Periodic Reporting for period 1 - NetriCan (Characterization of the role of netrin-1 in the regulation of the Epithelial-to-Mesenchymal Transition during tumor progression.)
Okres sprawozdawczy: 2020-12-01 do 2022-11-30
In 2020, an estimated 2,68 million new cases were diagnosed and about 1.26 million people died from cancer in Europe (European Cancer Information System). Among all cancer types, 90% of cancer-related deaths, are attributed to the metastatic dissemination of the disease. A specific cellular process called EMT was shown to be necessary to allow tumor cell dissemination to secondary sites and metastatic disease. First identified as an embryonic program, EMT has been shown by many to be reactivated during tumor progression. EMT not only contributes to metastasis, but also to the regulation of tumor cell plasticity by generating stem-like cells with tumor-initiating properties and resistance to conventional therapies.
Despite significant improvements for society, in prevention, diagnosis and targeted therapies, it remains a challenge to specifically target the primary tumor mass as well as the disseminated tumor cells that present EMT features. It is now widely accepted that efficient therapies will have to target and/or block the EMT process and allow conventional therapies to efficiently kill cells to treat patients with metastatic tumors. Preliminary in vitro and in vivo results support that inhibition of our target is associated with a shift of the tumor phenotype toward a more epithelial phenotype, potentially more sensitive to regular therapy.
The aim of the NetriCan project is to validate the hypothesis that invasive tumor cells turn on the expression of our target as a survival strategy to overcome, and potentially regulate, the stressful EMT program and accomplish the metastatic dissemination cascade. Thus, using our targeted therapy will impact the metastatic disease on two battlefronts: re-epithelializing the primary tumor will increase the efficiency of conventional chemotherapy or immune-checkpoint inhibitors; and preventing the pro-survival role of our target will kill the disseminated tumor cells.
The Netrican project demonstrated for the first time a new role for our target in regulating EMT and metastases in tumors, especially for gynaecological tumors such as endometrial cancer.
Despite significant improvements for society, in prevention, diagnosis and targeted therapies, it remains a challenge to specifically target the primary tumor mass as well as the disseminated tumor cells that present EMT features. It is now widely accepted that efficient therapies will have to target and/or block the EMT process and allow conventional therapies to efficiently kill cells to treat patients with metastatic tumors. Preliminary in vitro and in vivo results support that inhibition of our target is associated with a shift of the tumor phenotype toward a more epithelial phenotype, potentially more sensitive to regular therapy.
The aim of the NetriCan project is to validate the hypothesis that invasive tumor cells turn on the expression of our target as a survival strategy to overcome, and potentially regulate, the stressful EMT program and accomplish the metastatic dissemination cascade. Thus, using our targeted therapy will impact the metastatic disease on two battlefronts: re-epithelializing the primary tumor will increase the efficiency of conventional chemotherapy or immune-checkpoint inhibitors; and preventing the pro-survival role of our target will kill the disseminated tumor cells.
The Netrican project demonstrated for the first time a new role for our target in regulating EMT and metastases in tumors, especially for gynaecological tumors such as endometrial cancer.
By using different cell lines (human or mouse mammary and endometrial cancer cell lines), the Netrican project first demonstrated that our target was unregulated during the EMT process, together with various specific markers, and this was specific for mammary epithelial cells. On the opposite side, in endometrial cancer cells, our target was down regulated, model in which the regular EMT process does not occur properly. The EMT process was induced by various means such as treatment with a molecule called TGFbeta or expression of specific transcription factors known to induce the EMT. Different techniques were then used to inhibit the expression of our target and its receptor (shRNAs, CRISPR-Cas9) in different cell lines, in order to observe how it would affect the EMT process. The data showed that inhibiting our target or its receptor did block the establishment of the MET process, suggesting the importance of developing our targeted therapy to counteract tumor progression and metastases. To confirm such results in vivo, a specific mouse model of endometrial cancer was developed to test the efficiency of the treatment to block spontaneous metastasis and the results showed a significant efficacy. Moreover, the analysis of samples from cancer patients treated with the targeted therapy demonstrated a positive effector the treatment in reducing/blocking the MET process in the tumor, thus potentially inhibiting metastasis and improving survival in patients from the clinical trial.
These results are being evaluated and considered for publication in the Nature journal.
These results are being evaluated and considered for publication in the Nature journal.
The NetriCan project, along with other research projects in the lab and clinical investigations on the Netris Pharma side, allowed to move on to a phase II clinical trial with the anti-Netrin-1 antibody on patients with gynaecological tumors. Moreover, results from NetriCan broaden the spectrum of the clinical investigation by developing the anti-Netrin-1 strategy for combination therapy with immunotherapy in all cancer types, in collaboration with regional hospitals. This project also unravelled a new role for the Netrin-1 signalling pathway in the regulation of a cellular process called EMT, necessary for tumor progression and metastatic dissemination of the disease.