Targeting stromal components in pancreatic ductal adenocarcinoma: a review
Hani Shihadeh, Ahmad Yousef, Ahmad Al-Leimon, Hussein Abu-Rumman and Laith Kreshan
School of Medicine, University of Jordan, Amman 11118, Jordan
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related mortality, largely due to a lack of highly safe and effective therapeutic options. A large proportion of the tumour's mass consists of a dense fibrous stroma, which could provide valuable therapeutic targets. This review elucidates the various possible stromal targets in PDAC, methods of targeting them and the outcomes of this targeting in in-vitro studies, studies on murine models of PDAC and clinical studies. While targeting some stromal components in PDAC yielded disappointing results in clinical studies, others have shown promise in multiple settings. More research efforts should be directed towards identifying additional stromal targets and evaluating their therapeutic potential. In addition, comprehensive clinical studies are essential to evaluate the safety and effectiveness of agents targeting stromal components of PDA of agents targeting stromal components of PDAC, both as monotherapies and in combination with standard surgical and pharmacological treatments for PDAC to improve patient’s outcomes.
Keywords: pancreatic ductal adenocarcinoma, tumour stroma, cancer-associated fibroblasts, stroma-targeted therapy, tumour microenvironment
Correspondence to: Hani Shihadeh
Email: shihadehhani@gmail.com
Published: 24/09/2025
Received: 22/01/2025
Publication costs for this article were supported by ecancer (UK Charity number 1176307).
Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Introduction
The prevalence of pancreatic cancer has increased twofold during the last 25 years. Researchers have attributed this increase to many factors, including rising life expectancies globally and rising rates of smoking, obesity, diabetes and alcohol consumption, all of which are known risk factors for developing pancreatic ductal adenocarcinoma (PDAC) [1]. Pancreatic cancer is known for its abysmal prognosis, exhibiting a 5-year survival rate below 15% [2]. Thus, it is a major cause of cancer-related mortality and a considerable public health problem. Despite significant progress in the treatment of several prevalent cancers, such as lung cancer, breast cancer and hematologic malignancies, there have been no substantial breakthroughs in the management of pancreatic cancer in recent years, resulting in persistently high mortality rates.
Surgery, radiation therapy and chemotherapy are the major therapeutic modalities available to prolong survival and alleviate symptoms in patients with PDAC. The only potentially curative therapy for pancreatic cancer is surgical resection with or without adjuvant chemotherapy [3]. However, approximately 80% of patients with PDAC seek medical attention only after the disease is either locally advanced or metastatic stage, rendering them ineligible for curative-aim surgery. In those patients, palliative chemotherapy is the mainstay of treatment [4]. Gemcitabine monotherapy, gemcitabine in combination with nanoparticle albumin-bound paclitaxel (Nab-paclitaxel) or the FOLFIRINOX regimen (a four-drug combination of fluorouracil, leucovorin, oxaliplatin and irinotecan) are utilised as chemotherapy options for PDAC. However, these regimens have limited efficacy and considerable toxicity. Therefore, there is an urgent necessity to devise innovative therapies for pancreatic malignancies that offer improved efficacy and reduced toxicity [5].
PDAC is known for its densely fibrous stroma, which constitutes a significant portion of the tumour mass, potentially reaching up to 90% [6]. This stroma is composed of cancer-associated fibroblasts (CAFs), which are thought to be derived from pancreatic stellate cells (PSCs) and the extracellular matrix (ECM). The ECM is composed of collagen fibers, other fibers and a ground substance rich in proteoglycans and glycosaminoglycans (GAGs). Hyaluronic acid (HA) is the most abundant GAG in the pancreatic cancer stroma [7, 8]. The dense fibrous nature of stroma is likely responsible, at least partially, for many characteristics of PDAC, including clinical aggressiveness and resistance to chemotherapy, while also presenting as a potential therapeutic target. Efforts by researchers to completely ablate the tumour stroma in PDAC murine models led to more aggressive tumour behaviour and diminished survival rates in the mice [9, 10], suggesting that the tumour’s stroma might actually play a tumour-restraining role. Current efforts focus on developing novel stroma-targeting therapies that would reprogram the stroma in an advantageous manner and avoid the extremes of depletion and abundance. In this review, we aim to summarise the latest insights on targeting the stromal components of PDAC, including in vitro studies, studies on murine models, preclinical and clinical studies, focusing on their most relevant advancements and limitations.
Targeting HA
Background
HA is an essential glycosaminoglycan involved in maintaining connective tissue functionality [11]. In PDAC, HA is synthesised by CAFs and is 12 times greater in quantity than in a healthy human pancreas [12]. HA serves many functions supporting PDAC progression, including acting as a reservoir for growth factors and cytokines [13, 14]. In addition, binding of HA to its receptors, CD44 and RHAMM on tumour cells, activates many oncogenic pathways that promote PDAC cell proliferation, invasion and metastasis [15–17]. Being highly hydrophilic, HA attracts water and which increases the interstitial fluid pressure (IFP) within the tumour microenvironment [18]; the high IFP compresses tumour vasculature and results in decreased local bioavailability of systemically administered drugs in the tumour microenvironment [19, 20]. Clinical data also support the role of HA in tumour progression. PDAC patients with lower levels of HA in their tumours had a significantly increased overall survival (24.3 median survival time versus 9.3 months in patients with high HA levels, p < 0.05) [21]. Table 1 summarises the results of targeting HA in PDAC.
Effects of targeting the HA in preclinical studies
Researchers investigated the therapeutic potential of enzymatic remodeling of the tumour stroma by HA depletion using recombinant human hyaluronidase (rHuPH20); This enzyme degrades HA-dependent tumour ECM both in vitro and in vivo. Because rHuPH20 exhibits a short plasma half-life of less than 3 minutes following intravenous administration, a pegylated version (PEGPH20), with an improved half-life (10.3 hours), was developed and evaluated [14]. Depleting HA via hyaluronidase decreases the pressure within the tumour microenvironment and enhances intratumoural bioavailability of chemotherapeutic drugs [14, 18, 19, 22].
