From xenografts to the clinic: modelling new therapies in bladder cancer

From xenografts to the clinic: modelling new therapies in bladder cancer

From xenografts to the clinic: modelling new therapies in bladder cancer (#113)

Derek Raghavan ¹

Levine Cancer Institute, Charlotte, NORTH CAROLINA, United States

Bladder cancer is a paradigm of solid tumor malignancy (1), exhibiting significant tumor heterogeneity with elaboration of a broad range of biomarkers, moderate responsiveness to radiation and chemotherapy (1,2), and features that support the existence of solid tumor stem cell functions (3). We have used the xenograft model as a tissue amplifier (4), with subcutaneous or orthotopic implantation of tiny fragments of human bladder cancer, as a mechanism to study the characteristics of this disease, and to model novel treatments (5). We have demonstrated features underlying the heterogeneity of cytotoxic responsiveness (5), and the impact of multi-agent treatment. Initial clinical modeling of chemotherapy for bladder cancer showed modest responsiveness to single agent treatment (6), but our randomized trial showed statistically significant and clinically relevant improvements from multi-drug regimens (7). This led to neoadjuvant modeling, with a trajectory from single agents (6) to combined modality regimens (8,9), the latter showing statistically and clinically significant improvements in survival that created a paradigm shift. It appears that a plateau has been achieved for cytotoxic treatment, but immune modulation now appears highly promising in bladder cancer. However, the immune paresis associated with the xenograft model has limited the preclinical assessment of the utility of T-cell targeting via PD-L1 and lymphocyte function release via PD-L1 inhibition in this disease.

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Authors contributing to this presentation.

Raghavan, D

Dr. Raghavan, President of the Levine Cancer Institute, Charlotte, North Carolina, has served at senior level in oncology for more than 25 years, including roles as Director & Frank Rudy Distinguished Chair, Taussig Cancer Institute, Cleveland Clinic, Chair of Medical Oncology & Associate Director (Clinical Research), University of Southern California Norris Comprehensive Cancer Center, and Professor & Chair of Solid Tumor Oncology/Investigational Therapeutics, Roswell Park Cancer Institute. Trained initially in Australia, Dr. Raghavan completed a PhD at the University of London, and undertook post-doctoral research at the University of Minnesota. Upon his return to Australia, he developed a new paradigm of neoadjuvant therapy for bladder cancer, accompanied by the development of a series of preclinical models of heterogeneity and stem cell function in bladder cancer and prostate cancer. In the United States, he has served as Chair of the National Cancer Institute Cancer (NCI) Clinical Investigations Review Committee, Chair of the Veterans Administration Merit Review Board in Oncology, and has been a member of the FDA Oncology Drug Advisory Committee and the NCI Clinical Oncology Review Section. Dr. Raghavan has been Chair of the Cancer Communications Committee and the Health Disparities Advisory Group of the American Society of Clinical Oncology, a member of the ASCO Value Task Force, was a member of the Scientific Audit Committee of the EORTC for 7 years, has advised Cancer Research UK and the Irish Cancer Society, and the Italian Agency for Cancer Research, has been a member of the Scientific Advisory Board and the Board of Governors of Southwest Oncology Group, and has sat on the International Advisory Board of Deutsche Krebshilfe for more than 5 years. He has previously been the Chairman of the Medical Oncology Group of Australia and Chair of the Specialist Advisory Committee in Oncology of the Royal Australasian College of Physicians. Dr. Raghavan has published more than 250 papers and 12 books, with areas of focus including heterogeneity of tumor function, biology and management of cancers of the bladder, testis and prostate, new drug development in lung cancer, and geriatric oncology. He has been a member of editorial boards of Journal of Clinical Oncology, Clinical Cancer Research, European Journal of Cancer, Annals of Oncology, and many others, and has served on the external scientific advisory boards of 10 comprehensive cancer centers. He is the Editor-in-Chief (Medical Oncology) of HemOnc Today. He received the Frank Moran Award for Leadership in Cancer Research from the University of Michigan in 2003, was elected a Fellow of the American Association for the Advancement of Science in 2009, and a Fellow of the American Society of Clinical Oncology in 2010, and received a Statesman Award from ASCO in 2010. He was awarded a research doctorate in medicine (MD) from the University of Sydney in 2012.

From xenografts to the clinic: modelling new therapies in bladder cancer (#113)

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