Raymond M. Reilly
Professor, Ph.D.(Toronto)

MOLECULAR IMAGING AND TARGETED RADIOTHERAPY OF CANCER

Our research focuses on the discovery, preclinical development and translation to Phase I/II clinical trials of novel radiopharmaceuticals for molecular imaging and targeted radiotherapy of cancer.

Molecular Imaging is a powerful new imaging modality which probes the biology of tumours to permit their detection, but most importantly reveal their phenotypic properties. Molecular imaging which includes SPECT and PET nuclear medicine technologies has great potential for cancer detection as well as predicting and monitoring response to treatment, especially to new molecularly-targeted drugs (e.g. Herceptin). Our approach focuses on imaging the over expression of peptide growth factor receptors (e.g. EGFR, HER2 or IGF-1R) since these are often the targets for these drugs. In addition, we are interested in imaging leukemia stem cells using radiolabeled anti-CD123 antibodies; imaging of cytolytic vaccinia virus delivery to tumours using radiolabeled octreotide analogues, and imaging the tumour and normal tissue distribution of micellar drug delivery systems. In addition, we are conducting a Phase I/II clinical trial of radioimmunoguided surgery (RIGS) of breast cancer using radiolabeled trastuzumab Fab antibodies directed against HER2 which aims to improve the surgical management of the disease.

Targeted Radiotherapy is an extension of molecular imaging which utilizes radiopharmaceuticals for treatment of cancer. In this area, we are exploiting the nanometer-range Auger electrons emitted by ¹¹¹In to cause single-cell killing of tumour cells while avoiding toxicity to normal cells. We are developing novel radiotherapeutics directed towards EGFR, HER2 and EGFR overexpressed on breast cancer cells for treatment of metastatic disease. We are also exploring the treatment of acute myelogenous leukemia (AML) using radiolabeled antibodies directed against CD33 or CD123 epitopes. CD123 is particularly attractive because it is uniquely expressed on leukemic stem cells (LSCs), which are thought to be responsible for recurrence of the disease. In addition, we are developing gold nanoparticles targeted to HER2 which could be used to dramatically radiosensitize breast cancer cells to X-radiation treatment to improve the treatment of locally-advanced breast cancer (LABC). Finally, we are examining combining vaccinia cytolytic virus therapy with targeted radiotherapy for the treatment of peritoneal carcinomatosis. One radiotherapeutic agent (¹¹¹In-DTPA-hEGF) discovered in our laboratory has been tested in a Phase I clinical trial for treatment of metastatic breast cancer. An extension of this trial at the University of Oxford is being supported by Cancer Research – UK and is expected to commence in 2010.

Graduate students and post-doctoral fellows have opportunities to receive training in radiopharmaceutical design and development, preclinical evaluation as well as clinical investigation in early Phase I/II trials and our laboratory is an active participant in two CIHR-funded traing programs (Excellence in Radiation Research for the 21st Century and Strategic Training Program in Biological Therapeutics).

Selected Publications:

1. Hoang, B., Lee, H., Reilly, R.M., Allen, C. Non-invasive monitoring of the fate of ¹¹¹In-labeled block copolymer micelles by high resolution and high sensitivity microSPECT/CT imaging. Molec. Pharmaceut. 6: 581-592, 2009.

2. Cai, Z., Vallis, K.A. and Reilly, R.M. Computational analysis of the number, area and density of γ-H2AX foci in breast cancer cells treated exposed with to ¹¹¹In-DTPA-hEGF using Image-J software. Int. J. Radiat. Biol. 85:262-271, 2009.

3. McLarty, K., Cornelissen, B., Cai, Z., Scollard, D., Costantini, D., Done, S.J., Reilly, R.M. ¹¹¹In-DTPA-pertuzumab sensitively detects trastuzumab-mediated HER2 downregulation and tumor response in athymic mice bearing human breast cancer xenografts. J. Nucl. Med. 50: 1340-1348, 2009.

4. McLarty, K., Cornelissen, B., Scollard, D.A., Done, S., Chun, K. and Reilly, R.M. Associations between the uptake of ¹¹¹In-DTPA-trastuzumab, HER2 density and response to trastuzumab (Herceptin) in athymic mice bearing subcutaneous human tumour xenografts Eur. J. Nucl. Med. Mol. Imaging 36:81-93, 2009.

5. Costantini, D., Bateman, K., McLarty, K., Vallis, K.A. and Reilly, R.M. Trastuzumab resistant breast cancer cells remain sensitive to the Auger electron-emitting radiotherapeutic agent ¹¹¹In-NLS-trastuzumab and are radiosensitized by methotrexate. J. Nucl. Med. 49: 1498-1505, 2008.

6. Cai, Z., Chen, Z., Bailey, K.E., Scollard, D.A., Reilly, R.M., and Vallis, K.A. Relationship between induction of phosphorylated H2AX and survival in breast cancer cells exposed to ¹¹¹In-DTPA-hEGF. J. Nucl. Med. 49:1353-61, 2008.

7. Kersemans, V., Cornelissen, B., Minden, M., and Reilly, R.M. Drug-resistant acute myeloid leukemia (AML) cells and primary AML specimens remain are killed by ¹¹¹In-anti-CD33 monoclonal antibodies modified with nuclear localizing peptide sequences (NLS). J. Nucl. Med. 49: 1546-1554, 2008.

8. Costantini, D., Chan, C., Cai, Z., Vallis, K.A., Reilly, R.M. ¹¹¹In-trastuzumab (Herceptin) modified with nuclear localizing sequences (NLS): A novel Auger electron-emitting radiotherapeutic agent for HER2/neu-amplified breast cancer. J. Nucl. Med. 48: 1357-1368, 2007.

Mailing Address:

Leslie Dan Faculty of Pharmacy, University of Toronto
144 College Street
Toronto, Ontario Canada M5S 3M2

Tel: (416) 946-5522
FAX: (416) 978-8511

E-mail: raymond.reilly@utoronto.ca

Lab Web Link: http://phm.utoronto.ca/~rreilly/

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