Evolving trends in pancreatic cancer therapeutic development
Review Article

Evolving trends in pancreatic cancer therapeutic development

Imani Bijou1,2, Jin Wang1,3

1Department of Pharmacology and Chemical Biology, 2Department of Biochemistry and Molecular Biology, 3Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

Contributions: (I) Conception and design: All authors; (II) Administrative support: All authors; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Jin Wang. Department of Pharmacology and Chemical Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Email: wangj@bcm.edu.

Abstract: Despite advances in translational research, the overall 5-year survival for pancreatic cancer remains dismal and with rising incidence pancreatic cancer is predicted to be the second leading cause of cancer death for many developed countries. Surgical intervention followed by cytotoxic chemotherapy are currently the best options for treatment, but disease recurrence is very common. Efforts to develop new therapeutic agents and delivery systems are necessary to achieve better clinical efficacy with less toxicity. Promising prospects are arising with new preclinical and clinical therapeutic strategies using small molecule targeted therapies, RNAi, stromal therapies, and immunotherapies. With a better understanding of the biology to aid target selection and discovery of biomarkers to aid precision medicine, better opportunities will evolve to shape the therapeutic landscape, enhance patient quality of life and increase overall survival.

Keywords: Pancreatic cancer; chemotherapy; targeted therapy; personalized medicine


Received: 20 June 2019; Accepted: 18 September 2019; Published: 23 October 2019.

doi: 10.21037/apc.2019.09.01


Introduction

Pancreatic cancer has proven to be a challenge for both clinicians and translational researchers. The combination of poor diagnostic tools, nonspecific symptoms, and late presentation in addition to the lack of targeted therapies and large tumor heterogeneity has led to pancreatic cancer’s current status as the third leading cause of cancer death behind lung and colon cancer (1,2). By the year 2030, pancreatic cancer is predicted to be the second leading cause of cancer death (3). The prognosis is poor with fewer than 10% of patients alive from the disease after 5 years (1). Despite recent advances in understanding the complex nature of this disease, treatment options remain limited and more recently approved therapeutics have been rendered inefficacious. Surgical resection still provides the best chance of survival but is only possible for a small subset of pancreatic cancer patients (20%), with disease recurrence occurring in most cases. For those presenting with metastatic pancreatic cancer, toxic chemotherapy with dose-limiting side effects is the only option (4).

Pancreatic ductal adenocarcinoma (PDAC) is the most common histological type of pancreatic cancer (about 90%) and is the focus of this review (5). PDAC is an exocrine origin cancer originating in the ductal cells of the pancreas. Pancreatic cancer can also arise from other exocrine cell types like acinar cell carcinoma, pancreatoblastoma, and solid pseudo-papillary neoplasm. Additionally, neuroendocrine tumors can form in islet cells of the pancreas and are classified by the hormones produced. PDAC arises through a temporal progression of genetic mutations, therefore a better understanding of this sequential progression from noninvasive precursor lesions to malignancy may aid in more effective early diagnosis and intervention. Currently, there are three main precursor lesions, pancreatic intraepithelial neoplasms (PanIN), intraductal papillary mucinous neoplasms (IPMN), and mucinous cystic neoplasms (MCN). With current imaging techniques, PanIN lesions are below the detection limit. IPMNs and MCNs can be detected by radiological examination, but their effective use in diagnosis is still challenging. In addition to being difficult to detect, these lesions have unique biology that may affect therapeutic outcome (6). All three exhibit a multistep progression of morphological and genetic changes that can culminate in malignancy. PanIN lesions are the most well studied and present as a stepwise progression from low-grade PanIN to high-grade PanIN with progression driven by the activation of KRAS (7).


Current therapies

Surgery is still the best treatment option for pancreatic cancer, increasing the 5-year survival rate to about 20%. Unfortunately, only 20% of patients present with surgically resectable tumors. The remaining 80% of patients have either locally advanced or metastatic disease and receive chemotherapy (2). The current standard of care for pancreatic cancer is the nucleoside analog gemcitabine, which extends survival marginally to 6 months compared to 5-fluorouracil (5-FU) (8). For metastatic disease, other common approved chemotherapeutics are nab-paclitaxel in combination with gemcitabine and the four-drug combination FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin) (9,10). This regimen is highly toxic, and should only be given to patients with a good performance score (10). Thus far, randomized trials of gemcitabine plus other chemotherapeutic agents have mostly failed to exhibit increased benefit vs. gemcitabine alone in the clinic (2). Nab-paclitaxel is a notable exception; with the combination improving overall survival to 8.5 months (9). Despite these improvements, the common development of chemoresistance, either as a result of growth signaling pathways or stromal factors, to gemcitabine still necessitates better therapeutic options (11). Many different treatment modalities have been evaluated over the past decades but with varying levels of success and much room for improvement (Table 1).

Table 1
Table 1 Summary of clinical trials in patients with pancreatic cancer
Full table

Therapeutic potential of commonly mutated genes

The majority of pancreatic cancer cases are sporadic with only 10% familial cases presented. Targeting the products of the four most commonly mutated genes in pancreatic cancer has been a pharmacological challenge. The most common genetic mutations are activating mutations in the oncogene KRAS, and inactivating mutations in the tumor suppressors CDKN2A, TP53, and SMAD4 (12). The products of these genes are involved in large binding complexes and disrupting these protein-protein interactions with small molecules has been difficult to achieve clinical efficacy (13).

Kirsten rat sarcoma (KRAS) is mutated in more than 90% of PDAC cases (14). The most common KRAS mutation in PDAC is at the G12 residue to G12D (41%), G12V (34%), or G12R (16%). These mutations stabilize the GTP-bound active state, leading to persistent KRAS signaling through various effector proteins such as PI3K and RAF kinases. Constitutive KRAS signaling leads to increased cell proliferation, increased motility and invasion, and alteration of cell metabolism to sustain tumor growth (15). The importance of Ras signaling in a variety of cancer types has led to a new NCI effort to target RAS cancers by combining academic and industrial efforts in the Ras Initiative at the Frederick National Laboratory for Cancer Research (FNLCR) (https://www.cancer.gov/research/key-initiatives/ras). Recent years have shown increased efficacy of RAS inhibitors for other cancer types and some of these approaches have potential clinical benefit for pancreatic cancer patients. For example, Welsch et al. developed a pan-RAS inhibitor that has a low therapeutic index for PDAC but shows preclinical efficacy in breast cancer mouse models (16). Also, KRAS G12C allele-specific inhibitors have shown promise in preclinical research. Ostrem et al. (17) developed the first covalent inhibitor against G12C KRAS, and recently Amgen is currently recruiting for a phase 1 clinical trial for the small molecule inhibitor AMG 510 for G12C mutant solid tumors (NCT03600883). The G12C mutation is rare in pancreatic cancer cases (1%), however further investigations into allele-specific KRAS inhibitors open the possibility of a KRAS G12D inhibitor in the future (15). Another approach to target KRAS is by disrupting interactions between KRAS and KRAS effector proteins. The Reddy group developed a small molecule Ras-mimetic, rigosertib, to disrupt RAS binding interactions with its effector proteins, blocking the RAS-RAF-MEK signaling pathway. In vitro studies demonstrate that rigosertib treatment suppresses pancreatic cancer lesion development compared to the control, but in the clinical trial, the combination of rigosertib with gemcitabine did not show improvement compared to gemcitabine treatment alone in pancreatic cancer patients (18,19). Recently, an RNAi approach to target KRAS led to overall survival of about 18 months in locally advanced disease in phase I/IIa studies and is currently recruiting for stage IIb studies. To prevent KRAS translation, patients are given tumoral implantation of LODER (LOcal Drug EluteR) containing siRNA for KRASG12D. Administration of oligonucleotides has many challenges including delivery and maintaining activity but using LODER in vivo leads to prolonged regional drug release and effective delivery and protection of the siRNA. This study is promising with a good safety profile and a prolonged clinical benefit compared to gemcitabine (20).

