Repurposing Common Medications for Pancreatic Cancer Treatment

Rethinking Treatment: The Promise of Drug Repurposing in Pancreatic Cancer

Drug Repurposing: A New Frontier in Cancer Therapy

Drug repurposing (DR) refers to the innovative strategy of using existing, clinically approved drugs developed for other diseases to treat cancer. This approach can significantly speed up the availability of new treatments due to the drugs' already established safety profiles and known pharmacology.

Pancreatic Cancer: A Complex Therapeutic Challenge

Pancreatic cancer is one of the deadliest malignancies, characterized by low survival rates and limited treatment options. Its aggressive nature, coupled with factors such as dense tumor microenvironment and frequent late-stage diagnosis, creates significant barriers to effective therapy.

Benefits of Drug Repurposing in Pancreatic Cancer

DR offers a faster and less costly path compared to traditional drug development because it builds on existing knowledge of drug safety. This approach also provides opportunities to target critical cancer pathways and the tumor environment, potentially overcoming resistance seen with standard therapies.

By leveraging multi-disciplinary techniques—including computational analysis, electronic health records, and clinical studies—drug repurposing holds promise to expand treatment options for pancreatic cancer patients more rapidly than de novo drug discovery.

The Urgent Need for Innovative Solutions in Pancreatic Cancer

What challenges make pancreatic cancer difficult to treat?

Pancreatic cancer remains one of the most aggressive malignancies, with a dismal Pancreatic cancer five-year survival rate of about 10-13%. A critical difficulty stems from the fact that around 80% of diagnoses occur at advanced stages, leaving only approximately 20% of patients Eligibility for Pancreatic Cancer Surgery eligible for potentially curative surgery.

Limitations of Standard Therapies

Surgery, particularly the Whipple procedure, is currently the only curative option but is applicable mainly to patients with resectable tumors. Unfortunately, most pancreatic cancers are detected too late for surgery due to their stealthy progression.

Chemotherapy regimens such as FOLFIRINOX and gemcitabine-based therapies improve survival modestly but often come with substantial toxicity. Radiation therapy complements chemotherapy but is hindered by sensitivity of nearby organs and limited effectiveness in advanced disease.

Biological Hurdles

A dense Tumor Microenvironment in Pancreatic Cancer envelops pancreatic tumors, posing a serious barrier to drug delivery and immune cell infiltration. This fibrotic tissue obstructs penetration by chemotherapeutic agents and shields cancer cells from immune attack.

Additionally, inherent tumor biology includes KRAS Mutations in Pancreatic Cancer in over 90% of cases, contributing to aggressive growth and resistance to therapy. This resistance extends to standard drugs due to mechanisms such as altered drug metabolism and efflux.

The tumor’s immune-suppressive microenvironment also limits the success of Immunotherapy in pancreatic cancer that have been revolutionary in other cancers.

These intertwined challenges necessitate the development of novel strategies that can surmount stromal barriers, target resistant cancer pathways, and improve early detection to enhance treatment outcomes.

Drug Repurposing: A Strategic Shortcut to New Therapies

What is drug repurposing and why is it promising for pancreatic cancer?

Drug repurposing (DR) involves finding new therapeutic uses for existing, FDA-approved drugs originally intended for other diseases. This approach is particularly promising for Drug Repurposing in Pancreatic Cancer due to its poor prognosis and the limited effectiveness of current treatments.

DR accelerates therapy availability by leveraging drugs with established safety profiles, thus bypassing much of the lengthy and costly traditional drug development process. For pancreatic cancer, DR targets critical cancer pathways, expanding treatment options quickly and cost-effectively.

How does DR target pancreatic cancer-specific pathways?

Pancreatic cancer features complex biology, including nearly 90% of cases presenting KRAS Mutations in Pancreatic Cancer. DR exploits this by repurposing drugs that can inhibit KRAS signaling or interfere with related pathways such as autophagy and tumor microenvironment remodeling.

Examples of such targeted approaches include:

• Drugs inhibiting KRAS dependency and related signaling cascades.
• Agents like Chloroquine and hydroxychloroquine inhibit autophagy to sensitize cancer cells.
• Medications modulating the dense tumor stroma to improve drug delivery, such as Losartan reduces fibrosis and modulates immune microenvironment.

These mechanisms disrupt cancer cell survival and the protective environment that contributes to therapy resistance.

How does DR circumvent long drug development cycles?

