.png)
Exploring the Promise of Drug Repurposing in Oncology
What is Drug Repurposing?
Drug repurposing involves finding new therapeutic uses for existing, clinically approved medications. Instead of developing new drugs from scratch, researchers explore how known drugs, originally designed for other diseases, can effectively treat cancer. This strategy leverages the proven safety profiles and well-understood pharmacological properties of these medications.
Advantages of Drug Repurposing
One of the major benefits of drug repurposing is the reduced time and expense in bringing treatments to patients. Since safety and dosage information is already established, repurposed drugs can often move more rapidly through clinical trials compared with new drugs. This makes cancer therapy development more cost-effective and efficient.
Additionally, repurposed drugs are often more accessible and affordable, which is crucial for expanding cancer care, especially in low- and middle-income regions. Their broad availability and known side effect profiles support safer patient management during treatment.
Why Do We Need New Cancer Therapies?
Cancer remains a complex and heterogeneous disease with challenges like drug resistance and severe side effects from existing treatments. Despite advances, many patients experience limited options, prompting the urgent need for novel therapeutic approaches. Drug repurposing offers a promising avenue to overcome these hurdles by targeting multiple cancer pathways and the tumor microenvironment with already-approved medicines.
By discovering new applications for existing drugs, researchers hope to improve treatment efficacy, reduce toxicity, and enhance personalized cancer care.
Concept and Strategic Benefits of Drug Repurposing in Cancer Care
What is drug repurposing and what are its benefits in cancer therapy?
Drug repurposing is the process of identifying new therapeutic uses for existing drugs that are already clinically approved. Instead of developing novel drugs from scratch, this strategy capitalizes on medications with established safety and pharmacokinetic profiles. By doing so, it significantly shortens the time and cost involved in cancer drug development.
Advantages such as reduced costs and development times
Traditional cancer drug discovery can take 10 to 17 years and involves high costs and risks. Drug repurposing accelerates this timeline to approximately 3 to 12 years by avoiding early-stage safety testing. It also cuts costs by utilizing pre-existing data from previous clinical use, including toxicity and dosing information.
Known safety and pharmacokinetic profiles of repurposed drugs
Using drugs with already proven safety minimizes uncertainties and regulatory hurdles. This established knowledge improves clinical trial design and increases the likelihood of success. Repurposed drugs often have well-understood pharmacokinetics, allowing for better dosing strategies tailored to cancer therapy. Therapeutic innovation in drug repurposing
Impact on accelerating clinical translation
Because repurposed drugs have passed extensive regulatory scrutiny for their original indications, they can move through clinical phases more quickly for cancer treatment. This facilitates rapid translation from laboratory findings to patient care, filling urgent gaps in oncology treatments with cost-effective options. Drug repurposing for cancer therapy
Overall, drug repurposing presents a promising avenue to overcome the lengthy and expensive process of new cancer drug development, offering safer, faster, and affordable therapeutic alternatives that can be swiftly integrated into clinical practice.
Targeting Cancer Hallmarks with Repurposed Pharmaceuticals
How do repurposed drugs target the hallmarks of cancer?
Cancer progresses through several distinct hallmarks, including sustaining proliferative signaling, resisting cell death, reprogramming metabolism, evading immune destruction, promoting angiogenesis, and enabling invasion and metastasis. Repurposed drugs offer promising routes to disrupt these processes by acting on key molecular pathways (Drug repurposing for cancer therapy).
Salidroside, derived from Rhodiola rosea, inhibits the PI3K/AKT signaling pathway, playing a critical role in controlling cell proliferation in cancers such as prostate and nasopharyngeal carcinoma. By blocking this pathway, salidroside reduces uncontrolled tumor cell growth (Salidroside targeting PI3K/AKT pathway.
Triptolide, extracted from Thunder God Vine, induces non-apoptotic forms of programmed cell death such as pyroptosis and necrosis. These mechanisms help overcome resistance to apoptosis observed in many tumors (Triptolide in cell death pathways.
Leflunomide disrupts tumor metabolism by inhibiting dihydroorotate dehydrogenase (DHODH), critical for pyrimidine synthesis, leading to impaired DNA and RNA production necessary for cancer cell proliferation (Leflunomide and disulfiram for metabolism.
Disulfiram, traditionally an anti-alcoholism drug, targets cancer cell metabolism by inhibiting glycolysis and increasing oxidative stress, thereby making tumor cells more vulnerable to damage (Leflunomide and disulfiram for metabolism.
