Exploiting the molecular subtypes and genetic landscape in pancreatic cancer: the quest to find effective drugs

Nnenna Elebo; Ebtesam A. Abdel-Shafy; Stefano Cacciatore; Ekene Emmanuel Nweke

doi:10.3389/fgene.2023.1170571

Front Genet. 2023; 14: 1170571.

Published online 2023 Sep 18. doi: 10.3389/fgene.2023.1170571

PMCID: PMC10544984

PMID: 37790705

Exploiting the molecular subtypes and genetic landscape in pancreatic cancer: the quest to find effective drugs

Nnenna Elebo,^1
,² Ebtesam A. Abdel-Shafy,^2
,³ Stefano Cacciatore,² and Ekene Emmanuel Nweke^1
,^*

Author information Article notes Copyright and License information PMC Disclaimer

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is a very lethal disease that typically presents at an advanced stage and is non-compliant with most treatments. Recent technologies have helped delineate associated molecular subtypes and genetic variations yielding important insights into the pathophysiology of this disease and having implications for the identification of new therapeutic targets. Drug repurposing has been evaluated as a new paradigm in oncology to accelerate the application of approved or failed target-specific molecules for the treatment of cancer patients. This review focuses on the impact of molecular subtypes on key genomic alterations in PDAC, and the progress made thus far. Importantly, these alterations are discussed in light of the potential role of drug repurposing in PDAC.

Keywords: Pancreatic Cancer, drug repurposing, mutations, genomics, precision medicine

1 Introduction

Pancreatic Ductal Adenocarcinoma (PDAC) is the most common form of pancreatic cancer accounting for more than 90% of all pancreatic malignancies (Kleeff et al., 2016). This aggressive cancer, with a 5-year survival rate of about 12%, is one of the leading causes of cancer-related deaths worldwide (Siegel et al., 2022). It is predicted to be the second most common cause of cancer-related death in the United States by 2030 (Rahib et al., 2014). In low-to-middle-income countries such as South Africa, it is currently the seventh leading cause of cancer-related death (Statistics South Africa, 2023). Surgery remains the best treatment strategy. In recent years, there have been significant technological advancements which have led to elucidating key molecular mechanisms involved in the progression of PDAC. Several omics analyses such as genomics, transcriptomics, and metabolomics have been used to demonstrate the heterogeneity of PDAC between different tumours (inter-tumour) and within the same tumour (intra-tumour) (Cros et al., 2018; Elebo et al., 2021; Gutiérrez et al., 2021). The genetic landscape of pancreatic cancer explores the intricate genetic alterations that drive the initiation, progression and metastasis of pancreatic cancer. Examples include mutations in key genes such as KRAS, SMAD4, P53, and CDKN2A observed in pancreatic cancer (Falasca et al., 2016). In this era of precision medicine, these identified mechanisms can be exploited for diagnosis, treatment and management (Halbrooks et al, 2023). These emerging therapeutic approaches offer a glimpse into the discovery and development of novel effective drugs that could emerge from our improved understanding of the molecular subtypes and genetic landscape (Elebo et al., 2020; Nsingwane et al., 2020; Wang et al., 2021a). However, unlike other solid tumours, pancreatic cancer continues to show resistance to some of these novel therapies. This characteristic together with the lengthy and expensive process of the development of new drugs impedes the closing of the gap observed between our intricate understanding of the molecular and genetic landscape of PDAC and clinical benefit to patients. To leverage this understanding, consideration should be given to repurposing other well-known drugs for the treatment of the disease.

Hence this mini-review delves into the current knowledge regarding the molecular subtypes and genetic landscape of pancreatic cancer and their clinical impact. Then, we discuss some drugs that have been demonstrated to have potential clinical impact when repurposed for PDAC treatment highlighting recently completed and some ongoing clinical trials. Ultimately, we highlight the challenges of repurposing drugs for PDAC treatment and the opportunities for overcoming them.

