In the research and development of anti-tumor drugs, the target is undoubtedly one of the key factors to determine its success. The continuous emergence of new targets is of great significance for tumor treatment, gradually realizing precision medicine methods, overcoming drug resistance, and expanding the therapeutic field.
At present, the treatment of cancer patients still faces many challenges. For example, targeted therapies such as small molecule drugs and PD-1/L1 inhibitors are only effective for some patients. CAR-T cell therapy products have only made breakthroughs in the field of blood cancers. In addition, after cancer patients receive existing drug treatment, many will inevitably have recurrence, drug resistance and so on. To this end, some scientists are working hard to find new targets for cancer treatment in order to bring new treatment options to patients.
In this article, we will summarize the anti-tumor drug targets that have been newly discovered or have new indications recently.
1. Target For Lung Squamous Cell Carcinoma: mTOR
Non-small cell lung cancer (NSCLC) 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 - squamous cell carcinoma of the lung, only a small number of patients can receive targeted therapy.
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.
2. Target For Pancreatic cancer: 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. In an article titled "RBFOX2 modulates a metastatic singature of alternative splicing in pancreatic cancer" published in Nature on March 22, 2023, the researchers analyzed RNA splicing data from a large number of primary and metastatic PDAC tumors to identify differential splicing events associated with PDAC progression and found highly similar enrichment with RBFOX2 motifs.
Experiments showed that overexpression of RBFOX2 in patient-derived xenograft (PDX) metastatic PDAC cell lines significantly reduced the ability of these cells to metastasize in vitro and in vivo, while depletion of RBFOX2 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. Further analysis by RNA sequencing and splicing revealed that RBFOX2 splicing activity plays a role in the formation of cytoskeletal organization and fibroblast connections. Among them, splicing of myosin phosphatase RHO interacting protein (MPRIP) regulated by RBFOX2 has been shown to be associated with PDAC metastasis, cytoskeletal tissue changes, and induction of fibroblast junction. Thus, precise regulation of RBFOX2 alternative splicing events, such as MPRIP, may serve as a potential therapy for PDAC.
Figure 1. RBFOX2 acts as a metastatic tumour suppressor in pancreatic cancer progression.
(Source: References )
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.
3. Target for Glioblastoma: FGL2
As a member of the fibrinogen-like protein family, fibrinogen-like 2 (FGL2) has prothrombinase activity and immunomodulatory functions in viral infection and cancer development.
In a paper titled "FGL2-targeting T cells echibit antitumor effects on glioblastoma and recruit," published in Nature Communications on February 10, 2023 In the "tumor-specific brain-resident memory T cells", the researchers found that the expression of FGL2-specific T cells with a 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 showed a highly expanded library of T cell receptors, unlike those found in peripheral tissue. When adoptively transferred to the brains of immature mice with immunoactive or T-cell deficiencies, these CD8+ TRM cells rejected glioma cells. In terms of mechanism of action, T-αFGL2 cell therapy increased the number of CD69+CD8+ brain-resident memory T cells in tumor-bearing mice through CXCL9/10 and CXCR3 chemokine signaling. These findings suggest that tumor-specific brain-resident CD8+TRM cells may have important implications for preventing brain tumor recurrence.
Figure 2. Antitumor activity of T-αFGL2 in vivo.
(Source: References )
Therefore, FGL2 is considered an attractive target for glioblastoma immunotherapy.
4. 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 adjacent gastric mucosal epithelial cells together, preventing food and digestive juices in the stomach from leaking out of the cell space into the human internal environment.
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. Compared with mFLOFOX6 chemotherapy alone, adding Zolbetuximab and mFLOFOX6 chemotherapy, 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. Both the risk of death and the risk of progression were reduced by 25%.
5. New Targets For Liver Cancer: SULT1A1, PRRS35
Liver malignancies in adults, including intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC), are the second leading cause of cancer-related death worldwide. For patients with advanced ICC, the standard treatment is combination chemotherapy. For patients with advanced HCC, standard treatment is combined immunotherapy/multikinase inhibitors. Most received combination chemotherapy or immunotherapy, respectively, without specific biomarkers to choose from. Although these treatments have improved the response rate and overall survival of patients, the effect is still poor.
(1) SULT1A1: An article titled "SULT1A1-dependent suslfonation of alkylators is a Lineage-dependent vulnerability of liver cancers" published in Nature Cancer on March 13, 2023. This article presents the results of research on adult liver malignancies, including intrahepatic cholangiocarcinoma and hepatocellular carcinoma. In this study, through high-throughput screening, proteomics, and in vitro resistance models, the researchers identified a small molecule compound called YC-1 that has selective activity against cell line subpopulations from two liver cancer types.
This article presents the results of research on adult liver malignancies, including intrahepatic cholangiocarcinoma and hepatocellular carcinoma. In this study, through high-throughput screening, proteomics, and in vitro resistance models, the researchers identified a small molecule compound called YC-1 that has selective activity against cell line subpopulations 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.
Figure 3. Identification of selective YC-1 activity against liver cancer subsets.
