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.

Research Funding

  • September 1, 2018 - August 31, 2023 - Prevention and treatment of lethal metastases in group 3 medulloblastoma, Principal Investigator. Sponsor: NIH, Sponsor Award ID: R01NS106155
  • September 20, 2002 - August 31, 2023 - Brain Tumor SPORE Grant, Project Basic Science Leader. Sponsor: NIH/NCI, Sponsor Award ID: P50CA097257
  • February 1, 2018 - January 31, 2023 - Improving the efficacy of mTOR inhibition, Principal Investigator. Sponsor: NIH/NCI, Sponsor Award ID: R01CA221969
  • September 18, 2017 - August 31, 2022 - Discovering and Exploiting Mechanisms of Neuroblastoma Therapy Resistance, Project Leader. Sponsor: NIH/NCI, Sponsor Award ID: P01CA217959

Education

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

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. Coltin H, Sundaresan L, Smith KS, Skowron P, Massimi L, Eberhart CG, Schreck KC, Gupta N, Weiss WA, Tirapelli D, Carlotti C, Li KKW, Ryzhova M, Golanov A, Zheludkova O, Absalyamova O, Okonechnikov K, Stichel D, von Deimling A, Giannini C, Raskin S, Van Meir EG, Chan JA, Fults D, Chambless LB, Kim SK, Vasiljevic A, Faure-Conter C, Vibhakar R, Jung S, Leary S, Mora J, McLendon RE, Pollack IF, Hauser P, Grajkowska WA, Rubin JB, van Veelen MC, French PJ, Kros JM, Liau LM, Pfister SM, Kool M, Kijima N, Taylor MD, Packer RJ, Northcott PA, Korshunov A, Ramaswamy V. Subgroup and subtype-specific outcomes in adult medulloblastoma. Acta Neuropathol. 2021 Aug 18.  View on PubMed
  2. Qadeer ZA, Weiss WA. A SHHecret target of relapsed medulloblastoma: Astrocytes. J Exp Med. 2021 Sep 06; 218(9).  View on PubMed
  3. Yi JS, Sias-Garcia O, Nasholm N, Hu X, Iniguez AB, Hall MD, Davis M, Guha R, Moreno-Smith M, Barbieri E, Duong K, Koach J, Qi J, Bradner JE, Stegmaier K, Weiss WA, Gustafson WC. The synergy of BET inhibitors with aurora A kinase inhibitors in MYCN-amplified neuroblastoma is heightened with functional TP53. Neoplasia. 2021 06; 23(6):624-633.  View on PubMed
  4. Simonds EF, Lu ED, Badillo O, Karimi S, Liu EV, Tamaki W, Rancan C, Downey KM, Stultz J, Sinha M, McHenry LK, Nasholm NM, Chuntova P, Sundström A, Genoud V, Shahani SA, Wang LD, Brown CE, Walker PR, Swartling FJ, Fong L, Okada H, Weiss WA, Hellström M. Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma. J Immunother Cancer. 2021 Jun; 9(6).  View on PubMed
  5. Chopra M, McEntagart M, Clayton-Smith J, Platzer K, Shukla A, Girisha KM, Kaur A, Kaur P, Pfundt R, Veenstra-Knol H, Mancini GMS, Cappuccio G, Brunetti-Pierri N, Kortüm F, Hempel M, Denecke J, Lehman A, CAUSES Study , Kleefstra T, Stuurman KE, Wilke M, Thompson ML, Bebin EM, Bijlsma EK, Hoffer MJV, Peeters-Scholte C, Slavotinek A, Weiss WA, Yip T, Hodoglugil U, Whittle A, diMonda J, Neira J, Yang S, Kirby A, Pinz H, Lechner R, Sleutels F, Helbig I, McKeown S, Helbig K, Willaert R, Juusola J, Semotok J, Hadonou M, Short J, Genomics England Research Consortium , Yachelevich N, Lala S, Fernández-Jaen A, Pelayo JP, Klöckner C, Kamphausen SB, Abou Jamra R, Arelin M, Innes AM, Niskakoski A, Amin S, Williams M, Evans J, Smithson S, Smedley D, de Burca A, Kini U, Delatycki MB, Gallacher L, Yeung A, Pais L, Field M, Martin E, Charles P, Courtin T, Keren B, Iascone M, Cereda A, Poke G, Abadie V, Chalouhi C, Parthasarathy P, Halliday BJ, Robertson SP, Lyonnet S, Amiel J, Gordon CT. Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism. Am J Hum Genet. 2021 06 03; 108(6):1138-1150.  View on PubMed
