SphingoGene, Inc.
Discovering Novel Medicines to Improve Chemo- Radiation- and Gene Therapy of Cancer
Contact:
James S. Norris, Ph.D.
843.792.7915
Last updated: February 6, 2007
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Executive Summary
SphingoGene, Inc.is focused on the commercialization of small molecule therapeutics and siRNA’s that modify ceramide metabolism and result in cancer cell apoptosis. Sphingolipid metabolism is recognized as a key factor in tumor cell survival and metastasis. Ceramide is a “tumor suppressor sphingolipid” involved in regulation of cell growth, differentiation, senescence and programmed cell death. SphingoGene Inc. has designed inhibitors for enzymes which act to lower cellular ceramide. Inhibition promotes increased ceramide levels in cancer cells and cell death. Our mission is to treat cancer by combining our drugs with radiation, chemotherapy or gene therapy, all which induce ceramide as part of their mechanism of action. To determine a patient’s potential responsiveness to combination therapy, we are developing a diagnostic test to detect acid ceramidase (AC) levels. AC is over-expressed in more than 70% of prostate and head and neck squamous cell cancers (HNSCC) and is now recognized as a major factor in resistance to therapy. By focusing on the development of small molecule and siRNA inhibitors of a well-validated target, the company is growing into an organization with a pipeline of drugs that add value to existing cancer therapies and global pharmaceutical companies that market them. SphingoGene, Inc.is also developing a commercial Lipidomics laboratory to provide sphingolipid analysis for business entities on a fee for service basis to supplement our drug development efforts.
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Founding Scientists
SphingoGene, Inc.was founded in 2006 by a group of scientists from the Medical University of South Carolina including Drs. James Norris, John Dong, Yusuf Hannun, and Alicja Bielawska.
Mission
The SphingoGene mission is to commercialize our novel platform of small molecule therapeutics and siRNA’s which modify ceramide metabolism and promotes apoptosis. Our approach is novel because it is designed as a combination therapy with standard of care approaches to cancer treatments that specifically targets a pathway largely overlooked as an important resistance mechanism to cancer treatment. It will prolong lives and provide improve long term survival in our patient population.
Vision
Our goal is to treat patients with available cancer drugs or radiation in combination with AC modifying drugs to reduce aberrant ceramide metabolism and improve cancer patient survival.
Lead Generation and Validation
Description of Research
Since the human genome is now sequenced and continuing development of bioinformatic tools to analyze such complicated data sets are improving, our understanding of the causes of cancer is expanding rapidly. An aspect of this that is less well developed is the role of sphingolipid signaling in cellular homeostasis and death. As our understanding of this improves we have begun to realize that ceramide metabolism is a key player in resistance to therapies, including radiation, chemo and gene therapy. Realizing this our studies have lead to rationally designed compounds which act to increase intracellular levels of ceramide by targeting acid ceramidase (AC) and create a tumor phenotype more susceptible to gene, radiation, or chemotherapy induced cell death (Figure 1). These compounds are highly efficient at activating cell death in prostate, breast and head and neck cancers at nontoxic doses both alone and in combination with current cancer therapies in vivo. They can be administered to mice at doses ranging from 40-75 mg/kg. (Senkel CE, et al., Potent antitumor activity of a novel cationic pyridinium-ceramide alone or in combination with gemcitabine against human head and neck squamous cell carcinomas in vitroand in vivo. J. Pharmacol Exp. Ther, 317(3):1188-1199, 2006; Norris JS, et al., Combined Therapeutic Use of AdGFPFasL and Small Molecule Inhibitors of Ceramide Metabolism in Prostate and Head and Neck Cancers: A Status Report. Cancer Gene Therapy, 13:1045-1051, 2006; Norris JS, et al., The present and future for gene and viral therapy of directly accessible prostate and squamous cell cancers of the head and neck. Future Oncology 1(1):116-123, 2005 and Elojeimy S, et al. Role for acid ceramidase in resistance to FasL: novel therapeutic approaches based on combination of acid ceramidase inhibitors and FasL gene therapy. Molecular Ther., accepted, pending revision, 2007).
Why is this important?
a. Growing cancer cells are subjected to multiple stresses including anoxia, nutrient deprivation, and immune attack. All such insults lead to induction of ceramide, which under normal circumstances tends to result in cell cycle arrest and ultimately cell death (apoptosis or necrosis). However, the constantly changing genomes of cancer cells and the selective pressures involved in successful tumor formation provide escape mechanisms to surmount this homeostatic control point. One mechanism is to ensure that when ceramide is up regulated by stress it is also rapidly metabolized resulting in no net increase. Enzymes including acid and neutral ceramidase will do this and acid ceramidaseis up regulated in over 70% of tumors examined so far (Norris JS, et al. The Combined Therapeutic Use of AdGFPFasL and Small Molecule Inhibitors of Ceramide Metabolism in Prostate and Head and Neck Cancers: A Status Report. Cancer Gene Therapy, 13:1045-1051, 2006; Liu X, et al. Involvement of Sphingolipids in Apoptin-induced Cell Killing, Molecular Therapy 11(3):444-451, 2006; Liu, X, et al. Modulation of Ceramide Metabolism Enhances Viral Protein Apoptin’s Cytotoxicity in Prostate Cancer. Molecular Therapy, 14(5):637-646, 2006).
Ceramidase (acid, neutral, and alkaline species, acid 8p22-p21.3, neutral 10q11.21, alkaline 19p13.3) are of particular interest in this regard. Human acid ceramidasefrequently altered in cancer, maps to 8p22, a region of chromosome 8 frequently identified as altered in many types of human cancer. Acid ceramidase catalyses hydrolysis of ceramide to sphingosine and free fatty acids. Sphingosine-1-phosphate (S1P) is the product of phosphorylation of sphingosine by sphingosine kinase 1. S1P is broken down by sphingosine phosphate phosphatase and/or by sphingosine-phosphate lyase. S1P is primarily formed and released from platelets during thrombotic stimulation. S1P binds to members of the G-protein coupled receptor family namely the Edg receptors (recently renamed S1P receptors). It then mediates several biologic activities including mitogenesis, cell survival, adherence junction formation, endothelial cell morphogenesis into capillary-like structures, and angiogenesis, i.e. it is anti-apoptotic. Conversely, blocking acid ceramidase function reverses this process, increases ceramide levels and produces a pro-apoptoticphenotype.
b.Our recent work has focused on shifting the anti- to pro-apoptotic function by using compounds that were rationally designed to be competitive inhibitors of acid ceramidase. Our compounds have been shown to sensitize cancer cells to cell death when combined with AdGFPFasL, Apoptin, and Trail, chemotherapeutic drugs, and radiation. Our studies reveal the initiation of powerful lysosome-mediated signaling that appears to work through the intrinsic (type II) mitochondrial pathway and lead to apoptosis. By combining this small molecule with gene therapy significant attenuation (and/or cure) of xenografts has been achieved in vivo. Figure 2 is an example of such success in head and neck cancer.