A lead splicing-modifying antisense oligonucleotide (AON) delivered to 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 enhanced NUMB gene exon 9 inclusion.

Technology:

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 approval by the FDA and EMA of SPINRAZA® (nusinersen; Ionis Pharmaceuticals) for the treatment of spinal muscular atrophy.

Researchers at the CRG have systematically studied mechanisms of regulation of AS in the NUMB gene of the Notch pathway, which is frequently altered in lung and other tumor types, identifying key regions essential for cancer cell proliferation, against which to develop specific and effective AONs. After a systematic screen, a lead AON was identified and tested in vitro and in vivo, reducing 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 several genetic and orthotopic xenograft models of lung cancer. After successful completion of pre-clinical target validation, ongoing efforts are being devoted to finalizing optimization of the lead AON to pursue preliminary First-in-Human-enabling toxicity studies as the next technology development milestone.

Advantages:

• NUMB is a novel and actionable target for the treatment of lung and other tumor types
• NUMB target is upstream of Notch – an important pathway for cancer cell growth in a panoply 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
• Anti-cancer AONs appear as a promising first in class therapy
• 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.