Robert Kerbel

At A Glance

The overall goal of Dr. Kerbel’s preclinical translational research program is to develop effective and less toxic therapies for both early and late stage metastatic disease. Over the last decade his group has developed many models of early stage microscopic metastatic disease that can be used for adjuvant therapy, or other models involving late stage advanced macroscopic metastases, including brain and more recently, bone. These include breast, ovarian, liver, colorectal, and renal cell carcinomas as well as melanoma. The therapies being studied include antiangiogenic drugs, chemotherapy, including a concept called low-dose ‘metronomic’ chemotherapy, and more recently, immunotherapy.

Short Bio

Dr. Kerbel received his PhD in immunology Queen’s University in Kingston in 1972, after which he undertook postdoctoral training in tumor immunology at the Chester Beatty Research Institute in London England. He started his career as an independent researcher focusing on tumor immunology and tumor immunotherapy as an Assistant Professor and career awardee as a Research Scholar of the National Cancer Institute of Canada (NCIC) in the Department of Pathology Queen’s University from 1975. Until 1985, the focus of most of his work was in tumor immunology and therapy of metastatic disease. From 1981 until 1985, he was appointed Director of the Cancer Research labs at Queen’s. In 1985, he moved to Mount Sinai Hospital where he was recruited to develop a cancer research group. During this period he was the recipient of a Terry Fox Career Scientist Award from the NCIC. The focus of his research at that time changed to studying the biological basis of metastatic disease. In 1991, he moved to the Sunnybrook Health Sciences Center, where he was recruited to develop a program in cancer research. It is during this period where he began his studies on tumor angiogenesis and antiangiogenic therapy and then metronomic chemotherapy. He was awarded Tier 1 Canada Research Chair in Tumor Biology, Angiogenesis and Antiangiogenic Therapy in 2001. Dr. Kerbel's research has been supported over the years by grants from the Canadian Institute for Health Research, the National Cancer Institute of Canada, the Ontario Institute for Cancer Research, the Canadian Breast Cancer Foundation, Worldwide Cancer Research, and the National Institutes of Health, USA. He also has held or holds multiple sponsored research agreements with biotech and pharmaceutical companies. He has supervised over 40 graduate students and postdoctoral fellows since 1975, many of whom have gone on to become successful research scientists in academia and industry.

Research Synopsis

Dr. Kerbel has made multiple contributions in three different areas of research. The first involves the advancement of antiangiogenic therapeutics for which he is internationally recognized. These include understanding fundamental mechanisms of action of drugs that target the vascular endothelial growth factor (VEGF) and angiopoietin pathways, developing new more clinically relevant mouse tumor models to assess the activity of these (and other) drugs, understanding the basis of resistance to antiangiogenic agents, and uncovering mechanisms to help explain how they enhance the efficacy of chemotherapy. Second, Dr. Kerbel also has been at the forefront of pioneering the concept of metronomic chemotherapy whereby conventional chemotherapy drugs are administered at lower less toxic doses on a more frequent schedule over prolonged periods of time without any extended break periods. The concept has now gone all the way through evaluation at the randomized phase III clinical trial level and has been found to be effective as a maintenance (follow-up) therapy in colorectal and breast cancer patients with either early or late stage disease after they have received conventional upfront maximum tolerated dose/pulsatile chemotherapy. Third, the metastatic models that Dr. Kerbel’s lab has developed, up until recently, all involved the growth of human tumor cell lines or patient-derived xenografts (PDXs) in immune suppressed mice. The lines have been distributed to over 60 labs around the world in both academia and industry and have thus become an international resource for cancer research to study the basic biology and treatment of metastasis. A more recent initiative in Dr. Kerbel’s lab is to develop similar models of early and late stage metastatic disease involving mouse tumors grown in immunocompetent syngeneic mice that thus permit assessment of immunotherapy strategies including vaccines and immune checkpoint inhibitors.

