Metformin modulating immune response in pancreatic cancer activates AMPK and modulates immune activity, though clinical trial results have been mixed. Propranolol decreasing pancreatic tumor proliferation and Losartan enhancing drug delivery in pancreatic cancer also reduce immunosuppressive cells and remodel the tumor stroma to facilitate immune cell access.
Clinical trials combining immunotherapy with repurposed drugs
Ongoing clinical trials of repurposed drugs in pancreatic cancer are investigating the safety and efficacy of combining immunotherapy with repurposed agents in pancreatic cancer patients. Examples include trials with hydroxychloroquine in pancreatic cancer, disulfiram targeting pancreatic cancer stem cells, HIV inhibitors efavirenz and nelfinavir in pancreatic cancer, losartan enhancing drug delivery in pancreatic cancer, and propranolol decreasing pancreatic tumor proliferation. These studies aim to improve therapeutic responses by overcoming tumor resistance through dual mechanisms—immune activation and tumor environment modulation.
This integrated approach of immunotherapy combined with repurposed drugs that modulate autophagy and the tumor microenvironment holds promise for improving outcomes in pancreatic cancer, a malignancy notorious for resistance to conventional treatments.
The Role of Metformin: Current Status as a Repurposed Cancer Therapeutic
What mechanisms drive metformin’s anti-cancer effects?
Metformin, a common diabetes medication, exhibits potential anti-cancer effects through several biological pathways. It activates AMP-activated protein kinase (AMPK), which inhibits the mammalian target of rapamycin (mTOR) pathway. This inhibition slows down cancer cell growth and proliferation. Additionally, Metformin modulating immune response in pancreatic cancer, potentially enhancing anti-tumor immunity and altering the tumor microenvironment.
What have clinical trials revealed about metformin’s efficacy in pancreatic cancer?
Epidemiological studies have indicated that metformin use is associated with a reduced risk of certain cancers, including pancreatic cancer. However, large randomized clinical trials have so far failed to show a definitive survival benefit in pancreatic cancer patients treated with metformin. Despite these mixed results, ongoing trials are examining metformin's role, especially in combination with chemotherapy or immunotherapy, aiming to identify patient subgroups that might benefit most (Drug repurposing in pancreatic cancer).
What challenges limit metformin's adoption and what are future research directions?
One major challenge is the inconsistent clinical trial outcomes, which may relate to variations in patient selection, cancer molecular profiles, or disease stage. Determining biomarkers to predict response to metformin is a research priority. Moreover, understanding optimal dosing and timing, especially in combinational strategies, remains critical. Future research continues to explore metformin's potential as an adjunct therapy, hoping to clarify its role in pancreatic cancer management (Current pancreatic cancer treatments.
Understanding Remission and Long-Term Outcomes in Pancreatic Cancer Care
What does remission mean in pancreatic cancer, and can it occur without surgery?
Remission in pancreatic cancer means that no signs of the cancer are detected on scans or other medical tests, suggesting the disease is under control. However, this does not guarantee that every cancer cell has been eliminated; microscopic cancer cells might still remain, posing a risk for recurrence down the line.
Achieving remission is considered a critical milestone in treatment but is not synonymous with a cure. It serves as an important indicator that the cancer is responding well to therapy (Pancreatic cancer treatment challenges).
Is remission possible without surgery?
Yes, remission can occur without surgical intervention. Advances in chemotherapy regimens such as FOLFIRINOX and gemcitabine-based treatments, targeted therapies directed at specific mutations (like KRAS inhibitors) (Targeted therapy for pancreatic cancer), radiation therapy, and participation in clinical trials can all contribute to achieving remission.
For many patients, especially those with unresectable or metastatic disease, systemic therapies aim to control tumor growth and extend survival, sometimes leading to remission visible on imaging (Innovative pancreatic cancer treatment options).
Why is ongoing monitoring crucial after remission?
Because microscopic cancer cells might remain, continuous post-remission surveillance is essential. Regular imaging, blood tests, including tumor markers like CA19-9, and clinical evaluations help detect any signs of recurrence early (pancreatic cancer five-year survival rate).
This monitoring allows timely intervention, the adjustment of treatments as required, and overall management of patient health to improve long-term outcomes.
Maintaining a multidisciplinary care approach ensures that any changes in disease status are addressed promptly, maximizing chances for prolonged survival and quality of life (Multidisciplinary treatment plans.
Recent Breakthroughs and Challenges Shaping Pancreatic Cancer Treatment Landscape in 2025
What breakthroughs in pancreatic cancer treatment occurred in 2025?
