ACER2 in Chemotoxicity

Project Summary Cancer is a major cause of deaths in both men and women in the U.S. and worldwide. Despite some advances in targeted therapy and immunotherapy, traditional chemotherapy remains a major therapeutic modality for most cancers, including breast cancer (BC). However, the efficacy of chemotherapy is limited due to severe chemotoxicity, myelosuppression in particular. The specific goals of this application are to define a novel role for alkaline ceramidase 2 (ACER2) in mediating chemotherapy-induced myelosuppression and to develop a novel approach to targeting ACER2 for ameliorating this side effect. ACER2 is a member in the alkaline ceramidase family that the PI’s group identified. ACER2 catalyzes the hydrolysis of ceramide to generate sphingosine (SPH), a bioactive lipid implicated in both physiological and pathological programmed cell death (PCD). Our published data demonstrated that ACER2 is a novel transcriptional target of p53 and plays a key role in mediating PCD of human tumor cells in response to various DNA-damaging agents by accumulating SPH in cells. Our preliminary studies now find that doxorubicin (DOX), a widely used chemotherapeutic agent, induces PCD of human bone marrow hematopoietic stem/progenitor cells (HSPCs), which are responsible for sustaining hematopoietic homeostasis and regeneration after injury, by upregulating the ACER2/SPH pathway. We further reveal that knocking out the mouse alkaline ceramidase 2 gene (Acer2) protects mice from DOX-induced myelosuppression by blocking the generation of SPH in the bone marrow. These compelling results support our hypothesis that the ACER2/SPH pathway operates downstream of p53 to mediate chemotherapy-induced myelosuppression (CIM). As a further corollary, we hypothesize that blocking the ACER2/SPH pathway will mitigate CIM while improving overall survival in cancer patients who receive treatments with genotoxic chemotherapeutic drugs, such as DOX. To test these hypotheses, we will 1) establish that the ACER2/SPH pathway operates downstream of p53 to mediate chemotherapy-induced myelosuppression (Aim 1); 2) define the molecular mechanism by which the ACER2/SPH pathway mediates chemotherapy-induced PCD of HSPCs (Aim 2); and 3) Establish that targeting ACER2 with a small molecule inhibitor (AC2i) mitigates CIM while improving antitumor efficacy of chemotherapy in a preclinical model of BC (Aim 3). Successful completion of these aims will define the pathological role and mechanism of action of the ACER2/SPH pathway in myelosuppression and other adverse events of chemotherapy and chemoresistance and may lead to novel approaches to improving cancer therapy.