School of Medicine

Wayne State University School of Medicine

Anthony F. Shields

Anthony F. Shields, M.D., Ph.D.
Professor of Medicine & Oncology
Associate Center Director for Clinical Sciences
Karmanos Cancer Institute
Wayne State University
4100 John R., HW04HO
Detroit, MI 48201
shieldsa@karmanos.org 

 

Mentoring: Stephanie Blocker  ( Senior Student ) and Christopher McHugh ( MD/PhD ) Graduated 7/27/2016

Research Interests:

  • drug development using radiolabeled thymidine analogs, liposomes, and other drugs using PET
  • imaging cellular proliferation and stress in vivo
  • testing response to drug therapy for cancer

Research Description - Drug Discovery and Development:
The ultimate goal of our research is to understand the response of cancer to therapy using measurements of DNA synthetic pathways as imaged by positron emission tomography (PET). Ongoing studies have refined the techniques needed to obtain PET images with radiolabeled thymidine analogs, which are trapped in the DNA synthetic pathway. Studies that began in tissue culture and mice have now progressed to clinical trials. We have addressed a number of the problems associated with interpreting the PET images including the contributions to thymidine metabolism of intracellular pools, reutilization, and degradation. The most promising compound we have used to date is 18F-FLT (3'-deoxy-3'- fluorothymidine), which is an antiviral compound like AZT. It is trapped intracellularly after phosphorylation by thymidine kinase (TK) in a manner similar to the trapping of glucose analogs (FDG) after phosphorylation by hexokinase. This compound is stable to degradation and undergoes little metabolism, aside from glucuronidation. Studies in dogs and patients indicate that it readily visualizes proliferating organs such as the bone marrow, as well as tumors. Another analog,    18F-FMAU {1-(2’-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-thymine} is being studied in cell culture, animals and humans. Our in human studies found that FMAU was readily retained in tumors, but not in normally prolferating bone marrow. FMAU is retained by the action of thymidine kinase 2 (TK2), a mitochondrial enzyme. We have found that increased retention reflects cellular stress.  This is in contrast to FLT, which is retained by thymidine kinase 1 (TK1) the cytosolic enzyme associated with normal DNA synthesis.  We are now testing the hypothesis that imaging cellular stress with 18F-FMAU may provide an early measure of cancer treatment response. Furthermore, FMAU may be simpler to use than agents being developed to image apoptosis, since the time course of stress may be more predictable than changes in apoptosis, which are often short term. These approaches will need to be validated against more conventional measures of response and biopsies based measurements of cell proliferation and TK activity. We are also studying labeled drugs to image their in vivo pharmacokinetics and pharmacodynamics. FAU {1-(2’-deoxy-2’-fluoro-beta-D-arabinofuranosyl)-uracil} is a chemotherapeutic agentwhich is in phase I testing.  We conducted the first-in human phase 0 study of 18F-FAU to determine its suitability for imaging and to determine its potential as an antineoplastic agent. A phase I study using unlabeled FAU has started at Karmanos Cancer Institute and uses 18F-FAU and PET to monitor pharmacodynamics in tumors.

Selected Publications:

Griffeth LK, Hillner BE, Shields AF, Siegel BA. Positron emission tomography for subsequent treatment strategy in oncology. J Clin Oncol. 2014;32:2811-2.

Hillner BE, Siegel BA, Hanna L, Duan F, Shields AF, Quinn B, Coleman RE. Impact of 18F-Fluoride PET on Intended Management of Patients with Cancers Other Than Prostate Cancer: Results from the National Oncologic PET Registry. J Nucl Med. 2014;55:1054-1061.

O'Connell MJ, Colangelo LH, Beart RW, Petrelli NJ, Allegra CJ, Sharif S, Pitot HC, Shields AF, Landry JC, Ryan DP, Parda DS, Mohiuddin M, Arora A, Evans LS, Bahary N, Soori GS, Eakle J, Robertson JM, Moore DF Jr, Mullane MR, Marchello BT, Ward PJ, Wozniak TF, Roh MS, Yothers G, Wolmark N. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol. 2014;32:1927-34.

Patki M, Gadgeel S, Huang Y, McFall T, Shields AF, Matherly LH, Bepler G, Ratnam M. Glucocorticoid receptor status is a principal determinant of variability in the sensitivity of non-small-cell lung cancer cells to pemetrexed. J Thorac Oncol. 2014;9:519-26.

Hillner BE, Siegel BA, Hanna L, Duan F, Shields AF, Coleman RE. Impact of 18F-fluoride PET in patients with known prostate cancer: initial results from the National Oncologic PET Registry. J Nucl Med. 2014;55:574-81.

Huang J, Nair SG, Mahoney MR, Nelson GD, Shields AF, Chan E, Goldberg RM, Gill S, Kahlenberg MS, Quesenberry JT, Thibodeau SN, Smyrk TC, Grothey A, Sinicrope FA, Webb TA, Farr GH Jr, Pockaj BA, Berenberg JL, Mooney M, Sargent DJ, Alberts SR; Alliance for Clinical Trials in Oncology. Comparison of FOLFIRI with or without cetuximab in patients with resected stage iii colon cancer; NCCTG (Alliance) intergroup trial N0147. Clin Colorectal Cancer. 2014;13:100-9.

Salem ME, Jain N, Dyson G, Taylor S, El-Refai SM, Choi M, Shields AF, Critchfield J, Philip PA. Radiographic parameters in predicting outcome of patients with hepatocellular carcinoma treated with yttrium-90 microsphere radioembolization. ISRN Oncol. 2013 Sep 15;2013:538376.

André T, Iveson T, Labianca R, Meyerhardt JA, Souglakos I, Yoshino T, Paul J, Sobrero A, Taieb J, Shields AF, Ohtsu A, Grothey A, Sargent DJ; for the IDEA Steering Committee. The IDEA (International Duration Evaluation of Adjuvant Chemotherapy) Collaboration: Prospective Combined Analysis of Phase III Trials Investigating Duration of Adjuvant Therapy with the FOLFOX (FOLFOX4 or Modified FOLFOX6) or XELOX (3 versus 6 months) Regimen for Patients with Stage III Colon Cancer: Trial Design and Current Status. Curr Colorectal Cancer Rep. 2013;9:261-269.

Sprowl JA, Ciarimboli G, Lancaster CS, Giovinazzo H, Gibson AA, Du G, Janke LJ, Cavaletti G, Shields AF, Sparreboom A. Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2. Proc Natl Acad Sci U S A. 2013;110:11199-204.

Tehrani OS, Shields AF. PET imaging of proliferation with pyrimidines. PET imaging of proliferation with pyrimidines. J Nucl Med. 2013;54:903-12.

Bauer TM, El-Rayes BF, Li X, Hammad N, Philip PA, Shields AF, Zalupski MM, Bekaii-Saab T. Carbohydrate antigen 19-9 is a prognostic and predictive biomarker in patients with advanced pancreatic cancer who receive gemcitabine-containing chemotherapy: a pooled analysis of 6 prospective trials. Cancer. 2013;119:285-92.

Education and Training:
MD (1979): Harvard University, Massachusetts
PhD (1979): Massachusetts Institute of Technology, Massachusetts

Cancer Biology Courses Taught:
CB7240 Principles of Cancer Therapy