2 Molecular subtypes of PDAC

Several studies have stratified patients into distinct subtypes using cutting-edge techniques such as single-cell analyses (Pompella et al., 2020) (Table 1). For example, Collision et al. classified PDAC into three subtypes, namely, quasi-mesenchymal subtype which is the most aggressive, exocrine-like subtype, and the classical subtype with the best prognosis of all three (Collisson et al., 2011). They employed microarray gene expression for human and cell line models to pinpoint the genetic signature underlying each subtype. Bailey et al. (2016) identified four subtypes of PDAC (pancreatic progenitor, squamous, aberrantly differentiated endocrine exocrine (ADEX), and immunogenic) according to an integrated genomic analysis of 456 pancreatic cancer patients using a combination of whole genome, deep exome sequencing, and transcriptional profile. Another study used non-negative matrix factorisation to perform virtual microdissection of microarray results for PDAC categorization in two tumour-specific groups: classical and basal-like (Moffitt et al., 2015). Similarly, using integrated multi-omics profiling of 150 PDAC specimens two subtypes were identified as basal-like squamous and classical/pancreatic progenitors (Raphael et al., 2017). Most recently Chan-Seng-Yue and colleagues used a combination of whole genome and transcriptome sequencing as well as single-cell sequencing to classify the tumours into Basal-like A and B, hybrid, and classical A and B subtypes (Chan-Seng-Yue et al., 2020).

TABLE 1

Impact of the classification of tumour subtypes in the genetic events of PDAC.

Subtypes	Impact of Genomic Mutations
Basal-like	• Complete loss of CDKN2A Chan-Seng-Yue et al. (2020).
	• Elevated frequency of TP53 mutations Raphael et al. (2017).
	• KRAS mutation is stage-dependent: Metastatic basal-like tumours are enriched with KRAS mutants Chan-Seng-Yue et al. (2020).
	• SMAD4 gene alterations: SMAD4 gene is a key player in TGF-β signalling which is elevated in basal-like tumours.
Squamous	• Major KRAS imbalances at the late stage of PDAC Chan-Seng-Yue et al. (2020).
Classical	• Elevated frequency of complete loss of SMAD4 Bailey et al. (2016), Chan-Seng-Yue et al. (2020).
Classical	• GATA6 amplification Collisson et al. (2011).
ADEX	• Upregulation of genes involved in KRAS activation Bailey et al. (2016).
Immunogenic	• Elevated levels of genes associated with B and T immune cell populations Maurer et al. (2019), Zhou et al. (2021).

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The classical subtype is characterized by high expression of adhesion-associated and epithelial genes such as GATA binding protein 6 (GATA6), KRAS, and SMAD4 in addition to KRAS G12V high mutational level (Collisson et al., 2011; Moffitt et al., 2015). Progenitor is similar to the classical subtype and defined by expressing genes associated with early tumour development like steroid hormone biosynthesis, fatty acid oxidation, drug metabolism, and O-linked glycosylation of mucins (Bailey et al., 2016). The squamous subtype is characterized by inflammation, hypoxia, TGF-β signalling, metabolic reprogramming, and activation of the MYC pathway which are linked to poor outcomes (Bailey et al., 2016). The pancreatic squamous basal-like tumours were shown to be associated with mutations in TP53 that are essential in driving epithelial to mesenchymal transition (EMT) promoting metastasis (Raphael et al., 2017).

3 Clinical impact of molecular subtypes

Recent studies have demonstrated that different subtypes can impact on clinical outcomes of pancreatic patients (Dreyer et al., 2022). PDAC patients with the classical subtype were shown to have a better prognosis than those with the quasi-mesenchymal subtype after resection which could be due to the elevated expression of mesenchyme-associated genes and decreased GATA6 levels in the latter (Collisson et al., 2011). Pancreatic cancer development has been associated with the overexpression of GATA6 (Fu et al., 2008). Subtype-associated with long intergenic non-coding RNA (lincRNAs) may be vital in predicting the overall survival rate in PDAC via the subtype-specific selection burden on GATA6 (Glaß et al., 2020). Additionally, GATA6 could be used as a marker of response to chemotherapy because it regulates EMT and tumour dissemination (Martinelli et al., 2017; Deng et al., 2020).

