Cancer is a genetic disease caused by activating mutations in oncogenes and inactivating mutations in tumor suppressor genes. One major focus of modern cancer research has been the identification of these oncogenes and tumor suppressor genes, with the idea that their discovery and functional analysis would identify cancer pathways that could be targeted with novel therapeutics. Research in our lab focuses on the identification, functional analysis, and therapeutic targeting of several different tumor suppressor gene pathways that are commonly inactivated in glioblastoma multiforme. The specific genetic pathways we study are described in detail below.
STAG2 Inactivation and Aneuploidy
One of the most common features that distinguish cancer cells from normal cells is the presence of aneuploidy. We have recently discovered a cause of aneuploidy in GBM as well as in several other common human cancers – deletions, somatic mutations, and loss of expression of the STAG2 gene (Science 336:1039, 2011). Most recently we have discovered that STAG2 is among the most commonly mutated genes in bladder cancer (submitted for publication). The STAG2 protein is a key component of the multi-protein cohesin complex which regulates sister chromatid cohesion and helps ensure faithful chromosome segregation during mitosis. We are currently performing a variety of studies designed to further define the mechanism through which STAG2 inactivation leads to chromosomal instability, aneuploidy, and cancer. The broad goal of this research program is to determine the mechanism through which STAG2 inactivation leads to cellular transformation, making it possible to develop strategies for identifying novel anticancer therapeutics that specifically target aneuploid cells. This research is supported by R01CA169345 from the National Cancer Institute and an Innovation Award from Alex’s Lemonade Stand Foundation.
PTEN and Cell Size Control
PTEN is among the most commonly inactivated tumor suppressor genes in GBM. We have previously demonstrated that PTEN plays a central role in enforcing cell size arrest during radiation-induced cell cycle arrest (Cancer Res 64:6906, 2004). We hypothesize that loss of the cell size checkpoint contributes directly to the pathogenesis of GBM. Over the past few years, we made a number of observations directly related to the size checkpoint: (i) Like other checkpoints that are commonly defective in cancer cells, the PTEN dependent cell size checkpoint is inducible by ionizing radiation and DNA-damaging chemotherapeutic drugs (Mol Cell Biol 31:2756, 2011). (ii) The PTEN-dependent cell size checkpoint is Akt-independent; (iii) PTEN-dependent actin remodeling is required for cell size checkpoint control; (iv) Endogenous PTEN interacts at the membrane with a novel, PIP2-regulated actin remodeling complex; (v) Mutational inactivation of PTEN leads to activation of p53, suggesting the existence of crosstalk between the size checkpoint and the G1/G2 checkpoints (Mol Cell Biol 27:662, 2007). We are currently performing a number of projects designed to build on these advances to further evaluate the mechanistic basis and phenotypic consequences of PTEN inactivation in the pathogenesis of GBM. This research is supported by R01CA115699 from the National Cancer Institute.
Cdk4/6 Inhibitor Therapy for GBM
GBM is extremely aggressive tumor type, with an average survival of only 12-18 months. Therefore, there is a desperate need for new therapeutic approaches to treat this deadly disease. Numerous studies have clearly established that the cell cycle kinases cdk4 and cdk6 are activated during the pathogenesis of GBM, usually due to homozygous deletion of the INK4 locus (containing the p16INK4a and p15INK4b genes). Since cdk4 and cdk6 are activated in ~90% of GBMs and GBM has been clearly shown to be “addicted” to activated cdk4/6, these proteins represent an extremely promising molecular target for the treatment of GBM. In a collaborative effort between our lab and David James’ lab at UCSF Cancer Center, we demonstrated that PD0332991, a specific pharmacological inhibitor of cdk4/6, is remarkably effective in halting the growth of GBM in preclinical models (Cancer Res 70:3228, 2010). This study motivated the first clinical trial for testing a cdk4/6-specific inhibitor in GBM, which is currently underway at UCSF (PI: Michael Prados). Our ongoing work in this area has three main goals. First, we are working to distinguish between the roles of cdk4 and cdk6 in GBM pathogenesis and determine which enzyme is the key target of inhibition by PD0332991 in GBM. Second, we are working to determine the mechanisms of intrinsic and acquired resistance to cdk4/6 inhibition in GBM. Third, we are evaluating the efficacy and toxicity of PD0332991 in combination with radiotherapy and temozolomide. The broad goal of this research is to further develop the concept of cdk4/6 inhibition as a therapeutic strategy for GBM. This research is supported by R01CA159467 from the National Cancer Institute.