Traditional drug discovery typically spans a decade with high costs and failure rates. DR circumvents these by:

• Utilizing well-studied drugs already approved for other indications, providing faster transition to clinical testing.
• Employing computational methods, AI, and large databases to rapidly identify candidate drugs effective against pancreatic cancer targets.
• Initiating clinical trials sooner, as seen with Valproic Acid and Simvastatin Trial combined with chemotherapy in ongoing studies.

This strategy shortens the path to new, effective treatments for pancreatic cancer patients who currently face limited options.

Overall, drug repurposing offers a practical and innovative shortcut to expanding therapeutic possibilities by exploiting existing pharmacological tools against pancreatic cancer’s challenging biology.

Repurposed Medications Showing Preclinical and Clinical Promise

Which common drugs are being investigated for pancreatic cancer treatment?

Several medications originally approved for non-cancer uses have shown promise in Drug Repurposing in Pancreatic Cancer through various mechanisms.

Examples of repurposed drugs with antitumor effects

• Auranofin inhibits TrxR1 and HIF1α, an anti-rheumatic drug, inhibits thioredoxin reductase 1 (TrxR1) and hypoxia-inducible factor 1-alpha (HIF1α), inducing apoptosis and reducing antioxidant activity, with metastasis suppression demonstrated in mouse models.
• Anti-psychotic drugs haloperidol and penfluridol repurposing suppress pancreatic cancer cell proliferation by triggering endoplasmic reticulum (ER) stress and autophagy, leading to decreased tumor growth and migration.
• Disulfiram proteasome inhibition and cancer stem cell depletion, used to treat alcoholism, inhibits proteasome activity via copper complexes, reduces cancer stem cell populations, and enhances the effects of chemo- and radiotherapy.

Common non-cancer medications and their mechanisms

• Metformin disrupts mitochondrial respiration and activates AMPK, a diabetes medication, activates AMPK, disrupts mitochondrial respiration, and inhibits mTOR signaling, reducing cell proliferation and modulating immune responses. Its clinical efficacy is still under investigation.
• Statins reducing pancreatic cancer risk, routinely used for lowering cholesterol, have been linked to risk reduction by modulating inflammatory pathways and angiogenesis related to pancreatic cancer.
• Doxycycline activates proapoptotic genes and synergizes with gemcitabine, an antibiotic, activates pro-apoptotic pathways and impairs tumor sphere formation, showing synergistic effects with gemcitabine.

Ongoing clinical trials

• The VESPA study on drug repurposing for pancreatic cancer is currently exploring the combination of valproic acid (an anticonvulsant) and simvastatin (a cholesterol-lowering drug) with chemotherapy for metastatic pancreatic ductal adenocarcinoma. Early preclinical results indicate enhanced efficacy and reduced toxicity.
• This multi-center trial aims to enroll 240 patients and employs a patient-centered design that integrates cancer patient advocacy organizations. As of late 2023, initial patient enrollment has begun.

These repurposed drugs represent promising adjuncts or alternatives to conventional pancreatic cancer treatments, potentially accelerating availability due to their known safety profiles and diverse mechanisms targeting tumor biology.

Mechanistic Insights: How Repurposed Drugs Target Pancreatic Cancer

Through what mechanisms do repurposed drugs exert antitumor activity?

Repurposed drugs combat pancreatic cancer through diverse molecular and cellular mechanisms, targeting the disease’s complex biology at multiple fronts. One critical target is the KRAS signaling pathway, central to over 90% of pancreatic tumors, where drugs aim to inhibit mutant KRAS-driven proliferative signals. Some agents act by inducing apoptosis; for example, auranofin disrupts antioxidant defenses by inhibiting thioredoxin reductase 1, increasing cancer cell death.

Autophagy, a survival mechanism for cancer cells, is suppressed by drugs such as chloroquine and hydroxychloroquine, which also help restore immune system recognition by enhancing antigen presentation. Disulfiram, an alcohol abstinence drug, depletes cancer stem cells and inhibits proteasome activity, reducing tumor renewal and resistance.

The tumor microenvironment, characterized by dense fibrosis that impedes drug delivery, is modulated by drugs like losartan and pirfenidone. Losartan blocks angiotensin II receptor 1 (AT1R), reducing stromal collagen and improving chemotherapy penetration. Pirfenidone decreases extracellular matrix production and fibrosis, altering tumor-stroma interactions that support tumor growth.