Artemisinin and its derivatives exhibit anti-angiogenic properties by modulating NF-κB signaling, effectively reducing new blood vessel formation that tumors require for growth and metastasis (artemisinin and angiogenesis.
Statins impact cholesterol biosynthesis pathways, resulting in suppression of cancer growth and acting as reactivators of mutated tumor suppressor proteins such as p53 (statins as cancer growth suppressors.
Oleanolic acid demonstrates immune modulation alongside induction of ferroptosis, a regulated form of cell death dependent on iron and lipid peroxidation, further inhibiting tumor progression (oleanolic acid and immune modulation.
Repurposing these drugs capitalizes on their known safety profiles while targeting multiple cancer hallmarks, offering an innovative, multi-pronged approach to cancer therapy (Drug repurposing for cancer therapy.
Exploiting the Tumor Microenvironment with Repurposed Drugs
What are the components of the tumor microenvironment (TME)?
The tumor microenvironment includes various specialized niches such as immune cells, tumor-associated fibroblasts, metabolic alterations, hypoxia (low oxygen), acidity, mechanical forces, neural inputs, and the microbiome. Each component plays a role in sustaining tumor growth, promoting resistance, and aiding metastasis (tumor microenvironment components, immune cells in tumor microenvironment, hypoxia and acidity in tumors, mechanical forces in TME, microbiome influence on tumors.
In what ways can repurposed drugs modulate the tumor microenvironment?
Repurposed drugs target multiple TME components to disrupt tumor progression. They modulate immune cells by altering immune checkpoint pathways or reducing immunosuppressive signals. Metabolic reprogramming is targeted to cut off tumor energy supply. Drugs can alleviate hypoxia and acidity, which are tumor-protective niches. Mechanical forces affecting tumor stiffness and cell migration are also influenced. Moreover, altering the microbiome composition can boost antitumor immunity (repurposed drugs and cancer hallmarks, immune evasion in tumors, targeting tumor metabolism, modulating tumor microenvironment with repurposed drugs, immune cells as targets in TME.
For example, apigenin, a natural flavonoid, affects PD-L1 expression, enhancing immune recognition of cancer cells. Celecoxib, originally an arthritis drug, inhibits COX-2 and NF-κB, reducing inflammation and angiogenesis. Dietary fibers like inulin positively reshape gut microbiota to support immune responses against tumors (Apigenin and PD-L1 expression, Celecoxib inhibits COX-2 and NF-κB, Inulin modulation of gut microbiota in cancer prevention.
What examples of repurposed drugs target the TME?
- Apigenin: Modulates PD-L1 to restore immune activity.
- Celecoxib: Suppresses COX-2, reducing inflammation and tumor blood vessel formation.
- Inulin: Alters gut microbiota, enhancing antitumor immune surveillance.
- Metformin: Not only targets metabolism but modulates tumor stemness and microenvironment.
- Disulfiram: Interferes with tumor glycolysis, affecting the metabolic microenvironment (Salidroside targeting PI3K/AKT pathway, Disulfiram anti-cancer effects, Metformin in cancer treatment).
Why are multi-targeted approaches with repurposed drugs beneficial?
Targeting the TME from multiple angles can more effectively inhibit tumor growth and prevent adaptive resistance seen with single-target therapies. Repurposed drugs often have pleiotropic effects, allowing simultaneous modulation of immune evasion, metabolism, angiogenesis, and other TME hallmarks. This can translate into improved patient outcomes with potentially fewer side effects, leveraging well-known safety profiles (Advantages of drug repurposing, repurposed drugs in cancer treatment, Combination therapies using repurposed drugs.
Thus, exploiting the complexity of the TME through repurposed drugs represents a promising strategy in innovative cancer treatment.
Advances in Experimental Models and Screening Approaches
What experimental and computational methods support drug repurposing in cancer?
Drug repurposing in oncology greatly benefits from cutting-edge experimental and computational techniques that enable rapid and accurate identification of candidate drugs.
Patient-derived organoids and tumoroids serve as key experimental platforms. These 3D culture models derived directly from patient tumor tissues closely mimic the architecture, genetic makeup, and drug response profiles of primary tumors. They provide valuable insights into tumor heterogeneity and resistance mechanisms, making them indispensable for personalized drug screening and therapy optimization (Organoids and tumoroids in cancer research, Tumoroids as cancer models, Organoid and tumoroid cancer models, Models for drug screening in ovarian cancer).
