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Pancreatic cancer: The current status and future of personalized treatment
Pancreatic cancer: The current status and future of personalized treatment. Pancreatic cancer (PC) is an aggressive disease with a high incidence, accounting for approximately 3% of all newly diagnosed cancers in the United States and Europe. Up to 80% of patients have local progress or metastasis at the time of onset, and the prognosis is poor. Only 4-9% of patients can achieve a 5-year survival period.
The extremely complex genetic changes of PC have a profound impact on shaping the tumor microenvironment, thereby promoting tumor growth, drug resistance and immune escape mechanisms. Although the field of cancer treatment has undergone profound changes, chemotherapy is still the main method of PC treatment. Olaparib is the first drug that uses biomarkers to select populations to show significant advantages, opening the door to personalized treatment.
Although there are a large number of targeted drugs or immunotherapy studies that have failed to prove that they are superior to standard chemotherapy regimens, there are still some drugs that have shown good application prospects, and extensive clinical studies are currently underway, including immune checkpoint inhibitors, tyrosine Inhibitors of amino acid kinases and drugs that target metabolic pathways or the tumor microenvironment.
Molecular characteristics of pancreatic cancer
The molecular characteristics of PC show highly complex characteristics. High-frequency gene mutations in PC include KRAS (93%), TP53 (72%), CDKN2A (30%), SMAD4 (32%), RNF43 (7%), ARID1A (6%), TGF-βR2 (5%), GNAS (8%), RREB1 (5%) and PBRM1 (4%). In addition, other mutations with lower frequency were also found through joint analysis. The expansion of GATA6, ERBB2, KRAS, AKT, and MYC, and the loss of CDKN2A, SMAD4, ARID1A, and PTEN are the most common somatic aberrations.
Germline mutations of known susceptibility genes, such as BRCA1/2, PALB2, TP53, CDKN2A, ATM, PRSS1, STK11, MLH1, MSH2, MSH6, PMS2 and EPCAM, were observed in 8% of patients, in KRAS wild-type tumors Significantly enriched in. These tumors often have mutations in the RAS-MAPK pathway, leading to their over-activation.
In addition, the protein expression profiles in these samples show that the mTOR pathway is highly active. The analysis of DNA methylation, combined with mRNA expression data, showed hypermethylation of several genes, especially genes encoding tumor suppressor genes or regulatory factor miRNAs, which led to subsequent epigenetic silencing.
Based on the characteristics of PC molecular biology and targeted therapy, nearly 25% of PC patients may be candidates for precision medicine. Many genomic changes can be treated with specific drugs.
Poly ADP ribose polymerase inhibitors (PARPis) use the concept of synthetic lethality, that is, inactivating mutations in two or more different genes that are critical to cell integrity, thereby inducing cell death. The PARP-1 gene is involved in several stages of the DNA repair mechanism, especially in the prevention of single-strand breaks (SSB). Therefore, PARPis leads to the accumulation of unrepaired SSBs, which are eventually converted to DSBs. In this case, concomitant homologous recombination repair (HRR) defects, such as BRCA1/2 inactivating mutations, increase the tendency of synthetic lethality.
Olaparib is the only PARPi approved in PC. A phase II clinical trial evaluated the efficacy of Olaparib monotherapy (400 mg twice daily) in patients with recurrent pancreatic cancer with germline BRCA1/2 mutations. Twenty-three PC patients who had received gemcitabine treatment were included in the study. The objective response rate (ORR) was 21.7% (95% CI, 7.5-43.7), and stable disease (SD) was observed for ≥8 weeks in 34.8% of the patients. The median progression-free survival (PFS) was 4.6 months, and the overall survival (OS) was 9.8 months.