The relationship between KRAS dependence and subtypes was assessed using RNA interference (RNAi) to probe KRAS-mutant human PDAC cell lines and it showed classical subtypes are more dependent on KRAS than quasi-mesenchymal (Collisson et al., 2011). This suggests that KRAS-directed therapy could be vital in the classical PDAC subtype. The response of PDAC to chemotherapy is influenced by their subtypes; quasi-mesenchymal was shown to be more sensitive to gemcitabine while erlotinib was more effective in classical PDAC cell lines (Torres and Grippo, 2018).

ADEX subgroup identification is vital in the later stages of pancreatic development and differentiation via the upregulation of genes that regulate networks, such as NR5A2 involved in KRAS activation (Bailey et al., 2016; von Figura et al., 2014). The progenitor subtype is associated with IPMN and better survival than other subtypes (Bailey et al., 2016) while the squamous subtypes were significantly associated with poorer survival than ADEX and immunogenic subtypes (Hong et al., 2021). Furthermore, the immunogenic subtype is associated with immune cell infiltrates and cellular programs such as antigen presentation, B cell signalling pathway, CD4 and CD8 T-cells (Rooney et al., 2015; Bailey et al., 2016).

4 Key genomic aberrations in PDAC

4.1 Kirsten rat sarcoma viral oncogene homolog (KRAS)

KRAS pathway has been one of the most characterised pathways in PDAC. Genetic approaches have demonstrated that KRAS mutations occur in over 95% of PDAC tumours (Dreyer et al., 2017). A high mutational level of the KRAS gene in PDAC has been linked to disease initiation, growth, and progression (Buscail et al., 2020). They are deactivated when they bind to GDP and activated when GTP is attached. Activated KRAS initiates RAS kinase which in turn genetically dysregulates multiple pathways in PDAC that could serve as potential therapeutic targets. Until recently, KRAS has been tagged undruggable because it lacks a binding site for a competitive inhibitor (Gillson et al., 2020). Recently, AMG 510 has been developed as a drug used to maintain a high level of inactive KRAS by binding to only reactive mutant KRAS ^G12C (Canon et al., 2019). Phase I/II clinical trials involving 533 patients with KRAS ^G12C mutations from various cancers were carried out to investigate the efficacy of AMG510 as monotherapy or in combination with anti-PD-1 immune checkpoint blockers showed that 56% partial response and 46% stable disease (Govindan et al., 2019). About 60% of KRAS wild types have altered activation of the RAS-MAPK pathway, hence highlighting the importance of this pathway in therapy development (Martinelli et al., 2017). A drug called Compound 11 can disrupt KRAS interaction with Raf effector, inhibiting the MAPK growth pathway (McCarthy et al., 2019) which could be a potential therapy for PDAC. Another compound, MRTX849 was used in phase I clinical trials in patients with advanced cancers, and results demonstrated a high percentage of partial response (Hallin et al., 2020). Most recently, KRAS G12D inhibitor MRTX1133 have been shown to inhibit oncogenic KRAS signalling and reduce tumour growth via the inactivation of ERK pathway (Mao et al., 2022; Wang et al., 2022).

4.2 Tumour protein 53 (TP53)

TP53 mutations occur in over 70% of PDAC initiating the activation of KRAS mutation and are usually associated with poor outcomes (Masetti et al., 2018; Liu et al., 2021). They result in the loss of both DNA binding ability and gene transcription activation (Kern et al., 1992). TP53 is mutated and not deleted in most cancers which is achieved by p21 gene activation promoting growth arrest (Morton et al., 2010). It also increases the expression of cyclin-dependent kinase inhibitor (CDKN1A) which inhibits cell cycle progression (Cicenas et al., 2017). Class 1 and 2 histones deacetylases (HDAC1/HDAC2) which have been linked to metastasis and treatment resistance in PDAC also promote the expression of P53 in PDAC. Thus, a combined approach targeting the inhibition of HDAC1 and HDAC2 could be vital in the development of therapy (Stojanovic et al., 2017). The depletion of HDAC2 has been proven to induce apoptosis of pancreatic cancer cell lines (Schüler et al., 2010). Circulating TP53 has been linked to poor survival in PDAC patients treated with FOLFIRINOX (van der Sijde et al., 2021). A Phase II clinical trial (NCT02340117) study of combined targeted P53 gene therapy (SGT-53) with Gemcitabine/Nab-Paclitaxel for the treatment of metastatic pancreatic cancer is currently ongoing (Leung et al., 2021).