High-throughput screening (HTS) techniques allow the rapid testing of hundreds to thousands of existing drugs or compounds for anticancer activity in relevant models. HTS platforms can quickly identify promising repurposing candidates based on cellular viability, signaling pathway inhibition, or other functional readouts (High-throughput screening, High-throughput drug screening for glioblastoma, Experimental drug repurposing methods.
On the computational front, molecular docking helps predict how known drugs might physically interact with novel cancer targets at the molecular level (Molecular docking in drug discovery, Molecular docking in drug identification). Network analysis explores complex interactions between drugs, targets, and pathways to identify multitarget therapeutic opportunities, especially important given cancer's complexity (Network analysis for drug candidates, Drug-target network analysis for cancer treatment).
Moreover, artificial intelligence (AI) and machine learning approaches analyze large-scale biological data such as gene expression profiles, proteomics, and drug-target networks to predict drug efficacy, uncover hidden drug mechanisms, and prioritize candidates for experimental validation (AI in drug repurposing, Machine learning in drug discovery, AI in cancer diagnosis and treatment).
Together, these integrated experimental and computational methods accelerate drug repurposing by providing a robust framework to discover and validate novel anticancer applications of existing pharmaceuticals, thus advancing personalized medicine and improving treatment outcomes.
Repurposing Common Chronic Disease Drugs for Cancer Treatment
Which chronically used medications show promise for repurposing in cancer therapy?
Anti-diabetic drugs, especially metformin, have attracted significant attention for their potential anticancer properties. Metformin works mainly by activating AMP-activated protein kinase (AMPK), which inhibits the mTOR pathway, a critical regulator of cell growth and metabolism. This mechanism translates into reduced tumor stemness, decreased proliferation, and metastasis suppression. It is widely studied, with over 350 clinical trials underway, evaluating metformin’s impact across various cancers such as colorectal, breast, pancreatic, prostate, and lung.
Several anti-hypertensive drugs, including propranolol and captopril, are also promising repurposing candidates. Propranolol, a non-selective beta-blocker, suppresses β-adrenergic signaling pathways involved in tumor progression, inhibits angiogenesis, and modulates immune responses to enhance antitumor activity. Captopril, an ACE inhibitor, is investigated for its effects on tumor vascularization and chemo-resistance reversal. Both classes of drugs benefit from well-established safety profiles and tolerability, which support their suitability for long-term use in cancer patients.
Clinical Trials and Indications
Current trials assess these drugs as monotherapies and in combination with conventional chemotherapy or immunotherapy. Metformin has advanced to Phase III trials targeting five cancer types, while some antihypertensive agents have reached Phase IV stages, indicating growing clinical validation. They are being evaluated in colorectal, breast, prostate, pancreatic, neuroblastoma, and other cancers, highlighting their broad application potential.
Benefits of Repurposing These Drugs
The main advantages of repurposing anti-diabetic and anti-hypertensive medications are their known pharmacokinetics and safety, cost-effectiveness, and feasibility for chronic administration. Their low toxicity profiles allow usage at relatively low doses suitable for prolonged therapy, critical for targeting cancer stemness and microenvironment alterations over time. Additionally, as generics, they offer accessibility that could be pivotal in low- and middle-income settings, addressing global health disparities in cancer care.
Overall, chronic disease drugs like metformin and propranolol represent valuable, evidence-backed candidates for enhancing cancer treatment strategies, combining efficacy with safety and affordability.
Synergistic Combination Therapies with Repurposed Drugs
How can repurposed drugs be integrated into combination cancer therapies?
Repurposed drugs can be effectively combined with standard cancer treatments such as chemotherapy and radiotherapy to enhance therapeutic outcomes. By targeting multiple tumor escape routes concurrently, these drugs help overcome resistance mechanisms that often limit the efficacy of conventional therapies.
For example, nintedanib, originally used for pulmonary fibrosis, has been shown to reduce fibrosis within the tumor microenvironment. When added to chemotherapy in early-stage HER2-negative breast cancer, it improves drug penetration and treatment efficacy.
Another promising agent, vortioxetine, a low-cost antidepressant, selectively induces calcium influx in glioblastoma cells, leading to cell death. Clinical studies suggest that vortioxetine may act synergistically with chemotherapies, enhancing tumor shrinkage without significant harm to normal cells.