Additionally, some repurposed medications impact immune evasion. Chloroquine reduces immune escape by enhancing surface expression of MHC I molecules, thereby promoting immune recognition. Propranolol, a beta-blocker, reduces nerve density and stress-induced tumor progression, which can indirectly affect tumor immunity.

Together, these mechanisms—KRAS inhibition, proteasome and autophagy suppression, stromal modification, and immune modulation—highlight the multifaceted ways repurposed drugs exert antitumor effects in pancreatic cancer, tackling both the tumor cells and their supportive environment.

Overcoming Barriers: Challenges in Drug Repurposing for Pancreatic Cancer

What are the main challenges to successful drug repurposing in pancreatic cancer?

Drug repurposing for pancreatic cancer faces several significant hurdles. Biologically, the dense stromal microenvironment surrounding pancreatic tumors acts as a physical and biochemical barrier. This dense stroma restricts drug penetration and delivery, reducing therapeutic effectiveness. Additionally, pancreatic cancer displays high chemoresistance and tumor heterogeneity, meaning treatments that might work on some tumor cells fail against others, complicating treatment outcomes.

From a regulatory and market perspective, drug repurposing is slowed by complex approval processes and limited incentives for pharmaceutical companies to invest in off-patent drugs. Scientific and technological challenges include understanding new mechanisms of action and validating repurposed agents in rigorous clinical settings. Social skepticism around novel applications of existing drugs can further impede acceptance and funding.

Addressing these multifaceted challenges requires cohesive collaboration. The REMEDi4ALL project exemplifies this approach by uniting researchers, clinicians, industry representatives, regulators, funders, and patients. This multi-sector partnership fosters knowledge sharing and drives systemic changes needed for advancing repurposed therapies.

Together, overcoming biological barriers, navigating regulatory complexities, and encouraging collaborative innovation are essential to unlock the therapeutic potential of drug repurposing in pancreatic cancer.

Integrating Repurposed Drugs with Standard and Emerging Therapies

How are repurposed drugs used alongside standard pancreatic cancer treatments?

Repurposed drugs are increasingly integrated with existing Pancreatic cancer surgery options like chemotherapy, immunotherapy, and radiation to enhance treatment effectiveness.

Combining Repurposed Drugs with Chemotherapy and Radiation

Many repurposed agents synergize with chemotherapy drugs—[Gemcitabine Hydrochloride, nab-paclitaxel, and FOLFIRINOX chemotherapy regimen]—boosting cancer cell killing and reducing resistance. For example, Chloroquine and hydroxychloroquine inhibit autophagy, making tumors more sensitive to chemotherapy. Metformin disrupts mitochondrial respiration and activates AMPK, though clinical results vary. Radiation therapy benefits from drug combinations that protect healthy tissues or sensitize tumor cells, as seen with new radioprotective agents under development.

Emergence of Metronomic Low-Dose Chemotherapy

Using continuous low-dose (metronomic chemotherapy) chemotherapy regimens reduces toxicity and may inhibit tumor-initiating cells while preserving immune function. This approach is more tolerable for patients and can be combined with repurposed drugs to achieve synergistic effects, potentially controlling systemic tumor growth better than conventional high-dose cycles.

Synergy with Targeted and Immunotherapeutic Agents

Certain repurposed drugs modify the Tumor Microenvironment in Pancreatic Cancer, enhancing immune responses and improving delivery of targeted therapies. Combining repurposed agents like Losartan reduces fibrosis and modulates immune microenvironment with immunotherapies or KRAS inhibitors may help overcome intrinsic resistance mechanisms. Some repurposed compounds also regulate immune escape, supporting ongoing immunotherapy strategies and therapeutic vaccines.

Integrating repurposed drugs within multifaceted treatment regimens holds promise to improve outcomes in pancreatic cancer by overcoming biological barriers and enhancing therapeutic efficacy.

Clinical Trials and Real-World Applications Advancing Repurposing Efforts

What clinical research is underway exploring repurposed drugs for pancreatic cancer?

Several clinical trials are actively investigating repurposed drugs to improve outcomes for pancreatic cancer patients. One prominent study is the VESPA trial, which evaluates the combination of valproic acid (commonly used for epilepsy) and simvastatin (a cholesterol-lowering drug) alongside standard chemotherapy (gemcitabine and nab-paclitaxel). This trial targets metastatic pancreatic ductal adenocarcinoma, aiming to enhance progression-free survival and reduce treatment toxicity. As of late 2023, VESPA has enrolled patients across multiple centers in Italy and Spain, integrating patient advocacy groups like Cancer Patients Europe to ensure a patient-centered approach.

