Introduction of pancreatic cancer Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. In recent years, the incidence of PDAC is on the rise, and it is expected to become the second leading cause of cancer-related deaths by 2030, with poor prognosis. More than 80% of patients are in advanced stage at the time of diagnosis, and the overall 5-year survival rate is about 7%. Systemic chemotherapy is the main treatment for locally advanced (LAPC) and metastatic (MPC) patients. Gemcitabine has been treated with single drug for more than 20 years, and the latter line FOLFIRINOX and paclitaxel/Gemcitabine show better efficacy. However, targeted therapy plays a limited role in the treatment of PDAC, so there is an urgent need for new and more meaningful treatment methods.
Classification of pancreatic cancer subtypes Some epigenetic studies have proved that PDAC shows definite molecular heterogeneity. According to the current research, its molecular subtypes can be divided into four types according to different biological characteristics and prognosis correlation, namely, "squamous, pancreatic progenitor cells, immunogenicity, abnormally differentiated internal and external secretion or ADEX", which is classified based on the differential expression of important transcription factors and downstream targets of pancreas in lineage differentiation. Recently, the cancer genome research network has carried out genome research on PDAC, and combined with the comprehensive characterization of PDAC transcription/proteomics, two main subtypes have been identified: "basal-like/squamous" and "classic/pancreatic progenitor cells". Squamous subtypes mainly involve inflammation, hypoxia, metabolism, TGF-β signaling, activation of MYC pathway, autophagy, mutation of TP53 and KDM6A, transcription of TP63 (δ ΔNp63), etc. Squamous subtypes are considered as independent adverse prognostic factors. Pancreatic progenitor cell subtype is characterized by high-level transcription in pancreatic endoderm. PDX1 is one of the main transcriptional regulators in the formation of all pancreatic cell types, which plays a carcinogenic role. In addition, the expression of pancreatic cancer gene KRAS also led to the increase of PDX1 expression.
Molecular Signaling Pathways/Important Targets of Pancreatic Cancer Many classical tyrosine kinase receptors play an important role in pancreatic cancer, including epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), insulin-like growth factor receptor (IGFR), tropomyosin receptor kinase (TRK), vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). Other signal pathways include WNT/β-CATENIN, NOTCH, ROBO/SLIT, etc.
Potential targets and drugs for treating pancreatic cancer
NO.1 EGFR
Over 90% of PDAC detected EGFR overexpression, which played an important role in the recurrence and liver metastasis of PDAC. Clinical data suggest that EGFR upregulation may be related to more malignant tumor behavior and higher postoperative recurrence rate.
NO.2 FGF/FGFR
The fibroblast growth factor (FGF)/FGFR pathway plays a key role in the advanced stage of PDAC. FGFR1 and FGFR2 are over-expressed in PDAC, which are related to the stage and short survival time of advanced tumor. At the same time, the increase of FGF and FGFR levels in tumor tissues is related to the up-regulation of inducible nitric oxide synthase (iNOS) and the nitration of tyrosine protein, which proves to some extent that oxidative stress will participate in the PDAC process mediated by FGF pathway.
NO.3 IGF/IGFR
The high expression of insulin-like growth factor -1(IGF-1) and IGF1R is related to the deterioration degree and short survival time of PDAC, and the co-expression of IGF1R and EGFR is significantly related to the poor survival rate of PDAC. In addition, the serum IGF-1 content of PDAC patients is very high, and it can combine with insulin-like growth factor binding protein (IGFBPs). Recent studies have shown that high IGF-1/ low IGF-BP-3 concentration may be related to high risk, rapid progression and poor prognosis of PDAC.
NO.4 TRK
TRK gene fusion can lead to activation of downstream pathway, activation and proliferation of tumor cells. This situation and ROS1 fusion are relatively rare in pancreatic cancer, but there is no standard statistics on the actual incidence. The study of 47 resected PDAC samples showed that TRK receptor expression increased by 66% compared with normal adjacent tissues.
