Mechanisms and Cell Signaling Pathways of Autophagy and Apoptosis
For the past three decades, Dr. Gabriel Lopez-Berestein and his laboratory have studied cell signaling pathways involved in monocyte and white blood cell activation and differentiation, as well as regulatory mechanisms of cell death and survival. Several years ago we defined the role of retinoids in monocytic activation/differentiation and genes involved in their “terminal differentiation.” This body of work led to the identification of post-transcriptional events involved in promyelocytic leukemia cells. Most recently, Dr. Bulent Ozpolat explored the role of autophagy in leukemic and solid tumors showing that this process may be involved in both cell death and survival.
For more than a decade, Dr. Ana Tari, adjunct associate professor, studied the regulation of cell growth signaling pathways in leukemias, particularly chronic myelogenous leukemia (CML), and breast cancer. Early on, Tari focused on the role of the adaptor protein, Grb-2, demonstrating that its inhibition by antisense oligonucleotides (ASO) targeted to Grb-2 resulted in cell growth inhibition in leukemias and solid tumors. A liposomal carrier for a p-ethoxy-modified ASO resulted in a pharmaceutically feasible liposomal formulation and an IND for liposomal-Grb-2 was submitted to the FDA for a Phase I study in CML and related diseases.
Translational Application of siRNA Using Nanoparticle Carriers
Beginning in the early 1980s, we began exploring the use of liposomal carriers for therapeutic applications and were the first group in the U.S. to study the pharmacokinetics, distribution and safety of liposomal carriers in cancer patients. This study was fundamental for further development of this innovative technology. Since that time, our laboratory developed – from bench to clinic – several antifungals and antitumor therapeutics, such as lipid-based Nystatin and Amphotericin B for fungal infections, the latter now marketed as ABELCET, and Annamycin, Aroplati and Lipo–ATRA (ATRAGEN), among others, as anticancer therapeutics. It is worth noting that single-agent ATRAGEN can cure some patients with untreated acute promyelocytic leukemia without the use of chemotherapy.
Over the last six years, in close collaboration with Dr. Anil Sood, we developed an understanding of several pathophysiologic mechanisms in ovarian cancer leading to the development of novel targets and, subsequently, the translational application of siRNA to animal models using nanoparticle carriers. We showed that nanoliposomes delivered siRNA deep into tumor tissues resulting in specific down-modulation of the specific target and antitumor activity in several experimental tumor models. We are in the process of bringing one of these targeted therapies to clinical application.