The research program of Daphne Haas-Kogan, MD, focuses on developing targeted therapies for brain and pediatric malignancies. Her laboratory is primarily interested in histone deactylase (HDAC) inhibitors and phosphoinositide-3 (PI3)-kinase inhibitors, and has identified and characterized several agents that can effectively potentiate the radiation response of glioma and neuroblastoma tumors.
Current Research Projects
EGFR amplifications and mutations and PTEN mutations are two of the most common genetic alterations in glioblastoma (GBM). These therefore potentially represent both important therapeutic targets, as well as biomarkers of response to targeted therapies. Erlotinib is a potent and relatively selective inhibitor of epidermal growth factor receptor (EGFR) which has recently been approved for the treatment of non-small cell lung cancer, and is currently being tested for a number of additional indications. Studies examining erlotinib for the treatment of gliomas have disclosed encouraging results; however, objective tumor responses are documented in a limited number of patients. Our results (Haas-Kogan et al., 2005), and those of others (Mellinghoff et al., 2005), have suggested opportunities to enrich for patients who are likely to respond to erlotinib. Our studies analyzed PKB/Akt phosphorylation, and showed that only patients whose tumors showed low PKB/Akt phosphorylation demonstrated tumor shrinkage in response to erlotinib treatment.
These results suggest that increased PI3-kinase pathway activity results in resistance to erlotinib treatment in GBMs, even in tumors that show amplification and/or overexpression of EGFR. These results also prompt the question of whether increased PKB/Akt phosphorylation/activity is the causal downstream effector of PI3-kinase-mediated resistance, or whether it merely represents a marker for increased PI3-kinase activity, and the erlotinib resistance is conferred by other PI3-kinase effectors. We are using three Exelixis compounds in these studies: XL147 (PI3K inhibitor), XL765 (PI3K/mTOR inhibitor) and XL418 (PKB/S6K inhibitor). Although previous data suggest that dual PI3-kinase/mTOR inhibition is required to inhibit the proliferation of GBM tumor cells (Fan et al., 2006), this concept needs to be validated.
We use human GBM specimens that have been serially passaged in nude mice. In contrast to GBM cell lines propagated in cell culture, these xenografts maintain amplification and overexpression of EGFR when present in the resected primary tumor. 24 xenografts have been established, 10 of which have amplified EGFR (3 of these with amplified EGFRvIII). Two of these xenografts also contain mutations in the extracellular domain of EGFR, the significance of which in determining response to targeted therapies remains unknown. In addition to EGFR amplification, these glioma xenografts have also been analyzed for additional GBM signature lesions, including PTEN mutations, cdk4 amplification, mdm2 amplification, p53 mutation, and p16 deletion. Therefore, these xenografts represent an attractive animal model for single agent and combination therapy of PI3-kinase and EGFR inhibitors.
In our laboratory we seek to determine whether selected GBM xenografts are responsive to PI3K, PI3K/mTOR, or PKB/S6K inhibitors, either as monotherapy or in combination with erlotinib in vitro and in vivo. We are testing the ability of the three Exelixis compounds to regulate biochemical signaling and cell viability in the eight xenografts mentioned above in vitro and in vivo. We are further testing whether PI3-kinase inhibitors can confer erlotinib sensitivity. More
Novel therapies for neuroblastoma
Neuroblastoma, a tumor derived from the sympathetic nervous system, is the second most common pediatric solid cancer. The majority of children presents with advanced disease, and have less than 40% survival, due to frequent development of resistance to standard chemotherapy and radiation. A dearth of effective novel agents with tolerable toxicities has hampered improvements in survival for high-risk patients. Radiation plays an important role in the treatment of high-risk neuroblastoma. 131I-metaiodobenzylguanidine (131I-MIBG) is a form of radiation therapy that delivers radioactive 131I selectively to tumor cells. Although this targeted approach tends to minimize adverse effects, 131I-MIBG treatment is still limited by bone marrow toxicity, and by the tendency for tumors to become resistant. We have already shown in multiple clinical trials that 131I-MIBG is effective in producing responses in children with relapsed neuroblastoma in 40% of cases, but long term survival is rare in these resistant patients. Manipulation of biochemical pathways provides an approach to decrease tumor growth and increase radiation sensitivity.
In our laboratory we are investigating two novel approaches to neuroblastoma treatment. In the first, we are using a histone deacetylase inhibitor named vorinostat. In the second we are using PI3-kinase inhibitors. For both approaches we are testing the novel drugs as single agents as well as in combination with radiation—both external beam radiotherapy and 131I-MIBG. After our in vitro and in vivo clinical studies we are planning to test these therapies clinically through the National Cancer Institute funded “New Approaches to Neuroblastoma Therapy” (NANT) consortium, as well as newly diagnosed patients in the Children’s Oncology Group, the major national group focused on childhood cancer. More