William A. Weiss, M.D., Ph.D.
Associate Professor of Neurology, Pediatrics, and Neurological Surgery

Contact Information:
Email: weiss@cgl.ucsf.edu
Phone: (415) 502-1694
Fax: (415) 476-0133
Box 0663, U441-O

Links:
Lab Website
UCSF Cancer Center

Developmental and stem cell biology program

BMS Graduate Program

Mouse models for tumors of the nervous system

Our laboratory is broadly interested in developing and characterizing mouse models that faithfully recapitulate the biology and genetics of human tumors of the nervous system. Mouse tumors generated by targeting cancer genes to appropriate tissues in genetically engineered mice provide a system to 1) Identify the subsequent genetic events which promote tumorigenesis, 2) Study cancer stem and progenitor cells to understand their contribution to malignant progression, and 3) Develop novel diagnostic and therapeutic modalities.

Targeted expression of EGFR causes oligodendrogliomas in transgenic mice.
Gliomas are the leading cause of cancer death in children, and the most common primary adult brain tumor. Aberrant signaling through EGFR features prominently in this disease. We therefore generated a mouse model for glioma, by over-expressing activated EGFR under control of the S100 beta promoter. These mice developed oligodendroglioma, and are being used to explore progenitor cells for this tumor, and to develop preclinical therapeutic strategies. EGFR signals in-part through activation of PI3 kinase. Activation of PI3-kinase can also occur independently of EGFR. In such patients, blockade of EGFR would not block downstream signaling through EGFR. We therefore treated glioma xenografts with small molecule inhibitors of EGFR, and with siRNA directed against EGFR. These agents, in combination with inhibitors of PI3-kinase, showed cooperativity in blocking further growth of established glioma xenografts. To translate this result to patients, we collaborated with the Shokat lab, and used a collection of PI3K inhibitors synthesized by Knight and colleagues to survey a panel of glioma cell lines, demonstrating that concurrent inhibition of PI3K alpha and mTOR was required to maximally inhibit proliferation. Although blockade of mTOR alone led to activation of PI3K signaling, dual inhibition of PI3K alpha and of mTOR effectively blocked signaling through both kinases, abrogated the activation of PI3K observed using rapamycin as monotherapy, and arrested growth of tumors in-vivo. We are further interrogating signaling nodes in the EGFR-PI3K-MAPK pathways to identify similar mechanistic rationales for specific combinations of small molecules. We have also started identifying progenitor cells in glial neoplasms, and are specifically interrogating the impact of therapies on this important population.

Targeted expression of MYCN causes neuroblastoma in transgenic mice. Neuroblastoma is the third most common tumor of childhood. The proto-oncogene MYCN is amplified in one third of children with neuroblastoma. These tumors are generally incurable. We generated transgenic mice that over-express MYCN in the neural crest and develop neuroblastoma. Genome-wide screens revealed localized gains of mouse chromosome 11 (orthologous to human chromosome 17q commonly gained in human tumors), clustered loss of chromosomes 5, 9, and 16 (syntenic to clustered loss of chromosomes 3p, 4p, and 11q in human tumors), and amplification of the TH-MYCN transgene. Further genetic screening is utilizing gain-of-function mutagenesis to identify specific genes. To evaluate the importance of tumor-microenvironment interactions, we characterized malignant progression, angiogenesis, and angiogenic blockade in murine neuroblastoma. Murine tumors were highly proliferative and displayed a complex vasculature, expressing numerous angiogenic markers in common with human disease. Treatment with angiogenesis inhibitors caused near complete ablation of native tumors, highlighting the importance of tumor-microenvironment interactions in targeted therapy in neuroblastoma. We recently showed that PI3-kinase inhibition destabilized Mycn protein in this model, leading to decreased tumor mass. This approach represents a novel application of kinase inhibitors to destabilize a transcription factor active in cancer (Chesler et al, Cancer Research, in-press). We are currently collaborating with the Shokat lab to test isoform-selective inhibitors of PI3-kinases to identify drug-like molecules effective against Mycn, and well tolerated in-vivo. Cytoxan, an agent used as first line therapy in childhood neuroblastoma, led to p53-dependent apoptosis in murine neuroblastoma. Murine neuroblastoma tumors mutant at p53 were resistant to cytoxan, and are now being developed as a model for drug resistant relapsed neuroblastoma in children. To help us in the design of both treatment and of genetic experiments, we also rederived the TH-MYCN animals using the Tet system, allowing us to regulate transgene expression, and to image tumor-associated luciferase expression in-vivo.