The year 2025 has marked pivotal progress in pancreatic cancer care, particularly driven by early detection and targeted treatment strategies. A landmark effort by the Pancreatic Cancer Action Network’s Early Detection Initiative has enrolled thousands of participants to identify high-risk individuals using refined tools such as the ENDPAC (Enriching New-Onset Diabetes for Pancreatic Cancer) score. This metric leverages new-onset diabetes as a significant risk factor, substantially improving screening precision (Advances in Pancreatic Cancer Research).
Clinical trials have also made strides, with the RASOLUTE 302 trial pushing forward therapies targeting mutation-specific KRAS proteins, long considered 'undruggable.' These advances coincide with growing integration of AI technologies and liquid biopsies analyzing microRNAs and exosomes, enhancing the ability to diagnose pancreatic cancer at earlier, more treatable stages (Advances in Pancreatic Cancer Research.
The combination of biomarker-driven screening and innovative molecular therapies has opened promising pathways toward improved patient outcomes, heralding a new era in precision oncology for this challenging disease (Targeted therapies in pancreatic cancer).
What are the recent advances and challenges in pancreatic cancer care?
Significant advances include a deeper molecular understanding of dominant mutations, particularly in KRAS and DNA damage repair genes, which has led to the development of targeted therapies such as KRAS G12C inhibitors and PARP inhibitors like olaparib for BRCA-mutated cancers (Targeted therapy for pancreatic cancer.
Immunotherapy and multidisciplinary approaches combining surgery, chemotherapy, radiation, and targeted drugs are increasingly personalizing treatment. Additionally, novel treatment modalities—such as tumor treating fields (TTFields) with chemotherapy—have demonstrated survival benefits without added systemic toxicity (Tumour treating fields for pancreatic cancer).
Despite these advances, pancreatic cancer care faces formidable challenges. Predominantly due to nonspecific symptoms, most diagnoses occur at late stages when tumors are unresectable. Resistance to standard chemotherapy and tumor microenvironment-imposed drug delivery barriers complicate treatment effectiveness (Drug repurposing in pancreatic cancer treatment).
Ongoing research aims to overcome these hurdles by developing combination regimens, reprogramming the tumor microenvironment, and advancing early detection tools aided by AI and biomarker analysis. While treatment improvements have boosted survival rates modestly, the disease’s aggressive nature demands sustained innovation (Slow but steady progress improves pancreatic cancer survival rates.
Integration of AI and Liquid Biopsies for Diagnosis
Artificial intelligence-powered analyses of medical records and advanced liquid biopsy techniques are transforming pancreatic cancer diagnostics. These tools enable earlier identification of subtle disease markers, often years before clinical symptoms emerge, thereby increasing the window for potentially curative intervention (New hope for pancreatic cancer, AI-based analytical tool for pancreatic cancer).
Ongoing Challenges Including Late Detection and Drug Resistance
The silent progression and late presentation of pancreatic cancer remain major obstacles. The dense stromal tissue around tumors impedes drug penetration, and cancer stem cells contribute to therapy resistance and recurrence. Enhanced molecular profiling and tailored therapeutics are critical to addressing these persistent difficulties (Pancreatic cancer treatment challenges, Drug repurposing in pancreatic cancer, cancer stem cells and therapy resistance).
These 2025 breakthroughs underscore an accelerating trend of integrating diagnostics, precision medicine, and novel therapeutics aiming to improve outcomes in one of cancer's deadliest forms (Recent advances in pancreatic cancer research).
Conclusion: The Promise of Drug Repurposing in Transforming Pancreatic Cancer Treatment
Drug repurposing offers a compelling strategy to accelerate the development of new treatments for pancreatic cancer by leveraging the known safety profiles and pharmacology of existing approved drugs.
This approach can significantly shorten the time and reduce costs compared to creating novel drugs, addressing the urgent need for more effective, less toxic therapies in a disease with a 5-year survival rate of around 10%. Repurposed drugs target diverse mechanisms, including tumor metabolism, microenvironment modulation, cancer stem cells, and apoptosis induction, allowing them to work synergistically with current chemotherapy and immunotherapies.
Several repurposed candidates such as auranofin, disulfiram, chloroquine, and metformin are already under clinical evaluation, reflecting a growing integration of these agents into personalized medicine frameworks. Advanced biomarker testing and molecular profiling enable patient selection based on tumor genetics, enhancing the precision of repurposed drug application.
Looking ahead, ongoing clinical trials and bioinformatics analyses will clarify and expand the therapeutic roles of repurposed drugs. Integration with targeted therapies and novel vaccine or immune-based treatments holds promise for improving outcomes. Ultimately, drug repurposing represents a hopeful frontier that could transform the therapeutic landscape of pancreatic cancer by offering new, accessible, and multifaceted treatment options tailored to individual patient profiles.
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