Tuesday, April 16, 2024
4/16/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