The cyclin-dependent kinase inhibitor 2A (CDKN2A) gene encodes for p16/Ink4a and p14/Arf which inhibit cyclin-dependent kinase 4/6 (CDK4/6) and activate p53 respectively. Inactivation of this tumor suppressor leads to hyperactivation of CDK4/6 and increased proliferation (21,22). Attempts have been made to restore CDKN2A function via pharmacological inhibition of CDK4/6 using inhibitors like palbociclib. In the context of monotherapy, CDK inhibitor treatment usually results in resistance, but preclinical studies support the combination of CDK inhibitors with platinum-based chemotherapeutic agents like cisplatin (23). Currently, a clinical trial for palbociclib with cisplatin or carboplatin is recruiting for metastatic pancreatic cancer (NCT02897375) (24). Preclinical studies in patient-derived mouse xenograft models of PDAC demonstrate retinoblastoma protein (RB) high subtype-specific activity of CDK inhibitors, suggesting RB stratification of patients may lead to better clinical efficacy of CDK inhibitors (25).

P53 is a tumor suppressor normally functioning in regulating DNA repair, senescence, and apoptosis and commonly mutated in multiple cancer types (26,27). In pancreatic cancer patients, p53 accumulation is correlated with worse overall survival, and mutated p53 has been shown to decrease the success of chemotherapy (28). Gemcitabine induced apoptosis is dependent on p53 signaling. Mutation of p53 leads to gemcitabine chemoresistance, but this can be reversed by reactivating p53 using small molecules (CP-31398 and RITA) (29). Small molecules that reactivate p53 have been shown to induce cell death and are being investigated for clinical activity in hematological cancers. APR-246 is the first small molecule targeting p53 to enter clinical trials. This p53 reactivating molecule demonstrates a good safety profile in a phase 1 trial for refractory hematological cancer (NCT00900614) and is currently being tested in combination with various chemotherapeutics for hematological cancers, ovarian cancer, and esophageal cancer (30). The possible success of p53 reactivating molecules in solid tumors will be especially interesting as chemosensitizing agents to gemcitabine. In addition, targeting murine double minute 2 (MDM2), an E3 ubiquitin-protein ligase that mediates the degradation of p53, has been extensively explored as an alternative strategy to target the p53 pathway (31-33).

Mothers against decapentaplegic homolog 4 (SMAD4, also known as DPC4—deleted in pancreatic cancer 4) inactivation is found in half of advanced PDAC patients (34). SMAD4 is involved in the transforming growth factor-beta (TGF-β) signaling pathway. SMAD2/3/4 heterotrimeric complexes translocate into the nucleus and activate or repress transcription when TGF-β binds to its receptors. TGF-β can signal through both a SMAD4 dependent signaling pathway and act as a tumor suppressor and a SMAD4 independent signaling pathway acting as a tumor promoter (34). TGF-β signaling regulates a variety of processes like embryonic development, fibrosis, immune function, and wound healing, but the role of SMAD4 in growth arrest and apoptosis make it a tumor suppressor in PDAC by blocking mitogenic signaling (34). Once SMAD4 is deleted or inactivated, TGF-β downstream tumor suppressor signaling is lost while maintaining the SMAD4 independent tumor promoter signaling through Ras and ERK signaling (35). Due to the duality of TGF-β signaling, thus far inhibiting SMAD4 has not been a promising therapeutic approach, but high throughput screening has led to the discovery of a few lead compounds (36).

Other mutations in DNA repair and chromosomal stability genes, like BRCA1, BRCA2, PALB2, and ATM, occur in about 10% of cases but may have utility as steps are made towards precision medicine (12,37). In breast cancer, studies have shown that BRCA1/2 and PALB2 mutations lead to better response to platinum-based chemotherapy like cisplatin. This may benefit PDAC patients with BRCA mutants as this regimen is more tolerable than the FOLFIRINOX regimen (38). The four-drug regimen, cisplatin, nab-paclitaxel, capecitabine, and gemcitabine (PAXG), shows promising efficacy and safe therapeutic tolerability in stage IV PDAC patients. Compared to the nab-paclitaxel and gemcitabine combination, the PAXG regimen has a progression-free survival of 74% vs. 46% at six months. Additionally, the median overall survival was 14.4 months and progression-free survival was 8.3 months (39). This is comparable to an additional study evaluating the efficacy of cisplatin, gemcitabine, and nab-paclitaxel in stage IV pancreatic cancer that resulted in median overall survival of 16.5 months and progression-free survival of 10.1 months (40). Phase III clinical trials are necessary but results from multiple phase II studies suggest promise.

Additionally, these mutations may lead to sensitivity to PARP inhibitors like olaparib, veliparib, and niraparib based on preclinical studies (41). Olaparib was the first to be approved by the FDA for ovarian cancer patients with germline BRCA mutations who did not respond to chemotherapy in 2014, with FDA approvals for rucaparib and niraparib following in 2016 and 2017. For pancreatic cancer, there are currently five trials recruiting for studies with olaparib. Of the complete trials, those performed without patient stratification based on BRCA mutation status were less successful; olaparib treatment in combination with a trio of DNA damaging agents, irinotecan, cisplatin, and mitomycin C, resulted in high toxicity with modest efficacy (NCT01296763). From this study, there was one long term survivor with the BRCA2 mutation that experienced partial response for four years and ultimately died from acute myeloid leukemia (42). Recently, the Pancreas Cancer Olaparib Ongoing (POLO) trial has reported increased progression-free survival with olaparib in metastatic pancreatic cancer patients with germline BRCA mutations (NCT02184195). In the POLO study, patients with metastatic pancreatic cancer that did not progress during platinum-based chemotherapy received olaparib. Olaparib treatment did not exhibit a significant adverse-effect profile and extended progression-free survival compared to the placebo (7.4 vs. 3.8 months), and two patients in the treatment group had a complete response (43). A recent phase II study investigating rucaparib as a monotherapy in 19 patients with BRCA1/2 mutants had an overall response rate of 16% (NCT02042378), but a larger phase II trial is currently recruiting to evaluate rucaparib in patients with mutated BRCA1/2 or PALB2 (NCT03140670) (44).


Development of targeted therapies

Targeted therapies have shown success in other cancer types, for example, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitors for lung and colorectal cancer and PI3K and CKD4/6 inhibitors for breast cancer. However, no clinically significant targeted therapy has been approved for pancreatic cancer (45,46). Erlotinib is the only FDA approved targeted therapy for pancreatic cancer. Although statistically significant, erlotinib only extends lifespan by a few weeks compared to gemcitabine alone leaving an urgent need for new targets and improved therapeutics (47). Many combinations of cytotoxic agents with gemcitabine have been studied in clinical trials, but with little success. The lack of therapeutic success in pancreatic cancer can be attributed to multiple causes, including complex and redundant signaling pathways, poor patient stratification during clinical trials, and eventual drug resistance and disease recurrence. The complex interactions between signaling pathways make single targeted therapy less likely to be effective due to the redundancy and crosstalk between different pathways. This has been a major issue with targeting downstream effectors of KRAS. MAPK kinase inhibitors and PI3K inhibitors have shown little promise, with many failures in clinical trials. The main reason for failure of these approaches is the development of alternative compensating pathways upon monotherapy targeting KRAS or KRAS effector proteins (15). For example, studies have shown that KRAS G12D addiction can be circumvented by activation of YAP1 oncogene in pancreatic cancer (48). Although targeting KRAS itself and its effector molecules has been difficult, studies looking for druggable targets in KRAS dependent tumors have led to a few possibilities, for example, the KRAS associated proteins galectin-3, Son of Sevenless (SOS), and receptor for advanced glycation end-products (RAGE).