Table 1. Strategies to target HA in PDAC.
The therapeutic potential of combining the PEGPH20 with either gemcitabine or the FOLFIRINOX regimen was evaluated in many preclinical and clinical trials. When compared to gemcitabine alone, treatment with PEGPH20/gemcitabine combination significantly enhanced tumour suppression and prolonged survival in murine models of PDAC (median survival 15 days in PEGPH20/gemcitabine group versus 9 days in gemcitabine alone group, p = 0.0002) [19].
Researchers also examined whether hyaluronidase enhances could enhance the antitumour effect of immune checkpoint inhibitors. They hypothesised that hyaluronidase would enhance the intratumoural bioavailability of systemically administered immune checkpoint inhibitors or eliminate HA's possible immunosuppressive effects. Blair et al [23] found that adding PEGPH20 to an antibody against the immune checkpoint protein programmed death ligand-1 (PD-1) resulted in increased survival of murine models of PDAC and enhanced effector T cell infiltration of the tumour.
The rationale of using microbial vectors to deliver hyaluronidase into tumours is to provide preferential degradation of HA in the tumour without affecting that of normal tissues, thus achieving better efficacy and less toxicity. Ebelt et al [24] developed a novel, promising strategy for administering hyaluronidase using a live attenuated strain of the bacterium Salmonella typhimurium; this bacterium expresses a functional bacterial hyaluronidase; they colonise murine models of PDAC tumours following intravenous administration and induce tumour-specific HA depletion. Potentiated the cytotoxic effect of gemcitabine in these models [24].
VCN-01 is a genetically modified oncolytic adenovirus designed to proliferate only within tumour cells, sparing normal cells and express human hyaluronidase. In combination with gemcitabine, VCN-01 induced responses when administered intratumourally using endoscopic ultrasound in few patients [25].
Kudo et al [26] identified a novel phenotype of PDAC in both patients' samples and cell lines, called the HA activated-metabolism phenotype. This phenotype is characterised by high expression of genes involved in HA metabolism. They observed that patients with this phenotype of PDAC had a shorter overall survival. They also observed that 4-methylumbelliferone (4-MU), a synthetic inhibitor of hyaluronan synthase, inhibited the migration of PDAC cells in vitro [26].
4-MU also enhanced the anticancer effects of γδ T-cell immunotherapy in murine PDAC models by reducing the amount of ECM and increasing the infiltration of tumour-infiltrating lymphocytes [27]. Further research is needed to determine the efficacy and safety of 4-MU in human subjects.
Effects of targeting the HA in clinical studies
A phase Ib single-arm trial conducted in 2016 evaluated the safety and tolerability of PEGPH20 with gemcitabine. The combination demonstrated tolerability and potential therapeutic advantages in patients with advanced PDAC, particularly in those with tumours with high HA levels [28]. A HALO 202 trial, a randomised Phase II trial assessed the efficacy and tolerability of PEGPH20 in combined with Nab-Paclitaxel/Gemcitabine versus Nab-Paclitaxel/Gemcitabine alone in treatment-naïve PDAC patients; it revealed that the addition of PEGPH20 significantly improved the progression-free survival (PFS) (hazard ratio, 0.73; p = 0.049), especially in patients with high HA levels (HR, 0.51; p = 0.048). However, it failed to improve overall survival [29]. These trials showed that thromboembolic diseases, including venous thrombosis and cerebrovascular accidents, were the most common severe adverse effects in patients receiving PEGPH20. However, it is unclear whether thromboembolic disease occurred at significantly higher rates in patients treated with PEGPH20 compared to patients receiving standard therapy, especially since PDAC is a malignancy that is frequently linked to thromboembolic disease [28–30]. A randomised double-arm phase III trial compared PEGPH20 combined with nab-paclitaxel/gemcitabine to nab-paclitaxel/gemcitabine alone; it revealed no significant increase in the overall survival or PFS of PDAC patients with added PEGPH20. Addition of PEGPH20 was also associated with significant adverse effects [31]. A randomised double-arm phase Ib/II clinical trial examined PEGPH20 combined with FOLFIRINOX versus FOLFIRINOX alone in patients with metastatic PDAC who had not received any prior therapy. Unexpectedly, adding PEGPH20 to the FOLFIRINOX regimen decreased overall and PFS (HR, 2.07; p < 0.01) [32].
The MORPHEUS-PDAC randomised trial evaluated the combination of Atezolizumab, an anti-PD-L1 monoclonal antibody, with PEGPH20 compared to standard chemotherapy in patients with previously treated metastatic PDAC. It revealed that patients receiving Atezolizumab plus PEGPH20 had similar overall survival and PFS to those receiving standard chemotherapy. However, in Patients with high HA content, the combination therapy was associated with significantly longer overall survival compared to treatment with standard chemotherapy (HR = 0.41, 95% CI (0.20–0.84)) [33], suggesting a potential benefit in this biomarker-defined subgroup.
Targeting sonic hedgehog (SHh) pathway
Background
The SHh pathway is a biochemical pathway normally involved in embryonic organogenesis. It involves the Shh ligand, which is released from cells to interact with its cell surface receptor on neighboring cells known as the patched protein (PTCH); this binding results in the disinhibition of smoothened protein (SMO) in target cells, SMO then activates downstream pathways that ultimately result in activation of Gli1, Gli2 and Gli3 transcription factors, which in turn affect the target cell’s transcriptional activity. Activation of the SHh pathway is common in many cancers, including PDAC [10, 34]. Specifically, a paracrine loop in which SHh ligand is secreted from tumour epithelial cells to activate the SHh pathway in PSCs was identified in both murine models and patients’ samples of PDAC [35]. SHh pathway activates PSCs to synthesise more tumour stroma [36, 37]. The clinical literature supports the contribution of SHh in PDAC, as high expression of SHh ligand and Gli1 are predictive of shorter patient survival [38]. Table 2 summarises the results of targeting SHh pathway in PDAC.