NO.5 VEGF/VEGFR
Vascular endothelial growth factor VEGF (polypeptide) can promote the proliferation of endothelial cells by binding VEGFR-1 and VEGFR-2. It is reported that the high expression of VEGF mRNA in PDAC samples is related to high microvessel density and disease progression.
NO.6 WNT/β-catenin
Wnt/β-catenin pathway is involved in many cell functions, such as stem cell regeneration. Abnormal activation of Wnt pathway occurs when PDAC exceeds 65%. Recent studies have shown that activation of Wnt signal can easily lead to malignant development of PDAC.
NO.7 NOTCH
There is evidence that Notch plays an important role in carcinogenesis of pancreatic tumors. It is found that Notch signaling pathway can directly up-regulate Snail-1 and Slug, thus inducing epithelial-mesenchymal transition (EMT).
NO.8 ROBO/SLIT
ROBO/SLIT is related to cell adhesion, proliferation and survival. About 1/3 of PDAC patients showed mutation of SLIT-ROBO gene, which was often masked by methylation.
NO.9 TGF-β
TGF-β has the function of tumor suppressor gene, but it can promote angiogenesis and epithelial-mesenchymal transformation of cancer cells, and is one of the most important EMT inducing factors; TGF-β signal transduction is completed by transcription regulation of a series of target genes associated with SMAD2/3/4.
NO.10 Hh
Hh signaling pathway plays a key role in embryonic development and adult tissue maintenance. Its imbalance is closely related to tumorigenesis, and its overexpression is found in 70% of PDAC, thus promoting tumor growth and metastasis. Importantly, there is no overexpression of sHh ligand in healthy pancreas. In addition, some reports indicate that activation of Hh pathway can induce stem cell markers and participate in EMT activation.
NO.11 NRG1
NRG1 is a ligand interacting with ERBB3 and ERBB4 tyrosine kinase receptors, which can stimulate downstream signaling pathway. In PDAC, NRG1 fusion can act as a carcinogen driver, resulting in higher expression of NRG1-EGF domain and increased affinity with ERBB2/ERBB3 receptor complex. According to the latest data, ERBB inhibitors (such as afatinib and erlotinib) have obvious curative effect in PDAC patients with NRG1 rearrangement.
Latest clinical trial progress of target
NO.1 MEK inhibitor
Trametenib, a selective MEK1/2 inhibitor, inhibits MEK-dependent ERK phosphorylation and MEK1/2 activation by inhibiting Raf phosphorylation of MEK on S217. A randomized, double-blind Phase II clinical trial evaluated the efficacy of "gemcitabine+trimetinib" VS "gemcitabine+placebo" in 160 MPC patients. The results showed that there was no significant difference in OS and PFS between the groups. At present, the clinical trial worth looking forward to is "ribocilib+trimetinib" (NCT02703571) to evaluate the efficacy in LAPC or MPC. In addition, a phase II clinical trial of selumetinib is underway.
NO.2 IGFR inhibitor
Ganitumab is a monoclonal antibody against IGF1R, which can prevent IGF-1 and IGF-2 from binding to their receptors. A phase II randomized trial evaluated the efficacy of gemcitabine+Ganitumab vs gemcitabine+conamumab vs gemcitabine+placebo in 125 MPC patients. the results showed that OS and PFS in ganitumab group were significantly improved. Another Phase II randomized/double-blind/placebo-controlled trial evaluated the efficacy of "nab- paclitaxel/gemcitabine+Isiratumab" vs "Nab-paclitaxel/gemcitabine", and the results showed that there was no significant difference between mOS and mPFS.
NO.3 mTOR inhibitor
A phase II clinical evaluation of the efficacy of everolimus alone in the treatment of gemcitabine refractory MPC patients, although well tolerated, but the clinical efficacy is not obvious. In another phase I/II study, patients with LAPC and MPC were given gemcitabine plus temsirolimus. Although the side effects were controllable, it did not show obvious clinical efficacy.