In early-phase research, a Phase I clinical trial of pyrvinium pamoate, an anti-helminthic drug, is underway to establish safety, tolerability, and pharmacokinetics in patients with resectable pancreatic cancer. Preclinical data show promising anti-tumor activity, prompting dose-escalation studies before surgery to understand its potential synergy with standard treatments.

Another notable investigation, the PROSPER trial, tested the perioperative administration of propranolol (a beta-blocker) and etodolac (a non-steroidal anti-inflammatory drug). Although recruitment was limited, preliminary results indicated improved overall and disease-free survival, along with reduced metastasis rates. This trial exemplifies how repurposed drugs may modulate the perioperative environment to benefit patient outcomes.

Patient involvement is a critical component across these studies, fostering collaboration between researchers and patient communities. Engaging patients ensures that trials focus on meaningful endpoints and practical concerns, potentially accelerating the translation of repurposed drugs into clinical use.

These efforts demonstrate a growing and diverse pipeline of repurposed therapeutics actively being tested, with an emphasis on combining existing medications to enhance efficacy and tolerability for pancreatic cancer treatment.

The Future Landscape: Personalized Medicine and Regulatory Evolution

What does the future hold for repurposing common drugs in pancreatic cancer treatment?

The future of using repurposed drugs against pancreatic cancer appears promising, centered on a personalized medicine approach. Genetic and biomarker testing play a critical role, enabling treatments to be tailored to the specific molecular features of a patient’s tumor. For example, identifying mutations like those in the KRAS, BRCA1/2, or PALB2 genes can guide the use of targeted or repurposed agents with greater precision and efficacy.

Artificial intelligence (AI) and bioinformatics are revolutionizing drug discovery by rapidly screening existing drugs for new therapeutic potentials. These technologies analyze vast genomic and transcriptomic datasets to uncover promising repurposing candidates, accelerating the translation from lab findings to clinical evaluation.

To fully realize these advances, regulatory reform is crucial. Streamlining approval processes and harmonizing guidelines can enable faster access to repurposed drugs. Increased funding and incentive mechanisms will further bolster development, clinical trials, and multidisciplinary collaborations essential for overcoming the complex biological and systemic challenges pancreatic cancer presents.

Clinicians like Dr. Azriel Hirschfeld exemplify the integration of personalized and innovative therapies with compassionate patient care. Dr. Hirschfeld’s approach combines established chemotherapy and targeted treatments with repurposed medications, employing novel diagnostics such as liquid biopsies and low-dose combination chemotherapy. His patient-centered care emphasizes individualized treatment plans aimed at improving survival while maintaining quality of life.

Together, these emerging trends suggest a future where repurposed drugs, empowered by genetic insights and AI-driven discovery, can be efficiently delivered within a collaborative and adaptive regulatory environment to enhance therapeutic outcomes in pancreatic cancer.

Revitalizing Hope: Drug Repurposing as a Catalyst in Pancreatic Cancer Care

Unlocking New Therapeutic Pathways with Existing Drugs

Drug repurposing leverages medications already approved for other diseases to fight pancreatic cancer, targeting multiple cancer-driving pathways such as KRAS mutations, autophagy, and the tumor microenvironment. Drugs like valproic acid, simvastatin, and auranofin show promise in preclinical studies by inhibiting cancer growth and improving chemotherapy sensitivity. This approach accelerates treatment availability by building on known safety profiles and reduces the time and cost typically required for new drug development.

Collaborating to Overcome Barriers

Success in repurposing demands a united effort among researchers, clinicians, industry partners, regulators, and patient advocates. Initiatives like the REMEDi4ALL project exemplify this multi-stakeholder collaboration by organizing knowledge-sharing forums and tackling scientific, regulatory, and market challenges. Clinical trials such as the VESPA study test promising drug combinations, while ongoing research continues to identify novel targets and mechanisms, exemplifying a dynamic landscape of innovation.

Centering Patients and Fostering Innovation

Patient involvement guides research priorities and trial designs, ensuring treatments address both efficacy and quality of life. Embracing personalized medicine, novel drug delivery methods, and combination therapies promises continuous advances. By integrating cutting-edge science with compassionate care, drug repurposing reignites hope for patients battling this formidable disease, illustrating that innovation and collaboration are vital catalysts in transforming pancreatic cancer care.