Galectin 3, the β-galactoside-specific lectin, has multiple roles and has been implicated in metastasis in a variety of cancers (49). In pancreatic cancer, galectin-3 from cancer cells can activate pancreatic stellate cells (PSCs) in the stroma in a paracrine like mechanism leading to the production of proinflammatory cytokines via NF-kB signaling (50). Additionally, disruption of galectin-3 binding to the cell surface receptor integrin αvβ3 may contribute to KRAS addiction in both pancreatic and lung cancer. KRAS mutant pancreatic tumors in mice show decreased tumor progression upon addition of galectin 3 inhibitor GSC-100 when αvβ3 is expressed (51). Galectin-3 also has been shown to interact with Ras in PDAC cells, and knockdown of galectin-3 led to decreased Ras activity (52). Other galectin-3 inhibitors show anticancer activity in pancreatic cancer models, for example, RN1 and HH1-1. Both RN1 and HH1-1 disrupts the interaction between Gal-3 and EGFR affecting downstream signaling pathways (53,54).

SOS protein is a guanine nucleotide exchange factor converting GDP to GTP. Small molecule inhibitors of SOS1 were the first small molecule RAS binders to regulate RAS activity. SOS inhibitors have been shown to inhibit ERK phosphorylation by binding to the CDC25 domain of SOS, but further studies are needed to evaluate anti-cancer activity in PDAC models (55). RAGE has been shown to maintain KRAS signaling and high levels of NF-kB signaling leading to inflammation. RAGE inhibitors have shown reduced tumor growth in syngeneic mouse models of pancreatic suggesting the feasibility of targeting the KRAS/inflammation feed-forward loop (56).


Recent clinical trials

PEGPH20 (pegylated hyaluronidase for stromal modulation) is a promising strategy for patients with hyaluronic acid (HA) high pancreatic cancer. The idea behind this therapeutic is to modulate the stroma instead of targeting one specific part of a pathway. PEGPH20 in combination with the standard of care, gemcitabine with nab-paclitaxel, shows efficacy in Phase II trials with an increase in progression-free survival, 9.2 vs. 5.3 months, for patients with HA high tumors (NCT01453153) (57). This therapeutic is being investigated in phase III clinical trial (NCT02715804) currently for HA high stage IV pancreatic cancer. Double the patients in the treatment group had thromboembolic events compared to the control, which was a major concern from the phase II trial. After adding enoxaparin prophylaxis to both arms of the study, thromboembolic events were reduced to an insignificant difference. An additional concern is musculoskeletal events. The administration of dexamethasone was shown to reduce the severity of this event (57). Preclinical studies suggest that degradation of HA leads to a decrease in interstitial tumor pressure allowing for chemotherapeutics to distribute throughout the tumor more effectively (58). PEGPH20 breaks down HA crosslinking in the extracellular matrix. Given the success in vitro and in clinical trials thus far, hyaluronan may be a necessary component to sustain a protumorigenic microenvironment. Targeting other ECM components may enhance current chemotherapeutics by remodeling the tumor microenvironment.

The use of JAK/STAT pathway inhibitors shows a marginal improvement in overall survival across all patients. JAK/STAT signaling is an important modulator of inflammation and immunity. A subset of patients with above median C-reactive protein (CRP) levels receiving ruxolitinib and capecitabine showed an almost two-fold increase in overall survival (59). This is in agreement with a previous clinical trial (CALGB80303) that investigated the role of inflammation in patients with metastatic pancreatic cancer. The phase III study of gemcitabine and bevacizumab suggested that CRP and albumin levels have prognostic value in pancreatic cancer (60). Phase III studies of the JAK1/JAK2 inhibitor ruxolitinib, unfortunately, did not show improved clinical outcomes for patients with advanced/metastatic pancreatic cancer, even in groups with high CRP (61).

Bruton’s tyrosine kinase (BTK) is a non-receptor tyrosine kinase critical for B lymphocyte signaling. BTK also is important for macrophage functioning, acting as a node for innate and adaptive immunity (62). The BTK inhibitor ibrutinib is an anticancer drug primarily used for lymphoma but is currently being tested in the clinic for pancreatic cancer (63). Preclinical studies in mouse models suggest that treatment with ibrutinib may modulate the tumor microenvironment, making it less immune suppressive. BTK along with PI3Kγ regulate immune suppression via B cells and macrophages to mobilize CD8+ cells in pancreatic cancer models. Ibrutinib reprogramming of B cells leads to an increase in CD8+ T cells and suppressed tumor growth (64). Clinical trial results have not been released, but it is believed that ibrutinib acts by converting a Th2 response to a Th1 response, which will be important in the context of immunotherapy and its potential efficacy in pancreatic cancer (63,65). It is important to keep in mind that BTK inhibition via ibrutinib has off-target effects with many other kinases and has been shown to have cytotoxic cancer affects in BTK independent tumors (66).


Transcriptional coactivators and nuclear receptors

Targeting transcriptional coactivators is a viable therapeutic approach currently in the preclinical stage. Through protein-protein interactions, transcriptional coactivators activate oncogenic signaling via multiple effector proteins. Inhibition of transcriptional regulators has shown anti-cancer activity in multiple cancer types (67). Transcriptional coactivators implicated in pancreatic cancer include SRC-3, MTA1, and YAP and exhibit in vitro and in vivo anti-cancer activity in models of pancreatic cancer upon depletion.

Steroid coactivators act as a signaling hub and canonically signal through nuclear receptors (68). Many nuclear receptors like EGFR, IGF-1R, and MUC1 are implicated in pancreatic cancer disease progression (69). Nuclear receptor functioning is dependent upon coregulator recruitment leading to either enhanced transcription in the presence of coactivators or repressed transcription in the presence of corepressors (70). Coregulators can modify chromatin via changing acetylation and methylation states, performing chromatin remodeling, and recruiting other enzymes to form protein complexes. The Steroid Receptor Coactivator family includes SRC-1, SRC-2, and SRC-3 and has been shown to regulate metabolism and oncogenic signaling. SRC-3 is a scaffold protein bringing together nuclear receptors and other coregulators to form transcriptional complexes (71). SRC-3 levels are increased with the progression of PDAC, low in healthy pancreatic tissue, medium in PanIN lesions, and high in metastatic PDAC (72). SRC-3 also has nuclear receptor independent roles and some of these functions in other cancers include cell cycle, tumorigenesis, apoptosis, and invasion and migration (73).