Effects of targeting the SHh pathway in preclinical studies
Rhim et al [10] produced a murine PDAC model in which the gene coding for the Shh ligand was knocked out. Mice lacking the SHh gene developed tumours with a smaller stroma and had fewer activated PSCs. However, compared to mice with wild-type SHh PDAC, mice with knocked-out PDAC had shorter overall survival, suggesting that the Shh pathway, at least in these models, acts to impede tumour growth rather than to support it [10].
Cyclopamine, a naturally occurring steroidal alkaloid that binds and thus inhibits the SHh signaling pathway and blocks the SMO signaling transducer; when tested in a xenograft murine PDAC model, cyclopamine reduced the size of the tumour stroma and potentiated the antitumour effect of nab-paclitaxel, possibly due to enhanced drug delivery [39].
When combined with gemcitabine, Saridegib induced a temporary elevation in intratumoural vascular density and intra-tumoural gemcitabine bioavailability, leading to transient stabilisation of disease in murine PDAC models [40].
Itraconazole is a common antifungal drug; it inhibits ergosterol synthesis in fungi by targeting the cytochrome P450 enzyme 14-α-demethylase. Recently, researchers found that itraconazole inhibits the SHh pathway by inhibiting SMO by a distinct mechanism from that of cyclopamine and its derivatives [41, 42]. The antitumour effect of itraconazole was demonstrated in vitro [43, 44]. When combined with paclitaxel in a poly (ethylene glycol)-b-poly (D, L-lactide) micelle delivery system, itraconazole successfully inhibited the growth of a PDAC cell line in vitro and in murine models. This inhibition was partially due to the inhibition of the SHh pathway [45]. Itraconazole also inhibited migration and epithelial-to-mesenchymal transition of PDAC cell lines in vitro by inhibiting the SHh pathway and other mechanisms [46].
Table 2. Agents that target SHh pathway and their effect on PDAC.
There has been a growing interest in inhibiting the SHh pathway downstream of SMO, largely because some tumours, including PDAC, have shown activation of the Gli transcription factor independent of SMO [47, 48]. Oxy186, a novel chemical compound with favourable pharmacokinetic properties, directly inhibits Gli transcription factors. It inhibits the proliferation of PDAC cell lines in vitro [49].
Taxanes are a family of cytotoxic drugs whose main mechanism of action is hyperstabilisation of polymerised microtubules, leading to inhibition of mitosis. Of these, nab-paclitaxel is an approved treatment for PDAC in combination with gemcitabine. Mohelnikova-Duchonova et al [34] identified a novel mechanism of action of taxanes, as they observed that a new generation taxane, SB-T-1216, strongly inhibited the Shh pathway in vitro and murine models of PDAC.
Aberrant epigenetic modifications are now widely recognised as a hallmark of cancer [50]. PDAC development heavily relies on epigenetic modifications, particularly DNA methylation, which suppresses gene expression and transcription. This is evident by the fact that DNA methyltransferase 1 (DNMT1), a major enzyme involved in DNA methylation, is commonly overexpressed in human PDAC [51]. In addition, many tumour suppressor genes are aberrantly hypermethylated, and thus suppressed in PDAC [52]. On the other hand, many proto-oncogenes are aberrantly hypomethylated, and thus activated [53].
DNMT1 inhibition could suppress Hedgehog pathway activation and decrease tumour growth. n-Butylidenephthalide, an inhibitor of DNMT1, inhibits proliferation and induces apoptosis of the PDAC cell line in vitro. This inhibition was mediated by hypomethylation and induction of the PTCHD4 gene, which codes for the PTCH protein. Increased expression of PTCH proteins leads to more effective sequestering of SMO and, thus, inhibition of the SHh pathway [54].
TET1, also known as ten-eleven translocation cytosine dioxygenase, is a major enzyme involved in the demethylation of DNA. TET1 promotes the expression of the Gli1 transcription factor in PDAC, thus activating the SHh. Inhibition of SHh by vismodegib reversed the chemoresistance mediated by TET1 in PDAC cell lines, suggesting that the SHh pathway significantly contributes to the chemoresistance of PDAC [55].
Effects of targeting the SHh pathway in clinical studies
In a pilot single-arm clinical trial, a combination of vismodegib and gemcitabine was tested in patients with metastatic PDAC; the combination stabilised the disease in a few patients. However, nearly half of the patients experienced grade III adverse effects. The most common of which were anemia and elevated liver enzymes [56]. Another randomised double-arm Phase Ib/II trial compared gemcitabine/vismodegib combination to gemcitabine alone, it revealed that the combination had no superior response rates, PFS or overall survival [57].
Sonidegib was also investigated in combination with chemotherapy. A single-arm Phase I/II study for patients with metastatic PDAC setting sonidegib with gemcitabine/nab-paclitaxel after FOLFIRINOX treatment. The combination stabilised the disease in 58% patients and achieved a partial response in 13% patients. However, the treatment was associated with severe toxicities in some patients [58]. Sonidegib was evaluated with the FOLFIRINOX regimen in a single-arm phase 1b trial; this trial enlisted PDAC patients with locally advanced or metastatic disease who had not received previous chemotherapy. The combination stabilised 46% of patients and induced partial responses in 31% of patients [59].
On this basis, a phase Ib/II trial commenced to evaluate the safety and efficacy of Saridegib/gemcitabine combination with gemcitabine in metastatic PDAC. It showed that the combination was tolerable without unexpected toxicity, with preliminary evidence of clinical activity [60]. Similar findings were reported by Jimeno et al [61] in another phase I study. In a phase Ib study, Saridegib was evaluated in combination with FOLFIRINOX in patients with advanced pancreatic cancer. The treatment induced objective responses and decreased CA 19–9 levels, with most patients experiencing grades I–II adverse effects [62].
Targeting secreted protein acidic and rich in cysteine (SPARC)
Background
SPARC, also called osteonectin or basement membrane protein 40 (BM-40), is an ECM glycoprotein; it serves many physiological functions in the ECM, including bone mineralisation [63], sequestration of growth factors, cellular differentiation, migration and tissue repair [64]. SPARC
is expressed in the primary and metastatic PDAC lesions of PDAC several fold more than normal pancreatic tissue [65–67], and expression was predominantly localised in the tumour stroma. Patients with PDAC exhibiting high SPARC expression had a shorter overall survival than those with low SPARC expression (11.5 versus 25.3 months; p = 0.02) [65]. Table 3 summarises the results of targeting SPARC along with other stromal components in PDAC.
