Anil K. Sood, M.D.
Gynecologic Oncology and Cancer Biology
University of Texas MD Anderson Cancer Center
1515 Holcombe Blvd, Unit 1362, CPB6.3275
Houston, TX 77030
United States of America
(713) 404-8831 pager
My research program in cancer research encompasses three main areas of research: 1) neuroendocrine effects on ovarian cancer growth and progression; 2) anti-vascular approaches in ovarian cancer; and 3) development of novel nanoparticles for systemic in vivo delivery of siRNA. The trainees in my research group are heavily involved in all of these projects, as evidenced by their publications.
Therapeutic Gene Silencing In Vivo Using RNA Interference. While many new therapeutic targets have been identified, it is not possible to target all of these with conventional approaches such as small molecule inhibitors due to several reasons including: 1) large structure (eg, p130Cas) that would be difficult to target with a small molecule inhibitor; 2) kinase-independent functions, 3) high content of disorder in the native state; 4) multiple structural domains with independent functions, and 5) structure not fully known. In essence, the dearth of structural information precludes an effective use of other rational drug-design approaches. Moreover, most small molecule inhibitors lack specificity and can be associated with intolerable side effects. Similarly, while monoclonal antibodies have shown promise against specific targets such as VEGF, their use is limited to either ligands or surface receptors. The inability to target many novel, but promising targets with other approaches prompted us to utilize RNA interference (RNAi). Use of short interfering RNA (siRNA) as a method of gene silencing has rapidly become a powerful tool in protein function delineation, gene discovery, and drug development. The promise of specific RNA degradation has also generated much excitement as a possible therapeutic modality, but in vivo siRNA delivery has proven difficult. We have recently developed strategies for systemic siRNA delivery that allow therapeutic targeting of these and other proteins that would otherwise not be “drugable”. This strategy relies on highly efficient delivery of short interfering RNA (siRNA) systemically using a neutral nanoparticle. In proof-of-concept studies, we have targeted several genes that are critical for driving tumor growth and progression using this technology and demonstrated both in vivo gene silencing and therapeutic efficacy using orthotopic models of ovarian and other cancers. This work has been published in Cancer Cell, Nature Medicine, and Journal of the National Cancer Institute. Based on guidance from the FDA, we are conducting formal toxicology studies in anticipation of a first-in-human phase I trial with this novel therapeutic method. Our goals are now to develop highly targeted delivery methods for siRNA and non-coding RNAs.
Anti-Vascular Approaches in Ovarian Cancer. A major problem in management of ovarian cancer is metastasis. The progressive growth of primary tumor and metastases is dependent on an adequate blood supply (angiogenesis). Despite improvements in surgery and chemotherapy, the mortality rates in women with advanced ovarian carcinoma have remained largely unchanged. Targeting endothelial cells that support tumor growth is particularly promising because these cells are thought to be genetically stable and, therefore, less likely to accumulate mutations that would allow them to develop drug resistance. Vascular endothelial growth factor (VEGF) plays a critical role in neovascularization and consequent ovarian cancer growth and progression. Our findings demonstrate that a novel approach (high-affinity VEGF decoy receptor, VEGF Trap) for VEGF blockade is highly effective in combination with taxane chemotherapy in preclinical murine models and we have initiated a Phase I/II clinical trial as a part of the M. D. Anderson Ovarian Cancer SPORE grant. However, we recognize that despite the initial response rates to VEGF-targeted therapy, most patients eventually develop progressive disease. Therefore, new anti-angiogenic approaches are needed. We have completed a series of studies to provide a better understanding regarding the tumor vasculature over the last 5 years and some of the highlights include: 1) demonstration of the complexity of tumor vasculature in that a fraction of the vasculature in ovarian cancers is directly lined by tumor cells; 2) identification of gene differences in endothelial cells from tumor vasculature compared to normal ovarian endothelial cells; 3) development of novel metronomic chemotherapy approaches; 4) identification of mechanisms underlying VEGF-resistance; 5) clinical and functional characterization of novel angiogenesis targets including Src, focal adhesion kinase, PDGF-R, EphA2, and EphB4; 6) identification of new signaling pathways that allow pericytes to regulate endothelial cell survival in the tumor vasculature; and 7) combinatorial approaches for anti-vascular effects including the role of dual receptor (EGF-R and VEGF-R) targeting. These and other avenues constitute fertile areas for further research.
Neuroendocrine Modulation of Cancer Growth and Metastasis. Clinical studies have indicated that stress, chronic depression, social support, and other psychological factors can influence cancer onset and progression. Environmental and psychosocial processes initiate a cascade of information processing pathways in the central nervous system (CNS) and periphery, which subsequently trigger fight-or-flight stress responses in the autonomic nervous system (ANS) or defeat/withdrawal responses produced by the hypothalamic-pituitary-adrenal (HPA) axis. The adverse effects of chronic stress and associated hormones on the immune system have been known for a long time. However, the effects of these hormones on non-immune mechanisms of tumor growth and progression have not been well characterized. My laboratory made the novel observation that stress hormones can have direct effects on ovarian cancer cells via beta-adrenergic receptors and promote angiogenesis, tumor growth and progression. We have demonstrated direct modulation of pro-angiogenic cytokines and other metastasis-promoting genes such as FAK by key components of the sympathetic nervous system such as catecholamines. We have characterized these factors in pre-clinical and clinical settings and multiple publications have come out of this work including papers in Nature Medicine and Nature Reviews Cancer. Our ongoing work in this area of research is focused on dissecting the underlying pathways involved in cancer progression by neuroendocrine hormones using both in vitro and in vivo approaches that will be validated in human samples. Our long-term goal is to perform intervention studies to block the effects of stress biology on tumor growth. These strategies may include behavioral as well as pharmacological interventions.