Research

Psammomatous meningioma
Ciliated Tetrahymena
Classic medulloblastoma
Choroid meningioma
Desmoplastic medulloblastoma
Primary cilium
Angiomatous meningioma
Classic medulloblastoma
Papillary meningioma
Ciliated sea urchin embryo
Desmoplastic medulloblastoma
Meningioma invading bone

Research Program

Primary cilia (red and green) in Hedgehog-associated medulloblastoma

Signal transduction networks are essential for normal development. Misactivation of developmental pathways can cause congenital disorders and cancers in children, and reactivation of these pathways can drive cancer in adults. The Raleigh Laboratory studies how developmental pathways cause cancer. Our research makes use of biochemistry, molecular biology, cell biology, mouse genetics, genomics, bioinformatics and pharmacology to gain new insights into the molecular determinants of human malignancies. In addition to illuminating how developmental pathways function in cancer, our work aims to shed light on the fundamental mechanisms of developmental biology. 

To accomplish these multidisciplinary goals, the Raleigh Laboratory fosters broad collaborations with other basic science laboratories and clinicians at UCSF and abroad:

The Reiter Laboratory, UCSF Department of Biochemistry and Biophysics

The Brain Tumor Center, UCSF Department of Neurological Surgery

Dr. Michael McDermott, UCSF Department of Neurological Surgery

Dr. Arie Perry, UCSF Department of Pathology, Division of Neuropathology

Dr. Joanna Phillips, UCSF Department of Pathology, Division of Neuropathology

Dr. Steve Braunstein, UCSF Department of Radiation Oncology

Dr. Olivier Morin, UCSF Department of Radiation Oncology

The Xu Laboratory, University of Washington School of Pharmacy

 

 

Hedgehog signaling in cancer

T2-weighted MRI: Medulloblastoma

More children die from brain tumors than any other type of cancer, and current therapies leave survivors with devastating disabilities. The most common type of brain tumor in children is medulloblastoma. Approximately one-third of medulloblastomas arise when a developmental pathway, called Hedgehog, gets stuck in the 'on' position. Hedgehog proteins control tissue homeostasis, stem cell maintenance and developmental patterning in evolutionarily diverse organisms. In vertebrates, Hedgehog signals are transduced by the primary cilium, an antenna-like projection on the surface of most cells. We are interested in uncovering exactly how ciliary Hedgehog signals tell cancer cells to grow. To do so, we are investigating (i) how the Hedgehog pathway is misactivated in cancer, and (ii) how Hedgehog misactivation induces cancer cell growth. Understanding how Hedgehog signals cause cancers may show us how to turn off these signals, and potentially, lead to new therapies for medulloblastoma and other Hedgehog-associated malignancies.

Using mouse genetic models, bioinformatics and mass spectrometry, we discovered lipids that activate the Hedgehog pathway to express genes which tell cancers cells to grow. Blocking the function of these lipids inhibits cancer in preclinical mouse genetic models of Hedgehog-associated medulloblastoma. Downstream of the lipids that activate the pathway, we also discovered a cell cycle-activator that is a direct target of the Hedgehog transcriptional program. Once more, we found that blocking the activation of the cell cycle in mouse genetic models of Hedgehog-associated medulloblastoma inhibits the growth of cancer. Ongoing projects aim to (i) define the biosynthesis and trafficking of lipids that activate the Hedgehog pathway, (ii) identify additional Hedgehog pathway targets that cause cancer cells to grow, and (ii) determine the mechanisms of acquired resistance to molecular therapy in medulloblastoma. In the interim, work is underway to initiate a trial of molecular therapy for human medulloblastoma patients based on our data. 

 

Meningioma

T1-weighted post-contrast MRI: Meningioma

Meningioma, a tumor of the cerebral and spinal meninges, is the most common brain tumor in the United States. Surgery and radiation are effective therapies for most meningioma patients, but approximately one-quarter of meningiomas follow an aggressive clinical course characterized by recurrence and multiplicity. There are no effective systemic therapies or tractable mouse genetic models for meningioma. Moreover, the molecular drivers of meningioma are unknown. We are interested in illuminating how meningiomas grow to (i) understand meningeal formation, (ii) develop preclinical meningioma models, and (iii) reveal druggable targets for molecular therapy to improve outcomes for meningioma patients.

To accomplish these goals, we developed an integrated database containing tissue samples and comprehensive clinical and radiographic data from approximately 300 patients with meningioma. Using these unique resources, we discovered an integrated molecular signature through the genome, epigenome, transcriptome and proteome which drives meningioma growth. We identified a master transcription factor that regulates meningioma gene expression, and discovered that the Wnt pathway, which is required for normal development, promotes meningioma proliferation.

Ongoing projects aim to (i) determine if blocking meningioma gene expression inhibits meningioma cell growth, (ii) identify additional targets for meningioma molecular therapy, (iii) create clinical biomarker assays to predict meningioma behavior, and (iv) develop mouse genetic models of meningioma to further investigate the molecular signals which cause meningiomas to grow. Akin to medulloblastoma, work is also underway to initiate a trial of molecular therapy for human meningioma patients based on our data.