Effects of targeting SPARC in preclinical studies
Albumin, the most abundant human plasma protein, binds to SPARC with high affinity. It is plausible that coupling albumin with chemotherapeutic drugs would enhance the intratumoural bioavailability of these drugs in tumours expressing high SPRAC [68]. In PDAC, the high expression of PDAC might explain the clinical success of nab-paclitaxel, a specialised paclitaxel formulation conjugated with albumin in nanoparticles. Nab-paclitaxel succeeded in preclinical and clinical studies [69–72].
Effects of targeting the SPARC in clinical studies
Based on the results from the MPACT trial, which revealed that nab-paclitaxel/gemcitabine combination improved overall survival in patients with PDAC compared to gemcitabine alone (HR = 0.72, p < 0.001), the combination was FDA-approved [73]. Despite these findings, Hidalgo et al [74] reported that the expression of SPARC in patients’ sample and murine models of PDAC was not predictive of overall survival or efficacy of nab-paclitaxel [74].
Table 3. Various stromal components in PDAC, agents that target them and observed effects of targeting them.
Targeting angiotensin II (AT II)
Background
AT II is an octapeptide produced in the blood to serve many physiological functions, including blood pressure regulation, plasma potassium concentration and cardiac contractility. In addition to these widely recognised functions. AT II is involved in many processes in PDAC, it directly stimulates PSCs proliferation in vitro by activating the epidermal growth factor/extracellular signal-regulated kinase (ERK) pathway [75, 76]. Moreover, AT II receptor signaling inhibits the growth of pancreatic carcinoma cell both in vitro and in murine models of PDAC [77]. In addition, AT II stimulates the secretion of transforming growth factor-β (TGF-β), which activates PSCs to synthesize stromal components [78]. AT II can be easily targeted by the antihypertensive medications Angiotensin-converting enzyme inhibitors (ACEis) and AT II receptor blockers (ARBs).
Effects of targeting the AT II in preclinical studies
Several preclinical studies on PDAC models showed that losartan, a selective and competitive ARB, reduced stromal collagen and HA production when combined with gemcitabine. In addition, losartan inhibited angiogenesis by reducing the expression of vascular endothelial growth factor (VEGF) and enhanced intratumoural gemcitabine bioavailability [76, 79–83].
Effects of targeting the AT II in clinical studies
A large population study suggested that intake of ARBs and ACEis in patients with PDAC is associated with improved survival (HR = 0.80; 95% CI: 0.72, 0.89). However, the results may be due to the confounding beneficial cardiovascular effects of these medications [84]. A retrospective study found contradictory results; indicating no difference in survival and response rates between individuals administered losartan for any indication at the time of PDAC diagnosis and those who were not treated with it [85].
A single-arm clinical trial examined losartan, FOLFIRINOX and radiotherapy use in patients with unresectable, locally advanced, nonmetastatic PDAC; the regimen successfully downstaged the tumour so that it became resectable in 69% of patients. However, it remains to be determined whether losartan contributes to this benefit due to the nonrandomised design of the trial [86]. Another single-arm phase II trial evaluated gemcitabine in combination with candesartan for patients with treatment-naïve unresectable PDAC, the combination was not effective [87].
Targeting matrix metalloproteinases (MMPs)
Background
MMPs, a family of zinc-dependent proteolytic enzymes that degrade ECM proteins, facilitating tumour invasion and metastasis [88]. MMPs are normally kept in check by inhibitor proteins called Tissue inhibitors of matrix metalloproteinases (TIMPs). In PDAC, analysis of patients’ samples revealed that PSCs are a major source of MMPs and they are secreted in abundance at the invasive front of tumours. Secretion of MMPs by PSCs is stimulated by various paracrine signals from nearby carcinoma cells, including SHh ligand and cytokines such as IL-1 and TGF-β [89–92]. Eight types of MMPs were differentially expressed in PDAC, including MMP1, MMP2, MMP7, MMP9, MMP11, MMP12, MMP14 and MMP28. Patients with higher MMP1, MMP2, MMP7 and MMP9 expression had a worse prognosis [93]. PDAC also showed a loss of expression of TIMP2, which contributes to dysregulation of multiple MMPs in PDAC [94].
Effects of targeting the MMPs in clinical studies
In a Phase I clinical evaluation, marimastat, a soluble, broad-spectrum MMP inhibitor, increased overall survival comparable to gemcitabine [95]. However, the combination therapy of gemcitabine and marimastat had no significant improvement in overall survival compared to gemcitabine alone [96].
A phase III trial compared the efficacy and safety of Tanomastat (BAY12-9566), an oral MMP inhibitor with selectivity toward MMP-2, MMP-3 and MMP-9, to gemcitabine monotherapy in 277 patients with advanced pancreatic cancer. Tanomastat was less effective and more toxic than gemcitabine [97].
Pirfenidone
Background
Pirfenidone is an FDA-approved antifibrotic drug used for the management of idiopathic pulmonary fibrosis. It inhibits fibrosis by multiple mechanisms, including inhibiting TGF-β-stimulated collagen synthesis [98], fibroblast activation and proliferation [99], inflammation and angiogenesis [100].
Effects of pirfenidone in preclinical studies
The ability of pirfenidone to inhibit the proliferation of PDAC cells was confirmed by many in vitro and murine model studies. Multiple mechanisms were observed, including induction of cell cycle arrest [101], inhibition of TGM2/ NF-κB/PDGFB pathway [102], inhibition of CAFs proliferation [103] and enhancing drug delivery [103, 104]. Pirfenidone was never evaluated in a clinical study for the treatment of PDAC.