  6. Skowron P, Farooq H, Cavalli FMG, Morrissy AS, Ly M, Hendrikse LD, Wang EY, Djambazian H, Zhu H, Mungall KL, Trinh QM, Zheng T, Dai S, Stucklin ASG, Vladoiu MC, Fong V, Holgado BL, Nor C, Wu X, Abd-Rabbo D, Bérubé P, Wang YC, Luu B, Suarez RA, Rastan A, Gillmor AH, Lee JJY, Zhang XY, Daniels C, Dirks P, Malkin D, Bouffet E, Tabori U, Loukides J, Doz FP, Bourdeaut F, Delattre OO, Masliah-Planchon J, Ayrault O, Kim SK, Meyronet D, Grajkowska WA, Carlotti CG, de Torres C, Mora J, Eberhart CG, Van Meir EG, Kumabe T, French PJ, Kros JM, Jabado N, Lach B, Pollack IF, Hamilton RL, Rao AAN, Giannini C, Olson JM, Bognár L, Klekner A, Zitterbart K, Phillips JJ, Thompson RC, Cooper MK, Rubin JB, Liau LM, Garami M, Hauser P, Li KKW, Ng HK, Poon WS, Yancey Gillespie G, Chan JA, Jung S, McLendon RE, Thompson EM, Zagzag D, Vibhakar R, Ra YS, Garre ML, Schüller U, Shofuda T, Faria CC, López-Aguilar E, Zadeh G, Hui CC, Ramaswamy V, Bailey SD, Jones SJ, Mungall AJ, Moore RA, Calarco JA, Stein LD, Bader GD, Reimand J, Ragoussis J, Weiss WA, Marra MA, Suzuki H, Taylor MD. The transcriptional landscape of Shh medulloblastoma. Nat Commun. 2021 03 19; 12(1):1749.  View on PubMed
  7. Hahn WC, Bader JS, Braun TP, Califano A, Clemons PA, Druker BJ, Ewald AJ, Fu H, Jagu S, Kemp CJ, Kim W, Kuo CJ, McManus M, B Mills G, Mo X, Sahni N, Schreiber SL, Talamas JA, Tamayo P, Tyner JW, Wagner BK, Weiss WA, Gerhard DS, Cancer Target Discovery and Development Network . An expanded universe of cancer targets. Cell. 2021 03 04; 184(5):1142-1155.  View on PubMed
  8. Fisher MJ, Jones DTW, Li Y, Guo X, Sonawane PS, Waanders AJ, Phillips JJ, Weiss WA, Resnick AC, Gosline S, Banerjee J, Guinney J, Gnekow A, Kandels D, Foreman NK, Korshunov A, Ryzhova M, Massimi L, Gururangan S, Kieran MW, Wang Z, Fouladi M, Sato M, Øra I, Holm S, Markham SJ, Beck P, Jäger N, Wittmann A, Sommerkamp AC, Sahm F, Pfister SM, Gutmann DH. Integrated molecular and clinical analysis of low-grade gliomas in children with neurofibromatosis type 1 (NF1). Acta Neuropathol. 2021 04; 141(4):605-617.  View on PubMed
  9. Wolpaw AJ, Bayliss R, Büchel G, Dang CV, Eilers M, Gustafson WC, Hansen GH, Jura N, Knapp S, Lemmon MA, Levens D, Maris JM, Marmorstein R, Metallo SJ, Park JR, Penn LZ, Rape M, Roussel MF, Shokat KM, Tansey WP, Verba KA, Vos SM, Weiss WA, Wolf E, Mossé YP. Drugging the "Undruggable" MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers. Cancer Res. 2021 04 01; 81(7):1627-1632.  View on PubMed
  10. Luo X, Weiss WA. Utility of Human-Derived Models for Glioblastoma. Cancer Discov. 2020 07; 10(7):907-909.  View on PubMed
  11. Nobre L, Zapotocky M, Khan S, Fukuoka K, Fonseca A, McKeown T, Sumerauer D, Vicha A, Grajkowska WA, Trubicka J, Li KKW, Ng HK, Massimi L, Lee JY, Kim SK, Zelcer S, Vasiljevic A, Faure-Conter C, Hauser P, Lach B, van Veelen-Vincent ML, French PJ, Van Meir EG, Weiss WA, Gupta N, Pollack IF, Hamilton RL, Nageswara Rao AA, Giannini C, Rubin JB, Moore AS, Chambless LB, Vibhakar R, Ra YS, Massimino M, McLendon RE, Wheeler H, Zollo M, Ferruci V, Kumabe T, Faria CC, Sterba J, Jung S, López-Aguilar E, Mora J, Carlotti CG, Olson JM, Leary S, Cain J, Krskova L, Zamecnik J, Hawkins CE, Tabori U, Huang A, Bartels U, Northcott PA, Taylor MD, Yip S, Hansford JR, Bouffet E, Ramaswamy V. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma. Cell Rep Med. 2020 Jun 23; 1(3).  View on PubMed
