1. Background
Histone deacetylases (HDACs) have a pivotal role in the epigenetic control of gene expression, thereby greatly affecting cell integrity and cellular functions. Based on homology to yeast orthologues, four HDAC classes () are known in mammalian cells [Citation1]. Since deregulation of HDAC activity has been shown to promote tumorigenesis, the inhibition of HDACs by natural or synthetic agents (HDACis) is regarded as promising tool for cancer treatment. Meanwhile, several HDACis were extensively tested in clinical trials as monotherapy or combined with other anticancer drugs and radiation (). Mainly in hematological malignancies, HDACis revealed considerable therapeutic effects regarding tumor remission rates and disease-free survival. Despite extensive preclinical data with solid cancers, too, including pancreatic ductal adenocarcinoma (PDAC), only limited results from small phase I–II studies exist which only marginally support the propagation of HDACis in PDAC therapy.
Table 1. Classification of histone deacetylases and their properties.
Table 2. List of HDAC inhibitors, their class/isoenzyme selectivity, and use in clinical trials.
PDAC represents the fourth leading cancer-related deaths in western countries with an overall 5-year survival expectancy of <8% [Citation2]. Due to the rapid symptom-free progress and an already locally advanced or distant metastatic disease, a curative intended resection is feasible only for 10–20% of the patients. Moreover, only moderate improvements have been achieved with adjuvant chemotherapies (gemcitabine/±capecitabine, 5-fluorouracil [5-FU]) and no neoadjuvant treatments have been established so far to afford a resection option to borderline patients [Citation3]. For unresectable patients, the present chemo- and radiotherapeutic approaches—including treatment with 5-FU, gemcitabine alone, gemcitabine in combination with erlotinib or nab-paclitaxel, or the FOLFIRINOX regime—show still unsatisfactory response rates.
2. PDAC and role of HDACs
Besides rare familial predispositions, PDAC occurs sporadically. Among the risk factors, smoking, alcohol, diabetes, and chronic pancreatitis (CP) have a role. Already during CP inflammation, HDAC family members contribute to alterations in immune cell infiltration and later on to pancreatic fibrosis and cancer initiation [Citation4]. Moreover, essential modalities emerging from tumor–stroma interactions and favoring a malignant phenotype and therapy resistance relate to enhanced HDAC activity. This includes epithelial–mesenchymal transition, protection from hypoxia and oxidative stress, and metabolic alterations.
Like other malignant tumor cells, PDAC cells seem to be more sensitive to HDAC inhibition than nonmalignant cells, particularly due to their loss of checkpoint control proteins and checkpoint kinases. Consequently, HDACis induce cell cycle arrest and/or apoptosis in PDAC cells [Citation5–Citation7]. This relates to the increased expression of genes suppressing proliferation (p21/Waf1, p16/INK4) and dedifferentiation (E-cadherin) or forcing apoptosis (Bax, Bim, Noxa). Thus, the availability of HDACis opens new concepts for therapeutical interventions also in PDAC patients [Citation4–Citation8]. However, the impact of HDAC expression on PDAC is obviously more complex because elevated expression of HDAC class I and IIb members has been associated with favorable clinicopathological parameters [Citation9]. Thus, the status of certain HDAC class members could define the management and prognosis of PDAC patients. Further studies are therefore needed to elucidate the exact role of these enzymes and their suitability for PDAC therapy.
3. Clinical phase I/II studies with HDACis in PDAC
Whilst HDACis have been investigated in numerous clinical trials with patients suffering from hematological cancers and other solid tumors, there are only few studies so far that tested HDACis in PDAC patients (overviewed in [Citation8,Citation10,Citation11]).
A recent phase I study with 21 advanced PDAC patients investigated the maximally tolerated doses of concurrent SAHA/vorinostat and capecitabine with radiation in neoadjuvant chemoradiation of unresectable and borderline patients [Citation12]. The authors claimed potential activity of vorinostat in neoadjuvant chemoradiation to improve the intervention option in borderline patients. In another phase I study, the safety of vorinostat with the proteasome inhibitor NPI-0052/marizomib was tested in advanced solid tumor patients, including four PDAC patients [Citation13]. All evaluable PDAC patients revealed progress during treatment. Likewise, 29 patients with advanced solid tumors, including 6 with PDAC, were enrolled in a phase I study combining vorinostat and bortezomib, but all PDAC patients revealed no favorable responses. Thus, although combinations of vorinostat with proteasome inhibitors offer some potential for the treatment of certain advanced solid tumors, the conditions in PDAC seem to be less favorable.
A phase II study explored the activity of CI-994/tacedinaline in 17 PDAC patients that were orally treated with CI-994 per day. Albeit well tolerated, no significant antitumoral activity of CI-994 was noted [Citation10]. A phase II study with 174 PDAC patients revealed no benefit by combined treatment with CI-994 and gemcitabine over 3 weeks as compared to treatment with gemcitabine alone [Citation14]. Other phase I and II studies with CI-994 included patients suffering from different advanced solid tumors, including few PDAC patients [Citation10]. If administered alone or combined with capecitabine or with carboplatin plus paclitaxel, no favorable responses of CI-994 were reported in the respective PDAC patients.