Targeting connective tissue growth factor (CTGF)
Background
CTGF, also called Cellular Communication Network 2 (CCN2), is a cysteine-rich matricellular protein that is involved in many cellular functions, including cellular adhesion, migration, proliferation and differentiation [105]. Studies on tumour samples from patients revealed that CTGF is overexpressed in PDAC compared to the normal pancreas [106], and it contributes to autocrine and paracrine pathways which promote cellular growth, invasion, metastasis and angiogenesis in vitro and murine models of PDAC [107].
Effects of targeting the CTGF in preclinical studies
The main therapeutic approach designed to target CTGF is the monoclonal antibody pamrevlumab (FG-3019); Pamrevlumab successfully attenuated tumour growth, metastasis and angiogenesis and in a murine PDAC model [107]. Murine models of PDAC treated with the Pamrevlumab/gemcitabine combination had significantly prolonged survival compared with gemcitabine alone (median survival 29 versus 7.5 days, p = 0.03) [108].
Effects of targeting the CTGF in clinical studies
A phase I study assessed the combination of pamrevlumab, gemcitabine and erlotinib in advanced PDAC patients, it showed that overall survival improved with increasing doses of pamrevlumab with a good safety profile [109]. A randomised trial compared gemcitabine/nab-paclitaxel to gemcitabine/nab paclitaxel with pamrevlumab as neoadjuvant therapies in patients with locally advanced PDAC, it revealed that the addition of pamrevlumab improved the rate of successful resection was achieved in 8 (33% in patients treated with pamrevlumab + gemcitabine/nab-paclitaxel versus 8% in patients treated and with gemcitabine/nab-paclitaxel alone, p = 0.1193) [110].
Hypoxia-activated cytotoxic prodrugs
Background
The dense desmoplastic stroma of PDAC compresses the vasculature and induces hypoxia in the tumour microenvironment [111]. This hypoxia affects the expression of many genes in carcinoma and stromal cells, contributing to many PDAC characteristics, the most important being resistance to chemotherapy [112, 113]. In addition, hypoxia promotes tumour growth, invasion and metastasis [114–116]. Hypoxia-activated cytotoxic prodrugs were theorised to have greater efficacy and minimal toxicity as they are only activated in hypoxic environments. Evofosfamide (TH-302), a hypoxia-activated prodrug; is activated to its cytotoxic form, bromo-isophospharmide, only in hypoxic conditions [117, 118].
Effects of targeting the tumour hypoxia with hypoxia-activated prodrugs in preclinical studies
Evofosfamide improved sensitivity to radiation and gemcitabine/nab-paclitaxel in murine models of PDAC, suggesting that hypoxia is a primary contributor to chemoresistance and radioresistance [119, 120].
Effects of targeting the tumour hypoxia with hypoxia-activated prodrugs in clinical studies
A phase III clinical trial reported that the gemcitabine/evafosfamide combination had significantly prolonged PFS compared to gemcitabine with a placebo (HR = 0.77, p = 0.004). However, the addition of evafosfamide did not improve overall survival [121].
Targeting glutamine metabolism
Background
Altered cellular metabolism is widely recognised as a hallmark of cancer. Warburg metabolism is activated in cancer cells, where oxidative phosphorylation is inhibited. Moreover, pyruvate derived from glucose is no longer the source of Krebs cycle intermediates. Instead, glutamine uptake is activated, becoming the primary cellular source of Krebs cycle intermediates via anaplerotic reactions. In addition, glutamine becomes an essential source of cancerous cell’s lipids, proteins and nucleotides, and it is essential for maintaining cellular redox status [122–124]. In PDAC, reprogramming of glutamine metabolism is mediated by oncogenic Kirsten rat sarcoma viral oncogene homolog (K-RAS), the most commonly mutated protein in PDAC [125]. Increased glutamine catabolism is a major mechanism of hypoxia and chemoresistance in PDAC cells [126]. SLC38A5, a glutamine transporter, is overexpressed in gemcitabine-resistant PDAC patients compared to gemcitabine-sensitive ones [127]. Targeting the glutamine metabolic pathway might be a promising therapeutic approach for PDAC patients.
Effects of targeting the glutamine metabolism in preclinical studies
6-diazo-5-oxo-L-norleucine (DON) is a glutamine antagonist that inhibits many aspects of glutamine metabolism by competitively binding enzymes that utilise glutamine. It was tested for its ability to block PDAC tumour growth and metastasis using murine models. Recouvreux et al [129] found that cancerous cells bypass the effects of DON by increasing the availability of asparagine, suggesting that depleting asparagine by inhibiting the enzyme asparagine synthase, which utilises glutamine as a substrate, was necessary for inhibiting cellular growth. This theory is supported by the finding that combining DON with L-asparaginase, an enzyme that depletes asparagine, dramatically enhances DON's inhibitory effects in murine PDAC models [128, 129].
Sirpiglenastat (DRP-104) is a prodrug of DON; it increased the survival of murine models of PDAC when combined with trametinib (MAPK/ERK kinase inhibitor). The rationale behind combining trametinib with sirpiglenastat is that cancer cells overcome the metabolic stress caused by DRP-104 by activating the ERK pathway (ERK) signaling pathway. So, using the MEK (mitogen-activated protein kinase kinase) inhibitor trametinib reduces resistance to sirpiglenastat and enhances its effects on tumour growth [130].
Targeting glycogen synthase kinase-3β
Background
Glycogen synthase kinase-3β, a versatile cellular serine-threonine kinase, is involved in many physiological cellular processes, including glycogen metabolism, insulin signaling, cellular proliferation and differentiation. Although initially thought to act as a tumour suppressor by inhibiting the oncogenic Wnt/β-catenin pathway [131, 132]. It is now clear that GSK-3β plays a pro-oncogenic role in PDAC as well as other cancers. It supports the invasion, metastasis and chemoresistance of PDAC by activating several cellular pathways, including the NF-κB, CXCR4/MMP-2, RB protein/E2F pathways and many others [133–136].
Inhibiting GSK-3β may be a promising therapeutic strategy in PDAC. Several agents are available that inhibit GSK-3β, including the FDA-approved antihelminthic agent niclosamide, the experimental chemical 9-ING-41 and the most recently identified MJ34.
