A lead splicing-modifying antisense oligonucleotide (AON) locally delivered to the lungs of different mice models of lung cancer effectively reduces tumor growth in vivo.
The lead AON could be applicable to the targeted treatment of lung adenocarcinoma, lung squamous cell carcinoma, breast, liver, prostate, colon, cervix and other tumor types displaying a specific splicing-event in the Notch pathway.
Lung cancer is the second most common kind of cancer in men and women, and the leading cause of cancer-related death worldwide. 87% of all lung cancers are of the non-small cell lung cancer type (NSCLC) commonly detected at an advanced stage. Patients are initially treated with chemotherapy, with or without combinatorial radiation therapy. Unfortunately, NSCLCs are relatively insensitive to chemotherapy and radiation, resulting in a 5-year survival rate of 50%. 50% of NSCLC are lung adenocarcinomas (LUAD) and 30% are squamous cells carcinomas (SCC), and in both cases >70% are not treatable with targeted drugs (i.e. drugs directed against identified driver mutations such EGFR or other genetic events that are altered in the tumor vs non-tumor tissues).
Antisense oligonucleotides (AONs) are a new class of biological drugs approved or in development for the treatment of human diseases. Alternative splicing (AS) is a major mechanism of gene regulation in multicellular organisms that can be targeted with AONs, as shown by the recent approval by the FDA and the EMA of SPINRAZA® (nusinersen; Ionis Pharmaceuticals) for the treatment of spinal muscular atrophy. Researchers at the CRG systematically studied mechanisms of regulation of AS in a gene of the Notch pathway very frequently altered in lung and other tumor types, identifying 3 key regions essential for cancer cell proliferation, against which to develop specific and effective AONs. After a systematic screen, a lead AON was tested in vitro and in vivo, and was shown to reduce the clonogenic capacity of lung and other (e.g. colon, cervix) cancer cells independently of p53 status, as well as to reduce tumor growth in vivo in two different models of lung cancer: one genetic and one orthotopic. Work is ongoing towards pre-clinical validation of the target and drugs for the treatment of LUAD and SCC using patient-derived xenografts (PDX).
- Provides a new, actionable target for the treatment of lung and other tumor types
- The target is upstream of Notch – an important pathway for cancer cell growth in a variety of tumor types
- It can represent an Achilles' heel of lung cancer cells whose therapeutic potential has not been explored before
- Modulation of alternative splicing (AS) by antisense oligonucleotides (AONs) is a proven therapeutic strategy
- Our AONs shows deliverability and efficacy in vivo in different models of lung cancer
- They could be used alone or in combination with other therapeutic strategies for the treatment of cancer, its recurrence and metastasis.
Patent EP18162571 filed. Protects selected AONs against key regions of the target gene and their use for the treatment of cancer and other indications.