SRC-3 has been well studied in endocrine cancers, for example breast cancer, but its role in pancreatic cancer is not well understood. Microarray data suggests knockdown of SRC-3 influences AKT, P38 MAPK, ERK1/2, ubiquitin C, and NF-kB signaling affecting a variety of cellular functions. In addition to this SRC-3 has been shown to induce a pro-inflammatory microenvironment via the stabilization of mucins, MUC1 and MUC4, in pancreatic cancer (74). Inhibiting SRC-3 with small molecule bufalin displays anti-tumor activity in an orthotopic mouse model of pancreatic cancer but exhibits cardiotoxicity in humans decreasing its usefulness in the clinic (75). Since the discovery of bufalin as a small molecule inhibitor of SRC-3, the small molecule inhibitor SI-2 and small molecule stimulator MCB-613 have been optimized through medicinal chemistry and exhibit anti-cancer activity in breast cancer. In breast cancer cells, SI-2 has low nanomolar activity. Also in an orthotopic breast cancer mouse model, SI-2 administration inhibits tumor growth (76). Additionally, pan-SRC overstimulation inhibits tumor growth by inducing ER stress and ROS production (77).

Metastasis-associated protein (MTA1) can act as both a corepressor and coactivator depending on whether it is acting with or independently of nucleosome remodeling and deacetylation (NurD) complex components. MTA1 is a known oncogene, overexpressed in many cancers. Recent studies found that MTA1 activates HIF-α and VEGF signaling in pancreatic cancer metastasis (78). High levels of MTA1 are found in samples having increased lymph node metastasis and worse survival (79). The antioxidant pterostilbene has been shown to inhibit pancreatic cancer cell growth in vitro and in vivo (80). Also, studies in hepatocellular carcinoma suggest the anti-cancer activity of pterostilbene is due to destabilization of the MTA1-NuRD complex (81). Additionally, the coactivating activity of MTA1 with E2F1, which results in increased HA production and reduced infiltration of macrophages, can also be targeted with small molecule argatroban (82).

Yes-associated protein (YAP) is a transcriptional coregulator that acts as an effector in Hippo signaling via the TEAD transcription factor during embryonic development of the pancreas (83). In pancreatic cancer, YAP is overexpressed in patient tissue samples compared to normal tissue and high YAP levels correlate with poor survival (84). In vitro studies suggest that YAP signaling results in pancreatic cancer invasion and metastasis and promotes desmoplasia (85,86). A novel YAP inhibitor shows preclinical efficacy in esophageal cancer, and multiple independent studies have suggested statins can interfere with YAP activity in PDAC models (87,88). The FDA approved photosensitizing agent verteporfin has tumoricidal activity in pancreatic cancer by disrupting the YAP-TEAD complex, but other studies suggest verteporfins activity is not YAP selective and has anticancer activity independent of YAP signaling (89,90). Further experimental and preclinical studies investigating transcriptional coregulators as pancreatic cancer therapeutics are warranted before clinical trials are proposed, but studies in recent years suggest targeting transcriptional coregulators as a valid approach.


Tumor microenvironment in PDAC also reduces therapeutic efficacy

In addition to its varied genetic background, the tumor microenvironment in pancreatic cancer adds another level of complexity and heterogeneity. Complex interactions occurring between pancreatic cancer cells, endothelial cells, and immune cells in the stroma have presented barriers in therapeutic design and delivery unique to this cancer type. Pancreatic tumors seem to have an innate resistance, compared to the acquired resistance occurring against independent breast cancer therapies, to radiation and chemotherapy in part due to the stroma and its unique biophysical attributes (91). For example, microenvironment components like hyaluronan have been shown to lead to poor vascularization which then leads to poor drug delivery (92). Additionally, fibronectin secreted from PSCs has been shown to induce resistance to gemcitabine by inducing ERK1/2 activity (93).

Stromal cells can play both a protumorigenic role or an antitumorigenic role in a context dependent manner (94). Stromal components can promote tumor proliferation and migration. These components include a variety of cell types likes PSCs, leukocytes, and endothelial cells, along with extracellular matrix components like HA and collagen. PSCs are the major source of cancer-associated fibroblasts (CAFs). In the normal pancreas, these PSCs are quiescent but can be activated into CAFs (aka as activated PSCs or aPSCs) by tumor secreted factors such as platelet-derived growth factor (PDGF), TGF-β, TNF-α, macrophage inhibitory factor (MIF), IL-1, IL-6, IL-8, IL-10. Upon activation of PSCs, the secretion profile changes into a pro proliferation, inflammation, motility, invasion phenotype (95,96).

Ras mutations play a multifactorial role in PDAC and also have been shown to promote dense stromal desmoplasia via paracrine signals. If mutated KRAS is switched to unmutated KRAS using genetic approaches, the desmoplasia proliferation rate slows down after a few days (97). Desmoplasia is the proliferation of fibroblasts surrounding epithelial cells and this complex reaction involves multiple cells types in the microenvironment including leukocytes, fibroblasts, endothelial cells, and ECM components like collagen and hyaluronan. Many clinical trials have been conducted to address stromal implications of pancreatic cancer and disease progression (98). Targeting the stroma may facilitate the delivery of other therapeutics in combination by decreasing desmoplasia and increasing vascularity. The most promising stromal target is hyaluronan. Other attempts include targeting the sonic hedgehog pathway, matrix metalloproteases, and VEGF but with little success over gemcitabine treatment.

Sonic hedgehog (SHH) signaling activates stromal fibroblasts in cancer cells aiding in high levels of desmoplasia. Attempts to target Smoothened signaling downstream of SHH have resulted in multiple stopped or unsuccessful clinical trials (99). Follow-up studies investigating the lack of success demonstrate that genetic knockout or inhibition of smoothened leads to increased epithelial-mesenchymal transition, metastasis, and morbidity in mouse models (94). This suggests there is a balance between too much and too little when it comes to stromal elements in pancreatic cancer. SHH inhibitors have been tested in clinical trials but with little success. Modulation of SHH signaling and co-administration with cytotoxic agents may still be useful therapeutically but will require a fine balance to be useful clinically. MMP inhibitors have also not been successful in clinical trials with tanomastat performing worse than gemcitabine and newer analogs showing musculoskeletal toxicity (100). Knockdown studies in mouse models also show that the absence of MMP-9 leads to PDAC progression and metastasis (101). VEGF inhibitors, for example bevacizumab, target angiogenesis but also show no advantage over gemcitabine in phase 3 clinical trials (102).

Immune therapy has gained increased interest after the success of checkpoint inhibitors in melanomas, but as a monotherapy has proven ineffective in pancreatic cancer. The immunosuppressive microenvironment is the basis of resistance to immune therapies in pancreatic cancer (103,104). Pancreatic tumors are classified as “non-inflamed” or immune cold, lacking T cell infiltration (105). A major contributor to this is stromal secreted factors that recruit immunosuppressive cells like regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages (106). T cell recruitment to the tumor and tumor cell recognition and killing by tumor-infiltrating lymphocytes are necessary for effective antitumoral immune response. To overcome these challenges, efforts are being made to combine checkpoint inhibitors with agents that increase tumor immunogenicity allowing the recruitment and activation of effector T cells (103).


Metabolism

Generating energy to maintain uncontrolled cell proliferation by metabolic reprogramming is a hallmark of cancer (107). Normal cells metabolize glucose to enter the tricarboxylic acid cycle and produce ATP via oxidative phosphorylation. Cancer cells, in addition to meeting energy needs via ATP, must also produce the building blocks for the synthesis of proteins, nucleic acids, and lipids to match their proliferation rates.