Effects of targeting the GSK-3β in preclinical studies
Niclosamide showed several beneficial effects on PDAC cell lines in vitro. It inhibits cell proliferation, induces apoptosis through the intrinsic pathway and suppresses cell migration and invasion by antagonising. In PDAC murine models, niclosamide inhibited tumour growth and metastasis. Furthermore, niclosamide sensitises cancer cells to gemcitabine and reduces cancer immune evasion by downregulating PD-L1 expression [137].
9-ING-41 is another small-molecule inhibitor of GSK-3β. It showed therapeutic potential in preclinical models of PDAC. It may act by increasing the degradation of the protein TopBP1, which is involved in DNA repair, thus sensitising PDAC to DNA-damaging cytotoxic agents. It is currently being assessed in clinical trials for many solid tumours, including PDAC [138, 139].
MJ34 is a novel potent GSK3β inhibitor. It significantly reduces the growth and survival of human PDAC cells, mainly by inducing apoptosis in a β-catenin-dependent manner [140].
Vitamin A analogues
Background
In healthy individuals, PSCs exhibit a quiescent state, in which these cells store vitamin A and exhibit little synthetic activity. Once activated, PSCs acquire a secretory phenotype characterised by loss of vitamin A droplets, increased synthesis of ECM proteins (e.g., collagen and fibronectin) and enhanced proliferation and migration. Activated PSCs can be identified in tissue by their expression of the markers α-smooth muscle actin [141–143]. Activated PSCs are responsible for the dense fibrosis seen in PDAC, as it was observed that tumour cells secrete factors that activate PSCs to synthesise stromal components [144–146]. It is also observed that all-trans retinoic acid (ATRA), a vitamin A derivative, successfully reverses activation of PSCs both in vitro and in murine models of PDAC by altering genetic expression in these cells [147, 148].
Effects of targeting the Vitamin A pathway in preclinical studies
ATRA binds retinoic acid receptor β expressed in PSCs, resulting in many inhibitory effects, including transcriptional repression of myosin light chain 2, which results in impaired mechanosensing function of PSCs and reduced ability of cancer cells to penetrate through the basement membrane [149–150]. ATRA also reduces collagen synthesis in PSCs by inhibition of AP-1 transcription factor [147] and inhibition of TGF-β secretion, which acts in an autocrine fashion to maintain activation of PSCs [151]. Induction of quiescence of PSCs by ATRA also resulted in the inhibition of nearby cancer cells. Froeling et al [152] reported that ATRA significantly reduced pro-oncogenic Wnt/β-catenin signaling, resulting in slower tumour progression in vitro and murine models. In addition, ATRA enhanced infiltration of PDAC by antitumour CD8+ T cells in vitro [153]. Kuroda et al [154] showed that ATRA enhanced PDAC sensitivity to gemcitabine by upregulating deoxycytidine kinase (the rate-limiting enzyme of gemcitabine activation) in vitro.
Effects of targeting the Vitamin A pathway in clinical studies
Based on these broad observations, a phase I clinical trial evaluated the safety of a regimen combination of ATRA, Gemcitabine and Nab-paclitaxel for patients with PDAC, it revealed that the three-drug regimen was well tolerated and it may improve overall survival compared to Nab-paclitaxel/gemcitabine alone [155].
Vitamin D analogues
Background
Transcriptome studies of PSCs isolated from PDAC have shown that both quiescent and active PSCs strongly express the Vitamin D receptor (VDR); this receptor is activated by binding the active form of vitamin D (1,25-dihydroxycholecalciferol or vitamin D3) [156]. VDR is an intracellular receptor that acts as a master transcriptional regulator of PSCs, just like the RAR-β receptor. Activation of VDR induces quiescence of PSCs and inhibits fibrosis in PDAC [157]. Wang et al [158] 2015 reported that a low VDR expression in PDAC is associated with shorter survival. This may be related to the beneficial antistromal effects of vitamin D signaling [158].
Effects of targeting the Vitamin D pathway in preclinical studies
Calcipotriol reduced the tumour-promoting activity of CAFs, reduced the expression of mucin and antagonised the pro-oncogenic Wnt/β-catenin signaling pathway in vitro. However, calcipotriol inhibits antitumour T cell effector functions, which could potentially weaken the patients' antitumour immune response [159–161].
Vitamin D analogs, including Calcipotriol and paricalcitol, may be beneficial as chemosensitising agents, as multiple studies found that they enhance tumour response to gemcitabine both in vitro and in vivo [157, 161, 162]. Proposed mechanisms include increased intratumoural bioavailability of cytotoxic drugs and reduced expression of mucin.
Effects of a combination of vitamins A and D analogues
Combination therapy with the vitamins A and D analogs, 13-cis retinoic acid and 1,25-dihydroxy vitamin D3, significantly inhibits tumour invasion and the expression of MMPs in PDAC cells in vitro by blocking the JNK and NF-κB signaling pathways [163].
Targeting tumour vasculature/angiogenesis
Background
Angiogenesis, the ability to induce the growth of new blood vessels, is recognised as a hallmark of cancer. It is crucial for tumour development and progression, as tumours cannot grow beyond diffusion limitation without blood vessel formation [50]. Targeting angiogenesis is considered a potential therapeutic strategy in PDAC, as antiangiogenic drugs have succeeded in treating many solid tumours, including colorectal and renal cell carcinomas.
VEGF is a well-recognised pro-angiogenic factor that is overexpressed in many solid tumours. Its expression is associated with a higher frequency of liver metastasis and a shorter survival prognosis in patients with PDAC [164]. VEGF is secreted to act in a paracrine fashion. It binds to its receptors, vascular endothelial growth factor receptor (VEGFRs), which are receptor tyrosine kinases (RTK) that phosphorylate downstream proteins, finally promoting angiogenesis signaling.
The HGF/C-Met pathway operates by secretion of HGF in a paracrine fashion, which binds to the C-Met receptor, an RTK that phosphorylates downstream proteins. This pathway plays a vital role in tumour angiogenesis. The HGF/c-MET pathway is involved in many human physiological functions, including embryonic development and tissue repair. However, this pathway is not constitutionally active in healthy human adults except in malignant tumours. In addition to promoting angiogenesis, activation of this pathway promotes the growth and motility of PDAC cells [165]. Clinical data support the role of HFG/c-MET in the progression of PDAC. Serum levels of soluble HGF in PDAC patients are associated with disease progression [166], and high tumour expression of c-MET is associated with poor prognosis [167].
