Exploiting Mutant PPM1D-induced Metabolic Defects with Nanoparticle Encapsulated NAMPT Inhibitors

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PROJECT SUMMARY Diffuse Intrinsic Pontine Glioma (DIPG) is a leading cause of death from pediatric cancer, with an abysmal <1% five-year survival rate. The lethal nature of this cancer stems from the lack of effective treatment options, and while radiotherapy is the current standard of care, it can be considered is palliative at best. It is difficult to use surgery or chemotherapy as these tumors form within the blood brain barrier (BBB), in the pons region of the brainstem. Therefore, significant effort has been directed towards understanding the molecular profiles of DIPG, which can be targeted for selective tumor cell killing in these tumors. Recently, the Bindra laboratory published a novel discovery that truncating mutations in PPM1D, which are commonly found in DIPG, induce a global CpG Island hypermethylation phenotype (CIMP)-like state. This mutation leads to a diverse range of cellular phenotypes, including metabolic defects which we believe can be exploited for a therapeutic gain. To this end, we found that mutant PPM1D induces promoter hypermethylation in the NAD+ biosynthesis gene NAPRT, an important enzyme required to produce NAD+. Our group demonstrated that mutant PPM1D-induced NAPRT silencing confers exquisite sensitivity to a class of drugs which target NAMPT, another key NAD+ enzyme. This work was recently published in Nature Communications (Fons et al., 2019). Based on these novel findings, and the desperate need for new DIPG therapies, we propose to develop NAMPT inhibitors (NAMPTi’s) for the treatment of PPM1D-mutant DIPG. Blood-brain barrier (BBB)-penetrant NAMPTi’s have been developed and tested in clinical trials, however, their success has been limited by dose-limiting toxicities in the bone marrow and retina. To address these liabilities, this proposal aims to develop nanoparticle-encapsulated NAMPT inhibitors (NAMPTi-NPs) for direct delivery into the tumor microenvironment, and to validate them using in vitro and in vivo patient-derived models. My proposal will accomplish this goal with two aims: In Aim 1, we will create and optimize NPs that have high drug encapsulation efficiency, sustained retention of NAMPTi-NP in target sites, and demonstrate effective cell killing in NHA isogenic cell models and CCLE cell lines. Aim 2 will show the clinical feasibility of NAMPTi-NP via in vivo modeling that will encompass toxicity screens of free drug NAMPTi and NAMPTi-NP, as well as the biodistribution of these drugs within the brain. Lastly, we will show efficacy through reduction in size of PPM1D-mutant tumors treated with NAMPTi-NP. Altogether, this work will utilize a comprehensive and rigorous bench-based approach, coupled with computational and bioengineering methods, to develop a novel treatment for DIPG. My studies will serve as a critical proof-of- concept that seeks to establish an entirely new NP-based strategy targeting a key metabolic defect in DIPG. If successful, our approach can be applied to many other small molecules and brain tumors in the future.