Oncogenic KRAS expression is the most commonly mutated gene in PDAC and is also pivotal to metabolic reprogramming. Thus far KRAS has been a difficult drug target, but there may be therapeutic benefit in targeting its role in metabolism. In PDAC mouse models, KRAS activation leads to increased glucose uptake and subsequent glycolysis, increased hexosamine biosynthesis for glycosylation, and increased nonoxidative pentose phosphate synthesis for ribose synthesis (108). Additionally, KRAS G12D mutations are necessary to recycle building blocks necessary to sustain tumor growth. Autophagy and micropinocytosis are dependent upon KRAS activation and these processes allow for increased uptake of metabolites. Additionally, KRAS mutations lead to increased glucose uptake via upregulation of GLUT1 and subsequent flux through the non-oxidative arm of the pentose phosphate pathway to generate nucleotide precursors (109).

An additional difference between cancer metabolism and normal metabolism is through ion transport. Metal ions like zinc are used by metalloenzymes and transcription factors. The Li group has identified a key role of zinc transporter (ZIP4) in mediating pancreatic tumor growth, signaling transduction and metabolism. In vivo studies have demonstrated that overexpression of ZIP4 increases tumor volume (110). Additional studies show that genetic knockdown of ZIP4 inhibited pancreatic cancer invasion and migration in vivo by modulating known regulators of cell migration and invasion (111). Further studies are needed, but ZIP4 may be a potential target for the development of either small molecule based or RNAi based therapeutics (112).

Using metabolite profiling, in conjunction with other omics based methods, a few different stratifications have been proposed. Pancreatic cancer exhibits both large intratumoral (within the same tumor) and intertumoral (between patients) heterogeneity. Intratumor heterogeneity between histological samples shows a large difference in transcriptional profile (more than 1,000 genes) between tumor center and periphery (113). Despite this, tumor subtyping based on DNA, RNA, and metabolite profiling has been attempted but with little overlap between the studies (114). Transcriptome studies based on RNA signature have proposed 3 subtypes: quasi-mesenchymal, exocrine-like, and classical subtype from most aggressive to least aggressive (115). The metabolite profiling is divided into three subtypes: a slow-growing subtype, a glycolytic subtype with quasi-mesenchymal phenotype, and a lipogenic subtype with the classical phenotype (116). Metabolite profiling performed in PDAC cell lines may correlate with RNA based subtyping in tumors with advances in tumor metabolomics in the future. Metabolic clustering in PDAC cell lines identified profiles associated with glycolysis dependent, lipogenesis dependent, and redox dependent pathways. Based on the metabolic signature, cancer cell lines were either more or less sensitive to aerobic glycolysis inhibitors (116).


Conclusions

Pancreatic cancer is a challenging disease to treat and continued progress in understanding this disease is imperative. As the focus shifts to more personalized medicine, the current understanding of this disease must be used to stratify patients in clinical trials. Better design in clinical trials is also important. Patient stratification based on molecular/biomarker strategies only occurs in 8.6% of new study protocols registered between 2015–2018 (117). There is also the possibility that due to poor stratification of patients in the original planning of clinical trials, a therapeutic that is responsive in one or a few patients may be seen as an anecdote instead of having a true clinical benefit (118). Drugs targeted to specific subtypes may not improve general patient outcome but may greatly improve the outcome of patients with that particular tumor type. Also, immunotherapy is showing increased potential in other solid tumors and may be a promising approach for pancreatic cancer in the future (119,120). Pancreatic cancer cells secrete immunosuppressive factors to escape immune surveillance as recently reviewed by Neoptolemos and others (121). Early detection techniques also are imperative. The stepwise progression from low-grade PanIN (expressing MUC5 and harboring mutations in KRAS/CDKN2A) to high-grade PanIN (expressing MUC1 and mutant p53/SMAD4) is driven by the activation of KRAS. The window of opportunity is large with some studies analyzing the genetic evolution of disease suggesting at least 15 years between the initiating mutation and metastatic ability (122). With a better understanding of the disease, the translation into efficacious clinical trials is attainable.


Acknowledgments

Funding: This work is supported in part by National Institutes of Health Grants R01GM115622, R01CA207701, RF1AG062257, and R21CA213535 (to J Wang).


Footnote

Conflicts of Interest: J Wang is a cofounder and holds stock in CoActigon, Inc., which is developing steroid receptor coactivator inhibitors for clinical use. J Wang is also a cofounder of Chemical Biology Probes LLC. I Bijou has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.