NO.4 TRK inhibitor
Encouraging results have been obtained in the experiment of exploring TRK inhibitors. In 2018, a study re-enrolled 55 patients who had been enrolled in the larotrectinib treatment program: I entered the composition, I/II included children, and II included adults and adolescents; These patients have a variety of solid tumors involving TRK positive, and the only PC patient showed partial response, but unfortunately failed to achieve the expected PFS. Two other Phase I studies evaluated the safety and efficacy of Entretinib in different solid tumors (including PC). The results showed that Entretinib was well tolerated and ORR reached 100% in TRK-related solid tumors.
NO.5 NOTCH inhibitor
A variety of drugs targeting NOTCH pathway were studied in PDAC patients, such as anti-DLL4 antibody demcizumab, Notch2/3 receptor inhibitor tarextumab；; Two γ -secretase inhibitors RO4929097 and MK-0752. A double-blind/three-arm/randomized Phase II clinical study showed that "gemcitabine +nab- paclitaxel+placebo" vs "gemcitabine+paclitaxel +demcizumab" were used for the first-line treatment of MPC patients. The results showed that the demcizumab group was well tolerated, but there was no significant difference between mPFS and mOS. Two other phase II clinical trials (tarextumab and RO4929097) did not give positive clinical data.
NO.6 TGF-β inhibitor
Galunisertib, the first effective oral inhibitor of type I TGF-β receptor (ALK5); An Ib/II multicenter clinical trial to evaluate the efficacy of Galunisertib in patients with LAPC and MPC was divided into "gemcitabine+Galunisertib" vs "Gemcitabine+placebo". The results showed that mOS of Galunisertib group was 8.9 months, while that of placebo group was 7.1 months. In another study, phase I of the drug TGF-β inhibitor, PD-L1 monoclonal antibody Durvalomab (NCT 02734160) is underway.
NO.7 Hn inhibitor
IPI-926, a potential SMO transmembrane protein inhibitor; A multicenter Ib clinical study used FOLFIRINOX and IPI-926 together to evaluate the efficacy of LAPC and MPC patients. The results showed that ORR was 67%, and the level of CA19-9 in patients receiving IPI-926 maintenance treatment (even if FOLFIRINOX was stopped) showed a decrease. Unfortunately, another phase II trial (IPI-926+ gemcitabine) had poor clinical efficacy, which led to the early closure of the trial.
NO.8 PARP inhibitor
The data of a phase II study showed that the PARP inhibitor olaparib could control the condition of 23 patients with BRCA1/2 mutant PDAC. Another phase III POLO trial (international multicenter/randomized/double-blind/placebo-controlled) proved that olaparib can continue to maintain the treatment after 16 weeks of first-line platinum chemotherapy, and it has obvious effect (7.4 months vs3.8 months) compared with placebo-controlled, and has better safety. Another clinical trial (RUCAPANC) studied the efficacy and safety of rucaparib in refractory BRCA1/2 mutant LAPC and MPC. The results showed that 4 of 19 patients were relieved, and the disease control rate was 31.6%. Other PARP inhibitors, such as Veliparib, are also in phase II clinical practice for LAPC and MPC.
Attached table: the latest clinical progress of targeted drugs for pancreatic cancer
Summary
Although the development of drugs for pancreatic cancer has been going on all over the world, exciting information has not yet been obtained, which is quite similar to the feeling brought by the development of drugs for Alzheimer's disease.
At present, the conventional treatment of pancreatic cancer is still based on the first-line treatment of cytotoxic drugs, and the prognosis is very poor, and all indicators are frustrating. The development of targeted drugs has been in progress, but only erlotinib approved more than ten years ago has been included in the guidelines, and hundreds of other tinib drugs have not made obvious achievements (PARP inhibitors are the current focus). In recent years, the hot immunotherapy of PD-1/PD-L1 monoclonal antibody has encountered great difficulties for pancreatic cancer with complex microenvironment. In a word, the discovery and optimization of pancreatic cancer drugs are still difficult!
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