4.3 Cyclin-dependent kinase 2A (CDKN2A)

CDKN2A is a gene located at chromosome 9 which encodes proteins that control cell proliferation and their mutation increases the risk of pancreatic cancer (Hu et al., 2018). Germline CDKN2A variants are present in over 3% of pancreatic tumours which demonstrates their importance in carcinogenesis (Kimura et al., 2021). The inactivation of CDKN2A is mediated by the methylation of its promoter region. CDKN2A encodes two proteins; p14 and p16 which are responsible for cell cycle arrest, DNA repair constraints cyclin-dependent kinase 6 (CDK6) and cyclin-dependent kinase 4 (CDK4) which triggers the activation blocks G1 to S phase (Knudsen et al., 2016). Alterations of CDKN2A induce cyclin-dependent kinase 4 and 6 (CDK4/6) activity and lead to cell proliferation (Kimura et al., 2021). Consequently, inhibition of CDK4/6 could be a potential target in anti-tumour therapy in PDAC patients. Clinical studies targeting CDK4/6 inhibition in PDAC patients with CDKN2A loss or mutation (Clinical trials: NCT02501902, NCT02897375) have been demonstrated to be crucial in PDAC therapy (Al Baghdadi et al., 2019; Hidalgo et al., 2020).

4.4 Mothers against decapentaplegic homolog 4 (SMAD4)

SMAD4 is a tumour suppressor protein also known as DPC4 (deleted in pancreatic cancer 4). SMAD4 mutations occur in over 50% of PDAC cases promoting invasion, metastasis and poor prognosis via the inhibition of TGF-β signalling pathways by affecting cell arrest, apoptosis, invasion and metastasis (Huang et al., 2020). The correlation between SMAD4 gene inactivation with survival time suggests a poor prognosis in PDAC (Blackford et al., 2009; Singh et al., 2012). Resistance to PDAC treatment has been associated with SMAD4 loss limiting the vulnerability of pancreatic cancer cells to complex I inhibition via the promotion of mitophagy (Ezrova et al., 2021). Genomic and transcriptomic profiling analyses demonstrated that classical and progenitor subtypes are enriched with SMAD4 mutations compared to other subtypes (Chan-Seng-Yue et al., 2020).

5 Repurposing drugs in PDAC treatment

Drug repurposing also known as drug redirection and therapeutic switching involves the process of identifying new therapeutic use for old or existing drugs. It provides a solution to the time-consuming, laborious, expensive, and high-risk process of traditional drug discovery (Pushpakom et al., 2019; Nweke et al., 2021). These drugs can target single or multiple aberrations in targets or pathways which may in turn circumvent resistance (Sarmento-Ribeiro et al., 2019) (Figure 1; Table 2).

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FIGURE 1

Drug Repurposing Therapy in Pancreatic Ductal Adenocarcinoma Targeting Genomic Alterations and Molecular Subtypes. The Tumor microenvironment of PDAC is complex and heterogeneous. Several molecular subtypes such as classical, basal-like, squamous, immunogenic and ADEX have been identified thus far with diverse molecular perturbations. Repurposed drugs such as hydroxychloroquine, chloroquine, Nitroxoline, Perbendazole, Nitraparib, and Rucaparib are used in targeting genomic mutations in PDAC.

TABLE 2

Some repurposed drug for PDAC treatment.