References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69:7-34. [Crossref] [PubMed]
  2. Kleeff J, Korc M, Apte M, et al. Pancreatic cancer. Nat Rev Dis Primers 2016;2:16022. [Crossref] [PubMed]
  3. Rahib L, Smith BD, Aizenberg R, et al. Projecting Cancer Incidence and Deaths to 2030: The Unexpected Burden of Thyroid, Liver, and Pancreas Cancers in the United States. Cancer Res 2014;74:2913-21. [Crossref] [PubMed]
  4. Gillen S, Schuster T, Meyer Zum Büschenfelde C, et al. Preoperative/Neoadjuvant Therapy in Pancreatic Cancer: A Systematic Review and Meta-analysis of Response and Resection Percentages. PLoS Med 2010;7:e1000267. [Crossref] [PubMed]
  5. Fesinmeyer MD, Austin MA, Li CI, et al. Differences in Survival by Histologic Type of Pancreatic Cancer. Cancer Epidemiol Biomarkers Prev 2005;14:1766-73. [Crossref] [PubMed]
  6. Patra KC, Bardeesy N, Mizukami Y. Diversity of Precursor Lesions For Pancreatic Cancer: The Genetics and Biology of Intraductal Papillary Mucinous Neoplasm. Clin Transl Gastroenterol 2017;8:e86. [Crossref] [PubMed]
  7. Maitra A, Adsay NV, Argani P, et al. Multicomponent Analysis of the Pancreatic Adenocarcinoma Progression Model Using a Pancreatic Intraepithelial Neoplasia Tissue Microarray. Mod Pathol 2003;16:902-12. [Crossref] [PubMed]
  8. Burris HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403-13. [Crossref] [PubMed]
  9. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-703. [Crossref] [PubMed]
  10. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. N Engl J Med 2011;364:1817-25. [Crossref] [PubMed]
  11. Amrutkar M, Gladhaug IP. Pancreatic Cancer Chemoresistance to Gemcitabine. Cancers 2017;9:157. [Crossref] [PubMed]
  12. Roberts NJ, Norris AL, Petersen GM, et al. Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer. Cancer Discov 2016;6:166-75. [Crossref] [PubMed]
  13. Sun Q, Burke JP, Phan J, et al. Discovery of Small Molecules that Bind to K-Ras and Inhibit Sos-mediated Activation. Angew Chem Int Ed Engl 2012;51:6140-3. [Crossref] [PubMed]
  14. Witkiewicz AK, McMillan EA, Balaji U, et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun 2015;6:6744. [Crossref] [PubMed]
  15. Waters AM, Der CJ. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med 2018. [Crossref] [PubMed]
  16. Welsch ME, Kaplan A, Chambers JM, et al. Multivalent small molecule pan-RAS inhibitors. Cell 2017;168:878-89.e29. [Crossref] [PubMed]
  17. Ostrem JM, Peters U, Sos ML, et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 2013;503:548-51. [Crossref] [PubMed]
  18. Athuluri-Divakar SK, Vasquez-Del Carpio R, Dutta K, et al. A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling. Cell 2016;165:643-55. [Crossref] [PubMed]
  19. O'Neil BH, Scott AJ, Ma WW, et al. A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer. Ann Oncol 2015;26:1923-9. [Crossref] [PubMed]
  20. Golan T, Khvalevsky EZ, Hubert A, et al. RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients. Oncotarget 2015;6:24560-70. [Crossref] [PubMed]
  21. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 1993;366:704-7. [Crossref] [PubMed]
  22. Pomerantz J, Schreiber-Agus N, Liégeois NJ, et al. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell 1998;92:713-23. [Crossref] [PubMed]
  23. Iyengar M, O’Hayer P, Cole A, et al. CDK4/6 inhibition as maintenance and combination therapy for high grade serous ovarian cancer. Oncotarget 2018;9:15658-72. [Crossref] [PubMed]
  24. Guarducci C, Bonechi M, Benelli M, et al. Cyclin E1 and Rb modulation as common events at time of resistance to palbociclib in hormone receptor-positive breast cancer. NPJ Breast Cancer 2018;4:38. [Crossref] [PubMed]
  25. Chou A, Froio D, Nagrial AM, et al. Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer. Gut 2018;67:2142-55. [Crossref] [PubMed]
  26. Mangray S, King TC. Molecular pathobiology of pancreatic adenocarcinoma. Front Biosci 1998;3:D1148-60. [Crossref] [PubMed]
  27. Blandino G, Di Agostino S. New therapeutic strategies to treat human cancers expressing mutant p53 proteins. J Exp Clin Cancer Res 2018;37:30. [Crossref] [PubMed]
  28. Wörmann SM, Song L, Ai J, et al. Loss of P53 Function Activates JAK2–STAT3 Signaling to Promote Pancreatic Tumor Growth, Stroma Modification, and Gemcitabine Resistance in Mice and Is Associated With Patient Survival. Gastroenterology 2016;151:180-93.e12. [Crossref] [PubMed]
  29. Fiorini C, Cordani M, Padroni C, et al. Mutant p53 stimulates chemoresistance of pancreatic adenocarcinoma cells to gemcitabine. Biochim Biophys Acta 2015;1853:89-100. [Crossref] [PubMed]
  30. Deneberg S, Cherif H, Lazarevic V, et al. An open-label phase I dose-finding study of APR-246 in hematological malignancies. Blood Cancer J 2016;6:e447. [Crossref] [PubMed]
  31. Wang W, Qin JJ, Voruganti S, et al. Discovery and Characterization of Dual Inhibitors of MDM2 and NFAT1 for Pancreatic Cancer Therapy. Cancer Res 2018;78:5656-67. [Crossref] [PubMed]
  32. Li Y, Yang J, Aguilar A, et al. Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression. J Med Chem 2019;62:448-66. [Crossref] [PubMed]
  33. Zhao Y, Aguilar A, Bernard D, et al. Small-Molecule Inhibitors of the MDM2–p53 Protein-Protein Interaction (MDM2 Inhibitors) in Clinical Trials for Cancer Treatment. J Med Chem 2015;58:1038-52. [Crossref] [PubMed]
  34. Xia X, Wu W, Huang C, et al. SMAD4 and its role in pancreatic cancer. Tumour Biol 2015;36:111-9. [Crossref] [PubMed]
  35. Ahmed S, Bradshaw AD, Gera S, et al. The TGF-β/Smad4 Signaling Pathway in Pancreatic Carcinogenesis and Its Clinical Significance. J Clin Med 2017. [Crossref] [PubMed]
  36. Wang H, Stephens B, Von Hoff DD, et al. Identification and Characterization of a Novel Anticancer Agent With Selectivity Against Deleted in Pancreatic Cancer Locus 4 (DPC4)-Deficient Pancreatic and Colon Cancer Cells. Pancreas 2009;38:551-7. [Crossref] [PubMed]
  37. Raphael BJ, Hruban RH, Aguirre AJ, et al. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell 2017;32:185-203.e13. [Crossref] [PubMed]
  38. Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015;518:495-501. [Crossref] [PubMed]
  39. Reni M, Zanon S, Peretti U, et al. Nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in metastatic pancreatic adenocarcinoma (PACT-19): a randomised phase 2 trial. Lancet Gastroenterol Hepatol 2018;3:691-7. [Crossref] [PubMed]
  40. Jameson GS, Borazanci EH, Babiker HM, et al. A phase Ib/II pilot trial with nab-paclitaxel plus gemcitabine plus cisplatin in patients (pts) with stage IV pancreatic cancer. J Clin Oncol 2017;35:341. [Crossref]
  41. Antolin AA, Ameratunga M, Banerji U, et al. The off-target kinase landscape of clinical PARP inhibitors. preprint Pharmacology and Toxicology 2019.2019.
  42. Yarchoan M, Myzak MC, Johnson BA, et al. Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer. Oncotarget 2017;8:44073. [Crossref] [PubMed]
  43. Golan T, Hammel P, Reni M, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med 2019;381:317-27. [Crossref] [PubMed]
  44. Shroff RT, Hendifar A, McWilliams RR, et al. Rucaparib Monotherapy in Patients With Pancreatic Cancer and a Known Deleterious BRCA Mutation. JCO Precis Oncol 2018. doi: . [Crossref]
  45. Meadows KL, Hurwitz HI. Anti-VEGF Therapies in the Clinic. Cold Spring Harb Perspect Med 2012. [Crossref] [PubMed]
