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9 New targets of anti-tumor drugs in 2023
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9 New targets of anti-tumor drugs in 2023
In the research and development of anti-tumor drugs, the continuous emergence of new targets is of great significance to the treatment of tumors, gradually realizing precision medicine methods, overcoming drug resistance, and expanding the therapeutic field.
This article will take stock of the newly discovered or new indications of anti-tumor drug targets in the past year.
01 New target for gastric cancer: claudin-18.2
claudin-18.2 (CLDN 18.2) is a tight junction protein widely present in gastric mucosa. Under normal circumstances, it is responsible for firmly connecting the adjacent gastric mucosal epithelial cells together, preventing the food and digestive juice in the stomach from leaking from the intercellular space into the internal environment of the human body.
However, during tumor development, CLDN 18.2 is widely expressed in a variety of gastrointestinal tumors and participates in tumor proliferation, differentiation and migration.
At present, a variety of drugs targeting CLDN 18.2 are under research at home and abroad. Zolbetuximab is the first drug targeting CLDN 18.2. The median progression-free survival of patients with advanced gastric cancer was extended by nearly 2 months to 10.61 months, and the median overall survival was extended from 15.54 months to 18.23 months when the combination of Zolbetuximab and mFLOFOX6 was compared with mFLOFOX6 chemotherapy alone. Both the risk of death and the risk of progression were reduced by 25%.
The drugs under research in China include TST001 independently developed by Transcent Group and the CAR-T therapy developed by Keji Pharmaceutical, named CT041, both of which have made positive progress.
02 Lung squamous cell carcinoma targets: mTOR
Non-small cell lung cancer has always been an important area of targeted therapy. At present, many targeted drugs can only benefit patients with lung adenocarcinoma, while another major lung cancer subtype – lung squamous cell carcinoma, only a small number of patients can receive targeted therapy. treat.
Sapanisertib achieved an objective response rate of 27% and a median progression-free survival of 8.9 months in patients with advanced refractory lung squamous cell carcinoma by targeting the mTOR molecule downstream of the KEAP1/NRF2 pathway.
Currently, Sapanisertib combined with PD-1 is being studied in the treatment of advanced NRF2-mutated lung squamous cell carcinoma.
03 New targets in prostate cancer: PI5P4Kα, TRABID, PODXL
(1) PI5P4Kα :
The phosphatidylinositol kinase family plays an important role in the occurrence and development of tumors, and is an important target for anticancer drug research.
On February 1, 2023, in an article published in Science Advances, researchers studied the function of phosphatidylinositol-5-phosphate-4-kinase (PI5P4K), and verified the effect of PI5P4Kα subtype on androgen receptor Effects on receptor (AR) signaling, a pathway that supports prostate cancer cell survival.
Study shows that androgen deprivation affects phosphatidylinositol content and increases intracellular phosphatidylinositol (4,5) diphosphate levels, suggesting regulation of phosphatidylinositol in prostate cancer metabolic stress adaptation during androgen deprivation become increasingly important. This study supports PI5P4Kα as a potential target to address the growing resistance problem in prostate cancer therapy.
(2) TRABID :
On March 31, 2023, a study published in Nature Communications proved that TRABID deubiquitinase can bind to 53BP1 and regulate the stability of 53BP1 at the double-strand break site. When TRABID was overexpressed in prostate cancer cells, the cancer cells showed high sensitivity to PARP inhibitors.
The study noted that TRABID promoted non-homologous end-joining repair but not homologous recombination by prolonging the presence of 53BP1 at double-strand break sites, suggesting that TRABID overexpression can be used to predict homologous recombination deficiency and PARP in prostate cancer An indicator of the therapeutic potential of an inhibitor.
(3) PODXL :
glycocalyx components and sialomucin pocalylin (PODXL) is a transmembrane protein whose elevated expression is associated with poor clinical outcome in tumors. In a Science Advances article published on February 3, 2023, it is reported that PODXL can act as a decoy receptor for galectin-3 (GAL3), leading to the release of PODXL-GAL3 interaction.
