Pancreatic-Cancer Imageable Patient-Derived Orthotopic Xenografts (iPDOX)

Yang, Meng

Abstract

Individualized cancer treatment is an important goal, in particular, for pancreatic cancer, which is the most lethal human cancer. Novel transformative therapeutics are also urgently needed to cure this disease. Our laboratory pioneered the orthotopic growth of patient tumors, including colon cancer (1) and pancreatic cancer (2), in nude-mouse models where the tumors grow and metastasize as they did in the patient. Although there is presently much interest in growth of patient tumors in immunodeficient mouse models to individualize therapy and new names for these models have been coined, such as """"""""tumorgraft"""""""" and """"""""xenopatients"""""""", the current models are still subcutaneous ectopic xenografts in various types of immunodeficient mice. Such ectopic models do not metastasize and therefore do not sufficiently represent the patient. The present application, takes advantages of the patient-like orthotopic models our laboratory pioneered (1-6) as well as the in vivo imaging technology our laboratory also pioneered, based on fluorescent proteins (7), to develop imageable orthotopic models of patient pancreatic tumors for rapid screening for effective and individualized therapy. We have termed these models imageable patient-derived orthotopic xenografts (iPDOX). We have initially demonstrated that pancreatic cancer patient tumors can be made imageable by passage in transgenic nude mice expressing either green fluorescent protein (GFP), red fluorescent protein (RFP) or cyan fluorescent protein (CFP) whereby the patient tumors acquire and maintain the fluorescent stroma of the transgenic mice, even though tumor growth and passage (8-10). The current application proposes to develop the iPDOX models for screening for effective individualized therapy for pancreatic cancer patients whereby response to therapy can be monitored non-invasively in real time by fluorescence imaging. The new iPDOX derived from pancreatic cancer patients will individualize therapy and increase the probability of improved outcome and provide the opportunity to discover transformative therapeutics for this disease.
The specific aims of the Phase I application are as follows: 1) Establish a cohort of pancreatic-cancer iPDOX models by labeling the stroma with fluorescent proteins;2) Validate the imageable model by correlating fluorescence imaging area with both tumor weight and volume during iPDOX growth and metastasis. In the Phase II application, the pancreatic-cancer iPDOX models will be validated for rapid screening for transformative novel chemotherapy for pancreatic cancer.

Public Health Relevance

Individualized cancer treatment is an important goal, in particular, for pancreatic cancer, which is the most lethal cancer. Our laboratory pioneered the orthotopic (literally, correct place: tumors are transplanted on the same mouse organ they originated from in the patient) growth of patient tumors, in nude-mouse models which are immunodeficient such that they do not reject human tumors. Although there is presently much interest in growth of patient tumors in immunodeficient mouse models and new names for these models have been coined, such as tumograft and xenopatients, the current mouse models are subcutaneous xenografts (heterotopic in contrast to orthotopic: tumor from organs are transplanted under the skin instead of the equivalent organ of their origin) in various types of immunodeficient mice. Such models do not metastasize and therefore do not sufficiently represent the patient, especially pancreatic cancer which is highly metastatic in patients. The present application, takes advantages of the orthotopic models our laboratory has pioneered as well as the in vivo imaging technology our laboratory also pioneered, based on fluorescent proteins (7), to develop imageable orthotopic models of patient pancreatic tumors to screen for individualized and novel more effective therapy. We have termed these models imageable patient-derived orthotopic xenografts (iPDOX). We have recently initially demonstrated that pancreatic cancer PDOX can be made imageable by growth in transgenic nude mice expressing either green fluorescent protein (GFP), red fluorescent protein (RFP) or cyan fluorescent protein (CFP) or combination of these mice (8, 9). The tumors acquire and maintain the fluorescent stroma (non-cancer cells inter-acting with cancer cells in tumors) of the host which allows the primary and metastatic tumors to be imageable, including non-invasively, enabling the primary tumor size and metastasis to be visualized essentially instantly and progression and response to drugs followed over time in the live animal. The current Phase I and future Phase II applications propose to develop the iPDOX models for highly effective individualized therapy and for rapid screening of novel, more effective therapeutics of pancreatic cancer.