Drug	Original Indication	New Indication	Preclinical/Clinical Studies
Cucurmin	Colouring agent in food	Curcumin has been shown to modulate various pathways which are dysregulated in PDAC, they have an anticancer effect either as a single agent or in combination with other chemotherapy drugs Hosseini et al. (2017).	A phase I/II gemcitabine-based chemotherapy in combination with curcumin for treating Pancreatic cancer patients showed that the drug is well tolerable with increased efficacy Kanai et al. (2011).
Cucurmin	Colouring agent in food	Antiproliferative effect by induction of apoptosis and inhibition of both angiogenesis and oxidative stress Bimonte et al. (2016), Nagaraju et al. (2019).
Genistein	Phytoestrogen is used in the dietary management of skin health Irrera et al. (2017).	Exerts antitumour activity in pancreatic cancer cells via regulation of STAT3, cell cycle arrest, and ROS-mediated apoptosis Bi et al. (2018).	Both in vivo and in vitro studies showed that a combination of 5- Fluorouracil and genistein have more antitumour effects on human pancreatic cancer cells than when compared with either 5- Fluorouracil or genistein alone Suzuki et al. (2014).
Genistein			Phase I clinical trial of AXP107-11, a crystalline component form of genistein in combination with gemcitabine for unresectable pancreatic cancer patients showed that 44% of the patients survived longer than 6 months and 19% were alive after one year Löhr et al. (2016).
Spironolactone	Treatment of hypertension and heart failure Kosmas et al. (2018).	Inhibits DNA repair and acts as a chemosensitizer in combination with DNA-damaging reagents such as cisplatin Gold et al. (2019).	Decreases resistance to Gemcitabine and Osimertinib in pancreatic cancer cell lines Sanomachi et al. (2019).
Spironolactone		Reducing survivin expression which is an anti-apoptotic protein Sanomachi et al. (2019).
Parbendazole and Mebendazole	Anti-parasitic agents Son et al. (2020).	Promotes Apoptosis, DNA damage, and impairs cell migration Florio et al. (2019).	A phase 2a clinical study on the safety and efficacy of using mebendazole in treating gastrointestinal cancer showed high tolerability of the drugs Mansoori et al. (2021).
Parbendazole and Mebendazole	Anti-parasitic agents Son et al. (2020).	Reduces pancreatic tumour size and inhibits liver metastasis Williamson et al. (2021).
Berberine	Reduce blood glucose and insulin levels in type 2 Diabetes mellitus patients Cicero and Baggioni (2016).	Inhibits pancreatic cancer cell viability and metastases by regulating citrate metabolism Liu et al. (2020).	Clinical trials (NCT03281096) using Berberine Hydrochloride in Colorectal cancer patients are still ongoing.
Berberine		The proliferation of PDAC cells, retarding the development of their cycle in G1 and DNA synthesis inhibition Rauf et al. (2021).	Clinical trials (NCT03333265) Primary chemoprevention of Familial Adenomatous Polyposis with Berberine Hydrochloride.
Niclosamide	Treating tapeworm infections Kadri et al. (2018).	Exerts anticancer effects by inhibiting proliferation Kaushal (2021).	Reduces immune evasion and induces GSK-β mediated β-catenin degradation to promote gemcitabine activity which suppresses pancreatic cancer progression Guo et al. (2022).
Niclosamide	Treating tapeworm infections Kadri et al. (2018).	Elevated levels of Niclosamide induce apoptosis of pancreatic cancer cells via the mitochondrial apoptotic pathway Guo et al. (2022).
Ritonavir	Protease inhibitors for controlling HIV infection Cameron et al. (1998).	Inhibition of E2F and AKT pathways promotes the induction of apoptosis and cell cycle arrest Batchu (2014).	Potential use of ritonavir in combination with chemotherapy in human pancreatic tumour cell lines Batchu (2014).
Itraconazole	Antifungal infections Piérard et al. (2000).	Induced apoptosis via ROS generation Jiang et al. (2019).	Activates apoptosis via inhibition of TGF-β /SMAD2/SMAD3 signaling in pancreatic cancer cell lines Chen et al. (2018).
Disulfiram	Treatment of Alcoholism Chick et al. (1992).	Inhibition of the NF-κB pathway downregulates the stem genes Cong et al. (2017).	Disulfiram synergises with SRC inhibitors to suppress the growth of PDAC cells in vitro and in vivo Li et al. (2021).
Bazedoxifene	Treatment of osteoporosis Yavropoulou et al. (2019).	Activates IL-6 and IL-11 which mediates inhibition of STAT3 Wu et al. (2016).	Bazedoxifene is a potential new therapeutic option for PDAC treatment that is safe to use and at a low cost Burkhardt et al. (2019).

