Modulating tumor cell differentiation to enhance targeted neuroblastoma therapy
Mentor Name: Michael Chorny
Neuroblastoma (NB) remains the deadliest extracranial pediatric solid tumor.
Chemically modifying anticancer agents to allow their accumulation in neuroblastoma
tumors via a specific mechanism taking advantage of the norepinephrine transporter
(NET) can enhance both drug delivery selectivity and potency against aggressive
disease not responding to conventional therapies. In our proof-of-concept studies, a
novel anticancer drug endowed with NET targeting capacity achieved prolonged drug
presence in the tumor and markedly extended survival in clinically relevant models of
drug-resistant recurrent disease. Based on these results, we anticipate that potency
and selectivity of this approach can be further improved by promoting differentiation of
NB cells, in turn increasing their ability to produce NET. Studies included in this ALSF
POST project will allow the mentee to build an understanding of neuroblastoma
pathophysiology and the interplay between tumor cell biological features and
sensitivity to drug therapy by comparatively evaluating this combination strategy using
NB cells derived from newly diagnosed and recurrent tumors. If its effectiveness is
demonstrated in these studies and confirmed in preclinical evaluation experiments,
NET-targeted drug delivery enhanced by tumor priming with differentiation-promoting
agents can pave the way to a clinically viable, safe and effective new therapy for highrisk
NB patients.