Based on the results of a randomized, double-blind, placebo-controlled phase III POLO clinical trial, Olaparib was approved in PC. A total of 154 patients with metastatic PC and BRCA1/2 germline mutations were randomized to receive olaparib monotherapy (300 mg, twice daily) or placebo as maintenance therapy during first-line platinum chemotherapy, compared to placebo In the control group, the median PFS of the Olaparib group was significantly prolonged (7.4 months and 3.8 months, respectively; HR 0.53; CI 95% 0.35-0.82; p=0.004), and the average OS between the groups was similar.
Veliparib is an oral PARPi, compared with Olaparib, PARP inhibitory ability is lower. A single-arm phase II trial evaluated the efficacy in previously treated stage III/IV PC patients with germline BRCA1/2 or PALB2 mutations. Unfortunately, there is no record of tumor response, but SD has been observed to last ≥4 months in 25% of patients.
Recently, in a two-arm phase II trial, veliparib was added to the combination chemotherapy of cisplatin and gemcitabine. It was evaluated in 50 patients with stage III/IV untreated PC and germline BRCA1/2 or PALB2 mutations. Both groups showed high anti-tumor activity. The disease control rate (DCR) of the combined group was 100%, compared with 78.3% in the chemotherapy-only group (p=0.02), but there was no significant difference in ORR (74.1% and 65.2% in the combination group and the chemotherapy group; p=0.055). On the contrary, the hematological toxicity of the combination group increased significantly.
The single-arm phase II RUCAPANC clinical study investigated the efficacy and safety of oral PARPi-rucaparib (600 mg, twice daily) in 19 patients with locally advanced/metastatic PC, these patients containing germline or somatic BRCA1/2 mutation. Rucaparib showed acceptable toxicity characteristics with an ORR of 15.8% and a DCR of 31.6%.
In another single-arm phase II clinical trial, rucaparib was studied as a maintenance monotherapy and included patients with advanced pancreatic cancer who had BRCA1/2 or PALB2 mutations. Similarly, the drug showed encouraging anti-tumor activity and safety, with a median PFS of 9.1 months, an ORR of 36.8%, and 89.5% of patients achieved DCR ≥ 8 weeks.
Talazoparib is a new and effective oral PARPi. In a dose-escalation phase I trial, Talazoparib showed good tolerability and anti-tumor activity in patients with advanced solid tumors and germline BRCA1/2 mutations, with an ORR of 20% in 20 patients with advanced PC.
There are many ongoing studies of PARPi used alone or in combination with different drugs to treat patients with advanced PC.
The RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) cascade is closely related to the pathogenesis of PC, especially in tumors containing RAS or BRAF mutations.
Trametinib is an oral selective mitogen/extracellular signal-related kinase (MEK) 1/2 tyrosine kinase inhibitor. In a phase 1 clinical trial, it showed moderate anti-tumor activity as a monotherapy for PC. Subsequently, in a randomized phase II clinical trial, the combination therapy with gemcitabine was compared with gemcitabine monotherapy. However, there was no difference between the two groups in terms of median OS, PFS, and ORR. The results of another MEK1/2 inhibitor, pimasertib, were also disappointing.
Among the possible drug resistance mechanisms, the epidermal growth factor receptor (EGFR) is over-activated to prevent cell apoptosis through feedback activation of the AKT-PI3K pathway. This concept gave rise to the idea of double blocking MEK and EGFR. A single-arm phase II trial tested the combined effects of the EGFR inhibitor erlotinib and the MEK inhibitor selumetinib in 46 patients with advanced PC who had undergone multiple treatments. However, the effect was minimal and there was no objective response. Only 41% of patients had SD duration ≥ 6 weeks, and carcinoembryonic antigen (CEA) levels decreased (38%).
After the failure of this trial, in a phase II trial, the dual-blocking strategy focused on the downstream targets of MEK and AKT. The trial used selumetinib combined with MK-2206 (a selective pan-AKT inhibitor) or modified FOLFOX (Oxaliplatin and fluorouracil) are evaluated in patients with PC refractory to metastatic chemotherapy. Similarly, the combination therapy did not show the expected efficacy, and the median OS and PFS of the experimental group were shorter than those of the control group.
