Juliet Williams, PhD
Cambridge, Massachusetts, United States
Our group’s main focus is to use mouse models to understand the biology of cancer in the in vivo context and also the pharmacology of drugs. One of our great resources is a vast collection of human primary tumor tissue from which we have created approximately 900 models of cancer in immune compromised mice. We have shown that these xenografts, which have never touched plastic, represent the The Cancer Genome Atlas much more closely than the cell line collections that are grown in vitro. We are using our collection of primary derived tumors to understand what patients may benefit from certain agents. Because we have a vast array of xenografts to our disposition we screen compounds in what we call mouse clinical trials, where one mouse with one of our xenografts represents one patient. In this way we look for a population response, as you would in the human clinical trial setting, rather than a response in an individual model per se. These experiments have shown, so far, substantial translatability with responses in the clinic and uncovered novel combinations which have not been seen as effective in vitro. We are interested in looking at resistance mechanisms in these models in the context of genomic instability, and also how the biology of our models may change if placed orthotopically or at metastasis sites, which may be significant for translatability of the effect of certain agents, and the emergence of types of resistance.
Interfering with Resistance to Smoothened Antagonists by inhibition of the PI3K Pathway in Medulloblastoma.
Buonamici S, Williams J, Morrissey M, Wang A, Guo R, Vattay A, Hsiao K, Yuan J, Green J, Ospina B, Yu Q, Ostrom L, Fordjour P, Anderson DL, Monahan JE, Kelleher JF, Peukert S, Pan S, Wu X, Maira SM, García-Echeverría C, Briggs KJ, Watkins DN, Yao YM, Lengauer C, Warmuth M, Sellers WR, Dorsch M.
Sci Transl Med. 2010 Sep 29;2(51):51ra70.
1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity.
Miller-Moslin K, Peukert S, Jain RK, McEwan MA, Karki R, Llamas L, Yusuff N, He F, Li Y, Sun Y, Dai M, Perez L, Michael W, Sheng T, Lei H, Zhang R, Williams J, Bourret A, Ramamurthy A, Yuan J, Guo R, Matsumoto M, Vattay A, Maniara W, Amaral A, Dorsch M, Kelleher JF 3rd.
J Med Chem. 2009 Jul 9;52(13):3954-68.
Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions.
Williams JA, Guicherit OM, Zaharian BI, Xu Y, Chai L, Wichterle H, Kon C, Gatchalian C, Porter JA, Rubin LL, Wang FY.
Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4616-21.
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