Vidyaniketan College of pharmacy, Anjangaon surji Amravati, Maharashtra, India
Cancer is still the fourth major cause of morbidity and mortality despite the great progress made in the past few years in the understanding of the molecular mechanisms and the development of targeted therapeutic approaches. The very long and expensive timelines and the remarkably high failure rates that characterize the conventional drug development processes have lately brought attention to the concept of drug repositioning. Drug repositioning entails the search for new therapeutic applications for compounds that have long been approved and/or investigated for other diseases. This very appealing and innovative strategy has the capability to considerably reduce the costs and timelines associated with the drug development processes and also to overcome the safety concerns that are often caused by the conventional processes. This review aims to give a brief overview on the idea of the repositioning strategy for the treatment of cancer and its biological bases. The mechanisms that have the capability to behave in the role of antitumor compounds for those repositioned compounds include the interference of metabolic pathways, the prevention of angiogenesis, the induction of apoptosis and autophagy, the regulation of the immune system, the interference of the repair mechanisms for the DNAs, and the epigenetic mechanisms. The efficient repositioning compounds that have already demonstrated their therapeutic efficacy in the clinics are briefly discussed. Moreover, the promising techniques that have the ability to outline the new prospects for the repositioning strategy for the treatment of oncologic diseases in the near future are also briefly mentioned and discussed. This concerns the integration of the Artificial intelligence and big data for the repositioning strategy for the treatment of oncologic diseases. Additionally, the new concept for the repositioning strategy for the treatment of oncologic diseases also entails the concerns on intellectual property rights.
Cancer is a group of several diseases that arise in a progressive manner due to uncontrolled cellular proliferation [1,2]. Although each has distinct properties, all contribute to the disease through basic mechanisms [3,4]. The cells in cancer can be malignant or normal. They proliferate when no signals are given, ignoring signals for its end or apoptosis. They induce vascular proliferation towards malignancies; supply oxygen and nutrition; remove toxic material. They also evade the immune system's attention so it does not hinder their proliferation and survival. Cancerous cells often have a large assortment of alterations in chromosomes. The cells become so dependent on them that they cannot function normally without those changes [5]. Tumor progression is usually depicted as stages of mutation and growth. A normal cell is converted into a malignant cell with less than 10 mutations [2,6]. Stages include initial mutation, hyperplasia, dysplasia, in situ cancer, and invasive/malignant tumors. In situ cancer is characterized by abnormal development and appearance of the cell and its progeny, while invasive/malignant tumors allow the tumor to disseminate to other tissues and discharge cells into the lymph or bloodstream, potentially generating new malignancies. Malignant tumors can metastasize across the body, contributing to targeted therapy resistance [3]. Cancer-critical genes usually fall into two main classes: proto-oncogenes and tumor suppressor genes [7]. Proto-oncogenes promote cell growth, while tumor suppressor genes halt the process. Changes in the genes may lead to the hyperactivity of proteins that support growth-promoting pathways, causing cells to proliferate at a faster rate than they would without mutation [2]. Most malignancies fall into three major categories, which are carcinomas, sarcomas, and leukemias or lymphomas. Human cancers are dominated by carcinomas, accounting for 90%; whereas sarcomas form solid tumors that invade connective tissues. The immune system and blood-forming cells are responsible for lymphomas and leukemias, respectively, and account for 8% of all human malignancies. Tumors are also classified based on their cell type and tissue of origin [8]. Radiation and chemical carcinogens induce mutations and DNA damage, and can be regarded as “initiating agents” since mutations in critical target genes represent the earliest event in the process leading to malignancy. [9]
2. Drug repurposing strategies
In summary, drug repurposing can be divided into three stages: identifying the core targets of the disease (hypothesis generation), determining the efficacy of the drug through in vitro and in vivo models and proceeding to phase II clinical trials in cases where phase I trials have yielded adequate data. [10-12] The inception stage is critical since hypothesis generation is the key to any drug repurposing endeavor. [13] Historically, drug repurposing in oncology has largely been driven by either an understanding of the disease pathways or through serendipitous findings. Thus, designing innovative strategies to match existing drugs with newfound applications could increase the success of drug repurposing. Identification of a potential repurposed drug can be made using computational and experimental methods. The experimental approach considers tools such as induced pluripotent stem cell models and function-first phenotypic screenings (or reverse chemical biology), [14,15] while computational methods use target-centric, knowledge-driven, signature-aligned, pathway-focused, and mechanism-specific strategies. [16,17] More often, these techniques are synergistically utilized. Notably, high-throughput screening using sophisticated models can identify compounds that mitigate disease symptoms without necessitating pre-existing knowledge about the drug-target interactions. [18,19] Current computational methodologies, such as merging drug effects with clinical disease signatures and model systems that predict disease-modifying effects, are available for the selection of drug candidates suitable for drug repurposing in cancer. These tools can identify ligands, decode drug ingredient binding schemas, and highlight promising candidates from an expansive list of potential compounds. [18,20,21] In summary, although the idea of drug repurposing is long-established, it is only recently that technological advances, such as the ones outlined in this article, have led to the development of cutting-edge strategies that can be consciously paired with novel indications.
Experimental Approaches
Organoid Models of Cancer
Organoids are described as “stem cell-containing self-organizing structures” and tumoroids represent a special form of cancer organoids. [22] Organoids represent in vitro tissues that are derived from human stem cells, organ-specific progenitor cells, or even disassociated tumor tissues, that are cultured in special ECM-based media with relatively high success rates. Tumoroids reflect the primary tissue both architecturally as well as functionally and maintain the histopathological features, genetic profile, mutational landscape, and even responses to therapy. [23] The utilization of tumoroids is growing, and their value for basic research and the initial phases of drug development has been realized. [24] The antitumor efficacy of cisplatin was discovered to be significantly lower in PDOs prepared from NSCLC tissues compared to cell lines, which exemplified how patient-derived material can provide valuable information about possible resistance mechanisms.[25] Regarding gastrointestinal malignancies, several studies have utilized PDOs as tools to assess drugs and probe into likely therapeutic pathways.[26,27] Such models have successfully reflected the utility of tumoroids in the correct reproduction of KRAS-mutant metastatic rectal cancer with microsatellite stability following hepatic resection and treatment with neoadjuvant combination chemotherapies in colorectal cancer,[28] as well as assessed drug responses in HCC [29,30] and also model treatment resistance patterns observed in esophageal squamous cell carcinoma. [31]
Tejswini Gaikwad*, Rashee Shahu, Sunita Kode, Shivcharan Kamble, Pooja Rasal, Reinventing Medicines: Drug Repurposing as A New Frontier in Cancer Therapy, Int. J. Sci. R. Tech., 2025, 2 (12), 437-456. https://doi.org/10.5281/zenodo.18064187
10.5281/zenodo.18064187
