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Janet Houghton, Ph.D.StaffProfessor of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve UniversityDepartment of Cancer Biology |
Cancer therapeutics, new target identification, cell signaling, cell biology, animal models, novel developmental therapeutic approaches
Historically the laboratory has focused on the mechanism of action of anticancer agents that target specific signaling pathways in colorectal cancer. In particular the focus has been on 5-fluorouracil (FUra), which induces DNA damage via inhibition of thymidylate synthase, as well as mechanisms to synergize with the FUra-induced DNA damage response. These include identifying the importance of the Fas death receptor (downregulated in colorectal cancer, and belonging to the TNF superfamily of receptors), in regulating cell death in colon cancer cells, and the synergistic interaction with FUra for agents that upregulate Fas expression. This approach using combined FUra, leucovorin and recombinant human interferon-, was synergistic in cell culture models, in human colon carcinoma xenografts, and was successfully evaluated in Phase I clinical trial.
The focus of the current program is on Hedgehog (HH) signaling, which is aberrantly activated and plays an important role in genomic instability, oncogenesis and maintenance of the malignant phenotype in several human cancers. HH signaling is activated during oncogenesis and progression of primary colon cancers and in metastatic disease, in human colon carcinoma cell lines and xenograft models, although its actual role in cell survival in colon cancer is unknown. The canonical HH signaling pathway comprises the binding of HH ligands to the membrane receptor PTCH, which activates SMO, leading to activation of the GLI family of transcription factors that transcriptionally regulate downstream target genes that determine the HH signaling response. The program has determined the critical role of HH signaling in driving cellular survival in colon cancer, and the fundamental dependence of cell survival on the activation of GLI genes, downstream of SMO. Targeting of SMO is limited due to intrinsic and acquired drug resistance, and the additional activation of GLI genes by oncogenic, non-canonical signaling pathways independent of the HH-SMO axis. Transcriptional regulation of the HH signaling response at the level of GLI1 and GLI2, in contrast to SMO, constitutes a molecular switch between cell survival or cell death, and further studies will answer a fundamental question in HH biology. The identification of a DNA damage response following inhibition of GLI1/GLI2 function has been demonstrated by both pharmacologic and genetic approaches, and mechanisms downstream of GLI1/GLI2 that determine cell death or cell survival are currently being addressed. The development of drug resistance to agents that target SMO or GLI1/GLI2 in colorectal cancer models is providing 1) new and unique cellular mechanisms in drug resistance phenotypes, and 2) new targets with potential for therapeutic intervention. We utilize a combination of molecular, cellular, gene signature, and in vivo approaches that incorporate new model development including mouse models. The studies provide potential translational and clinical innovation both in new target identification, and in development of new innovative treatment strategies.
Houghton JA, Harwood FG, Tillman DM. Thymineless death in colon carcinoma cells is mediated via Fas signaling. Proc. Natl. Acad. Sci. USA 94:8144-8149, 1997.
Houghton JA, Harwood FG, Gibson AA, Tillman DM. The Fas signaling pathway is functional in colon carcinoma cells and induces apoptosis. Clin Cancer Res 3:2205-2209, 1997.
Gibson AA, Harwood FG, Tillman DM, Houghton JA. Selective sensitization to DNA damaging agents in a human rhabdomyosarcoma cell line with inducible wild-type p53 overexpression. Clin Cancer Res 4:145-152, 1998.
Tillman DM, Harwood FG, Gibson AA, Houghton JA. Expression of genes that regulate Fas signaling and Fas-mediated apoptosis in colon carcinoma cells. Cell Death Diff 5:450-457, 1998.
Houghton JA, Ebanks R, Harwood FG, Tillman DM. Inhibition of apoptosis following thymineless stress is conferred by oncogenic K-Ras in colon carcinoma cells. Clin Cancer Res 4:2841-2848, 1998.
Tillman DM, Petak I, Houghton JA. A Fas-dependent component in 5-fluorouracil/ leucovorin-induced cytotoxicity in colon carcinoma cells. Clin Cancer Res 5:425-430, 1999.
