Dr. Craig Peacock
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
BSc. 1991 University of Western Australia, Perth, Australia Microbiology/Biochemistry Ph.D 1997 University of Western Australia, Perth, Australia Immunology Post Doc 2003 University of Massachusetts Medical School Immunology Post Doc 2006 Johns Hopkins University School of Medicine Oncology
Improvements in cancer survival over the past few decades continue to be eclipsed by recurrence of
disease in many patients, which is often refractory to conventional therapy. My research is aimed at
interrupting this source of tumor recurrence by identifying unique molecular and biological characteristics of
resistant cells, which may serve as potential therapeutic targets.
My research is largely informed by the emerging view of tumor development as an aberrant recapitulation
of the normal processes operating during organogenesis and tissue repair. Of particular interest is Hedgehog
(Hh) signaling, an embryonic pathway that is important in regulating progenitor cell fates. Biological effects are
mediated through a pathway that involves ligand binding to the Patched1 (Ptch1) receptor, with release of
Smoothened (Smo) from inhibition and activation of downstream Gli transcription factors that regulate Hh
Tumors consist of heterogeneous cell phenotypes, nominally divided into: (i) a relatively well-differentiated
subset with limited proliferative capacity that constitute the bulk of the tumor and phenotypically characterize
the disease and (ii) a smaller, less differentiated subset that contains clonogenic progenitor cells with multilineage
potential (so called cancer stem cells [CSC]), responsible for initiation, expansion and metastasis of the
I have previously used multiple myeloma (MM) to investigate Hh pathway signaling in CSC regulation 1,
since it is a tumor with well-characterized populations of stem and differentiated cells 2. MM stem cells exhibit a
marked upregulation of Hh pathway genes, especially SMO. Targeted inhibition of Hh signaling suppresses
clonal growth capacity and enhances plasma cell phenotype acquisition, consistent with irreversible terminal
differentiation. By contrast, activation of Hh signaling results in expansion of MM stem cells, demonstrating that
the Hh pathway can induce division of MM stem cells without inducing differentiation.
CSCs are resistant to conventional cancer therapies making them a candidate source of tumor recurrence.
I am investigating the clonogenic and Hh pathway activity in a chemo-resistant fraction of small cell lung
cancer (SCLC) using novel, primary xenograft and tissue culture models 3. Since SCLC depends on Hh
signaling for growth 4, I am assessing the efficacy of several, small molecule SMO antagonists to block Hh
pathway activity and prevent SCLC recurrence.
The link between chronic tissue injury and cancer is well established, prompting speculation that
dysregulation of normal homeostatic mechanisms, such as Hh signaling 4, can initiate carcinogenesis. To test
the hypothesis that aberrant Hh signaling is sufficient for lung tumorigenesis, I am using a loxP recombination
system to constitutively express transgenic Shh ligand or activated Smo in the mouse airway. Using different
mouse strains that express tamoxifen-inducible, Cre recombinase in a tissue-specific manner, Hh activity can
be targeted to specific airway cell subsets at discrete stages of lung organogenesis, homeostasis or injury
repair. Since the basic identity of the tumor-initiating cell resulting from the above matings will be known, it
permits detailed comparisons to its normal counterpart. Using this approach also allows interrogation of both the connection between cell lineage and cancer phenotype, and the question of whether CSCs originate from
pre-existing stem cells and/or more differentiated cells that have acquired self-renewal properties.
The autochthonous tumors arising in mice in this fashion should more closely reflect the mechanisms and
pathobiology present in human cancer progression, including fundamental features of the tumor
microenvironment, such as stroma, vasculature and immune cells. Moreover, as tumors will be established
using inbred, MHC-matched mice, they can be readily passaged and expanded as syngeneic grafts in
immunocompetent animals, making them a valuable tool for drug development.
Daniel, V.C.; Peacock, C.D.; Watkins, D.N. Developmental signalling pathways in lung cancer. Respirology. 2006 May;11(3):234-240.
Peacock, C.D.; Wang, Q.; Gesell, G.S.; Corcoran-Schwartz, I.M.; Jones, E.; Kim, J.; Devereux, W.L.; Rhodes, J.T.; Huff, C.A.; Beachy, P.A.; Watkins, D.N.; Matsui, W. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4048-4053.
Matsui, W.; Wang, Q.; Barber, J.P.; Brennan, S.; Smith, B.D.; Borrello, I.; McNiece, I.; Lin, L.; Ambinder, R.F.; Peacock, C.; Watkins, D.N.; Huff, C.A.; Jones, R.J. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res. 2008 Jan 1;68(1):190-197.
Rudin, C.M.; Hann, C.L.; Peacock, C.D.; Watkins, D.N. Novel systemic therapies for small cell lung cancer. J Natl Compr Canc Netw. 2008 Mar;6(3):315-322.
Daniel, V.C.; Marchionni, L.; Hierman, J.S.; Rhodes, J.T.; Devereux, W.L.; Rudin, C.M.; Yung, R.; Parmigiani, G.; Dorsch, M.; Peacock, C.D.; Watkins, D.N. A primary xenograft model of small-cell lung cancer reveals irreversible changes in gene expression imposed by culture in vitro. Cancer Res. 2009 Apr 15;69(8):3364-3373.
Peacock, C.D.; Rudin, C.M. Skin deep and deeper: multiple pathways in basal cell carcinogenesis. Cancer Prev Res (Phila). 2010 Oct;3(10):1213-1216.