  12. von Achenbach C, Silginer M, Blot V, Weiss WA, Weller M. Depatuxizumab Mafodotin (ABT-414)-induced Glioblastoma Cell Death Requires EGFR Overexpression, but not EGFRY1068 Phosphorylation. Mol Cancer Ther. 2020 06; 19(6):1328-1339.  View on PubMed
  13. Fan Q, An Z, Wong RA, Luo X, Lu ED, Baldwin A, Mayekar MK, Haderk F, Shokat KM, Bivona TG, Weiss WA. Betacellulin drives therapy resistance in glioblastoma. Neuro Oncol. 2020 04 15; 22(4):457-469.  View on PubMed
  14. Russ JB, Weiss WA. Conversations on mutism: risk stratification for cerebellar mutism based on medulloblastoma subtype. Neuro Oncol. 2020 02 20; 22(2):175-176.  View on PubMed
  15. Dirks PB, Gilbert MR, Holland EC, Maher EA, Weiss WA. Translating Basic Science Discoveries into Improved Outcomes for Glioblastoma. Clin Cancer Res. 2020 06 01; 26(11):2457-2460.  View on PubMed
  16. Wong RA, Luo X, Lu M, An Z, Haas-Kogan DA, Phillips JJ, Shokat KM, Weiss WA, Fan QW. Cooperative Blockade of PKCα and JAK2 Drives Apoptosis in Glioblastoma. Cancer Res. 2020 02 15; 80(4):709-718.  View on PubMed
  17. An Z, Knobbe-Thomsen CB, Wan X, Fan QW, Reifenberger G, Weiss WA. Correction: EGFR Cooperates with EGFRvIII to Recruit Macrophages in Glioblastoma. Cancer Res. 2019 Nov 01; 79(21):5681.  View on PubMed
  18. Qadeer ZA, Valle-Garcia D, Hasson D, Sun Z, Cook A, Nguyen C, Soriano A, Ma A, Griffiths LM, Zeineldin M, Filipescu D, Jubierre L, Chowdhury A, Deevy O, Chen X, Finkelstein DB, Bahrami A, Stewart E, Federico S, Gallego S, Dekio F, Fowkes M, Meni D, Maris JM, Weiss WA, Roberts SS, Cheung NV, Jin J, Segura MF, Dyer MA, Bernstein E. ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures. Cancer Cell. 2019 11 11; 36(5):512-527.e9.  View on PubMed
  19. Suzuki H, Kumar SA, Shuai S, Diaz-Navarro A, Gutierrez-Fernandez A, De Antonellis P, Cavalli FMG, Juraschka K, Farooq H, Shibahara I, Vladoiu MC, Zhang J, Abeysundara N, Przelicki D, Skowron P, Gauer N, Luu B, Daniels C, Wu X, Forget A, Momin A, Wang J, Dong W, Kim SK, Grajkowska WA, Jouvet A, Fèvre-Montange M, Garrè ML, Nageswara Rao AA, Giannini C, Kros JM, French PJ, Jabado N, Ng HK, Poon WS, Eberhart CG, Pollack IF, Olson JM, Weiss WA, Kumabe T, López-Aguilar E, Lach B, Massimino M, Van Meir EG, Rubin JB, Vibhakar R, Chambless LB, Kijima N, Klekner A, Bognár L, Chan JA, Faria CC, Ragoussis J, Pfister SM, Goldenberg A, Wechsler-Reya RJ, Bailey SD, Garzia L, Morrissy AS, Marra MA, Huang X, Malkin D, Ayrault O, Ramaswamy V, Puente XS, Calarco JA, Stein L, Taylor MD. Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma. Nature. 2019 10; 574(7780):707-711.  View on PubMed
  20. Zhang L, He X, Liu X, Zhang F, Huang LF, Potter AS, Xu L, Zhou W, Zheng T, Luo Z, Berry KP, Pribnow A, Smith SM, Fuller C, Jones BV, Fouladi M, Drissi R, Yang ZJ, Gustafson WC, Remke M, Pomeroy SL, Girard EJ, Olson JM, Morrissy AS, Vladoiu MC, Zhang J, Tian W, Xin M, Taylor MD, Potter SS, Roussel MF, Weiss WA, Lu QR. Single-Cell Transcriptomics in Medulloblastoma Reveals Tumor-Initiating Progenitors and Oncogenic Cascades during Tumorigenesis and Relapse. Cancer Cell. 2019 09 16; 36(3):302-318.e7.  View on PubMed

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