Similar additive or synergistic effects have been reported with colforsin daropate (a forskolin derivative) combined with cisplatin in ovarian cancer models, where increased drug uptake and reduced oncogenic protein levels were observed.
Current clinical trials are actively evaluating these combination approaches to validate safety and efficacy, aiming to establish new multi-targeted cancer therapies that leverage the advantages of drug repurposing alongside existing treatments.
Nanotechnology-Enhanced Delivery of Repurposed Drugs
What role does nanotechnology play in improving repurposed drug therapies?
Nanotechnology significantly enhances the clinical potential of repurposed drugs in cancer therapy by enabling targeted delivery and reducing adverse effects. Nanocarriers for drug delivery such as liposomes, polymeric nanoparticles, and metallic nanoparticles are engineered to transport these drugs directly to tumor sites. This targeted delivery increases drug accumulation in malignant cells and minimizes systemic toxicity, a common limit of traditional chemotherapy.
Use of Nanocarriers and Their Benefits
- Liposomes: Gel-like vesicles that can encapsulate both hydrophilic and hydrophobic drugs, protecting them from degradation and facilitating sustained release at the tumor site.
- Polymeric Nanoparticles: Provide controlled drug release, increased stability, and improved bioavailability.
- Metallic Nanoparticles: Offer unique surface properties useful for both drug delivery and diagnostic imaging.
Examples of Nanocarrier Applications with Repurposed Drugs
- Niclosamide-loaded liposomes have shown enhanced effectiveness in melanoma by increasing drug concentration locally and reducing off-target exposure.
- Triptolide nanocarriers enable delivery of this potent natural product to cancer cells, inducing tumor-specific cell death while limiting systemic exposure.
Future Prospects
With continuing advancements, combining nanotechnology with drug repurposing holds promise to overcome drug resistance mechanisms often seen in cancer and improve patient outcomes. This integration offers a pathway towards precision oncology by maximizing therapeutic efficiency and safety, ultimately facilitating more effective, less toxic cancer treatments.
Targeting Cancer Stem Cells with Repurposed Medications
How can drug repurposing help target cancer stem cells?
Cancer stem cells (CSCs) are crucial drivers of tumor progression, metastasis, and resistance to therapy. They possess the ability to self-renew, differentiate, and evade conventional treatments, contributing to cancer relapse. Targeting these cells is therefore essential for improved cancer outcomes.
Drug repurposing for cancer stem cells offers a promising route to combat CSCs more efficiently. Several existing drugs, initially approved for other diseases, have demonstrated effects against CSC-related signaling pathways, including Wnt/β-catenin pathway in cancer therapy, Notch signaling and cancer, Hedgehog (Hdhg) pathway in cancer, and TGF-β pathway targeting. By interfering with these pathways, repurposed drugs can disrupt CSC maintenance and survival.
Examples of such drugs include:
Aspirin: Known for its anti-inflammatory properties, aspirin modulates signaling cascades important for CSC proliferation and survival.
Metformin: Commonly used for diabetes, metformin activates AMPK signaling and inhibits pathways like mTOR, impairing CSC self-renewal and metabolic fitness.
Niclosamide: An anti-parasitic agent that inhibits Wnt/β-catenin and Notch pathways, reducing CSC viability.
Curcumin: A natural compound with activity against multiple CSC pathways, including Hedgehog and TGF-β, inducing differentiation and apoptosis.
Combination therapies integrating repurposed drugs with micronutrients such as vitamins C, D, and B6 show potential to synergistically target CSCs and bulk tumor cells. These approaches may help overcome chemoresistance, reduce tumor recurrence, and improve overall therapeutic efficacy.
Overall, drug repurposing accelerates the discovery of CSC-targeted treatments by leveraging existing safety and pharmacokinetic data, thus offering a cost-effective and faster alternative to novel drug development. Drug repurposing for cancer stem cells
Current Clinical Trial Landscape and Research Initiatives
What is the status of clinical research on repurposed drugs for cancer?
Clinical research on repurposed drugs in oncology is rapidly expanding, with numerous ongoing trials evaluating their effectiveness across multiple cancer types. Metformin stands out with over 350 clinical trials investigating its anti-cancer potential, particularly in cancers such as colorectal, breast, pancreatic, prostate, lung, and cervical. Beta blockers, especially propranolol, are actively studied in trials for a range of malignancies including breast cancer, colorectal cancer, pancreatic cancer, and multiple myeloma. Statins also have ongoing evaluations, notably in head and neck cancers, where they may improve survival and enhance immunotherapy responses.
