University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
William A. Weiss, MD, PhD

William A. Weiss, MD, PhD

Professor, Departments of Neurology, Pediatrics, and Neurological Surgery, UCSF; Co-Leader, Pediatric Malignancies Program, UCSF Helen Diller Family Comprehensive Cancer Center
Evelyn and Mattie Anderson Endowed Chair in Cancer Resesarch, UCSF

Cancer Center Program Memberships

Pediatric Malignancies

Research Summary

We develop and use in-vivo models for neural cancers to: 1) Identify genetic events that promote tumorigenesis. 2) Study cancer stem and progenitor cells. 3) Evaluate new targets, chemical genetic approaches, and mechanistic rationales for combining targeted agents.

Stem cell biology, genetics, and developmental therapeutics in glioma. Aberrant EGFR signaling features prominently in glioma, the most common primary adult brain tumor. We generated a mouse model for glioma by over-expressing EGFR under the S100 beta promoter (Weiss, 2003). Expression of oncogenes in rare cancer-stem-like cells in the subventricular zone led to differentiation block and aberrant glial differentiation, resulting in astrocytoma (Persson, In revision). In contrast, murine oligodendrogliomas arose from abundant oligodendroglial progenitors in white matter. We described a progenitor origin for this more favorable form of glioma, demonstrating that a progenitor rather than a stem-cell origin underlies the improved outcome in patients (Persson, 2010). We were among the first to describe oncogene addiction driven by activated EGFR (Fan, 2002). We described and characterized dual inhibitors of PI3K and mTOR, demonstrating that these drugs blocked mTOR inhibitor-driven activation of Akt, that EGFR signaling to Akt was dispensable for arrest, that EGFR signaling to Protein Kinase C alpha was central to the ability of PI3K to signal to mTOR, and that blockade of PI3K, mTOR and autophagy converted cytostatic PI3K/mTOR inhibitors into cytotoxic agents (Fan, 2006-2010). Activated alleles of EGFR occur in brain and lung-cancers, yet EGFR inhibitors benefit only lung cancer. We traced this differential response to lower occupancy rates of EGFR inhibitors in brain as compared to lung cancer mutants (Barkovich 2012). EGFR is frequently co-amplified with EGFRvIII. We showed co-expression of EGFR and vIII in individual cells in human tumors, that vIII is a substrate for EGFR, and that co-expression drives STAT signaling (Fan et al, 2013).

Targeted expression of MYCN generate models of neuroblastoma and medulloblastoma in transgenic mice. Neuroblastoma is the third most common tumor of childhood. The proto-oncogene MYCN is amplified in 25% of neuroblastomas, marking incurable disease. We generated transgenic mice that mis-expressed MYCN in neural crest, that developed neuroblastoma, and that remain the standard GEM model used by the community (Weiss et al, 1997). Genome-wide screens revealed genetic alignment with human tumors (Weiss et al, 2002, Hackett et al, 2003). Through systems biology approaches, we identified altered neurotransmitter signaling through GABA as contributing to human and murine neuroblastoma, and described the alternative splicing landscape (Hackett et al, 2014; Chen et al, 2015). Murine neuroblastoma tumors mutant at p53 were therapy resistant, modeling relapsed, drug-resistant neuroblastoma (Chesler, 2006-8). MYCN blockade reduced VEGF signaling, promoting vascular collapse (Chanthery, 2012). We synthesized and solved the co-crystal structure of a new class of MYC/MYCN-degrading drugs that block a kinase-independent MYC/MYCN stabilizing function of Aurora Kinase, potently degrading MYCN in-vivo (Gustafson, Meyerowitz, Cancer Cell, 2014).

MYCN is mis-expresssed in the majority of medulloblastoma tumors. We used the Tet system to regulate MYCN expression and to image tumor-associated firefly luciferase expression in-vivo. Targeted expression of MYCN to the brains of transgenic mice led to luciferase and MYCN-positive medulloblastoma, (Swartling, 2010). We also transduced MYCN into murine neural stem cells, separately cultured from prenatal or postnatal mice, with cells from hindbrain generating medulloblastoma, and from forebrain generating glioma. Orthotopic transduction of prenatal cerebellar stem cells drove SHH-dependent, while both prenatal brainstem and postnatal cerebellar stem cells drove SHH-independent disease (Swartling 2012). Thus, distinct neural stem cell populations generated disparate brain tumors in response to MYCN.

Genome-wide sequencing efforts have generally failed to identify new driver mutations for the majority of high-risk neuroblastoma and medulloblastoma. In contrast, copy number analyses have identified recurrent regions of variation. Regions of gain or loss on any human chromosome correspond to multiple different chromosomes in the mouse, which is challenging to model. Thus, we are incorporating known driver mutations into engineered human induced pluripotent stem cells, and have generated humanized mouse models for neuroblastoma and medulloblastoma. These human based xenograft models represent a genetic platform to test copy number variation as cancer drivers, and to develop therapies.

LEADERSHIP. I am Professor of Neurology, Pediatrics, and Neurosurgery at UCSF, Director of Clinical Child Neurology at San Francisco General Hospital, Co-Leader of the Helen Diller Family Comprehensive Cancer Center’s Pediatrics Malignancies Program and Chair of the weekly seminar series in UCSF’s Helen Diller Family Comprehensive Cancer Center, and Project PI in UCSF’s Pediatric Brain Tumor Foundation Program. I edit Breaking Advances for Cancer Research, am associate editor of the NeuroOncology, Molecular and Cellular Biology, and Scientific Reports, serve on the Neuroblastoma Biology Committee for the Children’s Oncology Group, and am advise Research Programs at Stanford and at Saint Jude Children’s Research Hospital. I have organized two international meetings on mouse models for neural cancers for the NCI, was co-organizer of the Cold Spring Harbor Models and Mechanisms of Cancer meeting (2009-2014), and was founding organizer of the now annual Medulloblastoma in the Mountains, and Pediatric Infiltrating Glioma Meeings (which bring together international basic and clinical thought leaders to translate scientific findings into patient care). I was co-chair of the program meeting for the 2007 centennial AACR meeting, and have organized basic science sessions at annual AACR meetings for many years. I was an external advisor for programs at CHLA, Mayo Clinic and University of Calgary; and have been external reviewer of NCI’s Mouse Cancer Genetics Program (2003 and 2008) and of the Departments of Genetics and of Tumor Cell Biology at St. Jude’s Children’s Research Hospital (2009). I have been a good citizen of the NIH for many years, and was a permanent member of both the NINDS NSDA study section. I was also a permanent member of the Cancer Prevention and Research Institute of Texas (under Chuck Sherr).

MENTORING RECORD. I formally mentor neurologists Li Gan (Associate Prof of Neurology at UCSF) Hannah Green, MD (Associate Prof of Neurology at UCSF), and Audrey Foster-Barber (Associate Prof of Pediatric Neurology at UCSF), David Young (fellow in Child Neurology), Christopher McGraw (resident in Neurology), and Abrar Choudhury (first year MSTP). Other mentees include Clay Gustafson, MD-PhD (K08 recipient and Alex Lemonade Stand Career Awardee, Asst Prof of Pediatrics at UCSF), Anders Persson, PhD (independent investigator and Assistant Professor of Neurology at UCSF), Theo Nicolaides, MD, (K08 recipient, independent investigator and Assistant Professor of Pediatrics at UCSF), Qi-Wen Fan, MD-PhD, (up for promotion to Associate Professor of Neurology at UCSF), and Lou Chesler (former K08 recipient and Professor at ICR in London). I was formally a mentor to Jonathan Hecht, MD-PhD (Assistant Prof of Pediatric Neurology, Stanford), Manu Hegde MD-PhD (Assistant Prof of Neurology, UCSF), Sabine Mueller, MD-PhD (Assistant Professor of Pediatric Neurology at UCSF), Kendall Nash, MD (Assistant Professor of Pediatric Neurology at UCSF), Kyle Steinman, MD (Assistant Prof of Pediatric Neurology, Univ of Washington) and Raquel Gardner (Assistant Professor at UCSF). In addition to Drs. Fan, Gustafson, Nicolaides, and Persson, above, my former postdoctoral fellow mentees also include Yvan Chanthery, PhD (now Asst Professor at Santa Clara University), Lou Chesler, MD-PhD (former K08 recipient and now full Professor and independent investigator at the Royal Marsden Hospital, ICR, UK), and Fredrik J. Swartling, PhD, (Assistant Professor and independent investigator at Uppsalla University, Sweden). I mentor on average 4-5 postdocs in my lab. Miller Huang, a postdoc in my lab, was awarded a K99 in 2016. I have mentored 4 PhD students (all have graduated) and three MD-PhD student (one graduated) in my own lab, as well as a large number of medical students and undergraduates. In addition, I mentor a large number of graduate students as a non-thesis advisor, and through sitting on qualifying exam and thesis committees.

Education

Tufts University, Medford, MA, BS, 1978-1982, Biology
Stanford University, Stanford, CA, MD, PhD, 1982-1989, Medicine/Cancer Biology


Professional Experience

  • 1989-1991
    Children's Hospital, Boston MA, Intern and Resident in Pediatrics
  • 1991-1992
    University of California, San Francisco, Resident in Neurology & Child Neurology
  • 1994-1998
    University of California, San Francisco, Post-Doctoral Fellow (under J. Michael Bishop)
  • 1999-present
    University of California, San Francisco, Asst (1998), Associate (2004), Full Professor(2008), Neurology, Pediatrics, Neurosurgery
  • 2011-2012
    University of California, San Francisco, Director, Child Neurology Division

Honors & Awards

  • 1981
    Phi Beta Kappa
  • 1982
    BS degree awarded with honors (Summa Cum Laude)
  • 1994
    Daland Research Fellow, American Philosophical Society
  • 1996-2001
    Burroughs Wellcome Career Development Award
  • 1997
    UCSF Grumbach Research Award
  • 1997
    Child Neurology Society Young Investigator Award
  • 1999
    UCSF Brook Byers Award in Basic Science
  • 1999-2004
    Steering Committee Member and Nervous System Cancers Committee Chair: NCI sponsored Mouse Models for Human Cancer Consortium
  • 2001-2003
    Sydney Kimmel Scholar Award
  • 2002-2004, 2005
    Brain Tumor Society Scholar
  • 2005
    Integrative Research Award, UCSF Sandler Program in Basic Sciences
  • 2005
    Thrasher Research Fund Award
  • 2005
    Samuel Waxman Cancer Research Foundation Award
  • 2005
    Goldhirsh Foundation Award
  • 2006
    National Brain Tumor Foundation Award
  • 2006
    Burroughs Wellcome Translational Research Award
  • 2008
    Alex Lemonade Stand Foundation Award
  • 2002, 2008
    Accelerate Brain Cancer Cure Award
  • 2008, 2005, 2002
    Brain Tumor Society Award

Selected Publications

  1. Bolin S, Borgenvik A, Persson CU, Sundström A, Qi J, Bradner JE, Weiss WA, Cho YJ, Weishaupt H, Swartling FJ. Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma. Oncogene. 2018 Mar 07.
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  2. Ferrucci V, de Antonellis P, Pennino FP, Asadzadeh F, Virgilio A, Montanaro D, Galeone A, Boffa I, Pisano I, Scognamiglio I, Navas L, Diana D, Pedone E, Gargiulo S, Gramanzini M, Brunetti A, Danielson L, Carotenuto M, Liguori L, Verrico A, Quaglietta L, Errico ME, Del Monaco V, D'Argenio V, Tirone F, Mastronuzzi A, Donofrio V, Giangaspero F, Picard D, Remke M, Garzia L, Daniels C, Delattre O, Swartling FJ, Weiss WA, Salvatore F, Fattorusso R, Chesler L, Taylor MD, Cinalli G, Zollo M. Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-ß-OTX2-SNAIL via PTEN inhibition. Brain. 2018 Feb 27.
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  3. Garzia L, Kijima N, Morrissy AS, De Antonellis P, Guerreiro-Stucklin A, Holgado BL, Wu X, Wang X, Parsons M, Zayne K, Manno A, Kuzan-Fischer C, Nor C, Donovan LK, Liu J, Qin L, Garancher A, Liu KW, Mansouri S, Luu B, Thompson YY, Ramaswamy V, Peacock J, Farooq H, Skowron P, Shih DJH, Li A, Ensan S, Robbins CS, Cybulsky M, Mitra S, Ma Y, Moore R, Mungall A, Cho YJ, Weiss WA, Chan JA, Hawkins CE, Massimino M, Jabado N, Zapotocky M, Sumerauer D, Bouffet E, Dirks P, Tabori U, Sorensen PHB, Brastianos PK, Aldape K, Jones SJM, Marra MA, Woodgett JR, Wechsler-Reya RJ, Fults DW, Taylor MD. A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases. Cell. 2018 Feb 22; 172(5):1050-1062.e14.
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  4. Ilkhanizadeh S, Sabelström H, Miroshnikova YA, Frantz A, Zhu W, Idilli A, Lakins JN, Schmidt C, Quigley DA, Fenster T, Yuan E, Trzeciak JR, Saxena S, Lindberg OR, Mouw JK, Burdick JA, Magnitsky S, Berger MS, Phillips JJ, Arosio D, Sun D, Weaver VM, Weiss WA, Persson AI. Antisecretory Factor-Mediated Inhibition of Cell Volume Dynamics Produces Antitumor Activity in Glioblastoma. Mol Cancer Res. 2018 Feb 05.
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  5. An Z, Aksoy O, Zheng T, Fan QW, Weiss WA. Epidermal growth factor receptor and EGFRvIII in glioblastoma: signaling pathways and targeted therapies. Oncogene. 2018 Mar; 37(12):1561-1575.
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  6. Chen L, Alexe G, Dharia NV, Ross L, Iniguez AB, Conway AS, Wang EJ, Veschi V, Lam N, Qi J, Gustafson WC, Nasholm N, Vazquez F, Weir BA, Cowley GS, Ali LD, Pantel S, Jiang G, Harrington WF, Lee Y, Goodale A, Lubonja R, Krill-Burger JM, Meyers RM, Tsherniak A, Root DE, Bradner JE, Golub TR, Roberts CW, Hahn WC, Weiss WA, Thiele CJ, Stegmaier K. CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2. J Clin Invest. 2018 Jan 02; 128(1):446-462.
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  7. Zheng T, Ménard M, Weiss WA. Neuroblastoma Metastases: Leveraging the Avian Neural Crest. Cancer Cell. 2017 Oct 09; 32(4):395-397.
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  8. Jahangiri A, Nguyen A, Chandra A, Sidorov MK, Yagnik G, Rick J, Han SW, Chen W, Flanigan PM, Schneidman-Duhovny D, Mascharak S, De Lay M, Imber B, Park CC, Matsumoto K, Lu K, Bergers G, Sali A, Weiss WA, Aghi MK. Cross-activating c-Met/ß1 integrin complex drives metastasis and invasive resistance in cancer. Proc Natl Acad Sci U S A. 2017 Oct 10; 114(41):E8685-E8694.
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  9. Zanca C, Villa GR, Benitez JA, Thorne AH, Koga T, D'Antonio M, Ikegami S, Ma J, Boyer AD, Banisadr A, Jameson NM, Parisian AD, Eliseeva OV, Barnabe GF, Liu F, Wu S, Yang H, Wykosky J, Frazer KA, Verkhusha VV, Isaguliants MG, Weiss WA, Gahman TC, Shiau AK, Chen CC, Mischel PS, Cavenee WK, Furnari FB. Glioblastoma cellular cross-talk converges on NF-?B to attenuate EGFR inhibitor sensitivity. Genes Dev. 2017 Jul 19.