Effects of targeting the tumour angiogenesis in preclinical studies
Bevacizumab is a VEGF-inhibiting antibody that is FDA-approved for the treatment of many solid malignancies. In a preclinical murine model of PDAC, addition of Bevacizumab and cetuximab (epidermal growth factor receptor (EGFR) inhibitory antibody) with gemcitabine/FOLOFRINOX significantly reduced pancreatic tumour weight compared to mice treated with chemotherapy alone [168].Cabozantinib is a small-molecule tyrosine kinase inhibitor (TKI) of both c-MET and VEGFR-2; it is FDA-approved for the treatment of renal and hepatocellular carcinoma. Preclinical studies showed that cabozantinib increased the efficacy of gemcitabine, inhibited tumour growth, reduced vasculature, tumour aggressiveness, cancer stem cell population and inhibited metastasis [169]. Another c-MET inhibitor, Crizotinib, successfully shrunk tumours, enhanced survival, enhanced systemic and intratumoural bioavailability of gemcitabine and inhibited peritoneal dissemination in murine models of PDAC [170, 171]. Capmatinib is a highly selective C-Met inhibitor that has also shown efficacy in preclinical models of PDAC [172].
Effects of targeting the tumour angiogenesis in clinical studies
A treatment regimen of Bevacizumab combined with FOLFIRINOX was tolerable in PDAC patients in a small single-arm phase I clinical trial [173]. A phase III clinical trial was conducted to compare gemcitabine/bevacizumab versus gemcitabine/placebo regimens in 602 advanced PDAC patients. It revealed that the addition of bevacizumab did not improve survival [174]. In another phase III trial, the addition of bevacizumab to the gemcitabine/erlotinib regimen resulted in increased PFS compared to gemcitabine/erlotinib alone (HR = 0.73; p = 0.0002). However, it failed to improve overall survival. Ramucirumab is a monoclonal antibody that targets VEGFR2, it has been investigated in clinical trials for PDAC. A phase II clinical trial was conducted to compare PFS between mFOLFIRINOX with or without Ramucirumab as first-line therapy in 82 patients with metastatic PDAC. Results showed that the overall survival rates and PFS have not been significantly impacted between the two arms of treatment [175]. The clinical efficacy of cabozantinib is being evaluated in randomised phase II studies involving many solid tumours, which include PDAC.
Other TKIs
Background
The role of RTKs is not confined to angiogenesis; instead, they play a crucial role in other aspects of promoting carcinogenesis, including constitutional activation of the cell cycle, reprogramming cellular metabolism and other functions. Examples of RTKs implicated in PDAC include EGFR, fibroblast growth factor receptor (FGFR), insulin-like growth factor-I receptor and VEGFR, among others. In normal cells, RTK activity is tightly regulated. Dysregulation and constitutive activation of RTKs is a common feature of many cancers, including PDAC. Many TKIs are now approved for treating many solid and hematological cancers. Therefore, targeting different types of RTKs may provide benefits in PDAC [176]. Table 4 summarises the results of targeting different RTKs in PDAC.
Table 4. Different TKIs, their target and their effects on PDAC.
Effects of targeting other tyrosine kinases in preclinical studies
Erlotinib is a small-molecule TKI that specifically targets EGFR, resulting in the inhibition of downstream K-RAS. It showed significant antitumour activity against pancreatic cancer in preclinical and early clinical evaluations when combined with gemcitabine [177, 178]. Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK), an important tyrosine kinase that regulates intracellular signaling in B lymphocytes. The infiltration of BTK-expressing cells correlates with poor outcomes in PDAC. Ibrutinib effectively limits the growth of PDAC in both transgenic and patient-derived xenograft models of PDAC [179]. Nintedanib is a broad-spectrum TKI targeting VEGFR, PDGFR and FGFR; it is FDA-approved for treating idiopathic pulmonary fibrosis. When investigated in a murine model of PDAC, Nintedanib reduced the tumour's vascular density and collagen content and interestingly, it induced a transformative shift in the desmoplastic and immune landscape, increasing the number of antitumour CD8+ T cells and reducing tumour-protecting FOXP3+ T cells. Thus, it enhanced the antitumour effects of anti-PD-1 immunotherapy [180, 181]. Additionally, Nintedanib enhanced the activity of another form of immunotherapy: chimeric antigen receptor natural killer cells in a xenograft murine model [182]. Sunitinib, another TKI, has been shown to reduce tumour growth, endothelial cell proliferation, fibroblast proliferation and median survival in murine xenograft models, mainly when used in combination therapies [183].
The FGF signaling pathway, regulated by 18 growth factors and four FGFRs tyrosine kinases, is crucial for cell growth, development and differentiation. Disruptions in this pathway are linked to various malignancies, including PDAC [184]. In PDAC, the activation of FGF/FGFR signaling is essential for disease progression and interacts with other pathways in pancreatic cancer, underscoring the complexity of FGF signaling. The therapeutic potential of targeting this pathway is significant, as evidenced by using TKIs to treat cancers driven by aberrant FGF signaling [185–187].
A study investigated a combination of gemcitabine with BGJ398 (infigratinib), a pan-FGFR inhibitor, revealing potential mechanisms for improved efficacy [188]. Beyond this specific interaction, FGFR inhibitors offer broader benefits, potentially improving treatment outcomes for many PDAC treatment strategies in several ways [189].
