Novel Therapy of Heterogeneous B-cell Acute Lymphocytic Leukemia by Targeting Convergent Oncogenic Mediators STATs
B-cell acute lymphoblastic leukemia (B-ALL) is the most common leukemia among children. Although intensive chemotherapy is able to cure most children, approximately 20% of patients will relapse, not respond to most advanced therapy and eventually die. Multiple genetic abnormalities have been identified that cause the disease, but recent studies are highlighting a set of common mediators that are abnormally activated as a result of numerous genetic abnormalities. Diverse abnormalities converge on these mediators and affect the fate of the cancer cells. Addressing these central regulators, rather than various genetic normalities, could be a more effective approach to control a wide range of ALL abnormalities.
We propose that optimal way to achieve this is by using silencer molecules that are able to eradicate these central regulators from the cells. To realize this goal, we will develop and test nanoparticles that can deliver silencer molecules specifically to the cancer cells causing B-ALL in circulation. We plan to design the nanoparticles with the right antibodies to ‘seek’ the cancer cells; once bound and internalized by the cancer cells, the nanoparticles will release the silencer molecules, eradicating the central mediators of cancer growth and eventually the cancer cells. Our studies will create a therapeutic intervention that has the potential to eradicate leukemic cells that arise from different types of genetic abnormalities. Our therapy will have the potential to improve the effectiveness of treatment in high-risk B-ALL patients irrespective of genetic abnormality, preventing relapse and death.
Project Update 2020
We are investigating the use of nanoparticles for siRNA delivery that are formed by using lipid-modified cationic polymers. By mixing the siRNA with such polymers, we formed ~100 nm nanoparticles that were suitable for uptake in ALL cell lines and primary patient-derived cell samples. Initial studies identified the optimal lipid-substituted polymers that gave best siRNA delivery to ALL cell lines SUP-B15 and RS4;11. STAT5A gene expression was downregulated in ALL cell lines using the polymeric delivery systems, which consequently reduced cell growth and inhibited the formation of colonies in ALL cells. With regard to the ALL primary cells obtained from patients, siRNA-mediated STAT5A gene silencing was observed in four out of eight patient cells using our leading polymeric delivery system, accompanied by the significant reduction in colony formation in three out of eight patients with the same delivery system. In both BCR-ABL positive and negative groups, three out of five patients demonstrated marked inhibition in cell growth using the STAT-5 siRNA nanoparticles. Three patient samples (out of 10) did not show any positive results with our delivery systems. Differential therapeutic responses to siRNA therapy observed in different patients could result from variable genetic profiles and patient-to-patient variability in delivery. The outcomes of this study confirmed the therapeutic potential of siRNA in combination with designer nanoparticles from lipopolymers as a delivery system.