Research Project
9844131
PROJECT ABSTRACT Neuroblastoma (NB) is the most common extracranial solid tumor in children, with only approximately 50% of children with high-risk disease surviving for 5 years in spite of intense chemotherapy. Clearly, new and more effective therapies are desperately needed for NB patients. High-risk NB is often associated with MYCN gene amplification (40-50% of cases), and so N-Myc has been considered as a prime target for new NB drugs. Sphingolipid metabolism is being increasingly recognized as a key pathway in cancer biology. Extensive research demonstrates the roles of ceramides, dihydroceramides, sphingosine and sphingosine 1-phosphate (S1P) in regulating tumor cell proliferation, death and drug resistance, as well as host angiogenesis, inflammation and immune response. In particular, sphingosine kinases (SK1 and SK2) are validated sites for manipulation of the ceramide/S1P rheostat that regulates the balance between tumor cell proliferation and death, as well as tumor sensitivity to radiation and chemotherapy. Dihydroceramide desaturase (DES1) controls the balance between saturated and unsaturated ceramides (sphinganine and sphingosine cores, respectively) and this regulates proliferative and autophagic signaling. We have identified orally-available SK inhibitors with activity in vitro and in vivo, and our clinical phase II dual SK2/DES1 inhibitor (ABC294640, also known as opaganib and YELIVA) has antitumor and anti-inflammatory activities in several in vivo preclinical models. ABC294640 has excellent safety and pharmacologic profiles in nonclinical (including 3-month GLP high-dose toxicology studies in rats and dogs) and ongoing clinical studies. Mechanistically, ABC294640 attenuates Akt signaling and the expression of c-Myc and Mcl-1 in multiple cancer cell lines. Our new studies demonstrate that ABC294640 also down regulates N-Myc mRNA and protein expression in NB cells and has therapeutic activity in NB xenografts. Therefore, we hypothesize that SKs and DES1 are key regulators of NB tumor growth, and that ABC294640 in particular has excellent potential for use in NB patients. To determine the potential for targeting SKs and DES1 to treat NB, we will conduct the following Specific Aims in this phase 1 SBIR project: 1) To define the functional and biochemical effects of SK and DES1 inhibitors on NB cells in vitro; and 2) To evaluate the antitumor activity of ABC294640 in orthotopic xenografts of murine NB cells in immunocompetent mice. These studies are designed to provide proof-of-concept for treating NB patients with an SK/DES1 inhibitor, and more specifically, will provide the efficacy data needed to support a clinical trial of ABC294640 in NB patients. Because ABC294640 is already in phase II clinical testing in adult cancer patients, demonstration of efficacy against NB xenografts in the proposed studies could be rapidly translated into clinical trials in children having this disease.