EGFR is a transmembrane tyrosine kinase receptor, and overexpression of EGFR often occurs in advanced PCs. EGFR mutation is a predictor of non-small cell lung cancer, but it is not clear whether the same state exists in PC. In a phase III clinical trial, gemcitabine combined with the EGFR inhibitor erlotinib was tested in 569 patients with advanced PC. Median OS (6.24 months vs 5.91 months; HR0.82; CI 95% 0.69-0.99; p=0.038) and PFS (3.75 months vs 3.55 months; HR 0.77; CI 95% 0.64 -0.92; p=0.004) are slightly prolonged, but there is a significant difference.
In order to explore the further effects of erlotinib, the phase III LAP07 clinical trial recruited 449 patients with advanced PC who received chemotherapy or radiotherapy and chemotherapy in the previous randomization phase, and then treated with gemcitabine alone or in combination with erlotinib. The results were disappointing. There was no difference between the two groups, leading to an invalid interim analysis and termination of the trial.
A subsequent trial analyzed the efficacy of combination therapy with gemcitabine and erlotinib in 88 patients with metastatic PC. These patients contained EGFR mutations. The mutations involved exon 20 (50%) and exon 19 (37%). ), exon 21 (10%) and exon 18 (3%). Compared with the chemotherapy alone group, the combined administration group improved in either median PFS (3.8 months vs. 2.4 months; p<0.001) or OS (7.2 months vs. 4.4 months; p<0.001). Patients with EGFR mutations benefited the most from combination therapy. Compared with EGFR wild-type patients, median PFS (5.9 months vs 2.4 months; p=0.004) and OS (8.7 months vs 6.0 months; p=0.044 ) Is longer. The most common mutation is L778P in exon 20, which accounts for 24% of all mutations.
In addition, for monoclonal antibodies to EGFR, a recent meta-analysis evaluated four randomized controlled trials testing cetuximab in patients with advanced PC, and the results showed no significant differences in OS, PFS, or ORR compared with the control group.
Another EGFR-targeting humanized monoclonal antibody nimotuzumab and gemcitabine were tested in the first-line treatment of 18 patients with advanced PC. Results ORR was 11.1%, DCR was 55.6%, median PFS and OS were 3.71 months and 9.29 months, respectively. Recently, in a two-arm clinical phase IIb trial (NCT00561990), in 186 patients with advanced KRAS wild-type PC, the combination of nimotuzumab and gemcitabine as the first-line treatment improved the 1-year survival rate (34% vs 19 %, HR 0.69; P=0.03).
KRAS targeting agents
Kirsten rat sarcoma virus oncogene homolog (KRAS) is a subtype of RAS family proteins and is a small cytoplasmic protein with GTPase activity. KRAS is the most common genomic alteration in PC, accounting for more than 90% of cases. Mutations that activate this oncogene can promote cell growth, proliferation and survival, and play an important role in the process of carcinogenesis. 98% of KRAS mutations occur in exon 2 (codon 12), G12D and G12V are the most common mutations, followed by G12A/C/S (2% each) and G12L/F (<1%).
Due to the prevalence of KRAS mutations in PC, targeting KRAS or its downstream pathways may be crucial in PC. However, the development of effective KRAS inhibitors is one of the most challenging goals in oncology research. Encouragingly, several small KRAS-binding molecules (such as Sotorasib, Adagrasib) have recently been developed to show good anti-tumor effects in various cancer types. This brings hope to a small number of PC patients with G12C mutations.
Currently, there are multiple ongoing clinical trials that are evaluating multiple strategies for KRAS mutant PCs.
