Haas-Kogan Laboratory

The research program of Daphne Haas-Kogan MD focuses on developing targeted therapies for brain and pediatric malignancies. Her research has identified and characterized several agents that can effectively potentiate the radiation response of glioma and neuroblastoma tumors. The goal of Dr. Haas-Kogan’s research is to characterize aberrant signaling pathways in central nervous system and pediatric tumors and investigate agents that target these signaling cascades. Dr. Haas-Kogan has a broad background in neuro-oncology, radiation oncology, and molecular biology, with specific training and expertise in key research areas for this application. As a resident in radiation oncology and fellow in neuro-oncology she characterized pathways that underlie resistance of gliomas to standard treatment such as radiation. As a faculty member with a joint appointment in Radiation Oncology and Neurological Surgery she has expanded her research to include signaling pathways in gliomas and inhibitors that target elements within these pathways.

Dr. Haas-Kogan has been the PI on clinical trials testing molecular therapeutics in pediatric gliomas and holds leadership positions in the Children’s Oncology Group and Pediatric Brain Tumor Consortium. As a translational scientist Dr. Haas-Kogan has taken findings from the laboratory and used them to design clinical trials for adults and children with gliomas. She has successfully carried out laboratory research, designed clinical trials, and established a robust clinical practice in radiation oncology, focusing on brain tumors and pediatric malignancies.

Current Research Projects

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Signaling inhibitors for glioma and neurobastoma
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.

Recent pre-clinical work from Dr. Haas-Kogan’s laboratory has investigated the anti-neoplastic effects of dual PI3K/mTOR inhibitors as single agents and in combination with radiation and temozolomide. The dual inhibitor XL765 showed significant cytotoxic activity in vitro against a panel of primary glioma and neuroblastoma cell lines independent of their genetic backgrounds. These results demonstrate that in orthotopic models, XL765 + radiation have additive effects in vitro and XL765 + temozolomide have synergistic anti-tumor activity in vitro and in vivo (Prasad G, Sottero T, Yang X, Mueller S, James CD, Weiss WA, et al. Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide. Neuro-oncology. 2011;13(4):384-92).

Our work with XL765 (Sanofi-Aventis/Exelixis) exemplifies our commitment to tranlating our laboratory findings into clinical practice for patients with pediatric and brain tumors. The pre-clinical results from our laboratory combined with ongoing adult trials have led to a Phase 1 clinical study within the Pediatric Brain Tumor Consortium (PBTC) that Drs. Haas-Kogan and Mueller will co-chair. This will be the first test of this type of agent in pediatric patients, and would pave the way for future combination studies of dual PI3K/mTOR inhibitors in pediatric brain tumors and in neuroblastoma.

Dr. Haas-Kogan has extended her work on signaling inhibitors to include both adult and pediatric low-grade gliomas (LGGs). Her studies of adult LGGs document that, as opposed to the mutation of PTEN in de novo malignant gliomas, the methylation of the PTEN promoter is frequently responsible for PTEN inactivation and PI3K activation in adult and pediatric LGG. Resultant PI3K/AKT/mTOR activation in approximately half of adult and pediatric LGG provided a biological rationale for initiation of a Phase 2, single institution, UCSF trial in which adults with recurrent LGG are treated with the mTOR inhibitor everolimus, a study that is ongoing. Of the 24 enrolled patients, 11 continue on active treatment, and, remarkably, 3 continue to have stable disease on everolimus, for nearly two years, despite multiple prior recurrences. Molecular analyses on all accrued patients are critical to this study and will test the hypothesis that PI3K/mTOR activation predicts response to mTOR inhibition. Thus, results from our pre-clinical work have yielded mechanism-based clinical studies with appropriate therapeutic biomarkers to investigate the basis for variable responses to therapy.
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SAHA (vorinostat) makes tumors sensitive to radiation

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 the role of radiosensitizers in neuroblastoma, with the goal of enhancing the efficacy of a targeted radiopharmaceutical metaiodobenzylguanidine (MIBG) for treatment of this tumor, derived from the sympathetic nervous system. Ninety percent of neuroblastoma tumors express the human norepinephrine transporter (hNET) that is responsible for uptake of MIBG, a norepinephrine analogue. Phase 1 and 2 clinical trials with 131I-MIBG at UCSF showed a high response rate in refractory neuroblastoma. Work in Dr. Haas-Kogan’s laboratory, established a working human xenograft metastatic model of neuroblastoma using luciferase labeled NB1691, and then proceeded to show the efficacy of a histone deacetylase (HDAC) inhibitor in combination with radiation therapy to inhibit growth of the tumors (Mueller S, Yang X, Sottero TL, Gragg A, Prasad G, Polley MY, Weiss WA, Matthay KK, Davidoff AM, DuBois SG, and Haas-Kogan DA. Cooperation of the HDAC inhibitor vorinostat and radiation in metastatic neuroblastoma: efficacy and underlying mechanisms Cancer Letters. 2011, in press). This pre-clinical study led to a NANT phase I combining vorinostat, an HDAC inhibitor approved for lymphoma, combined with 131I-MIBG.
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