Regulation of NUMB alternative splicing by RBM10 and control of cancer cell proliferation

Jordi Hernández Ribera

Juan Valcárcel Júarez

Gene Regulation, Stem Cells and Cancer

The results obtained during Dr. Jordi Hernández's research at the CRG have been the basis for the construction of the project of modulation of alternative splicing to treat lung cancer. During his PhD studies, Dr. Hernández characterized the effects of different mutations in RBM10, a splicing factor with tumor suppressor activity (1). In addition, part of his research also focused on the design of new compounds capable of modulating the splicing of NUMB, a gene involved in the proliferation of tumor cells, especially relevant to lung cancer. Lung cancer is the second most common type of cancer (2) and the main cause of cancer death worldwide (1.8 million new cases are diagnosed and 1.6 million deaths per year according to the World Health Organization (3)). Non-small cell lung cancer (NSCLC) is the most common subtype, accounting for 87% of all lung cancers. NSCLC is considered an urgent medical need due to its high incidence, the lack of effective therapies, and the high mortality rate associated with it, exceeding 85%. Estimates of the growth of the NSCLC market range from $6.21 billion in 2015 to $26.8 billion in 2025. This increase is associated with the social impact of lung cancer. Adenocarcinoma (LUAD) is the most common histopathological subtype of lung cancer, accounting for 50% of cases. Although multiple pathways have been discovered that are altered in lung cancer, the majority of LUAD patients do not have any specific treatment and have to resort to classical chemotherapy. For LUAD, chemotherapy is usually ineffective, tumors become resistant, and have serious side effects (4). NUMB splicing has been reported as altered in all human samples sequenced in the Cancer Genome Research Atlas. This suggests that it is a common alteration in LUAD and that our compounds may have a large number of patients who could benefit if the treatment is effective in humans.

Our short-term goal is to demonstrate the efficacy of our compounds to treat lung cancer. The long-term goal of this project is to create a spin-off that develops drugs that modulate splicing as a therapeutic tool and use our current results as a showcase for our knowledge in the field and our capabilities. In order to create this company, we need access to capital from venture capitalists. New drug development projects are extremely long and expensive and require the help of specialized investors. We have already initiated communications with venture capital groups (such as Caixa Capital Risc) who have shown interest in the project.

Alternative Splicing Modulation; Lung Cancer Treatment; RBM10 Mutations; Splicing Factor; Tumor Suppressor Activity; NUMB Splicing; Tumor Cell Proliferation; Lung Cancer; Cancer Mortality; Non-Small Cell Lung Cancer (NSCLC); Urgent Medical Need; Adenocarcinoma (LUAD); Chemotherapy Resistance; Cancer Genome Research Atlas; Novel Compounds; Therapeutic Development.