Title: SRPK1 inhibitors for treatment of Acute Myeloid Leukemia
Funder: Cancer Research UK

Abstract: Background: Approximately 10% of the 1 million people worldwide who suffer from Acute Myeloid leukemia (AML) have a genetic change that affects the Mixed Lineage Leukemia gene (MLL). These patients have very poor prognosis and there are no effective therapies. We have found that in the laboratory, this genetic change means that the cancer cells require the activity of a specific protein, called SRPK1, to stay alive. This is a type of protein that adds phosphate groups to specific sequences in other proteins that are associated with changes in gene expression, called splicing, that allows cancer cells to use lots of different routes to grow and proliferate. Drugs are being developed against this SRPK1 protein for other diseases but have not yet been developed for leukemia. Aims: To find out whether SRPK1 is the right target for the 10% of AML with the MLL gene re-arranged. Methods: We will use leukemia tissues from AML patients with and without the rearrangement and see if they are killed by drugs that target SRPK1. We will determine whether these drugs can be used to treat mice that harbour the patients’ leukemia cells. We will also use splicing specific RNA expression methods (digital droplet PCR) to find specific markers that tell us which patients with the re-arrangement respond best to treatment. Finally, we will use ELISA and PCR to find markers that will tell us whether a patient is responding to treatment, by determining change in these markers in mice harbouring patient derived leukemias. How the results will be used. If successful in all three parts (validating SRPK1 as a target, identifying a companion diagnostic, and finding a response biomarker), then, working with local pharmaceutical companies, we will go on to develop specific drugs to treat these patients.

Lay abstract: Background: Approximately 10% of the 1 million people worldwide who suffer from Acute Myeloid leukemia (AML) have a genetic change that affects the Mixed Lineage Leukemia gene (MLL). These patients have very poor prognosis and there are no effective therapies. We have found that in the laboratory, this genetic change means that the cancer cells require the activity of a specific protein, called SRPK1, to stay alive. This is a type of protein that adds phosphate groups to specific sequences in other proteins that are associated with changes in gene expression, called splicing, that allows cancer cells to use lots of different routes to grow and proliferate. Drugs are being developed against this SRPK1 protein for other diseases but have not yet been developed for leukemia. Aims: To find out whether SRPK1 is the right target for the 10% of AML with the MLL gene re-arranged. Methods: We will use leukemia tissues from AML patients with and without the rearrangement and see if they are killed by drugs that target SRPK1. We will determine whether these drugs can be used to treat mice that harbour the patients’ leukemia cells. We will also use splicing specific RNA expression methods (digital droplet PCR) to find specific markers that tell us which patients with the re-arrangement respond best to treatment. Finally, we will use ELISA and PCR to find markers that will tell us whether a patient is responding to treatment, by determining change in these markers in mice harbouring patient derived leukemias. How the results will be used. If successful in all three parts (validating SRPK1 as a target, identifying a companion diagnostic, and finding a response biomarker), then, working with local pharmaceutical companies, we will go on to develop specific drugs to treat these patients.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS