Johnson, Candace S., Ph.D.

Deputy Director
Chair, Department of Pharmacology & Therapeutics
Wallace Chair in Translational Research
Professor of Pharmaceutical Sciences at UB
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo, New York   14263
Tel: (716) 845-8300
Fax: (716) 845-1258
E-mail: candace.johnson@roswellpark.org

Dr. Candace S. Johnson joined the faculty of Roswell Park Cancer Institute in February 2002, and is currently Deputy Director of the Institute, Chair of the Department of Pharmacology and Therapeutics, the Wallace Family Chair for Translational Research, and Professor of Oncology. From 1997-2002, Dr. Johnson served as Deputy Director of Basic Research at the University of Pittsburgh Cancer Institute, and Professor of Pharmacology and Medicine at the University of Pittsburgh School of Medicine. Dr. Johnson earned her doctoral degree in Immunology from Ohio State University, Columbus, in 1977. From 1977 to 1981, she completed research and postdoctoral fellowships in Immunology/Cell Biology at the Michigan Cancer Foundation, Detroit. 

At Roswell Park, Dr. Johnson is charged with coordinating correlative research efforts for the clinical aspects of their research programs; providing leadership, mentorship and progress review to physician scientists; and developing training programs for basic and clinical scientists. Dr. Johnson's research interests include translational research to facilitate the efficient application of promising laboratory findings in clinical studies; preclinical design and development of more effective therapeutic approaches to cancer using highly-characterized tumor models; the mechanisms of vitamin D mediated antiproliferative effects either alone or in combination with other cytotoxic agents and the isolation and characterization of tumor-derived endothelial cells with the potential to target for therapeutic intervention. These research projects are funded by a number of grants from the National Cancer Institute and the Department of Defense. Dr. Johnson has authored or co-authored more than 150 journal publications, book chapters and abstracts. She is a member of the National Institutes of Health Reviewers Reserve and has served as a member of the National Cancer Institute (NCI) Experimental Therapeutics-2 study section and the NCI review group Subcommittee A-Cancer Center (Parent Committee). She also is a member of many professional and scientific societies, Associate Editor of Molecular and Cellular Differentiation, Oncology, and Molecular Pharmacology, and member of the editorial board of Oncology Reports, Molecular Cancer Therapeutics and Molecular Pharmacology.

Program

Vitamin D, novel agents, prostate cancer, and experimental therapeutics

Studies are focused on the pre-clinical development and design of more effective therapeutic approaches to cancer using mouse tumor model systems.  Project areas include the mechanisms of vitamin D-mediated anti-proliferative effects either alone or in combination with conventional cytotoxic agents; the effect of vitamin D on cell cycle control and apoptosis in prostate model systems; the effect of glucocorticoids on vitamin D-mediated anti-tumor and hypercalcemic effects through the vitamin D receptor (VDR); the isolation and characterization of tumor-derived endothelial cells with the potential to target for therapeutic intervention; and elucidating the mechanisms involved in the differential response of tumor-derived endothelial cells to vitamin D and steroids with therapeutic implications.  Dr. Johnson has a wide variety of highly characterized and readily available murine syngeneic and human xenograft tumor models to evaluate therapeutic efficacy as well as to examine potential mechanisms of action.  In addition, Dr. Johnson provides the basic science interface to a number of clinical studies based on these studies in collaboration with Dr. Donald L. Trump, CEO and President, Roswell Park Cancer Institute.

Progress

1,25 dihydroxycholecalciferol (vitamin D or calcitriol), a central factor in bone and mineral metabolism, is a potent antiproliferative agent in a wide variety of malignant cell types.  We have demonstrated that calcitriol has significant antitumor activity in vitro and in vivo in murine squamous cell carcinoma (SCC), human xenograft prostatic adenocarcinoma (PC-3) and rat metastatic prostatic adenocarcinoma Dunning (MLL) model systems.   Calcitriol induces G0/G1 arrest, modulates p27Kipl and p21Waf1/Cipl, the cyclin dependent kinase (cdk) inhibitors implicated in G1 arrest.  Calcitriol also induces cleavage of caspase 3, PARP and the growth-promoting/pro-survival signaling molecule mitogen-activated protein kinase (MEK) in a caspase-dependent manner.  In association with this effect, full length MEK and phospho-Erk (P-Erk) are lost.  The phosphorylation and expression of Akt, a kinase regulating a second cell survival pathway, is also inhibited after treatment with calcitriol.  In contrast to changes that occur during cytotoxic drug induced apoptosis, the pro-apoptotic signaling molecule MEKK-1 is significantly upregulated by calcitriol. 

We have demonstrated that dexamethasone (dex) potentiates the antitumor effect of calcitriol and decreases calcitriol-induced hypercalcemia. Both in vitro and in vivo, dex significantly increases vitamin D receptor (VDR) ligand binding in the tumor while decreasing binding in intestinal mucosa, the site of calcium absorption.   Phospho-Erk (P-Erk) and phospho-Akt (P-Akt) were also significantly decreased with calcitriol/dex, as compared to either agent alone. In a phase II trial in androgen independent prostate cancer (AIPC) using high dose (12 mg/day QD x3, weekly) oral calcitriol and dex (4 mg QD x4, weekly), we saw a 50% reduction in prostate specific antigen (PSA) in 31% of the patients and no hypercalcemia.  These studies suggest that glucocorticoids may differentially modulate calcitriol-mediated effects; we believe this has important therapeutic implications.

Calcitriol significantly enhances the in vitro and in vivo antitumor efficacy of the platinum analogues, cisplatin and carboplatin as well as the taxanes, paclitaxel and docetaxel. Enhancement of drug-mediated apoptosis by calcitriol is associated with an increase in PARP-, MEK- and caspase-cleavage and MEKK-1 with a decrease in P-Erk and P-Akt.  In addition, the expression of the p53 homolog, p73, is strongly induced by calcitriol and p73 can sensitize tumor cells to the cytotoxic effects of platinum and taxanes.  Based on these pre-clinical data, we performed two phase I clinical trials of calcitriol with either carboplatin or paclitaxel and administered higher doses of calcitriol than previously reported without toxicity.  From the pharmacokinetic (pk) data of oral administration, the serum calcitriol AUC was not proportional to calcitriol dose suggesting a decrease in bioavailability.  In addition, calcitriol increases the expression of the epidermal growth factor receptor (EGFR).  When calcitriol is combined with the EGFR receptor tyrosine kinase inhibitor, ZD 1839 (‘Iressa’), a significant enhancement of antitumor activity is observed in vitro and in vivo and this activity is associated with a significant decrease in P-Erk and P-Akt.

Therefore, calcitriol has significant pro-apoptotic effects and can synergize with other cytotoxic modalities that potentially share the same targets, P-Akt, P-Erk, MEKK-1 and/or p73.  Based on this data, we continue to examine the potential efficacy and mechanisms of calcitriol in combination with taxanes or EGFR tyrosine kinase inhibitors both clinically and pre-clinically. 

Publications: 

Chung I, Karpf AR, Muindi JR, Conroy JM, Nowak NJ, Johnson CS, Trump DL. Epigenetic silencing of CYP24 in tumor-derived endothelial cells contributes to selective growth inhibition by calcitriol. J Biol Chem 282(12):8704-8714 (2007).

Deeb KK, Johnson CS and Trump DL. Vitamin D signaling pathways in cancer: potential for anticancer therapeutics. Nature Rev Cancer 7:684-700 (2007).

Rassnick KM, Muindi JR, Johnson CS, Balkman CE, Ramnath N, Yu W-D, Engler KL, Page RL, and Trump DL. In Vivo and In Vitro evaluation of combined calcitriol and cisplatin in dogs with spontaneously occurring tumors. Cancer Chemother Pharmacol 62:881-891 (2008).

Ma Y, Yu W-D, Hershberger PA, Flynn G, Kong R-X, Trump DL, and Johnson CS. 1,25D₃ potentiates the anti-tumor activity of cisplatin through increased p73 and enhanced apoptosis in squamous cell carcinoma model system. Mol Cancer Ther 7:3047-3055 (2008)

Menezes RJ, Cheney RT, Husain A, Tretiakova M, Loewen G, Johnson CS, Jayaprakash VV, Moysich KB, Salgia R, Reid ME. Vitamin D receptor expression in normal, premalignant and malignant human lung tissue. Cancer Epidemiol Biomarkers Prev 17(5) 1104-10 (2008)

Fakih MG, Trump DL, Johnson CS, Tian L, Hollis B, Muindi J, Sunga AY. Chemotherapy is linked to severe vitamin D deficiency in patients with colorectal cancer. Int J Colorectal Dis 24(2):219-24  (2009)

Chung I, Han G, Seshadri M, Gillard B, Yu W-D, Foster BA, Trump DL, Johnson CS.  Role of VDR in Anti-proliferative Effects of Calcitriol in Tumor-Derived Endothelial Cells and Tumor Angiogenesis in vivo. Cancer Research 69(3) 967-75 (2009)

Below are links to Pub Med for Dr. Johnson’s publications while at Roswell Park Cancer Institute (2002 – present) and earlier.

Dr. Johnson’s Publications from RPCI

Dr. Johnson’s Earlier Publications