Targeting the tumor microenvironment
PC has a unique tumor microenvironment, which is characterized by the existence of a dense and heterogeneous matrix, which is mainly composed of cells with different functions, such as fibroblasts, myofibroblasts, immune cells and pancreatic stellate cells, blood vessels, and extracellular Matrix and soluble protein. These components work together to promote tumor growth and metastasis, and exert high static pressure in tumor blood vessels, which may limit cell transport, especially immune cell transport. Therefore, targeting the tumor microenvironment may be an effective strategy to overcome drug resistance and promote PC immune infiltration.
Hedgehog (Hh) signaling is an important pathway in the process of embryogenesis. It is composed of Sonic Hh (SHh), IndianHh and Desert Hh, receptor proteins PTCH 1, PTCH 2, and SMO, and transcription factors (Gli1, Gli2, and Gli3). The Hh pathway plays a key role in the occurrence of PC. The maintenance of Hh signal is conducive to abnormal proliferation, and SHh activates pancreatic stellate cells, and promotes connective tissue proliferation and hypoxic microenvironment by producing cytokines, chemokines, growth factors and excessive extracellular matrix. The resulting microenvironment is conducive to tumor occurrence and development, as well as tumor invasion, metastasis, immune escape and treatment resistance.
In a phase Ib/II trial, the combination of SMO antagonist Vismodegib and gemcitabine was evaluated. 106 patients with previously untreated PC were included, but it failed to improve the efficacy of chemotherapy drugs compared with placebo .
In addition, another SMO antagonist, saridegib, was used in combination with 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in a phase 1 trial, and was subsequently used in combination with gemcitabine in a phase 2 trial. Both trials were conducted in previously untreated patients with advanced PC. Although the phase I trial reported early evidence of anti-tumor activity and acceptable safety, the phase II study showed the harmful effects of the experimental drug, leading to the suspension of the trial after the initial analysis.
Polyethylene glycol hyaluronidase alpha (PEGFH20) has been shown to degrade hyaluronic acid in TME in preclinical animal models, thereby increasing drug delivery to cancer cells. PEGPH20 was studied in a phase II trial that included 279 previously untreated PC patients who were randomly divided into protein-bound paclitaxel and gemcitabine (with or without PEGPH20). The median PFS in the experimental group increased significantly (p=0.049), and the ORR increased (45% vs 31%), but the benefit of OS was not recorded.
TGF-β is another potential target of PC because it can promote cell growth, epithelial cell to mesenchymal cell transformation, extracellular matrix remodeling and immunosuppression. Galunisertib is a type I TGF-β receptor inhibitor that was used in combination with gemcitabine in a phase Ib/II trial as the first-line treatment for advanced PC. In the phase II part, 156 patients were randomly divided into two groups, one group received Galunisertib treatment and the other group received placebo treatment. The median OS was 7.1 months in the placebo group and 8.9 months in the galunisertib group, and the drug was well tolerated.
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is involved in the signal transduction of a variety of molecules, including cytokines, interleukins and growth factors. Humans have four JAK family members (JAK1, JAK2, JAK3 and TYK2) and seven STAT family members (STAT1-4, STAT5A, STAT5B and STAT6). JAK/STAT pathway often changes in cancer, mainly due to the up-regulation of STAT3 and STAT5A/B, which play an important role in cell proliferation, apoptosis, metabolic changes, EMT, and promotion of immunosuppressive response.
The oral STAT3 inhibitor Napabucasin showed good activity in a phase Ib/II trial involving 59 patients with metastatic PC, combined with protein-bound paclitaxel and gemcitabine. The DCR is 78%, including 2 CR (3.4%) and 26 PR (44.1%). The medians of PFS and OS were 7.1 months and 9.6 months, respectively. Among the 50 evaluable patients, DCR was 92.0%, ORR was 56%, and no dose-limiting adverse events occurred.
Based on these results, a randomized phase III study was started to evaluate the efficacy and safety of napabucasin combined with protein-bound paclitaxel and gemcitabine as the first-line treatment for patients with metastatic PC. Unfortunately, after an interim analysis, the trial was terminated due to ineffectiveness.
