Discovery of new differentiation agents for neuroblastoma therapy
Summary
Neuroblastoma (NBL), one of the most common and lethal types of childhood cancers, arises from the neural
crest precursor cells failing to complete differentiation. This failure in differentiation is the rationale for
differentiation therapy, a treatment to induce malignant cells to resume the differentiation process, which
arrests tumor growth. Currently, differentiation therapy plays a critical role in treating high-risk NBL, and 13-
cis-retinoic acid (RA) is the differentiation agent that is used as the standard of care in this type of cancer.
However, resistance to RA is common, and there are few alternatives to treat resistant patients. We have
developed a high-content screening (HCS) approach for identifying agents that induce differentiation of NBL
cells. The objective of this study is to discover new differentiation-inducing compounds from the Chembridge
DiversetTM synthetic compound library and a natural product library using the HCS approach. Although
compounds with promising anti-cancer activities have been identified from these libraries previously, they have
not been screened for NBL differentiation agents. Our pilot screen of 880 compounds from the Chembridge
library in an RA-resistant cell line has identified two potent differentiation-inducing compounds that are
structurally distinct from RA. This supports the hypothesis that new drug candidates can be identified from
these libraries to develop novel differentiation therapies for NBL resistant to current differentiation agents. Four
specific aims are proposed: Aim 1, Further screen the two libraries to identify additional compounds whose
differentiation-inducing potency is higher or comparable to RA. Aim 2, Prioritize the hits for further investigation
using additional functional analysis. We will investigate the identified hits by employing a panel of human NBL
and non-NBL cancer cell lines to select compounds that have generic and strong differentiation-inducing
activity in NBL cell lines with a broad range of genetic backgrounds and minimal non-specific cytotoxicity in
non-NBL cell lines. Aim 3, Perform focused structure-activity relationship (SAR) studies for high priority hits
and identify 3 compounds that have the most promising therapeutic potential. Aim 4, Use in vivo NBL models
to determine the proof-of-principle therapeutic potential of the 3 selected compounds. We will conclude this
project by a preliminary mode of action experiments with the most effective compound by combined gene
expression profiling and informatics analyses, which will provide preliminary data for our mechanistic studies in
the next grant period. The study is innovative because it exploits novel experimental approaches, discovers
novel differentiation agents for NBL and provides the proof-of-principle demonstration of the capabilities of our
drug screening strategy. The study is significant because it is expected to pave the way to develop more
effective therapeutics for NBL. In addition, given the need to develop alternative methods to treat cancers that
are resistant to traditional therapeutic agents, it is expected that the success of this study will have an impact
on promoting the exploration of differentiation therapy in a broader spectrum of pediatric cancers.