Harwood FG, Kasibhatla S, Green DR, Houghton JA. Regulation of FasL by NF-B and AP-1 in Fas-dependent thymineless death of colon carcinoma cells. J Biol Chem 275:10023-10029, 2000.
Petak I, Tillman DM, Harwood FG, Houghton JA. Fas -dependent and -independent mechanisms of cell death following DNA damage in human colon carcinoma cells. Cancer Res 60:2643-2650, 2000.
Petak I, Douglas L, Tillman DM, Vernes R, Houghton JA. Rhabdomyosarcoma cell lines are resistant to Fas- and highly sensitive to TRAIL-induced apoptosis. Clin Cancer Res 6:4119-4127, 2000.
Petak I, Tillman DM, Houghton JA. P53-dependence of Fas induction and acute apoptosis in response to 5-fluorouracil-leucovorin in human colon carcinoma cell lines. Clin Cancer Res 6:4432-4441, 2000.
Schwartzberg L, Petak I, Stewart C, Turner PK, Ashley J, Tillman DM, Douglas L, Mihalik R, Weir A, Tauer K, Shope S, Houghton JA. Modulation of the Fas signaling pathway by interferon- in therapy of colon cancer: Phase I trial and correlative studies of interferon-, 5-fluorouracil and leucovorin. Clin Cancer Res 8:2488-2498, 2002.
Petak I, Danam RP, Tillman DM, Vernes R, Howell SR, Brent TP, Houghton JA. Hypermethylation of the gene promoter and enhancer region can regulate Fas expression and sensitivity in colon carcinoma Cell Death Diff 10:211-217, 2003.
Petak I, Vernes R, Szekely Szuks K, Anozie M, Izeradjene K, Douglas L, Tillman M, Houghton JA. A caspase-8-independent component in TRAIL/APO2L-induced cell death in human rhabdomyosarcoma cells. Cell Death Diff 10:729-39, 2003.
Tillman DM, Izeradjene K, Szekely Szucs K, Douglas L and Houghton JA. Rottlerin sensitizes colon carcinoma cells to TRAIL-induced apoptosis via uncoupling of the mitochondria independent of PKC. Cancer Res 63:5118-5125, 2003.
Geller J, Petak I, Szekely Szucs K, Nagy K, Tillman DM, Houghton JA. Interferon--induced sensitization of colon carcinomas to ZD9331 targets caspases, downstream of Fas, independent of mitochondrial signaling and the IAP survivin. Clin Cancer Res 9:6504-6515, 2003.
Turner PK, Houghton JA, Petak I, Tillman DM, Douglas L, Schwartzberg L, Billups C, Tan M, Panetta J, Stewart CF. Pharmacokinetics and pharmacodynamics of subcutaneous interferon gamma in patients receiving 5-fluorouracil and leucovorin. Cancer Chemother Pharmacol 53:253-260, 2004.
Geller JI, Szekely-Szucs K, Petak I, Doyle B, Houghton JA. P21Cip1 is a critical mediator of the cytotoxic action of thymidylate synthase (TS) inhibitors in colorectal carcinoma cells. Cancer Res (in press), 2004.
Izeradjene K, Douglas L, Delaney A, Houghton JA. Casein kinase I (CKI) attenuates TRAIL-induced apoptosis by regulating the recruitment of FADD and procaspase-8 to the death-inducing signaling complex. Cancer Res 64:8036-8044. 2004.
Izeradjene K, Douglas L, Delaney A, Houghton JA. Influence of Casein Kinase II (CK2) in TRAIL-induced apoptosis in human rhabdomyosarcoma cells. Clin Cancer Res 10:6650-6660, 2004.
Izeradjene K, Douglas L, Delaney A, Martin S, Houghton JA. Casein Kinase II (CK2) regulates FADD and caspase-8 recruitment to the death-inducing signaling complex (DISC) in TRAIL-induced apoptosis in human colon carcinoma cell lines. Oncogene 24:2050-2058, 2005.