Ruxolitinib is a JAK1/2 inhibitor that was used in combination with capecitabine in two randomized phase III trials in patients with advanced PC who had disease progression after first-line treatment. After an interim analysis, the study was again terminated due to invalidity. Currently, itacitinib, a JAK1 inhibitor, is being used in combination with pembrolizumab for the evaluation of advanced solid tumors (including PC).
The tropomyosin receptor kinase (TRK) family includes three transmembrane protein receptors (TrkA, TrkB, and TrkC, encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively), which regulate many aspects of neuronal development and function. Chromosomal translocations involving NTRK1/2/3 genes result in constitutive activation and abnormal expression of TRK kinase.
Recently, specific targeted therapy for NTRK fusion-positive tumors has emerged. Larotretinib is a highly selective oral TRK inhibitor that has been tested in 3 single-arm clinical trials involving a total of 55 TRK fusion-positive cancer patients. The results are encouraging; the ORR is 75%, 71% of the patients still have a sustained response and 55% of the progression-free patients after 1 year. The only PC patient achieved PR, DOR and PFS did not.
Based on these results, in November 2018, the FDA approved Larotretinib for the treatment of adult and pediatric patients with NTRK fusion-positive tumors.
Targeting tumor metabolism
Cancer cells exhibit a large number of metabolic modifications, such as changes in pH homeostasis and related modifications of the ion transport system, which may be potential targets for treatment. In PC, mutations in genes that drive cell growth, such as KRAS, have been shown to alter metabolic pathways.
Devimistat is a selective inhibitor of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, these two enzymes are the key enzymes of the tricarboxylic acid cycle in tumor cells. Tricarboxylic acid represents a source of resistance to DNA damaging agents. Therefore, the use of devimistat may enhance the sensitivity of tumors to chemotherapeutic drugs (such as platinum derivatives). A phase I trial tested the efficacy and safety of the combination of devimistat and modified FOLFIRINOX in patients with metastatic PC. The ORR was 61%, including 3 CRs. Based on these results, a phase III trial of modified FOLFIRINOX combined with devimistat is currently being conducted in patients with metastatic PC.
Hydroxychloroquine as a potential anti-tumor drug comes from its inhibitory effect on autophagy. Autophagy can support the late growth of tumors through the catabolism of intracellular organelles and provide nutrients for tumor proliferation. A phase II trial used hydroxychloroquine as a single agent to treat patients with metastatic PC, but failed to demonstrate anti-tumor activity.
Another phase II trial evaluated the addition of hydroxychloroquine to gemcitabine/protein-bound paclitaxel as a first-line treatment for patients with advanced PC. The study failed to prove the benefit of hydroxychloroquine on OS, but compared with chemotherapy alone, the ORR of the experimental group was significantly improved (38.2% vs 21.1%, p=0.047).
Recently, a phase II study explored the addition of high-dose hydroxychloroquine to gemcitabine/protein-bound paclitaxel as a preoperative treatment for patients with resectable PC. The study proved that compared with the chemotherapy alone group, the pathological tumor response of the hydroxychloroquine plus chemotherapy group was significantly improved (p=0.00016). At present, there are still some trials in progress, the purpose is to evaluate the efficacy of different combinations of hydroxychloroquine in PC.
It is well known that PC is ineffective against immunotherapy, mainly due to immunosuppressive TME, which is characterized by a lack of high-quality tumor-infiltrating effector T cells and a heterogeneous dense matrix as a barrier to immune cell infiltration.
At present, the only potential target population for PC immunotherapy is the subgroup of patients with microsatellite high instability (MSI-H) tumors, in which the immune checkpoint inhibitor pembrolizumab has shown satisfactory ORR. However, this subgroup only represents a small percentage (less than 1%) of PC patients.