For his achievements Dr. Kerbel has been awarded the 2004 Canadian Cancer Society Robert Noble Award for Excellence in Cancer Research, the Breast Cancer Research Award from the European Institute of Oncology in 2008, a Man of Distinction Honor by the Israel Cancer Research Fund in 2011, and the Colin Thomson Memorial Medal from Worldwide Cancer Research in 2013. He was a recipient of a tier 1 Canada Research Chair in Tumor Biology, Angiogenesis and Antiangiogenic Therapy from 2001-2015.

Dr. Kerbel’s contributions have also been recognized by the over 850 invitations to give lectures around the world since he began his career, his numerous memberships on scientific peer review journal editorial boards, and memberships on scientific advisory boards in both industry and academia.

Recent Publications

• Shaked, Y., Bertolini, F., Rawn, K., Man, S., Rogers, M.S., Cervi, D., Foutz, T., Voskas, D., Dumont, D.J., Ben-David, Y., Lawler, J., Henkin, J., D’Amato, R.J. and Kerbel, R.S.  (2005) Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis: implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 7: 101-111.
• Ferrara, N. and Kerbel, R.S. (2005) Angiogenesis as a therapeutic target: advances and prospects.  Nature, 438: 967-974.
• Munoz, R., Man, S., Shaked, Y., Lee, C.R., Wong, J., Francia, G., and Kerbel, R.S. (2006) Highly efficacious non-toxic preclinical treatment for advanced metastatic breast cancer using combination oral UFT – cyclophosphamide metronomic chemotherapy.  Cancer Res., 66: 3386-3391.
• Kerbel, R.S. (2006) Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science, 312: 1171-1175.
• Shaked, Y., Ciarrocchi, A., Franco, M., Lee, C.R., Man, S., Cheung, A.M., Hicklin, D.J., Chaplin, D., Foster, F.S., Benezra, R., and Kerbel, R.S.  (2006) Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science, 313: 1785-1787.
• Bertolini, F., Shaked, Y., Mancuso, P., and Kerbel, R.S. (2006) The multifaceted circulating endothelial cell in cancer: from promiscuity to surrogate marker and target identification. Nature Reviews Cancer, 6: 835-845.
• Folkins, C., Man, S., Shaked, Y., Xu, P., Hicklin, D.J., and Kerbel, R.S. (2007) Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res. 67: 3560-3564.
• Ebos, J.M.L., Lee, C.R., Christensen, J.G., Mutsaers, A.J., and Kerbel, R.S. (2007) Multiple circulating pro-angiogenic factors systemically induced by sunitinib malate (SU11248) are tumor-independent and correlate with anti-tumor efficacy. Proc. Nat’l Acad. Sci. (USA), 104: 17069-17074.
• Cruz-Munoz, W., Man, S., Xu, P., and Kerbel, R.S. (2008) Development of a preclinical model of spontaneous human melanoma CNS metastasis. Cancer Res., 68: 4500-4505.
• Kerbel, R.S. (2008) Tumor angiogenesis. New Engl. J. Med. 358: 2039-2049.
• Shaked, Y., Henke, E., Roodhart, J., Mancuso, P., Langenberg, M., Colleoni, M., Daenen, L.G., Man, S., Xu, P., Emmenegger, U., Tang, T., Zhu, Z., Witte, L., Streiter, R.M., Bertolini, F., Voest, E., Benezra, R., and Kerbel, R.S. (2008) Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell, 14: 263-273.
• Ebos, J.M.L., Lee, C.R., Cruz-Munoz, W., Bjarnason, G.A., Christensen, J.G., and Kerbel, R.S. (2009) Acceleration of metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell, 15: 232-239.
