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Prokineticins in pregnancy pathologies

Published on 24 April 2024
Responsible for the project

Nadia Alfaidy

The scientific project led by Dr. Nadia Alfaidy, Director of research at INSERM and head of the MAB2 team, is in line with the theme she proposed when she was recruited by INSERM in 2005. Her project focuses on the study of pregnancy pathologies. Dr. Alfaidy is particularly interested in the study of two non-tumoral pathologies of pregnancy, preeclampsia (PE) and preterm birth (PTB), and a tumoral pathology of the placenta, gestational choriocarcinoma (GC), a malignant cancer that occurs following abnormal pregnancies. Unlike PE, which is caused by superficial trophoblast invasion of the decidua "transformed endometrium", resulting in failure to establish feto-maternal circulation, GC is associated with excessive trophoblast invasion. PTB, on the other hand, usually occurs spontaneously upon a rupture of the fetal membranes, a condition conductive of bacterial infection..
Dr. Alfaidy is studying these pathologies in relation to prokineticins (PROKs), a new family of pro-inflammatory and pro-angiogenic factors, discovered in 2001. Dr. Alfaidy has been working on PROKs since 2003. The centralization of her projects on the study of PROKs throughout this period has made her group, and recently her team, central for the study of PROKs worldwide.

Prokineticins family

The PROK family comprises two members, PROK1 also known as EG-VEGF (Endocrine Gland derived-Vascular Endothelial Growth Factor) and PROK2 also known as BV8 (Bambina Variegata). Members of the PROK family have different expression profiles and preferential sites of action. While PROK2 is associated with the nervous system, PROK1 is associated with the reproductive system and endocrine organs. PROK receptors (PROKR1, PROKR2) are coupled to G proteins and bind PROK1 and PROK2 with almost identical affinities. These receptors mediate the angiogenic and inflammatory responses of both ligands.
Recent studies obtained from Alfaidy’s group have demonstrated that deregulations in the expression of members of the PROK family are associated with the development of PE, PTB and GC.

Strategies & Implementations

     Prokineticins in pre-eclampsia
Dr. Alfaidy's group identified EG-VEGF/PROK1 as a potential biomarker of the occurrence of PE and demonstrated that maintaining its placental production beyond the first trimester of pregnancy contributes to the development of PE in mice. This work was published in the journal Hypertension in 2016. Since 2006, her group has published 60 articles on the mechanisms of function of this ligand in relation to this pathology. Members of her team who work on preeclampsia are mostly clinicians in obstetrics and gynecology (x4), have developed three clinical studies (NCT014490489, NCT00695942, NCT05188066) and demonstrated the therapeutic potential of PROK1 receptor antagonization. In this context, the group is supported by the unit if valorization, Inserm Transfert, for the development of a PROK1 blocking antibody. Studies are underway to bring these studies to the clinic.

     ​Prokineticins in prematurityé
Predicting preterm birth in asymptomatic women remains a major challenge for the public health system. Spontaneous preterm births (sPTB) due to spontaneous induction of labor account for 40-45% of all preterm births, and are considered the leading cause of neonatal mortality and morbidity. Dr. Alfaidy's interest in prematurity dates back to her post-doctoral training at the University of Toronto. This interest continued in the Inserm laboratory she joined in Grenoble in 2003. The study of this pathology is now at the heart of the activities of her group and the team she leads. Her work on prematurity has been consolidated by the addition to her team of a clinician specialized in high-risk pathologies, Pr. Tiphaine Barjat. In 2021, the team demonstrated in the clinical trial (NCT00695942- Pr. Barjat) that PROK1 is a reliable biomarker of sPTB as early as the 20th week of pregnancy (international patent-EP 22305143.4). The team also demonstrated that PROKs are directly involved in associated-placental inflammation found in sPTB, with direct consequences on fetal brain development. Thanks to this result, Inserm Transfert has funded the MAB2 team in 2024 to validate the informational value of PROK1 as a biomarker for sPTB and to develop therapeutic tools linked to its signaling to alleviate the handicaps associated with this pathology. This project is being led by two PhD students, Morgane Desseux (Thesis funded by Focus Biomarkers-CEA) and Margaux Digonnet (Thesis funded by an international France-Canada collaboration).

     Prokineticins in two female cancers
Because of the similarity between trophoblastic invasion processes and those of tumor cells, the human placenta can be described as a tumor. Nevertheless, this invasion is controlled in time and space. In some cases, trophoblasts intrinsic feature of invasion facilitate their switch into veritable tumor cells. This is the case with gestational choriocarcinoma (GC), a cancer that most often develops as a result of abnormal pregnancies known as hydatidiform mole (HM). Over the past ten years, Dr. Alfaidy's group has been studying this cancer in relation to prokineticins. The group has
i ) demonstrated that PROK1 and its receptor PROKR2 are increased in CG patients (cohort from an international collaboration),
ii) developed an orthotopic mouse model of GC (proprietary technology) and
iii) used this model to demonstrate that the antagonist of PROKR2 could be considered as a potential therapeutic target for the treatment of this cancer. This work was published in the journal Clin Cancer Res, 2017.
In the context of the cancer, Dr. Alfaidy’s group is also interested in an inflammatory protein called the NLRP7 protein, a member of the inflammasome family and whose gene is mutated in over 50% of HM. In 2017 and 2019 a PhD student, D. Reynaud, and a post-doc, Dr. R. Abi Nahed characterized the role of this protein in normal pregnancies, in pathological pregnancies (intrauterine growth retardation (IUGR)), and in GC. Part of the work of these two researchers was recently published in the journal Cancers and is featured on its cover page.
As the PROK system is highly expressed in the ovary, Dr. Alfaidy's group is also studying the involvement of the PROK2 member and its receptor PROKR1 in ovarian cancer. This project is carried out in collaboration with Prof. S Conlan-Swansea University. A treatment combining PROK2 and an antibody conjugated to a cytotoxic molecule is being characterized in a mouse model of ovarian cancer in Alfaidy’s group. This project is led by a PhD student, Mélanie Boudaud, whose thesis is co-supervised by Dr. Alfaidy and Prof. S. Conlan.

NLRP7 functions in inflammasome dependant manner in normal trophoblasts and independent manner in tumor trophoblast

PhD Students involved in the project:

Margaux Digonnet
Characterization of the role of the prokineticin family members in perinatal inflammation: Case of chorioamnionitis.

Morgane Desseux
Characterization of the informational value of PROK1 as a new biomarker of preterm birth in an infectious context.

Mélanie Boudaud
Enhancing the efficacy of ADCs in the ovarian cancer tumor micro-environment.