Alternative Splicing in PNET: an unexplored source of therapeutic targets

Year: 2021
Institution: Alexander Fleming Biomedical Sciences Research Center
Country: Greece
Award Type: Pilot
NET Type: Pancreas
Science Type: Basic

Description

Kafasla and her research team will work to identify alternative forms of a given protein (called isoforms) that are specific and present in pancreatic tumor cells. The team will analyze alternative splicing events in pancreatic NET cells as well as normal cells.

What question will the researchers try to answer?

Different protein “versions” are produced when alternative splicing is deregulated in cancer cells. In many cases, these protein versions act as dominant drivers in the development of cancer cells. Furthermore, several subtypes of cancer depend on splicing function for cell survival. These are among the findings that led to a growing interest in targeting alternative splicing for cancer treatment. Many compounds targeting either the alternative splicing process or specific cancer-driving protein versions are in clinical trials. The role of alternative splicing in the pathogenesis of pancreatic NETs (PNETs) has not been investigated in the preliminary results of Dr. Kafasla’s research show that alternative splicing is highly affected in PNETs and her team will continue to explore this.

Why is this important?

Deregulated alternative splicing is a hallmark of cancers, affecting many characteristics of cancer cells. Cancer cells alter the alternative splicing process to favor their survival and growth, and several molecular subtypes of cancer depend on such altered alternative splicing for cell survival. As a result, alternative splicing has been characterized as the Achilles’ heel of cancer, making cancer cells more vulnerable to splicing-targeting drugs than normal cells. A better understanding of these changes in alternative splicing in cancer cells can become a tool to use in the fight against PNETs.

What will researchers do?

Her team will analyze publicly available datasets for alternative splicing changes between normal and cancer tissues from patients. They aim to detect splicing changes – protein “versions” that are increased or decreased during tumorigenesis or that are functionally altered in cancer cells. These changes will be validated in human cells and in mouse models of NETs and then correlated with specific cancer cell characteristics and with distinct states of PNET development.

How might this improve the treatment of NETs?

The models used for these studies are commonly used by PNET researchers, but the contribution of alternative splicing in tumor characteristics is still a black box. The detailed analysis of these models by their team will advance the research field enormously. Alternative splicing has been targeted successfully in other disease settings and many drugs targeting alternative splicing are already in clinical trials for different types of cancer. Our work aims to pave the way for implementation of such targeting in PNETs.

What is the next step?

Once the alternative splicing changes in PNETs is characterized, their studies will be extended to patient-derived animal and cellular models of the disease. They will not only target general splicing functions but also disease-specific molecules at different stages from early development to final tumorigenesis.