• Francia, G., Cruz-Munoz, W., Man, S., Xu, P., and Kerbel, R.S. (2011) Perspective: Mouse models of advanced spontaneous metastasis for experimental therapeutics. Nature Rev Cancer 11: 135-141.
• Ebos, J.M.L., and Kerbel, R.S. (2011) Disease progression changes in response to antiangiogenic therapy: Implications for invasion and metastasis. Nature Rev Clin Oncol 8: 210-221.
• Cruz-Muñoz, W., Jaramillo, M.L., Man, S., Xu, P., Banville, M., Collins, C., Nantel, A., Morgan, S.S., Cranmer, L.D., O’Connor-McCourt, M.D., and Kerbel, R.S. (2012) Roles for endothelin receptor B and BCL2A1 in spontaneous CNS metastasis of melanoma. Cancer Res 72: 4909-4919.
• Hackl, C., Francia, G., Milsom, C., Man, S., Xu, P., and Kerbel, R.S. (2013) Metronomic oral topotecan prolongs survival and reduces liver metastasis in improved preclinical orthotopic and adjuvant therapy colon cancer models. GUT 62: 259-271.
• Guerin, E., Man, S., Xu, P., and Kerbel, R.S. (2013) A model of postsurgical advanced metastatic breast cancer more accurately replicates the clinical efficacy of antiangiogenic drugs. Cancer Res 73: 2743-2748.
• Kuczynski, E., Sargent, D., Grothey, A., and Kerbel, R.S. (2013) Drug rechallenge and treatment beyond progression in oncology: examples, mechanisms and implications of reversible drug resistance. Nature Rev Clin Oncol, 10: 571-587.
• Ebos, J.M., Mastri, M., Lee, C.R., Tracz, A., Hudson, J.M., Attwood, K., Cruz-Munoz, W.R., Jedeszko, C., Burns, P., and Kerbel, R.S. (2014) Neoadjuvant antiangiogenic therapy reveals contrasts in primary and metastatic tumor efficacy. EMBO Molecular Medicine 6: 1561-1576.
• Pham, E., Birrer, M.J., Eliasof, S., Garmey, E., Lazarus, D., Lee, C.R., Man, S., Matulonis, U., Peters, C.G., Xu, P., Krasner, C.N., and Kerbel, R.S. (2015) Impact of CRLX101, a HIF-1α targeting nanoparticle-drug conjugate with camptothecin payload, with or without bevacizumab in advanced ovarian cancer. Clin Cancer Res, 21:808-818.
• Jedeszko, C., Paez-Ribes, M., Di Desidero, T., Man, S., Lee, C.R., Xu, P., Bjarnason, G.A., Bocci, G., and Kerbel, R.S. (2015) Orthotopic primary and postsurgical adjuvant therapy renal cell carcinoma models reveal potent anti-tumor activity of metronomic oral topotecan with pazopanib. Sci Transl Med. 7(282):282ra50.
• Wu, F.T.H., Lee, C.R., Bogdanovic, E., Prodeus, A., Gariépy, J. and Kerbel, R.S. (2015) Vasculotide reduces endothelial permeability and tumor cell extravasation in the absence of binding to or agonistic activation of Tie2. EMBO Molecular Medicine, 7: 770-787.
• Kerbel, R.S., and Grothey, A. (2015) Gastrointestinal cancer: Rationale for metronomic chemotherapy in phase III trials. Nat Rev Clin Oncol 12: 313-314.
• Kuczynski, E.A., Lee, C.R., Man, S., Chen, E., and Kerbel, R.S. (2015) Effects of sorafenib dose on acquired reversible resistance and toxicity in hepatocellular carcinoma. Cancer Res. 75: 2510-2519.
• Jayson, G.C., Kerbel, R.S., Ellis, L.M., and Harris, A.L. (2015) Antiangiogenic therapy in oncology: current status and future directions. Lancet, in press.
• Kuczynski, E.A., Yin, M., Bar-Zion, A., Lee, C.R., Butz, H., Man, S., Daley, F., Vermeulen, P.B., Yousef, G.M., Foster. F.S., Reynolds. A.R., and Kerbel, R.S. (2015) Co-option of liver vessels and not sprouting angiogenesis drives acquired sorafenib resistance in hepatocellular carcinoma. J Nat’l Cancer Inst., accepted, pending minor revisions.