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5.1 Aspirin

Notably, drugs such as aspirin, a non-steroidal anti-inflammatory (NSAID) medication have been shown to have anti-neoplastic effects because of their ability to inhibit the prostaglandins precursors, COX-1 and COX-2 enzymes that regulate inflammatory processes (Sleire et al., 2017). Acetylation of aspirin inhibits activation of the transcription factor NF-κB that regulates the expression of genes involved in apoptosis and metastasis (Sleire et al., 2017). Risch and colleagues demonstrated an inverse relationship between the use of Aspirin and the risk of pancreatic cancer in a Chinese cohort (Risch et al., 2017). Zhang’s team demonstrated the anticancer effects of Aspirin on PDAC cell lines. This study recorded the multifunction of Aspirin to alter the expression of reprogramming factors, increase the efficacy of gemcitabine, inhibit tumour growth, and reduce the production of extracellular matrix components such as collagen and fibronectin (Zhang et al., 2015). Aspirin can inhibit neuraminidase-1 (Neu-1) which regulates the activation of toll-like receptors, several receptor tyrosine kinases, and their signalling pathways (Haxho et al., 2016). Targeting Neu-1 by using repurposed drugs could be of potential for inhibiting proliferation and tumorigenesis in PDAC (Qorri et al., 2022). Recent studies showed that a combination of Aspirin, Oseltamivir Phosphate and Gemcitabine could promote the inhibition of survival pathways required for progression in Pancreatic cancer cell lines (Qorri et al., 2020).

5.2 Metformin

This is an oral biguanide used to treat diabetes but is associated with decreased overall cancer incidence (Gandini et al., 2014). The anti-neoplastic effect of metformin could be due to the inhibition of mTOR and ROS (Candido et al., 2018). It is also associated with DNA damage and activation of AMPK (Algire et al., 2012). Metformin has been demonstrated to have an antitumour effect on PDAC cells by suppressing hepatic nuclear factor gamma (HNF4G) activity and could be a target for precision treatment (Wang et al., 2021b). A phase 2 trial (NCT01210911) and recent meta-analysis studies have shown the significant role of metformin in improving the overall survival rate in advanced pancreatic cancer patients (Dulskas et al., 2020; Shi et al., 2020). Although many studies have suggested that metformin might improve survival in PDAC (Amin et al., 2016; Cerullo et al., 2016), several are contrary (Kordes et al., 2015; Chaiteerakij et al., 2016; Reni et al., 2016) hence further prospective and clinical trials are essential to confirm these findings.

5.3 Vitamins

Vitamin D is a fat-soluble steroid that can be gotten from sun exposure diet and dietary supplements, and are responsible for increasing intestinal absorption of calcium, magnesium, and phosphate. Vitamins D₂ and D₃ are the most important compounds in this group. Studies have demonstrated that Vitamin D reduces the risk of pancreatic cancer by regulating cell cycle and differentiation. Although the effect of Vitamin D on the molecular mechanism underlying pancreatic cancer development is not well understood, Vitamin D receptors (VDR) are involved in several metabolic pathways, immune responses, and malignancies (Cannon et al., 2016). Treating PDAC mice with a high dose of calcipotriol, an analogue of Vitamin D has demonstrated that VDR could modulate inflammatory cytokines and growth factors and reduce inflammation and fibrosis (Sherman et al., 2014). Several clinical trials (NCT03472833 and NCT00238199) have been carried out to investigate the use of high-dose Vitamin D/Calcitriol in PDAC and results showed that Vitamin D could be used as standard therapy in pancreatic cancer patients (Ng et al., 2019; Katayama et al., 2020).

Vitamin C is water-soluble vitamin commonly gotten from fruits and vegetables. Ascorbic acid can act as an antioxidant, immunomodulator, and anti-cancer. Hence, Vitamin C derivatives have been repurposed for cancer therapy as shown in several PDAC clinical studies in which they are either used alone or in combination with conventional chemotherapy (Hirschfeld and Bruckner, 2016; Polireddy et al., 2017).

