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2021 top ten targets and drugs for precision treatment of pancreatic cancer.
2021 top ten targets and drugs for precision treatment of pancreatic cancer. The most complete summary is here!
Pancreatic cancer can be called the “king of cancer”. Its early diagnosis is difficult, its malignancy is high, its efficacy is poor, its mortality rate is high, and its median overall survival is less than one year. It is the third leading cause of cancer death in the world.
In recent years, the incidence of pancreatic cancer has continued to increase worldwide. It is estimated that pancreatic cancer will become the second most common cause of cancer death in 2040.
In recent years, as the basis of precision treatment, genetic testing has made significant progress in the treatment of a variety of solid tumors. However, due to the complexity of the molecular classification of pancreatic cancer and the heterogeneity of tumors, the clinical significance of most gene mutation information is still not clear, which limits the application of targeted therapy based on genetic testing in the clinical diagnosis and treatment of pancreatic cancer.
POLO Study: Start a new journey of precision treatment of pancreatic cancer
The 2019 American Society of Clinical Oncology (ASCO) annual meeting announced the most important POLO study in the field of pancreatic cancer. This study is the first large-scale phase III clinical study based on biomarkers for precise treatment of advanced pancreatic cancer.
Preliminary results showed that metastatic pancreatic cancer patients with germline BRCA gene mutations (gBRCAm) received platinum-based first-line chemotherapy better than wild-type patients; based on the better safety of PARP inhibitors, this study will target the PARP of gBRCAm The inhibitor olaparib was used in the maintenance treatment of pancreatic cancer. The results showed that compared with placebo, olaparib as a maintenance treatment drug can significantly prolong the progression-free survival of patients with metastatic pancreatic cancer (7.4 months vs. 3.8 months, HR = 0.53, P = 0.004).
Based on this research, olaparib was approved by the U.S. Food and Drug Administration (FDA) for the first-line maintenance treatment of patients with metastatic pancreatic cancer carrying gBRCAm.
This is an important sign that pancreatic cancer has entered the era of precision treatment.
So, in addition to BRCA mutations, can pancreatic cancer patients benefit from targeted therapies corresponding to other oncogene mutations?
In recent years, a large number of studies have found that the main genetic changes in pancreatic cancer cover about more than 60 genes in 12 core pathways. Among them, KRAS, TP53, CDKN2A and SMAD4 are the most common somatic mutations in pancreatic cancer.
90% of patients have KRAS mutations, and 25% to 80% of patients have TP53, CDKN2A, and SMAD4 mutations. In addition, some genes such as hENT, SPARC, PDX1, STK11, ATM, BRAF, NTRK, EGFR, MSI-H/dMMR, Her-2, etc. have also been confirmed to play an important role in the treatment of pancreatic cancer.
KRAS mutation: AMG510
Although KRAS mutations are common, targeted drugs are lacking. KRAS G12C is a specific submutation of KRAS, which accounts for 2% of pancreatic cancers.
After 30 years of research, AMG 510 is the first KRAS G12C inhibitor to reach the clinical stage! Studies have shown that AMG 510 is well tolerated in advanced KRAS G12C mutant solid tumors. Among 9 patients (without pancreatic cancer), 6 patients have stable disease and 1 patient has partial remission. At present, the US FDA has approved AMG 510 for KRAS G12C positive non-small cell lung cancer and colorectal cancer. The AMG510 opened a historic gap, and it also gave us the hope of breaking through pancreatic cancer.
In addition, basic research has found that the combination of autophagy inhibitor hydroxychloroquine and MAPK inhibitor trametinib can slow tumor growth and prolong survival in mice transplanted with human pancreatic tumors with KRAS mutations. The effect of this combination therapy was also confirmed in a patient with advanced pancreatic cancer. Within 2 months, the level of the pancreatic cancer marker CA19-9 decreased by 95%; after 4 months, the patient’s tumor size decreased. 50%.
NTRK fusion: larotinib or emtratinib
NTRK fusion gene accounts for about 0.34% of the pancreatic cancer population, and multiple TRK inhibitors are currently under clinical research.
In the NAVIGATE study, the remission rate of Larotrectinib for NTRK fusion patients (55 cases in total) reached 75%, including 1 case of pancreatic cancer (partial remission). In addition, the STARTRK-2 study evaluated the efficacy of Entrectinib. In a subgroup analysis, 3 patients (2 cases with TPR-NRTK fusion mutation, 1 case with SCL4-ROS1 fusion mutation) received Entrectinib Partial remission was achieved in all cases of tinib treatment.