Selected publications
Chesler, L., Goldenberg, D., McMillan, A., Tehan, T., and Weiss, W.A.  Cyclophosphamide shows efficacy in a MYCN-driven transgenic mouse model for neuroblastoma, and induces apoptosis through p53 and PUMA-dependent pathways, Submitted.

Chesler, L, Goldenberb, D, Seales, I. T., Struett, C, Kim, G., Song, S., McQuillen, P, Bergers, G., Brekken, R., and Weiss, W. A. Importance of tumor: microenvironment interactions in a murine tumor of the PNS.  Submitted

Fan, Q-W, Goldenberg, D, and Weiss, W.A.  In-vivo delivery of siRNA directed against DEGFR blocks growth of glioma. Submitted. 

Goh, S., and Weiss, W, A. Genotype: phenotype correlations in tuberous sclerosis:  Who and how to treat.  Ann. Neurol.  In-press.

Persson, A., Fan, Q-W., Phillips, J., and Weiss, W.A. (2006) Glioma. In Gilman, S. Editor:  Neurobiology of Disease, First Edition. Elsevier, San Diego, CA.  In-Press

Chesler, L., Goldenberg, D., Kim, G., McMillan, A., Seales, I, Rowitch, D., Kenney, A., Matthay, K. K., and Weiss, W. A.  Inhibition of PI3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma.  Cancer Research, In-Press.

Knight, Z. A., Gonzalez-Perez, B., Feldman, M., Zunder, E., Goldenberg, D. D., Loewith, R., Balla, A., Balla, T., Weiss, W. A., Williams, R. A., and Shokat, K. M. (2006) A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling, Cell, 125: 733-747.

Fan, Q-W, Knight, Z., Goldenberg, D. D., Shokat, K. M., and Weiss, W.A. (2006) A dual PI3-kinase/mTOR inhibitor reveals emergent efficacy in glioma, Cancer Cell, 9: 341-349.

Fan, QW, and Weiss, W.A. (2006) Chemical genetics approaches to the development of cancer therapeutics, in Balmain, A., and Montell, D., eds, Curr Opin Genet Dev, 16: 1–7.

Ching, T-T, Maunakea, A.K., Jun, P., Hong, C., Zardo, G., Pinkel, D., Alberston, D. G., Fridlyand, J., Mao, J-H., Shchors, K., Weiss, W. A., And Costello, J. (2005)  Epigenome analyses using BAC microarrays identifies evolutionary conservation of tissue-specific methylation of SHANK3.  Nature Genetics, 627: 645-651.

Fan, Q-W, and Weiss, W.A. (2004) RNA interference against a glioma-derived allele of EGFR induces blockade at G2M.  Oncogene, 24:829-927.

Weiss, W. A., and Banerjee, A.  (2004) Can mouse models for brain tumors inform treatment in pediatric patients Seminars in Cancer Biology, 14: 71-77.

Hackett, C, Hodgson, J. G, Law, M., Fridlyand, J., , Kazutoyo Osoegawa, K., , de Jong, P. J., Nowak, N. J., Pinkel, D., Albertson, D. G., Jain, A., ,Jenkins, R, Gray, J., and Weiss, W.A. (2003).  Genome wide array CGH analysis of murine neuroblastoma; Distinct patterns of chromosomal gains and loss parallel those found in human tumors.  Cancer Research, 63:266–5273.

Fan, Q-W, Specht, K., Zhang, C., Goldenberg, D. D., Shokat, K. M., and Weiss, W.A. (2003).  Combinatorial efficacy achieved through two-point blockade within a signalling pathway: a chemical genetic approach.  Cancer Research, 63:8930–8938.

Burkhart, C. A,, Cheng, A., Madafiglio, J., Kavallaris, M., Mili, M., Marshall, G. M., Weiss, W. A., Khachigian, L. M., Norris, M. D., and Haber, M.  (2003) In vivo administration of N-myc antisense oligonucleotides reduces tumorigenesis in a murine model of neuroblastoma. J Natl Cancer Inst. 95:1394-403.

Weiss, W.A., Aldape, K, Hackett, C., Kuriyama, H., Kuriyama, N., Milshteyn, N, Burns, M, Roberts, T., Wendland, M., DePinho, R., and Israel, M. (2003) Genetic determinants of malignancy in a mouse model for oligodendroglioma. Cancer Research 63: 1589-1595.