In a phase II trial, the anti-CTLA-4 monoclonal antibody ipilimumab was evaluated in 27 patients with locally advanced or metastatic PC, but there was no survival benefit. A recent phase II trial evaluated a dual immune checkpoint blocking strategy using anti-CTLA4 and anti-PD-L1 drugs, again without encouraging results. Subsequently, a combined strategy of standard chemotherapy (gemcitabine plus protein-bound paclitaxel) and addition of the PD-1 inhibitor pembrolizumab was evaluated in a phase Ib/II trial. The median OS and PFS were 9.1 months and 15.0 months, respectively. But the trial did not reach its primary endpoint, which was a CR rate of >15%. A recent phase II trial evaluated dual immune checkpoint blockade combined with first-line chemotherapy, and received durvalumab combined with tremelimumab combined with standard chemotherapy. Unfortunately, the addition of immune checkpoint inhibitors did not result in a significant median OS, PFS, or ORR improve.
The combination of ICI and tumor vaccines is also being explored. GVAX is a whole-cell vaccine composed of irradiated allogeneic PC cells that can secrete granulocyte-macrophage colony stimulating factor through genetic engineering, which seems to transform tumors from non-immunogenic to immunogenic. In addition, its administration resulted in the up-regulation of immune checkpoint molecules (such as PD-1 and PD-L1), indicating its potential synergy with ICI. In a phase II trial, ipilimumab plus GVAX appeared to produce a benefit in terms of median OS compared with ipilimumab alone, although it did not reach statistical significance.
Algenpantucel-L is an allogeneic PC vaccine consisting of two human PDAC cell lines (HAPa-1 and HAPa-2), which express α-galactose by using retrovirus to transfer mouse αGT gene. Algenpantucel-L was tested as an adjuvant treatment of chemotherapy and radiotherapy in 70 patients with PC resection. The addition of algenpantucel-L improved disease-free survival (DFS) and OS. However, subsequent phase III trials did not confirm the previous findings.
Indoleamine 2,3 dioxygenase (IDO) is a tryptophan catabolism enzyme, which plays a key role in the normal regulation of peripheral immune tolerance and immune therapy resistance mechanism. A phase I study showed that IDO inhibitor indoximod and gemcitabine/protein-bound paclitaxel combined chemotherapy have good anti-tumor activity. The ORR of 33 patients with metastatic PC was 37% (including 1 CR).
Chemokines and their receptor CCL2/CCR2 axis drive chemotactic resistance and immunosuppressive mechanisms in the tumor microenvironment. Therefore, CCR2 blockade may be a promising PC immunotherapy strategy. PF-04136309 is a CCR2 inhibitor, used in combination with FOLFIRINOX for marginally resectable and locally advanced PC patients, with an ORR of 49%. Recently, a phase Ib study tested the effect of PF-04136309 in combination with standard chemotherapy in 21 previously untreated patients with advanced PC. However, the anti-tumor activity is similar to that obtained by chemotherapy alone (ORR 23.8%), and relatively high (24%) pulmonary toxicity is observed, which raises concerns about the safety of this combination.
Currently, there are multiple ongoing clinical trials that are evaluating multiple strategies for immunotherapy to treat PC.
Compared with other types of tumors, there is little progress in the treatment of pancreatic cancer, and chemotherapy is still the main method of treatment. The approval of Olaparib maintenance therapy for BRCA mutant PC represents an encouraging achievement in the personalized treatment of such refractory diseases, and opens the door to the study of various drugs that have potential synergistic effects with PARPi, including Immunotherapy and tyrosine kinase inhibitors.
The emergence of new drugs, including NTRK inhibitors for NTRK fusion-positive tumors or pembrolizumab for MSI-H tumors and other therapies that have nothing to do with tumor types, ensure the implementation of genetic testing to find new treatments in different subgroups of PC patients Program. The molecular heterogeneity of PC may require a variety of treatment methods based on individual tumor characteristics.
In short, although there have been many disappointing results in the past, some investigative treatments have shown promising prospects, and these represent solid hope for the future of personalized medicine for PC.
(source:internet, reference only)