Therapeutic Antisense Oligonucleotides Targeting NUMB Alternative Splicing in Lung Adenocarcinoma

Introduction

Lung cancer is the leading cause of cancer-related deaths, with 1.8 million deaths expected globally in 2021. Lung adenocarcinomas (LUAD) represent 1/3 of all lung cancer cases. Despite notable advances, current treatments remain ineffective, resulting in <25% survival beyond 5 years.

Unmet Need

Due to the high heterogeneity of molecular abnormalities driving lung cancers, targeted therapies are applicable to only a small subset of patients. There is therefore an urgent unmet need for developing novel therapeutic approaches generally applicable to LUAD patients.

Alternative Pre-mRNA Splicing

Alternative pre-mRNA splicing (AS) allows the synthesis of different protein variants from a single gene by differential selection of exonic sequences. Increased inclusion of exon 9 of the gene NUMB encodes a protein isoform that promotes cancer cell proliferation. This occurs in the vast majority of LUAD tumours, correlating with worse disease prognosis.

Innovative Therapeutic Approach

Supported by the ERC PoC VALSL, we developed an innovative therapeutic approach based on the use of Antisense Oligonucleotides (AONs) that regulate NUMB AS. Our proprietary AONs:

• Correct NUMB pathological splicing
• Inhibit cancer cell proliferation
• Reduce tumour growth in four different mouse models of LUAD, including 2 Patient-Derived Xenograft models

Future Developments

With support from the EIC Transition, we will bring this technology to a stage where it is ready to be validated in clinical trials. We will:

1. Optimise our lead AONs by improving their chemistry, formulation, and administration
2. Carry out regulatory pre-clinical studies

These will pave the way to the first application of AON-based splicing modulation in clinical oncology.

Commercialisation Plans

To commercialise this technology, we also aim to develop the business plan for a spin-off company, AON Therapeutics. In the long term, our project has the potential to generate compounds, presentations, and delivery methods that can be applicable to other target AS events and/or cancer types, as well as to other AS-related diseases.