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IUCT-Oncopole & Artios join forces to overcome resistance to therapies for familial breast cancer

20/04/2023

The IUCT-Oncopole is launching an ambitious national project in collaboration with Artios Pharma Limited (Artios), a clinical stage biotech company pioneering the development of novel small molecule therapeutics that target the DNA damage response (“DDR”) process to unravel the mechanisms of resistance to anti-PARP therapies in patients with metastatic breast cancer with germline mutations of the BRCA1 and/or 2 genes. Entitled REPARP (REpair factor expression as biomarker of PARP inhibitor resistance), its ambition is to deliver medicines that improve the survival of these patients.

New ways to combat poor prognosis in breast cancer

Metastatic cancer occurs when the disease (tumour) has spread from the breast and local lymph nodes to other parts of the body (metastasis), such as the bones, liver or lungs. Fewer than 10% of breast cancers are metastatic at the time of diagnosis, but it is estimated that 15-20% of patients with early diagnosed breast cancer will go on to develop metastases. The aim of current metastatic treatments is to slow down the progression of a disease that unfortunately cannot be cured. Poly ADP-ribose polymerase (PARP) inhibitors are a promising new class of molecules and are prescribed alone or in combination with hormone therapy for breast cancer. This targeted therapy has reduced the risk of relapse in patients with a BRCA1 and/or 2 mutation in both the metastatic and early stages. However, at the metastatic stage, some patients present a disease that is resistant to this treatment from the outset or eventually develop resistance, i.e. their disease progresses despite the treatment.

BRCA1 and BRCA2 play a major role in a pathway for repairing chromosomal breaks known as homologous recombination. They act like ‘mechanics’ in our cells. In the case of BRCA1 and/or 2 mutations, this repair pathway is impaired. PARP inhibitors act by increasing the rate of breaks leading to tumour cell death. PARP is a major player in the alternative DNA repair pathways used by cancer cells for survival in the case of BRCA1 and/or 2 mutations.
Recent laboratory studies suggest that tumour cells resistant to PARP inhibitors set up another alternative repair pathway mediated by the DNA Polymerase or POLQ, which acts as a substitute ‘mechanic’. POLQ inhibitors being developed by Artios (Phase I underway; NCT04991480) could prevent or treat this resistance to PARP inhibitors.

The IUCT-Oncopole’s and Artios’ expertise in translational research underpins the REPARP project.

The REPARP project consists of using tumour and fluid samples (blood samples) taken at different times during treatment with PARP inhibitors to explore whether the POLQ repair pathway is established and is associated with therapeutic resistance. This would allow the identification of patients who could
benefit from further treatment with POLQ inhibitors. The aim is to include 120 patients throughout the 25 national centres participating in the study. Results are expected in three years.

“PARP inhibitors have significantly improved the treatment of cancers, but long-term use can often lead to resistance that is challenging to overcome,” said Prof. Florence Dalenc Department of Medical Oncology The IUCT-Oncopole. “Analyzing tumour samples can help us better understand why some patients experience a lack of efficacy to PARP inhibitors. These learnings can help improve treatment decisions for different patient types and help determine potential drug combinations with synergistic activity that can restore sensitivity to PARP inhibition.”

Prof. Florence Dalenc (Department of Medical Oncology), and Drs. Jean-Sébastien Hoffmann and Camille Franchet (Department of Anatomy and Pathologic Cytology – CHU de Toulouse, directed by Prof. Pierre Brousset) are coordinating this study. Pathological and imaging analyses are carried out by the Imag’IN platform (https://www.imagin-labs.net/imagin_v2/) coordinated by Drs. François-Xavier Frenois and Nathalie Van Acker. The translational part on liquid biopsy (obtained from blood) is undertaken by the team directed by Dr. Anne Pradines (Laboratory of Oncological Medical Biology) and is funded by the National Cancer Institute (INCa).

The translational and bioinformatics team at Artios, led by Dr. Sarah Holt and Dr. Suraj Menon respectively, will also be heavily involved in the analysis of the liquid and tumour biopsy samples using the Artios DcoDeR Platform.

Published: 13.04.23

Article sourced from www.artios.com