Department of Neurosurgery

Projects

Mechanisms of hypoxia-induced tumor progression

The Huang laboratory is interested in the molecular mechanisms of hypoxia-induced tumor progression. Hypoxia—deficiency in oxygen supply—is tightly associated with tumorigenesis, as well as with cerebral and myocardial ischemia. When challenged by low oxygen tension, cells strive for oxygen homeostasis by activating hypoxia-inducible factor 1α (HIF-1α), a master regulator of oxygen homeostasis. Activated HIF-1α not only attempts to maintain intracellular energy production by inducing angiogenesis and glycolysis, but also limits energy consumption by means of inhibiting cell proliferation and DNA repair.1 Our research objectives are to identify novel pathways regulating HIF-1α activity, to elucidate the role of HIF-1α in tumor development, and to identify the molecular basis for therapeutic alteration of HIF-1α activity.

Our research focuses on the role of HIF-1α in tumorigenesis and the molecular basis for HIF-1α therapeutics. Solid tumors, including brain tumors, contain hypoxic regions that are often associated with diminished apoptotic potential and resistance to chemotherapy and radiation therapy. The role of HIF-1α in tumorigenesis has been implicated by elevated expression of HIF-1α and HIF-2α, a close member of the HIF-α family, by the correlation of their overexpression with poor diagnosis, and by their role in the induction of angiogenesis and genetic instability. We have recently proposed that the novel HIF-1α–Myc pathway is essential for the hypoxic induction of cell-cycle arrest2 and genetic instability.3 Based on our hypotheses, we are in the process of unraveling the mechanisms by which HIF-1α contributes to hypoxia-induced genetic instability and tumor progression. A variety of experimental approaches are used, including molecular biology, cell biology, genomics, animal models, and human specimens. Given the essential role of HIF-1α in tumor development, we also have a great interest in developing novel therapeutics targeting HIF-1α in both cell culture and animal models for the treatment of tumors and ischemic diseases. We believe that a comprehensive understanding of the biological functions of HIF-1α and HIF-2α is key to the successful development of potential therapeutics.4

  1. To, K. K., Koshiji, M., Hammer, S., Huang, L. E. Genetic instability: the dark side of the hypoxic response. Cell Cycle 4, 881-2 (2005).
  2. Koshiji, M. et al. HIF-1α induces cell cycle arrest by functionally counteracting Myc. EMBO J 23, 1949-56 (2004).
  3. Koshiji, M. et al. HIF-1α induces genetic instability by transcriptionally downregulating MutSα expression. Mol Cell 17, 793-803 (2005).
  4. Huang, L. E. Targeting HIF-α: when a magic arrow hits the bull's eye. Drug Discov Today 9, 869 (2004).

Genetic abnormalities that cause pediatric brain tumors

Medulloblastoma, a cancer that arises in the developing cerebellum, is the most common solid tumor in children. Medulloblastomas result from defects in signal transduction pathways governing the growth and differentiation of neural progenitor cells. A barrier to improving patient treatment is collateral damage to the developing nervous system caused by radiation and chemotherapy.

The overall objective of Dr. Fults's current research is to identify signaling molecules that mediate the genesis and progression of medulloblastoma. To do this, he is using a mouse model of medulloblastoma that he developed using the RCAS/tv-a system. This system utilizes a retroviral vector (RCAS), derived from avian leukosis virus (ALV), and a transgenic mouse line (Ntv-a) that produces TV-A (the cell surface receptor for ALV) under control of the Nestin gene promoter.

Nestin is an intermediate filament protein expressed by neuronal and glial progenitor cells. This system makes it possible to express exogenous proteins in nestin-expressing neural progenitor cells inside the brain of live mice. Dr. Fults found that activation of the Sonic hedgehog signaling pathway in neural progenitor cells of the cerebellum induces medulloblastoma formation. Tumor induction is enhanced by activation of insulin-like growth factor (IGF) signaling and over-expression of the oncogenic transcription factors, c-Myc and N-Myc.

The long-range benefit of this research will be the identification of potential targets for anti-cancer drugs or future gene therapy strategies. Insights into the molecular pathogenesis of medulloblastoma will also be directly relevant to brain development.

Benign and malignant brain tumor angiogenesis and biology

The Jensen laboratory is interested in both benign and malignant brain tumor angiogenesis, biology, and developing novel treatment modalities for these tumors. The first emphasis is on the role of Hypoxia-Inducible Factor-1 in maligant brain tumor angiogenesis and growth.

We are currently using siRNA techniques to inhibit HIF-1 in mouse tumor models with hopes of initiating human clinical trials in the near future. A second emphasis is toward an understanding of the biology of and the treatment of unresectable or recurrent meningiomas. Current investigations include the use of calcium channel antagonists to potentiate common chemotherapeutic approaches to the treatment of meningiomas.

We have also examined the role of COX-2 in meningioma development and growth. We have successfully inhibited the growth of meningiomas with COX-2 inhibitiors. To better understand meningioma biology, we have developed animal models and evaluated currently available cell lines. Our hope is to provide cutting edge approaches to treat both benign and maligant brain tumors and transition these to Phase I Human clinical trials.