The Winship Cancer Institute of Emory University is a key institution championing repurposed drug research. They conduct multiple clinical trials focusing on not only improving patient outcomes in various cancers but also on strategic goals such as preventing recurrence and boosting the efficacy of immunotherapies. These trials explore monotherapy and combination therapies utilizing repurposed agents to target tumor adaptation, inflammation, and the tumor microenvironment.
Many repurposed drugs have advanced to Phase III and IV trials, reflecting strong clinical interest and validation of repurposing approaches. Trial endpoints commonly include evaluating tumor response, progression-free survival, recurrence prevention, and enhancement of immunotherapy efficacy. The expanding clinical trial landscape underscores drug repurposing’s promise as a cost-effective and expedited strategy to introduce novel cancer therapies.
Challenges and Ethical Considerations in Drug Repurposing
What challenges and ethical issues affect the development and use of repurposed drugs in cancer care?
Drug repurposing in oncology comes with several significant challenges. Pharmacologically, finding the optimal dosing and ensuring sufficient bioavailability for cancer treatment can be difficult since drugs were originally formulated for other indications. This mismatch can affect the drug's therapeutic effectiveness against cancer (Pharmacological considerations in repurposing.
Regulatory and patent challenges also stand in the way, especially for off-patent medications. Without patent protection, pharmaceutical companies often have little commercial incentive to invest in the expensive clinical trials required to approve new cancer indications. This lack of financial backing limits available funding and slows clinical adoption (Patent and regulatory hurdles for repurposed drugs, Intellectual property challenges in drug repurposing, patent issues and market exclusivity).
Ethical concerns arise mainly from the limited high-quality evidence supporting some repurposed drugs’ efficacy in cancer. The uncertainty in risk-benefit profiles complicates physicians' ability to make informed decisions and obtain truly informed patient consent. Patients might be exposed to unknown side effects or ineffective treatments without robust trial validation (Ethical challenges of drug repurposing in oncology, Clinical evidence gaps in drug repurposing).
Overcoming these hurdles demands innovative collaborative frameworks involving academia, industry, clinical investigators, and regulatory agencies. Dedicated funding mechanisms and novel trial designs targeting repurposed drugs are crucial to support rigorous clinical validation. Only through such collective efforts can repurposed drugs be safely and effectively integrated into cancer care, ensuring ethical standards are met while maximizing patient benefit (Collaborative networks in oncology repurposing, Clinical validation of repurposed drugs, Challenges and cautions in drug repurposing.
Future Perspectives: AI and Precision Oncology in Repurposing Efforts
How is artificial intelligence transforming drug repurposing in cancer therapy?
Artificial intelligence (AI) is revolutionizing drug repurposing by rapidly analyzing complex biological data to identify existing drugs with new anticancer potentials. Machine learning techniques process vast datasets, including gene expression profiles, protein interactions, and drug-target networks, to predict candidates for repurposing efficiently and cost-effectively. This approach significantly reduces the time and cost associated with traditional drug development (AI in drug repurposing for cancer therapies.
Integration of genomic and omics data for personalized medicine
The combination of AI with genomic and other omics data allows personalized medicine approaches where repurposed drugs are matched to specific molecular characteristics of a patient's tumor. By understanding the tumor’s unique signaling pathways and mutations, AI-guided drug repurposing tailors treatment strategies that maximize efficacy and minimize toxicity (Drug repurposing in oncology.
Examples of AI-driven repurposing successes
Drugs like metformin, originally an antidiabetic agent, and propranolol, a beta-blocker, were identified by AI models as promising repurposing candidates for certain cancers. These discoveries have accelerated clinical research and trials, showcasing AI’s role in transforming candidate drug identification (Drug repurposing in cancer therapy.
Potential impact on timely and cost-effective therapy development
The application of AI not only accelerates the discovery of repurposed drugs but also improves the precision of cancer therapy. This could lead to faster development of affordable cancer treatments, addressing unmet medical needs and enhancing patient access globally. As AI-driven repurposing evolves, it holds promise for improving survival and quality of life for cancer patients worldwide (AI in drug repurposing for cancer therapies.
.png)
.png)