  46. Masoud V, Pagès G. Targeted therapies in breast cancer: New challenges to fight against resistance. World J Clin Oncol 2017;8:120-34. [Crossref] [PubMed]
  47. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25:1960-6. [Crossref] [PubMed]
  48. Kapoor A, Yao W, Ying H, et al. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell 2014;158:185-97. [Crossref] [PubMed]
  49. Farhad M, Rolig AS, Redmond WL. The role of Galectin-3 in modulating tumor growth and immunosuppression within the tumor microenvironment. Oncoimmunology 2018;7:e1434467. [Crossref] [PubMed]
  50. Zhao W, Ajani JA, Sushovan G, et al. Galectin-3 Mediates Tumor Cell-Stroma Interactions by Activating Pancreatic Stellate Cells to Produce Cytokines via Integrin Signaling. Gastroenterology 2018;154:1524-37.e6. [Crossref] [PubMed]
  51. Seguin L, Camargo MF, Wettersten HI, et al. Galectin-3, a Druggable Vulnerability for KRAS-Addicted Cancers. Cancer Discov 2017;7:1464-79. [Crossref] [PubMed]
  52. Song S, Ji B, Ramachandran V, et al. Overexpressed Galectin-3 in Pancreatic Cancer Induces Cell Proliferation and Invasion by Binding Ras and Activating Ras Signaling. PLoS One 2012;7:e42699. [Crossref] [PubMed]
  53. Zhang L, Wang P, Qin Y, et al. RN1, a novel galectin-3 inhibitor, inhibits pancreatic cancer cell growth in vitro and in vivo via blocking galectin-3 associated signaling pathways. Oncogene 2017;36:1297-308. [Crossref] [PubMed]
  54. Yao Y, Zhou L, Liao W, et al. HH1-1, a novel Galectin-3 inhibitor, exerts anti-pancreatic cancer activity by blocking Galectin-3/EGFR/AKT/FOXO3 signaling pathway. Carbohydr Polym 2019;204:111-23. [Crossref] [PubMed]
  55. Burns MC, Howes JE, Sun Q, et al. High-throughput screening identifies small molecules that bind to the RAS:SOS:RAS complex and perturb RAS signaling. Anal Biochem 2018;548:44-52. [Crossref] [PubMed]
  56. Azizan N, Suter MA, Liu Y, et al. RAGE maintains high levels of NFκB and oncogenic Kras activity in pancreatic cancer. Biochem Biophys Res Commun 2017;493:592-7. [Crossref] [PubMed]
  57. Hingorani SR, Harris WP, Hendifar AE, et al. High response rate and PFS with PEGPH20 added to nab-paclitaxel/gemcitabine in stage IV previously untreated pancreatic cancer patients with high-HA tumors: Interim results of a randomized phase II study. J Clin Oncol 2015;33:4006. [Crossref]
  58. Provenzano PP, Cuevas C, Chang AE, et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 2012;21:418-29. [Crossref] [PubMed]
  59. Hurwitz HI, Uppal N, Wagner SA, et al. Randomized, Double-Blind, Phase II Study of Ruxolitinib or Placebo in Combination With Capecitabine in Patients With Metastatic Pancreatic Cancer for Whom Therapy With Gemcitabine Has Failed. J Clin Oncol 2015;33:4039-47. [Crossref] [PubMed]
  60. Nixon AB, Pang H, Starr MD, et al. Prognostic and Predictive Blood-Based Biomarkers in Patients with Advanced Pancreatic Cancer: Results from CALGB80303 (Alliance). Clin Cancer Res 2013;19:6957-66. [Crossref] [PubMed]
  61. Hurwitz H, Van Cutsem E, Bendell J, et al. Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies. Invest New Drugs 2018;36:683-95. [Crossref] [PubMed]
  62. Weber ANR, Bittner Z, Liu X, et al. Bruton’s Tyrosine Kinase: An Emerging Key Player in Innate Immunity. Front Immunol 2017;8:1454. [Crossref] [PubMed]
  63. Tempero MA, Coussens LM, Fong L, et al. A randomized, double-blind, placebo-controlled study of ibrutinib, a Bruton tyrosine kinase inhibitor, with nab-paclitaxel and gemcitabine in the first-line treatment of patients with metastatic pancreatic adenocarcinoma (RESOLVE). J Clin Oncol 2016;34:TPS2601. [Crossref]
  64. Gunderson AJ, Kaneda MM, Tsujikawa T, et al. Bruton’s Tyrosine Kinase (BTK)-dependent immune cell crosstalk drives pancreas cancer. Cancer Discov 2016;6:270-85. [Crossref] [PubMed]
  65. Massó-Vallés D, Jauset T, Serrano E, et al. Ibrutinib Exerts Potent Antifibrotic and Antitumor Activities in Mouse Models of Pancreatic Adenocarcinoma. Cancer Res 2015;75:1675-81. [Crossref] [PubMed]
  66. Wu J, Liu C, Tsui ST, et al. Second-generation inhibitors of Bruton tyrosine kinase. J Hematol Oncol 2016;9:80. [Crossref] [PubMed]
  67. Rohira AD, Lonard DM. Steroid receptor coactivators present a unique opportunity for drug development in hormone-dependent cancers. Biochem Pharmacol 2017;140:1-7. [Crossref] [PubMed]
  68. Oñate SA, Tsai SY, Tsai MJ, et al. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 1995;270:1354-7. [Crossref] [PubMed]
  69. Damaskos C, Karatzas T, Kostakis ID, et al. Nuclear Receptors in Pancreatic Tumor Cells. Anticancer Res 2014;34:6897-911. [PubMed]
  70. McKenna NJ, Lanz RB, O'Malley BW. Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 1999;20:321-44. [PubMed]
  71. Lonard DM, O'Malley BW. Molecular Pathways: Targeting Steroid Receptor Coactivators in Cancer. Clin Cancer Res 2016;22:5403-7. [Crossref] [PubMed]
  72. Henke RT, Haddad BR, Kim SE, et al. Overexpression of the Nuclear Receptor Coactivator AIB1 (SRC-3) during Progression of Pancreatic Adenocarcinoma. Clin Cancer Res 2004;10:6134-42. [Crossref] [PubMed]
  73. Ma G, Ren Y, Wang K, et al. SRC-3 Has a Role in Cancer Other Than as a Nuclear Receptor Coactivator. Int J Biol Sci 2011;7:664-72. [Crossref] [PubMed]
  74. Kumar S, Das S, Rachagani S, et al. NCOA3-mediated upregulation of mucin expression via transcriptional and post-translational changes during the development of pancreatic cancer. Oncogene 2015;34:4879-89. [Crossref] [PubMed]
  75. Song X, Chen H, Zhang C, et al. SRC-3 inhibition blocks tumor growth of pancreatic ductal adenocarcinoma. Cancer Lett 2019;442:310-9. [Crossref] [PubMed]
  76. Song X, Chen J, Zhao M, et al. Development of potent small-molecule inhibitors to drug the undruggable steroid receptor coactivator-3. Proc Natl Acad Sci U S A 2016;113:4970-5. [Crossref] [PubMed]
  77. Wang L, Yu Y, Chow DC, et al. Characterization of a Steroid Receptor Coactivator Small Molecule Stimulator that Overstimulates Cancer Cells and Leads to Cell Stress and Death. Cancer Cell 2015;28:240-52. [Crossref] [PubMed]
  78. Sun X, Zhang Y, Li B, et al. MTA1 promotes the invasion and migration of pancreatic cancer cells potentially through the HIF-α/VEGF pathway. J Recept Signal Transduct Res 2018;38:352-8. [Crossref] [PubMed]
  79. Pavlidis ET, Pavlidis TE. Current Molecular and Genetic Aspects of Pancreatic Cancer, the Role of Metastasis Associated Proteins (MTA): A Review. J Invest Surg 2018;31:54-66. [Crossref] [PubMed]
  80. McCormack DE, Mannal P, McDonald D, et al. Genomic Analysis of Pterostilbene Predicts Its Antiproliferative Effects Against Pancreatic Cancer In Vitro and In Vivo. J Gastrointest Surg 2012;16:1136-43. [Crossref] [PubMed]
  81. Qian YY, Liu ZS, Pan DY, et al. Tumoricidal activities of pterostilbene depend upon destabilizing the MTA1-NuRD complex and enhancing P53 acetylation in hepatocellular carcinoma. Exp Ther Med 2017;14:3098-104. [Crossref] [PubMed]
  82. Goody D, Gupta SK, Engelmann D, et al. Drug Repositioning Inferred from E2F1-Coregulator Interactions Studies for the Prevention and Treatment of Metastatic Cancers. Theranostics 2019;9:1490-509. [Crossref] [PubMed]
  83. Cebola I, Rodríguez-Seguí SA, Cho CHH, et al. TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors. Nat Cell Biol 2015;17:615-26. [Crossref] [PubMed]