Izeradjene K, Douglas L, Tillman DM, Delaney AB, Houghton JA. Reactive oxygen species regulate caspase activation in TRAIL-resistant human colon carcinoma cell lines. Cancer Res 65:7436-7445, 2005.
Martin S, Phillips DC, Szekely-Szucs K, Elghazi L, Desmots F, Houghton JA. Cyclooxygenase-2 Inhibition sensitizes human colon carcinoma cells to TRAIL-Induced apoptosis through clustering of DR5 and concentrating death-inducing signaling complex components into ceramide-enriched caveolae. Cancer Res 65:11447-11458, 2005.
Phillips DC, Martin S, Doyle BT, Houghton JA. Sphingosine-induced apoptosis in rhabdomyosarcoma cell lines is dependent on pre-mitochondrial Bax activation and post-mitochondrial caspases. Cancer Res 67:756-764, 2007.
Nawrocki ST, Carew JS, Douglas L, Cleveland JL, Humphreys R, Houghton JA. Histone deacetylase inhibitors enhance lexatumumab-induced apoptosis via a p21Cip1-dependent decrease in survivin levels. Cancer Res 67:6987-6994, 2007.
Phillips DC, Hunt JT, Moneypenny CG, Maclean KH, McKenzie PP, Harris LC, Houghton JA. Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression. Cell Death Differ 14:1780-1791, 2007.
Carew JS, Nawrocki ST, Reddy VK, Bush D, Rehg JE, Goodwin A, Houghton JA, Casero RA Jr, Marton LJ, Cleveland JL. The novel polyamine analogue CGC-11093 enhances the antimyeloma activity of bortezomib. Cancer Res 68:4783-4790, 2008.
Nawrocki ST, Carew JS, Maclean KH, Courage JF, Huang P, Houghton JA, Cleveland JL, Giles FJ, McConkey DJ. Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA. Blood. 112:2917-2926, 2008.
Lobo GP, Waite KA, Planchon SM, Romigh T, Houghton JA, Eng C. ATP modulates PTEN subcellular localization in multiple cancer cell lines. Hum Mol Genet 17:2877-2885, 2008.
Jani TS, Devecchio J, Mazumdar T, Agyeman A, Houghton JA. Inhibition of NF-B signaling by quinacrine is cytotoxic to human colon carcinoma cell lines (cc) and is synergistic in combination with TRAIL or oxaliplatin. J.Biol Chem 285:19162-19172, 2010.
Shi T, Mazumdar T, DeVecchio J, Duan Z-H, Agyeman A, Aziz M, Houghton JA. cDNA microarray gene expression profiling of Hedgehog signaling pathway inhibition in human colon cancer cells. PLoS ONE 5: 1-23, 2010 (pii: e13054; PMID 20957031).
Mazumdar T, DeVecchio J, Shi T, Jones J, Agyeman A, Houghton JA. Hedgehog (HH) signaling drives cellular survival in human colon carcinoma cells. Cancer Res 71: 1092-1102, 2011.
Dabir S, Kluge A, Aziz MA, Houghton JA, Dowlati A. Identification of STAT3-independent regulatory effects for protein inhibitor of activated STAT3 by binding to novel transcription factors. Cancer Biol Ther 12: 122-134, 2011.
Mazumdar T, DeVecchio J, Agyeman A, Shi T, Houghton JA. Inhibition of Hedgehog (HH) survival signaling at the level of the GLI genes induces DNA damage and extensive cell death in human colon carcinoma cells. Cancer Res 71:5904-5914, 2011.
Al-harbi S, Hill B, Mazumder S, Singh K, DeVecchio J, Choudhary G, Rybicki LA, Kalaycio M, Maciejewski JP, Houghton JA, Almasan A. An anti-apoptotic Bcl-2 family expression index predicts the response of chronic lymphocytic leukemia to ABT-737. Blood 118:3579-3590, 2011.
Mazumdar T, Devecchio J, Agyeman A, Shi T, Houghton JA. The GLI genes as the molecular switch in disrupting Hedgehog signaling in colon cancer. Oncotarget 2:638-645, 2011.