Effects of targeting other tyrosine kinases in clinical studies
A multicenter randomised Phase III trial was conducted to compare the therapeutic effects of gemcitabine plus erlotinib compared to gemcitabine alone in patients following resection of pancreatic cancer. Erlotinib successfully improved PFS and overall survival. It is thought that erlotinib is particularly effective in tumours with activated EGFR and wild-type K-RAS. This is not the case in PDAC, as in most cases, K-RAS is constitutionally activated downstream of EGFR [190]. In the phase III RESOLVE trial, the combination of ibrutinib with nab-paclitaxel/gemcitabine was tested in treatment-naïve patients with metastatic PDAC. Unfortunately, the combination did not improve survival [191]. A phase II single-arm trial evaluated dasatinib as the initial treatment for patients with metastatic PDAC. The findings indicated that dasatinib alo Dasatinib and masitinib are oral TKIs that target multiple proteins, including BCR-ABL, c-Src, c-KIT, platelet-derived growth factor receptor β and EphA2. They are FDA-approved for the treatment of chronic myeloid leukaemia, gastrointestinal stromal tumours and c-KIT mutated melanoma, among other tumours. The findings indicated that dasatinib alone did not demonstrate clinical effectiveness in treating metastatic PDAC [192]. Despite increased toxicity and manageable side effects, masitinib significantly increased overall survival when combined with gemcitabine compared to gemcitabine alone. This finding was observed in a randomised, placebo-controlled phase III trial [193].
Conclusion and future perspectives
Targeting the dense fibrotic stroma of PDAC offers a multipronged therapeutic strategy. While many anti-stromal therapies have yielded mixed results in clinical trials, the underlying principle of improving intratumoural drug delivery and modulating the tumour microenvironment remains highly promising.
A key area requiring further investigation is the role of HA and its modulation via hyaluronidase. The MORPHEUS PDAC trial, while demonstrating similar overall survival between standard chemotherapy and the atezolizumab/PEGPH20 combination, highlighted a potentially crucial subgroup of patients. In patients with high HA content, atezolizumab plus PEGPH20 demonstrated superior overall survival compared to standard therapy. The HALO 202 trial also demonstrated that with high tumour HA content had a greater benefit from the addition of PEGPH20. These findings suggest that the efficacy of hyaluronidase-based therapies is dependent on the tumour's HA content, a factor that should be considered for future clinical trials. Careful comparison of outcomes across different HA strata will provide crucial insights into the optimal use of these agents and potentially lead to more personalised approaches to PDAC treatment.
Given the success of atezolizumab/hyaluronidase combinations in enhancing antitumour immune responses in patients with other solid tumours, including non-small-cell lung carcinoma, hepatocellular carcinoma, melanoma and other tumours [194]. Further investigation is warranted to explore the mechanisms by which hyaluronidase enhances the efficacy of immune checkpoint inhibitors, which may include improved intratumoural bioavailability of these agents, especially considering their high molecular weight as monoclonal antibodies or elimination of potential immunosuppressive effects of HA. Research to identify biomarkers whose expression may predict response to hyaluronidase, which may include HA, PD-L1 and enzymes involved in HA metabolism is warranted. Other innovative strategies to enhance drug delivery to the tumour, including the use of microbial vectors and antibody-drug conjugates, remain largely unexplored in PDAC and should be investigated further.
The role of SHh pathway in PDAC is controversial. While Rhim et al [10] found that SHh pathway actually restricts tumour growth in murine models, High expression of SHh pathway proteins in patients’ samples is predictive of a bad prognosis. Further research is warranted to understand the context-dependent functions of the SHh pathway. Although the majority of clinical trials did not demonstrate any advantage of including SHh inhibitors into standard cytotoxic chemotherapy, most of these trials had small sample sizes and employed a single-arm design. More comprehensive, large controlled clinical trials are warranted to determine the true effects of SHh pathway in PDAC. The therapeutic potential of SHh inhibitors other than cyclopamine derivatives remain underexplored.
The trials conducted by Murphy et al [86] and Picozzi et al [109, 110] highlight the promising potential of antistromal therapies as neoadjuvant treatments to downstage the tumour in patients with locally advanced PDAC and facilitate surgical resection. Most trials that evaluated the various antistromal therapies were conducted on patients with metastatic disease, leaving their potential benefits as neoadjuvant therapies largely unexplored. As PDAC is associated with high recurrence rates after surgical resection, further research is needed to optimise the best strategies of neoadjuvant therapy, aiming to reduce recurrence rates and improve survival. Considering the well-defined role of MMPs in cancer invasion, we think that matrix metalloproteinase inhibitors might be particularly beneficial in this setting.
Considering the promising results from targeting CTGF, further research should be directed towards identifying more growth factors that are secreted from PDAC’s CAF, which may play an important role in tumour-stroma interactions that support tumour growth, invasion, metastasis and chemoresistance.
The findings on the effects of vitamin A and nintedanib in enhancing tumour infiltration by cytotoxic T cells are particularly promising. These insights suggest that targeting the stromal components of PDAC may significantly improve the efficacy of immune checkpoint inhibitors in PDAC without microsatellite instability. Further research should focus on elucidating the immune microenvironment of PDAC, with particular emphasis on understanding how the tumour stroma contributes to immune evasion. Efforts should be directed towards developing strategies to enhance the efficacy of immunotherapies in PDAC.
Given the modest success of erlotinib in PDAC and because the most common driving mutation in human PDAC in KRAS G12D mutation, we think that targeting the EFGR-KRAS-MAPK pathway might be a successful strategy for treating PDAC. While sotorasib and adagarsib, the only commercially available KRAS inhibitors, have demonstrated success in the treatment of solid tumours, including non-small cell lung carcinoma and colorectal carcinoma, they only inhibit K-RAS with G12C mutation. MTRX1133 is an experimental inhibitor of KRAS with G12D mutation, it might become the first breakthrough therapy for PDAC [195]. As loss-of-function mutations in the CDKN2A gene, which codes for p16, an important cyclin-dependent kinase inhibitor, are common in PDAC [196], we think that treatment with cyclin-dependent kinase inhibitors (e.g., palbociclib) might also be a promising strategy.
Finally, most trials evaluating antistromal therapies in PDAC were conducted in a small number of patients or utilised a single-arm design. More comprehensive controlled clinical trials are needed to understand the true effect of these agents.
Conflicts of interest
The authors have no conflicts of interest to disclose.
Funding
This study was not funded. There are no sources of funding.
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