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Tumor Xenotransplantation: The Ultimate Testing Platform for Chemotherapy Drugs

Published: Tuesday, Jan 27, 2009
Conventional cancer chemotherapy has enjoyed mixed success because it fails to differentiate patients by the unique molecular characteristics of their disease.

We know that only a fraction of patients respond to first-line chemotherapy, while the efficacy of adjuvant therapy can vary significantly. This is evident in early stage breast cancer, with which only about 10% of women experience recurrence but all receive adjuvant chemotherapy. A better understanding of breast cancer recurrence could spare most women the trouble, expense, and toxicity of chemotherapy, and save the healthcare system billions of dollars per year.



Biomarkers and Cell Culture

Biomarkers help in selecting candidates for various cancer treatments, but only a handful of validated drug–biomarker combinations have been approved, most notably Her2-neu, ERCC1, and K-ras for treating with trastuzumab, platinum compounds, and bevacizumab, respectively. The problem with biomarkers is that they test for only one specific therapy. An assay for sensitivity to platinum, for example, says nothing about what other drugs might work.

Cultured tumor cell sensitivity testing involves culturing fresh tumor cells and testing them against one or more chemotherapy agents, either in vitro or after implantation into test animals. These tests predict resistance to chemotherapy agents, but not sensitivity. That is, they easily eliminate drugs that do not work, but only poorly predict those that do. Poor predictability is a consequence of cells losing the primary tumor’s physical, biochemical, and even genetic characteristics.

Xenotransplantation

Biomerk Tumorgrafts™ (“tumor xenograft”), under development by Champions Biotechnology, Inc., represents a dramatic break from the paradigms of correlative biomarker testing and cell- or tissue-based chemotherapy assays. Tumorgrafts involve harvesting tumor tissue from patients through biopsy or surgery and implanting it in immune-incompetent mice. The tumors are “grown” in these animals and re-transplanted to expand the test animal population to dozens or hundreds of mice. I developed Tumorgraft technology along with Manuel Hidalgo, MD, PhD, at the Johns Hopkins School of Medicine.

A Tumorgraft established in mice provides a living test bed for investigating anti-neoplastic agents and combinations, including experimental agents.

Grafted tumors growing in test animals retain the salient characteristics of the original human cancer. The animals may be used to screen anticancer drugs and combinations to personalize treatment for the patient donating the tumor tissue, or can serve as screening platforms for new drugs and combinations or for discovering biomarkers for recurrence, toxicology, or treatment efficacy. Unlike cultured tumor cells in vitro or after transplantation into test animals, Tumorgrafts have been shown to predict both resistance and susceptibility to chemotherapy agents, generating data that might take years to otherwise uncover.

The Tumorgraft platform is not appropriate for every cancer patient. It requires approximately four to six months to generate enough tumorbearing mice to perform studies. A Tumorgraft candidate must therefore be expected to live at least six months. Tumorgraft development and testing is also an expensive process that is not currently covered by insurance.

Benefits

The greatest benefit of Tumorgrafts is the potential to discover treatments that work, while sparing patients from toxicities of drugs that will be ineffective in their particular case. In addition to the resulting treatment efficacy, the patient may also be afforded a significant reduction in the costs of care, as well as improvement in quality of life.

Tumorgrafts have profound implications for drug development and personalized medicine. The high failure rate for new drugs is in part a function of relying too heavily on “generic” subject populations during human clinical testing. Tumorgrafts, when coupled with advanced biomarker and genetic testing, will enable investigators to hone in on cancers that are distinct within their phenotype and accurately match them with the therapy most likely to work.

In addition to cancer type, stage, origin, patient age and sex, and treatment history, Tumorgraft characterization includes gene expression, mutations, comparative genomic hybridizations, methylation, and analysis of the proteome and microRNA. This opens the possibility for long-term studies of the efficacy of chemotherapy in specific cancer genotypes. A large database correlating molecular data with treatment outcomes might eventually eliminate the need to grow the tumors in mice.

Tumorgrafts fill a significant unmet need for cancer drug screening. Unlike biomarkers, which test for only one therapy, or assays based on cultured cells, Tumorgrafts are designed to reproduce human disease in a robust animal model. Genomic and proteomic data generated through Tumorgrafts could eventually serve as the ultimate correlate between chemotherapy regimens and cancer, bridging the gap between phenotype and genotype.


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