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  10. Levin VA, Abrey LE, Heffron TP, Tonge PJ, Dar AC, Weiss WA, Gallo JM. CNS Anticancer Drug Discovery and Development: 2016 conference insights. CNS Oncol. 2017 Jul 18.
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  11. Fan QW, Nicolaides TP, Weiss WA. Inhibiting 4EBP1 in Glioblastoma. Clin Cancer Res. 2018 Jan 01; 24(1):14-21.
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  12. Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, Garzia L, Torchia J, Nor C, Morrissy AS, Agnihotri S, Thompson YY, Kuzan-Fischer CM, Farooq H, Isaev K, Daniels C, Cho BK, Kim SK, Wang KC, Lee JY, Grajkowska WA, Perek-Polnik M, Vasiljevic A, Faure-Conter C, Jouvet A, Giannini C, Nageswara Rao AA, Li KKW, Ng HK, Eberhart CG, Pollack IF, Hamilton RL, Gillespie GY, Olson JM, Leary S, Weiss WA, Lach B, Chambless LB, Thompson RC, Cooper MK, Vibhakar R, Hauser P, van Veelen MC, Kros JM, French PJ, Ra YS, Kumabe T, López-Aguilar E, Zitterbart K, Sterba J, Finocchiaro G, Massimino M, Van Meir EG, Osuka S, Shofuda T, Klekner A, Zollo M, Leonard JR, Rubin JB, Jabado N, Albrecht S, Mora J, Van Meter TE, Jung S, Moore AS, Hallahan AR, Chan JA, Tirapelli DPC, Carlotti CG, Fouladi M, Pimentel J, Faria CC, Saad AG, Massimi L, Liau LM, Wheeler H, Nakamura H, Elbabaa SK, Perezpeña-Diazconti M, Chico Ponce de León F, Robinson S, Zapotocky M, Lassaletta A, Huang A, Hawkins CE, Tabori U, Bouffet E, Bartels U, Dirks PB, Rutka JT, Bader GD, Reimand J, Goldenberg A, Ramaswamy V, Taylor MD. Intertumoral Heterogeneity within Medulloblastoma Subgroups. Cancer Cell. 2017 06 12; 31(6):737-754.e6.
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  13. Diep BA, Hilliard JJ, Le VT, Tkaczyk C, Le HN, Tran VG, Rao RL, Dip EC, Pereira-Franchi EP, Cha P, Jacobson S, Broome R, Cheng LI, Weiss W, Prokai L, Nguyen V, Stover CK, Sellman BR. Targeting Alpha Toxin To Mitigate Its Lethal Toxicity in Ferret and Rabbit Models of Staphylococcus aureus Necrotizing Pneumonia. Antimicrob Agents Chemother. 2017 Apr; 61(4).
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  14. Fan Q, Aksoy O, Wong RA, Ilkhanizadeh S, Novotny CJ, Gustafson WC, Truong AY, Cayanan G, Simonds EF, Haas-Kogan D, Phillips JJ, Nicolaides T, Okaniwa M, Shokat KM, Weiss WA. A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma. Cancer Cell. 2017 03 13; 31(3):424-435.
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  15. Jones C, Karajannis MA, Jones DTW, Kieran MW, Monje M, Baker SJ, Becher OJ, Cho YJ, Gupta N, Hawkins C, Hargrave D, Haas-Kogan DA, Jabado N, Li XN, Mueller S, Nicolaides T, Packer RJ, Persson AI, Phillips JJ, Simonds EF, Stafford JM, Tang Y, Pfister SM, Weiss WA. Pediatric high-grade glioma: biologically and clinically in need of new thinking. Neuro Oncol. 2017 02 01; 19(2):153-161.
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  16. Li H, Weiss WA, Medved M, Abe H, Newstead GM, Karczmar GS, Giger ML. Breast density estimation from high spectral and spatial resolution MRI. J Med Imaging (Bellingham). 2016 Oct; 3(4):044507.
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  17. Zhang J, Yao TW, Hashizume R, Hariono S, Barkovich KJ, Fan QW, Prados M, James CD, Weiss WA, Nicolaides T. Combined BRAFV600E and MEK blockade for BRAFV600E-mutant gliomas. J Neurooncol. 2017 02; 131(3):495-505.
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  18. An Z, Weiss WA. Cholesterol: An Achilles' Heel for Glioblastoma? Cancer Cell. 2016 11 14; 30(5):653-654.
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  19. Matthay KK, Maris JM, Schleiermacher G, Nakagawara A, Mackall CL, Diller L, Weiss WA. Neuroblastoma. Nat Rev Dis Primers. 2016 11 10; 2:16078.
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  20. Rinkenbaugh AL, Cogswell PC, Calamini B, Dunn DE, Persson AI, Weiss WA, Lo DC, Baldwin AS. IKK/NF-?B signaling contributes to glioblastoma stem cell maintenance. Oncotarget. 2016 Oct 25; 7(43):69173-69187.
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