5.4 Beta blockers

These are drugs that prevent the stimulation of adrenergic receptors. Beta adrenoreceptors are G-protein coupled receptors that are expressed by pancreatic cancer cells (Weddle et al., 2001) and have been demonstrated to prolong overall survival (Udumyan et al., 2017; Renz et al., 2018). They play an important role in tumour growth, proliferation, and inhibition of apoptosis via protein kinase A (PKA) pathways (Upadhyaya et al., 2020). The effects of beta-blockers on cancer prognosis were reported to be associated with improved overall survival among pancreatic cancer patients (Na et al., 2018). Long-term use of beta-blockers such as Atenolol, Propranolol, and Carvedilol is correlated with decreased risk of pancreatic cancer (Saad et al., 2020). Atenolol, a beta blocker used for treating hypertension (Wadworth et al., 1991) could be potentially repurposed to inhibit pancreatic cancer cell growth via the modulation of NF-κB using functional network analysis (Hermawan et al., 2020). Propanolol is also another example of a beta-blocker used for treating hypertension, tremors, and other cardiovascular disorders (Hardison et al., 2016) which has been demonstrated to be a potential repurposed PDAC therapy drug. Phase II randomised placebo-controlled PROSPER trial is currently ongoing to assess the safety of the administration of propranolol and etodolac in resectable PDAC (Hüttner et al., 2020).

5.5 Hydroxychloroquine and chloroquine

These are aminoquinoline compounds that are used to treat malaria (Rebelo et al., 2021). Hydroxychloroquine is also used in treating rheumatoid arthritis and lupus (Rebelo et al., 2021). These drugs have been shown to have anti-cancer effects. Chloroquine inhibits autophagy by enhancing the ability of ERK inhibitors to mediate antitumour activities in KRAS-driven PDAC (Bryant et al., 2019). Autophagy is essential in maintaining homeostasis and neutrophil extracellular traps (NETs) formation whereby damaged organelles and other intracellular components are recycled (Boone et al., 2015). Autophagy has also been shown to be vital for PDAC growth and progressions in tumours with P53 alterations (Yang et al., 2014). Also, chloroquine has been demonstrated to inhibit NETs formation thereby reducing the hypercoagulability of murine PDA cells (Boone et al., 2018). Clinical phase II trials (NCT01494155) using hydroxychloroquine and chemoradiation for resectable PDAC. Patients were given hydroxychloroquine in addition to chemoradiotherapy with photons before surgery while only hydroxychloroquine was administered to them afterwards and results showed that about 26 patients survived over 18 months (Raldow et al., 2020). Several clinical trials are currently ongoing or have been carried out (NCT04386057, NCT01978184, NCT04524702, and NCT01273805) to evaluate the role of chloroquine or hydroxychloroquine in combination with other chemotherapy regimens with some results showing that the combination therapy was well tolerated and could be further explored.

5.6 Nitroxoline

Nitroxoline is an antibiotic used in treating bacterial and fungal infections such as urinary tract infections (Shim and Liu, 2014). Nitroxoline has been shown to inhibit angiogenesis and tumour growth by promoting the acetylation of P53 (Zhang et al., 2000) and has shown an anticancer effect on pancreatic, leukaemia, and ovarian cancer (Jiang et al., 2011). More recently, Nitroxoline treatment has been shown to downregulate Na⁺/K⁺ ATPase and increases intracellular ROS which further suppresses cell migration and invasion via the inhibition of the P13K/AKT pathway in AsPC-1 pancreatic cancer cell lines (Veschi et al., 2020). Combination therapy involving Nitroxoline, Nelfinavir, and chemotherapy agent erlotinib has shown great potential in improving the treatment of PDAC, hence future studies and trials could be vital (Veschi et al., 2018).

5.7 Perbendazole

Widely, Parbendazole is used in treating parasite infections in animals. This drug has been shown to possess antiproliferative effects because it has been shown to inhibit growth, promote apoptosis, and induced DNA damage response in pancreatic cancer cell lines (Florio et al., 2019). Perbendazole drastically interferes with cell cycle progression by promoting G2/M arrest in two pancreatic cancer cell lines AsPC-1 and Capan-2 cells (Florio et al., 2019). P53 mutant AsPC-1 showed decreased cyclin B1 levels, a key component in the control of cell cycle progression from G2 to M phase after Perbendazole treatment (Vogel et al., 2004).