Seven PDAC patients were enrolled in a phase II study testing LBH589/panobinostat combined with bortezomib [Citation15]. High-grade non-hematological toxicities and no tumor response were reported. Another phase I trial tested oral panobinostat combined with gemcitabine in 17 advanced solid tumor patients, including 3 PDAC patients, of which 1 had stable disease under treatment.
A phase I study tested FK228/romidepsin combined with gemcitabine in 33 advanced solid tumor patients, including 9 PDAC-patients. This treatment allowed to obtain stable disease in five PDAC patients.
In two phase I studies with advanced solid tumor patients, one PDAC patient either was enrolled for testing the safety and activity of MS-275/entinostat given alone and in combination with 13-cRA, respectively. Stable disease was seen in the first setting, whereas progressive disease was noted after combined treatment.
A phase I study tested the safety of oral treatment with MGCD0103/mocetinostat at escalating doses in 38 advanced solid tumor patients, including 2 PDAC patients. Treatment was well tolerated, but without objective tumor response.
Three PDAC patients were enrolled in a phase I study with 39 advanced cancer patients for testing LAQ824/dacinostat at escalating doses, but no tumor response and marked hematological and non-hematological side effects were reported.
A phase I study with 23 advanced solid tumor patients, including 3 PDAC patients, tested the safety of combined treatment with PXD101/belinostat given daily for 5 days plus carboplatin and/or paclitaxel. Overall, moderate non-hematological and some more severe hematological toxicities were reported. One PDAC patient showed partial remission after receiving belinostat and carboplatin.
One PDAC patient was enrolled in a phase I study with 48 advanced cancer patients testing valproic acid given at 2 days together with epirubicin, and partial remission was reported. By contrast, the only PDAC patient enrolled in a phase I study with 21 cancer patients subjected to 4-phenylbutyrate treatment twice a day over 2 weeks showed progressive disease.
4. Conclusion
Although clearly affecting PDAC cells in preclinical settings, HDACis did not show yet relevant antitumoral activity in clinical studies with PDAC patients. This certainly reflects the quite poor condition of PDAC patients at the time of diagnosis, when tumors already locally advanced and spread into distant organs. In addition, the complexity of the actions of HDACs may be particularly eminent in PDAC, limiting the efficacy of HDACis. It remains to be speculated whether pan- or isoenzyme-specific HDACis will be more efficient, and how HDAC isoenzymes cooperate with other oncogenic pathways and/or are part of tumor–stroma interactions.
5. Expert opinion
Major obstacles for curative treatment of PDAC are its advanced stage when diagnosed, the desmoplasia surrounding and protecting the tumor cells, and the profound genetic heterogeneity without clear defined genetic molecular and/or druggable targets (e.g. kRas-mutations). For the vast majority of PDAC patients, presenting with unresectable tumors, more effective therapies are needed to increase the median survival time of currently 6–11 months. Likewise, improved adjuvant treatment strategies are required to extend the disastrous life expectancy of even patients with resectable PDAC, and neoadjuvant concepts are in the focus of interest to offer resectability options to borderline patients.
HDACis which have proven successful in treating hematological tumor entities seem to be helpful. However, robust clinical data on HDACis in PDAC patients are lacking. Only few studies with low patient numbers have been conducted yet, with most patients already in quite poor condition. So far, treatment strategies combining HDACis with conventional drugs like gemcitabine failed to improve the outcome. This indicates that gemcitabine is not a good option in combination with HDACis. This problem was observed for other promising molecular targeted strategies in PDAC, like proteasome- or MEK/Akt-pathway inhibitors. Instead, other classical chemotherapeutic drugs like 5-FU or capecitabine could be interesting, or novel drugs like proteasome or BET protein inhibitors.
It has also to be kept in mind that the extensive tumor cell heterogeneity and desmoplasia in PDAC greatly influence the efficacy of anticancer drugs and HDACis. Thus, differential HDAC expression and activity in PDAC and stromal cells, respectively, may shape tumor–stroma interactions conferring HDACi resistance. This includes alterations in tumoral metabolism, e.g. by metabolic symbiosis and compartmentalization, that impact on the epigenome and thereby favor cancer stemness development and chemoresistance. Blocking metabolic symbiosis, e.g. by monocarboxylate transporter-1 inhibitors, like AZD3965, or targeting the tumor milieu to yield higher concentrations of anticancer compounds in tumor cells, as shown, e.g. for gemcitabine combined with Nab-paclitaxcel, might enhance the therapeutic efficacy of HDACis.
Altogether, more insight into the distribution and mode of action of HDACs in both tumor and stromal cells is needed, as well as a better knowledge on HDAC isoenzyme involvement. Besides advancements in developing more selective HDACis that can be combined with conventional chemotherapies/radiotherapies, novel small molecules targeting the tumor microenvironment would be helpful. Such HDACi-based concepts then need to be clinically tested soon, in order to provide new therapy options for PDAC patients.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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References
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