(Source: References )
(2) PRRS35: Liver cells mainly function by secreting proteins that regulate cell proliferation, metabolism and intercellular communication. During the progression of hepatocellular carcinoma (HCC), the hepatocyte secretome is dynamically altered, which is both a consequence and a causative factor of tumorigenesis.
An article entitled "Secreted protease PRSS35 suppresses hepatocellular carcinoma by disabling CXCL2-mediated neutrophil extracellular traps" published in Nature Communications on March 18, 2023 reveals the tumor suppressor effect of 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 the hepatocyte secretome in cancer development and provides the basis for clinical translation of PRSS35 as a therapeutic target or diagnostic biomarker.
Figure 4. PRSS35 is a secreted protein that decreased in HCC patients
(Source: References )
6. New Targets For Prostate Cancer: PI5P4Kα, PODXL, TRABID
(1) PI5P4Kα: Phosphatidylinositol (PI) regulatory enzymes are often altered in cancer and have become a key research object for drug development, and it is an important target for anticancer drug research.
On February 1, 2023, an article entitled "PI5P4Kɑ supports prostate cancer metabolism and exposes a survival vulnerability during androgen receptor inhibition" was published on Science Advances. Researchers investigated the function of phosphatidylinositol-5-phosphate-4-kinase (PI5P4K) an validated the effect of the PI5P4Kα isoform on androgen receptor (AR) signaling, a signaling pathway that supports prostate cancer cell survival.
Figure 5. PIP4K2A expression correlates with low androgen receptor signaling
(Source: References )
(2) PODXL: glycocalyx component and salivary mucin pocalylin (PODXL) is a transmembrane protein whose elevated expression is associated with poor clinical outcomes in tumors, leading scientists to think that it might serve as a mechanism for cancer metastasis targeted biomarkers. Given that PODXL is also required for function in normal tissues, it is imperative to determine the tumor-specific environment that regulates PODXL function.
On February 3, 2023, an article entitled "Spetial regulation of the glycocalyx component podocalyxin is a switch for prometastaic function" was published on Science Advances. The study identified an unexpected function of PODXL as a decoy receptor for galactin-3 (GAL3), in which PodxL-GAL3 interaction releases GAL3 to inhibit integrin-based invasion. Through experiments, the researchers identified the molecular mechanism that controls the transition of PODXL to the transmission-promoting glycocalyx component, while revealing that PODXL acts as a decoy receptor to mitigate the invasion inhibition of GAL3, and demonstrating that this level of change can be used to identify prostate cancer patients with high metastasis and poor prognosis.
Figure 6. PODXL promotes the formation of invasive tunnels in the ECM
(Source: References )
(3) TRABID: On March 31, 2023, a paper entitled "TRABID overexpression enables synthetic lethality to PAPR inhibitor via prolonging 53BP1 retention at double-strand breaks" was published in Nature Communications.
Studies have demonstrated that TRABID deubiquitinase can bind to 53BP1 and regulate the stabilization of 53BP1 at double-strand break sites. 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 rather than homologous recombination by prolonging the presence of 53BP1 at the double-strand break sites, suggesting that TRABID overexpression can be used as a predictor of homologous recombination defects in prostate cancer and the therapeutic potential of PARP inhibitors.
Figure 7. TRABID regulates 53BP1 foci formation at DSB sites
(Source: References 7])
In addition to these targets mentioned above, there are also applications of new targets in the treatment of other tumors. For example, at the ASCO conference in 2023, Professor Christina Wu from the Mayo Medical Center studied four novel therapeutic targets in colorectal cancer (CRC). Important clinical studies including HER2 amplification, KRAS G12C mutation, NTRK fusion and RET fusion were summarized and reported. In terms of ADC drugs, many targets have also been used, 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.
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. RBFOX2 modulates a metastatic signature of alternative splicing in pancreatic cancer. Retrieved Mar 22, 2023, from https://www.nature.com/articles/s41586-023-05820-3
. FGL2-targeting T cells exhibit antitumor effects on glioblastoma and recruit tumor-specific brain resident memory T cells. Retrieved Feb 10, 2023, from https://www.nature.com/articles/s41467-023-36430-2
. SULT1A1-dependent sulfonation of alkylators is a lineage-dependent vulnerability of liver cancers. Retrieved Mar 13, 2023, from https://www.nature.com/articles/s43018-023-00523-0
. Secreted protease PRSS35 suppresses the hepatocellular carcinoma by disabling CXCL2-mediated neutrophil extracellular traps. Retrieved Mar 18, 2023, from https://www.nature.com/articles/s41467-023-37227-z
. PI5P4Kα supports prostate cancer metabolism and exposes a survival vulnerability during androgen receptor inhibition. Retrieved Feb 01, 2023, from https://www.science.org/doi/10.1126/sciadv.ade8641
. Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function. Retrieved Feb 03, 2023, from https://www.science.org/doi/10.1126/sciadv.abq1858
. TRABID overexpression enables synthetic lethality to parp inhibitor via prolonging 53BP1 retention at double-strand breaks. Retrieved Mar 31, 2023, from https://www.nature.com/articles/s41467-023-37499-5