Carlotta A. Glackin, Ph.D. received her BA/BS degrees at University of California, Los Angeles (UCLA) and University of Colorado (CU), Boulder in Biochemistry and Molecular Cellular Developmental Biology respectively. She then pursued her Ph.D. research in Molecular Biology under the guidance of Dr. James Bonner and continued her postdoctoral training in Molecular and Developmental Biology with Dr Barbara Wold’s group at the California Institute of Technology, Pasadena, CA.
In 1993, she started as an Assistant Research Professor in the Division of Anatomic Pathology at City of Hope Medical Center and received tenure in 2000 as an Associate Professor in the Division of Molecular Medicine and Department of Developmental and Stem cell Biology at the Beckman Research Institute of the City of Hope. She has been internationally recognized for her work in stem cell research and in 2007 received Awards from the Medical Research Council of South Australia where she spent a sabbatical with Dr Stan Gronthos’ Stem Cell group, at the Institute of Medical and Veterinary Science in Adelaide. South Australia. She has also received many national and foundation research grants over the years including: National Institutes of Health/National Cancer Institute (NIH/NCI), Department of Defense (DoD/BCRP), Susan G Komen, Foundation for Women’s Cancer, STOP CANCER, and the City and City of Hope Cancer Center Grants.
Currently, Dr. Glackin’s research focuses on the TWIST family of basic helix-loop-helix transcription factors vital in development and reactivated in many cancers, including breast and ovarian. TWIST proteins regulate epithelial to mesenchymal transition (EMT), the process underlying metastatic spread. Furthermore, recent studies from multiple groups have correlated mesenchymal characteristics with a cancer stem cell phenotype, angiogenesis, and chemoresistance to a variety of agents. The Glackin lab is pursuing many lines of research to understand how TWIST operates in women’s cancers, and how it could be targeted for new cancer therapies. Her recent therapeutic pilot studies demonstrate efficacy in tumor size and weight in animal models. With this success, she hopes to generate additional funds for larger pre-clinical studies at City of Hope to gain critical data required for FDA approval for a human phase I/II clinical trial at City of Hope. Dr. Glackin’s research provides another promising approach to therapy that could bring healing to so many women battling cancer.
Selected Glackin Laboratory Research Projects:
1) Understanding the role of TWIST in drug resistant epithelial ovarian cancer (EOC)
The vast majority of EOC patients present with advanced metastatic disease, but will respond well to first-line chemotherapy consisting of a platinum drug and/or paclitaxel. Unfortunately, most of these patients will relapse with disease that is both metastatic and drug resistant, leading to a five-year survival rate under 20%. We are investigating the role of TWIST family proteins in these relapses. We have identified several genes and pathways that are differentially expressed in cells where TWIST is present versus those where it is silenced. Of these, many relate to survival signals and resistance to apoptosis, while others upregulate DNA repair machinery that fixes platinum lesions on DNA. We are actively working to determine which pathways are most important and which can be targeted therapeutically.
2) Using siRNA and nanoparticles to target TWIST directly in EOC
Because transcription factors are difficult to target with small molecule drugs due to their nuclear localization, we employ siRNA to target TWIST mRNA, in order to reduce metastasis and re-sensitize cancer cells to conventional chemotherapeutic agents. We have designed and validated two siRNAs against TWIST and in collaboration with Drs Jeff Zink and Fuyu Tamanoi at UCLA, have created a polyethylenimine (PEI) coated mesoporous silica nanoparticle (MSN) to be utilized as a delivery system for the siRNA, which would be translatable from the bench to the clinic. Fluorescent microscopy demonstrated that all tested cell lines efficiently take up MSNs, delivering their siRNA cargo to the cell interior. Furthermore, TWIST knockdown sensitized cells to chemotherapy. We will utilize cell lines and patient derived xenografts to test TWIST knockdown as a therapeutic approach in various forms of ovarian cancer, as a combination therapy with standard chemo. We will also evaluate the effects of TWIST knockdown using MSNs in animal models on a metastatic phenotype in the hopes that MSNs will be a platform for therapies to prevent both metastatic spread and acquired resistance in ovarian and other cancers.
3) Using siRNA and nanoparticles to target TWIST in triple negative breast cancer
While rare, the triple negative (ER, PR, HER2 non-expressing) subtype of breast cancer is particularly aggressive and difficult to treat. Because it lacks commonly targeted receptors, antibody drugs are of little use. Therefore, as in EOC, new therapies are needed and once again we propose TWIST as a promising target. Triple negative breast cancer (TNBC) often metastasizes and has a large cancer stem cell population, both of which suggest TWIST involvement. We have demonstrated that treatment using our siRNA/nanoparticle approach to knock down TWIST in a melanoma is sufficient to reduce tumor growth in a mouse model, and we are working to duplicate these results in TNBC. In both EOC and TNBC, we will be using next-generation nanoparticles capable of delivering both siRNA against TWIST and traditional chemotherapy drugs with a single particle, with either pH-specific or on-command release of their cargo.
4) Understanding and targeting TWIST protein-protein interactions
We and others have shown that TWIST binds to other proteins via its unique C-terminal Twist Box or WR Domain. We have generated a series of mutations in the WR domain and assessed their impacts on binding to a particular TWIST partner, NFkB p65. This binding interaction is of interest in cancers, as the two proteins synergistically upregulate the expression of interleukin-8, which in turn activates the proteases that chew through extracellular matrix. It is this degradation of the matrix that allows invasion and metastasis to occur, and thus is an additional point at which TWIST’s pro-metastatic functions may be targeted. To this end, we are also conducting proof of concept studies to inhibit TWIST-p65 binding with an eye towards translation to the clinic. There are many more binding partners for TWIST, and we are working to identify and characterize the interaction between several of these factors. We hope to identify novel pathways regulated by TWIST, and add to the growing list of cancer processes regulated by TWIST.
5) Structural biology and TWIST
In collaboration with Dr John Williams and the City of Hope Structural Biology Core, we are working to generate crystallographic structures of TWIST protein-protein complexes. The WR domain of TWIST, used to form these complexes, is unique to the TWIST family, and so would make an excellent drug target. However, precise 3D models of a target site are required for drug design, and we aim to be the first to produce such data on TWIST.
Information listed here is obtained from Pubmed, a public database; City of Hope is not responsible for its accuracy.