  84. Diep CH, Zucker KM, Hostetter G, et al. Down-Regulation of Yes Associated Protein 1 Expression Reduces Cell Proliferation and Clonogenicity of Pancreatic Cancer Cells. PLoS One 2012;7:e32783. [Crossref] [PubMed]
  85. Yang S, Zhang L, Purohit V, et al. Active YAP promotes pancreatic cancer cell motility, invasion and tumorigenesis in a mitotic phosphorylation-dependent manner through LPAR3. Oncotarget 2015;6:36019-31. [Crossref] [PubMed]
  86. Jiang Z, Zhou C, Cheng L, et al. Inhibiting YAP expression suppresses pancreatic cancer progression by disrupting tumor-stromal interactions. J Exp Clin Cancer Res 2018;37:69. [Crossref] [PubMed]
  87. Song S, Xie M, Scott AW, et al. A Novel YAP1 Inhibitor Targets CSC-Enriched Radiation-Resistant Cells and Exerts Strong Antitumor Activity in Esophageal Adenocarcinoma. Mol Cancer Ther 2018;17:443-54. [Crossref] [PubMed]
  88. Rozengurt E, Sinnett-Smith J, Eibl G. Yes-associated protein (YAP) in pancreatic cancer: at the epicenter of a targetable signaling network associated with patient survival. Signal Transduct Target Ther 2018;3:11. [Crossref] [PubMed]
  89. Wei H, Wang F, Wang Y, et al. Verteporfin suppresses cell survival, angiogenesis and vasculogenic mimicry of pancreatic ductal adenocarcinoma via disrupting the YAP-TEAD complex. Cancer Sci 2017;108:478-87. [Crossref] [PubMed]
  90. Dasari VR, Mazack V, Feng W, et al. Verteporfin exhibits YAP-independent anti-proliferative and cytotoxic effects in endometrial cancer cells. Oncotarget 2017;8:28628-40. [Crossref] [PubMed]
  91. Renaud JP, Chung CW, Danielson UH, et al. Biophysics in drug discovery: impact, challenges and opportunities. Nat Rev Drug Discov 2016;15:679-98. [Crossref] [PubMed]
  92. Jacobetz MA, Chan DS, Neesse A, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 2013;62:112-20. [Crossref] [PubMed]
  93. Amrutkar M, Aasrum M, Verbeke CS, et al. Secretion of fibronectin by human pancreatic stellate cells promotes chemoresistance to gemcitabine in pancreatic cancer cells. BMC Cancer 2019;19:596. [Crossref] [PubMed]
  94. Rhim AD, Oberstein PE, Thomas DH, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 2014;25:735-47. [Crossref] [PubMed]
  95. Nielsen MFB, Mortensen MB, Detlefsen S. Key players in pancreatic cancer-stroma interaction: Cancer-associated fibroblasts, endothelial and inflammatory cells. World J Gastroenterol 2016;22:2678-700. [Crossref] [PubMed]
  96. Sun Q, Zhang B, Hu Q, et al. The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer. Theranostics 2018;8:5072-87. [Crossref] [PubMed]
  97. Collins MA, Bednar F, Zhang Y, et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest 2012;122:639-53. [Crossref] [PubMed]
  98. Bijlsma MF, van Laarhoven HW. The conflicting roles of tumor stroma in pancreatic cancer and their contribution to the failure of clinical trials: a systematic review and critical appraisal. Cancer Metastasis Rev 2015;34:97-114. [Crossref] [PubMed]
  99. Catenacci DVT, Junttila MR, Karrison T, et al. Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer. J Clin Oncol 2015;33:4284-92. [Crossref] [PubMed]
  100. Winer A, Adams S, Mignatti P. Matrix Metalloproteinase Inhibitors in Cancer Therapy: Turning Past Failures Into Future Successes. Mol Cancer Ther 2018;17:1147-55. [Crossref] [PubMed]
  101. Grünwald B, Vandooren J, Gerg M, et al. Systemic Ablation of MMP-9 Triggers Invasive Growth and Metastasis of Pancreatic Cancer via Deregulation of IL6 Expression in the Bone Marrow. Mol Cancer Res 2016;14:1147-58. [Crossref] [PubMed]
  102. Kindler HL, Niedzwiecki D, Hollis D, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol 2010;28:3617-22. [Crossref] [PubMed]
  103. Hilmi M, Bartholin L, Neuzillet C. Immune therapies in pancreatic ductal adenocarcinoma: Where are we now? World J Gastroenterol 2018;24:2137-51. [Crossref] [PubMed]
  104. Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer. N Engl J Med 2012;366:2455-65. [Crossref] [PubMed]
  105. Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov 2019;18:197-218. [Crossref] [PubMed]
  106. Ene-Obong A, Clear AJ, Watt J, et al. Activated Pancreatic Stellate Cells Sequester CD8+ T-Cells to Reduce Their Infiltration of the Juxtatumoral Compartment of Pancreatic Ductal Adenocarcinoma. Gastroenterology 2013;145:1121-32. [Crossref] [PubMed]
  107. Hanahan D, Weinberg Robert A. Hallmarks of Cancer: The Next Generation. Cell 2011;144:646-74. [Crossref] [PubMed]
  108. Ying H, Kimmelman AC, Lyssiotis CA, et al. Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism. Cell 2012;149:656-70. [Crossref] [PubMed]
  109. Sousa CM, Kimmelman AC. The complex landscape of pancreatic cancer metabolism. Carcinogenesis 2014;35:1441-50. [Crossref] [PubMed]
  110. Li M, Zhang Y, Liu Z, et al. Aberrant expression of zinc transporter ZIP4 (SLC39A4) significantly contributes to human pancreatic cancer pathogenesis and progression. Proc Natl Acad Sci U S A 2007;104:18636-41. [Crossref] [PubMed]
  111. Liu M, Yang J, Zhang Y, et al. ZIP4 Promotes Pancreatic Cancer Progression by Repressing ZO-1 and Claudin-1 through a ZEB1-Dependent Transcriptional Mechanism. Clin Cancer Res 2018;24:3186-96. [Crossref] [PubMed]
  112. Li M, Zhang Y, Bharadwaj U, et al. Down-regulation of ZIP4 by RNA Interference Inhibits Pancreatic Cancer Growth and Increases the Survival of Nude Mice with Pancreatic Cancer Xenografts. Clin Cancer Res 2009;15:5993-6001. [Crossref] [PubMed]
  113. Nakamura T, Kuwai T, Kitadai Y, et al. Zonal Heterogeneity for Gene Expression in Human Pancreatic Carcinoma. Cancer Res 2007;67:7597-604. [Crossref] [PubMed]
  114. Cros J, Raffenne J, Couvelard A, et al. Tumor Heterogeneity in Pancreatic Adenocarcinoma. Pathobiology 2018;85:64-71. [Crossref] [PubMed]
  115. Collisson EA, Sadanandam A, Olson P, et al. Subtypes of Pancreatic Ductal Adenocarcinoma and Their Differing Responses to Therapy. Nat Med 2011;17:500-3. [Crossref] [PubMed]
  116. Daemen A, Peterson D, Sahu N, et al. Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors. Proc Natl Acad Sci U S A 2015;112:E4410-7. [Crossref] [PubMed]
  117. Heestand GM, Kurzrock R. Molecular landscape of pancreatic cancer: implications for current clinical trials. Oncotarget 2015;6:4553-61. [Crossref] [PubMed]
  118. Chang DK, Grimmond SM, Evans TRJ, et al. Mining the genomes of exceptional responders. Nat Rev Cancer 2014;14:291-2. [Crossref] [PubMed]
  119. DeLeon TT, Salomao MA, Aqel BA, et al. Pilot evaluation of PD-1 inhibition in metastatic cancer patients with a history of liver transplantation: the Mayo Clinic experience. J Gastrointest Oncol 2018;9:1054-62. [Crossref] [PubMed]
  120. DeLeon TT, Zhou Y, Nagalo BM, et al. Novel immunotherapy strategies for hepatobiliary cancers. Immunotherapy 2018;10:1077-91. [Crossref] [PubMed]
  121. Neoptolemos JP, Kleeff J, Michl P, et al. Therapeutic developments in pancreatic cancer: current and future perspectives. Nat Rev Gastroenterol Hepatol 2018;15:333-48. [Crossref] [PubMed]
  122. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010;467:1114-7. [Crossref] [PubMed]
doi: 10.21037/apc.2019.09.01
Cite this article as: Bijou I, Wang J. Evolving trends in pancreatic cancer therapeutic development. Ann Pancreat Cancer 2019;2:17.