Experimentally, the researchers identified the molecular mechanisms that control the conversion of PODXL to pro-metastatic glycocalyx components and revealed that PODXL acts as a decoy receptor to alleviate the invasion-inhibitory effect of GAL3. Studies have demonstrated that changes in this level can be used to identify prostate cancer patients with high metastases and poor prognosis.
04 New targets for liver cancer: SULT1A1, PRRS35
(1) SULT1A1 :
An article published in Nature Cancer on March 13 this year introduced the research results of adult liver malignant tumors (including intrahepatic cholangiocarcinoma and hepatocellular carcinoma). This tumor is the second leading cause of cancer-related death worldwide. In this study, through high-throughput screening, proteomics and in vitro resistance models, the researchers identified a small molecule compound named YC-1 with selective activity against cell line subsets from two liver cancer types .
The data demonstrated that this selective activity is associated with the expression of the liver-intrinsic cytoplasmic sulfotransferase SULT1A1. Through computational analysis, the researchers also identified a broader class of anticancer compounds that depend on SULT1A1. This study suggests that SULT1A1 has the potential to be a potential new target for liver cancer drug development.
(2) PRRS35 :
During the progression of hepatocellular carcinoma, the secretome of hepatocytes will undergo dynamic changes, which is not only the result of tumorigenesis, but also one of the pathogenic factors leading to tumor development.
A recent article published in Nature Communications reveals a tumor suppressor role for the protease PRSS35 in hepatocellular carcinoma.
Studies have shown that active PRSS35 can inhibit the protein level of CXCL2, thereby inhibiting the progression of HCC. This study expands our understanding of the role of hepatocyte-secreted proteins in cancer development and provides the basis for clinical translation of PRSS35 as a therapeutic target or diagnostic biomarker.
05 Pancreatic cancer target: RBFOX2
Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with high invasiveness and strong metastatic ability. Currently, it is unclear what the driver mutations that lead to PDAC metastasis are.
A recent study published in the journal Nature showed that overexpression of the RBFOX2 gene in metastatic PDAC cell lines derived from patient xenografts (PDX) significantly reduced the metastatic ability of these cells in vitro and in vivo.
Conversely, depletion of the RBFOX2 gene in primary pancreatic tumor cell lines increased the metastatic potential of these cells. These findings suggest that RBFOX2 may have a potential role in inhibiting PDAC metastasis.
This study provides important clues for in-depth understanding of the metastasis mechanism of PDAC and lays the foundation for utilizing the splicing regulation of RBFOX2 gene as a potential therapeutic strategy for PDAC.
06 Glioblastoma target: FGL2
Fibrinogen-like 2 (FGL2) has prothrombinase activity and immunomodulatory functions in viral infection and cancer development.
Studies have shown that T cells expressing a FGL2-specific single-chain variable fragment (T-αFGL2) can induce tumor-specific CD8+ tissue-resident memory T (TRM) cells, thereby preventing glioblastoma recurrence.
These CD8+ TRM cells displayed an expanded T-cell receptor repertoire and were able to reject glioma cells. By increasing the number of specific signaling molecules, T-αFGL2 cell therapy is expected to increase the number of CD69+CD8+ brain-resident memory T cells, which is of great significance in preventing glioblastoma recurrence.
Therefore, FGL2 is considered an attractive target for glioblastoma immunotherapy.
The above are the new targets that are of great significance in a variety of cancers this year.
In addition, there are also applications of new targets in the treatment of other tumors.
For example, at the ASCO conference in 2023, Christina Wu from Mayo Medical Center Professor, summarized and reported important clinical research on four new therapeutic targets in colorectal cancer (CRC), including HER2 amplification, KRAS G12C mutation, NTRK fusion and RET fusion ; in terms of ADC drugs, many targets have also been Applications, such as FolRa, TROP2, ITGB6, etc.
The identification of new targets of drugs is of great significance to advancing cancer treatment, and provides a new option for overcoming drug resistance and realizing precision medicine.
Continued research and innovation in this area will help provide more effective, targeted and personalized treatments for cancer patients, ultimately improving patient outcomes and quality of life.
9 New targets of anti-tumor drugs in 2023
(source:internet, reference only)