April 12, 2024

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First time discovered: Netrin-1 inhibitors may overtime chemotherapy resistance

First time discovered: Netrin-1 inhibitors may overtime chemotherapy resistance



 

First time discovered: Netrin-1 inhibitors may overtime chemotherapy resistance. 

Scientists have discovered for the first time that Netrin-1 inhibitors can inhibit the epithelial-mesenchymal transition of tumors, or prevent cancer metastasis and overtime chemotherapy resistance.

Netrin-1 is a protein that is upregulated in multiple cancer types. Clinical studies have tested the strength of Netrin-1 neutralizing antibody NP137 in patients with advanced solid tumors.

 

On Aug 02, the “Nature” magazine published two related papers online. French and Belgian scientific research teams jointly analyzed the data of endometrial cancer patients in the study and analyzed the mechanism of action of NP137.

The researchers found that blocking Netrin-1, in addition to inducing tumor cell death, can also inhibit epithelial-mesenchymal transition (EMT), which may help reduce resistance to standard treatments .

 

In the clinical study, 8 of 14 patients with advanced endometrial cancer achieved stable disease (SD) and 1 achieved partial response (PR) .

 

First time discovered: Netrin-1 inhibitors may overtime chemotherapy resistance First time discovered: Netrin-1 inhibitors may overtime chemotherapy resistance

 

 

Netrin-1 is an embryonic-secreted laminin-associated glycoprotein that plays key roles in neuronal navigation, angiogenesis, and cell survival.

Netrin-1 is mainly expressed during embryonic development and is also expressed in human tumors such as inflammation-related colorectal cancer, breast cancer and lung metastases, neuroblastoma, lymphoma, and melanoma.

 

In preclinical studies, researchers have found that blocking the interaction of Netrin-1 with its receptor can trigger cancer cell death and inhibit tumor growth.

 

Netrin-1 neutralizing antibody NP137 can block the interaction between Netrin-1 and receptor UNC5B.

In a phase 1 clinical study (NCT02977195), the safety and efficacy of NP137 were initially evaluated against advanced solid tumors, including endometrial cancer (EC).

 

Fourteen patients with advanced endometrial cancer were included in the study, and NP137 was administered biweekly until clinical progression.

Eight patients (57.1%) achieved stable disease, and one patient achieved a partial response defined by RECIST1.1, with a 51.16% reduction in lesions at 6 weeks and a 54.65% reduction in lesions at 6 months .

 

First time discovered: Netrin-1 inhibitors may overtime chemotherapy resistancepatient response

 

To understand the relationship between Netrin-1 and tumor growth, the researchers performed experiments in Pten f/f mice, which rapidly develop endometrial carcinoma in situ.

 

It can be seen that NP137 increases cancer cell apoptosis; RNA sequencing showed that after NP137 treatment, EpCAM epithelial markers increased significantly, mesenchymal gene expression decreased, epithelial gene expression increased, and EMT score decreased significantly.

 

The above results indicate that Netrin-1 inhibition has a dual effect on tumor cells, on the one hand triggering cancer cell death and on the other hand inhibiting EMT .

 

First time discovered: Netrin-1 inhibitors may overtime chemotherapy resistanceNP137 treatment increases tumor cell apoptosis (top) and inhibits EMT (bottom)

 

In treated patients, a significant reduction in EMT score and transformation of the epithelial phenotype was also observed.

 

Analysis at the single-cell level showed that NP137 significantly reduced the proportion of tumor cells, and also had an effect on immune cells, increasing the number of CD8-positive T cells and NK cells. Spatial transcriptome data revealed increased number and strength of interactions between T cells and tumor cells, decreased M2 macrophages, and increased MHC class I/II antigen presentation.

 

A large number of studies have pointed out that EMT is the main cause of chemotherapy resistance.

So the researchers tested NP137 in mice in combination with carboplatin-paclitaxel, the standard treatment for endometrial cancer.

The experimental results showed that the combined effect of the two was better than carboplatin-paclitaxel alone, indicating that Netrin-1 inhibitors may be used to reduce drug resistance to conventional therapies.

 

Another study, conducted in mice with cutaneous squamous cell carcinoma, also confirmed that targeting Netrin-1 inhibited EMT.

 

This is the first time that the regulation of Netrin-1 on EMT has been clearly demonstrated. EMT plays a role in multiple stages of tumor occurrence, progression, metastasis, and drug resistance, but there is still no drug that can substantially interfere with the characteristics of EMT. Perhaps, NP137 will be the key to breaking the game.

 

The combination of NP137 with carboplatin-paclitaxel and pembrolizumab is being explored in the ongoing phase 2 clinical study GYNET (NCT04652076), and we can look forward to its upcoming answers.



 

 

 

 

References:

[1] Cassier, PA, Navaridas, R., Bellina, M. et al. Netrin-1 blockade inhibits tumor growth and EMT features in endometrial cancer. Nature (2023). https://doi.org/10.1038/s41586- 023-06367-z

[2] Lengrand, J., Pastushenko, I., Vanuytven, S. et al. Pharmaco logical targeting of netrin-1 inhibits EMT in cancer. Nature (2023). https://doi.org/10.1038/s41586-023 -06372-2

First time discovered: Netrin-1 inhibitors may overtime chemotherapy resistance

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