In 2018, larotinib became the first pan-tumor tissue small molecule targeted drug approved by the FDA for NTRK fusion. In August 2019, Entratinib was also approved by the FDA as a NTRK/ROS1 fusion regardless of tumor type. Small molecule targeted drugs.
Immune checkpoint inhibitors have achieved amazing results in multiple cancers. In pancreatic cancer, the PD-1 monoclonal antibody Pembrolizumab (Pembrolizumab) has been approved for use in MSI-H/dMMR tumors. MSI/MMR testing should be considered in the second-line treatment of patients with severely metastatic pancreatic cancer.
In addition, anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) inhibitors and anti-programmed cell death receptor 1 (programmed cell death protein 1, PD-1) inhibitors combined with standard gemcitabine chemotherapy Clinical trials are ongoing.
EGFR mutation: Erlotinib
30%-89% of pancreatic cancers have EGFR overexpression. In a phase III, double-blind, placebo-controlled clinical study, 569 patients with advanced or metastatic pancreatic cancer were randomized to receive erlotinib combined with gemcitabine and gemcitabine monotherapy. The overall survival and progression-free of patients in the combined treatment group The survival time was significantly improved. The median survival time was 6.24 months, and the 1-year survival rate was 23%; the median survival time of the control group was 5.91 months, and the survival rate was 17%.
VEGFR is highly expressed in more than 90% of pancreatic cancers and is involved in a variety of angiogenesis processes, including vascular penetration, endothelial cell proliferation, migration and survival. A phase II clinical study showed that sunitinib for maintenance treatment of metastatic pancreatic cancer can improve the prognosis.
Notch access: MK-0752
Both Notch ligands and receptors are highly expressed in pancreatic cancer tissues. The Notch pathway can induce epithelial-mesenchymal transition (EMT) to play an important carcinogenic role in pancreatic carcinogenesis.
At present, most studies on NOTCH pathway inhibitors such as Demcizumab, Tarextumab and RO4929097 have been negative. A phase I multi-center study from the United Kingdom showed promising results. The study included 44 patients with metastatic pancreatic cancer who were treated with gemcitabine and MK-0752 as first-line or second-line treatment. One patient achieved a definite partial remission. 13 The patient has stable disease.
MEK mutation: trametinib
Changes in the structure of MEK and its expression level are related to the occurrence of tumors and other diseases. At present, a variety of MEK inhibitors have been discovered, and some of them have been used in the treatment of tumors.
A randomized, double-blind, phase II trial evaluated the efficacy of gemcitabine plus trametinib in 160 patients with metastatic pancreatic cancer, and found that compared with gemcitabine plus placebo group, the overall survival of patients (8.4 months vs 6.7 Months) and progression-free survival (16.1 weeks vs 15.1 weeks) were not statistically significant; and clinical trials of other MEK1/2 inhibitors such as Selumetinib also ended in failure.
Another phase I/II clinical study (NCT02703571) evaluating the efficacy of trametinib combined with ribosomes in locally advanced pancreatic cancer or metastatic pancreatic cancer is ongoing.
IGF mutation: Ganitumab
Ganitumab is an anti-IGF1R monoclonal antibody that blocks the binding of IGF-1 and IGF-2 to their receptors. A phase II clinical study evaluated the safety and efficacy of gemcitabine combined with Ganitumab in the treatment of metastatic pancreatic cancer, and found that compared with the gemcitabine combined with placebo group, the treatment group tolerated the treatment well and achieved a longer overall survival This is the only clinical trial with positive results so far.
mTOR inhibitors: everolimus and temsirolimus
The main mTOR inhibitors currently used in clinical practice are everolimus and temsirolimus. A phase II study evaluated the efficacy of everolimus monotherapy in patients with metastatic pancreatic cancer resistant to gemcitabine, but the clinical efficacy was not obvious. Another phase I/II study from the Greek Cancer Collaboration Group used gemcitabine and temsirolimus in locally advanced pancreatic cancer or metastatic pancreatic cancer to no avail.
Although the research on pancreatic cancer-related genes, molecular pathways and other mechanisms has gradually intensified in recent years, the currently available genomic data has become the basis for the development of biomarker-driven clinical trials, but currently very few targeted drugs have been approved, such as TP53, There are no effective targeted drugs for common mutations such as CDKN2A and SMAD4.
As more and more new potential therapeutic targets are discovered, a large number of studies are needed to verify the clinical application prospects of new biomarkers.
(source:internet, reference only)