5.8 Niraparib and Rucaparib

These are poly ADP ribose polymerase (PARP) inhibitors used as maintenance treatment for advanced ovarian, fallopian tube, or peritoneal cancer responding to platinum-based chemotherapy (Musella et al., 2018; Akay et al., 2021). They induce cytotoxicity by inhibiting PARP enzymatic activities which stimulate the formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death (Lee, 2021). PARP inhibitors target somatic or germline mutations of DNA repair genes such as BRCA1/2, and PALB2 (Akay et al., 2021). Phase II clinical trial studies are currently ongoing including; (NCT03553004) which treats metastatic PDAC patients after previous chemotherapy (NIRA-PANC) with Niraparib, and (NCT03601923) treats patients with a mutation in a DNA repair gene with Nariparib (Kasi et al., 2019). Furthermore, phase 2 trials of PARP inhibitor Rucaparib in pancreatic cancer patients with somatic BRCA mutations or deleterious germline have been done (NCT02042378) and some are still ongoing (NCT03140670) (Domchek et al., 2016; Binder et al., 2019). Rucaparib provided clinical benefits to advanced PDAC patients with BRCA mutation and may be an option earlier in the treatment course (Domchek et al., 2016).

6 Challenges and limitations of drug repurposing in PDAC treatment

Drug repurposing capitalises on matching the established mechanisms of existing drugs with the disease profile. Although, the past years have shown a leap in our understanding of the inception and progression of PDAC, the molecular underpinnings are still being unravelled. Hence matching the right drug with the right molecular subtype becomes a big challenge when the intricacies of the disease are only partially understood. Pancreatic cancer is characterised by its high degree of complexity and intra-tumoural heterogeneity (Hayashi et al., 2021). Different molecular subtypes may coexist within a single tumour and the genetic landscapes vary between patients (Cros et al., 2018). This heterogeneity poses a challenge when attempting to identify drugs that can effectively target multiple subtypes or mutations. Additionally, there is still an insufficient number of clinical trials assessing the efficacy of repurposed drugs against PDAC therefore available evidence is limited in terms of patient populations, dosing regimens, and long-term outcomes. The development of drug resistance is a common challenge in cancer treatment (Kurt Yilmaz and Schiffer, 2021) and repurposed drugs might not have been optimised for long-term efficacy in the context of pancreatic cancer. Resistance mechanisms that arise due to the unique genetic landscape of pancreatic cancer could undermine the initial benefits of repurposed therapies (Dagogo-Jack and Shaw, 2018). Also, repurposing drugs can introduce the risk of unanticipated side effects or adverse reactions that were not previously observed in their original use. Ensuring patient safety and minimising these risks becomes a critical concern in repurposing efforts. Finally, drug repurposing often involves using existing medications that are already under patent protection (Talevi and Bellera, 2020). Navigating the complexities of intellectual property rights and licensing agreements can pose significant barriers to repurposing potentially limiting access to certain drugs.

7 Conclusion and future perspectives

With the preponderance of enigmatic drug resistance in cancer treatment, there is an unmet need to delve into a new trajectory of therapeutic strategies. Stratification of PDAC into clinically and genetically associated groups could open a gateway for discovering novel biomarkers. New technologies such as single-cell-RNA-sequencing and single-cell-omics could be explored to provide a more comprehensive classification of PDAC patients in the different subtypes based on their biology, prognosis, therapeutic targets, and pharmacologic response to drugs. Strikingly, drug repurposing has been implemented for cancer research to facilitate the drug design process and cost. Repurposing drugs to target genomic alterations in PDAC subtypes is the future perspective that should be leveraged for personalized medicine. Hence more future clinical studies targeting repurposed drugs in PDAC could be beneficial in identifying effective treatments.

Funding Statement

EEN is supported by the National Research Foundation (NRF) (Grant number: 138367). SC is supported by the National Research Foundation (NRF) (Grant number: 138113).

Author contributions

NE, EA-S, SC, and EEN contributed to the writing of the article. NE, EA-S, SC, and EEN critically edited the article. All authors contributed to the article and approved the submitted version.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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