New Model Development More information...

New Model Development

An important goal of the TXCCR is to develop new in vitro and xenograft models so that new models that have characteristics that may be more predictive can be tested against the currently employed panel of models.

All new cell lines and xenografts initiated by the TXCCR are validated as originating from a particular patient by short tandem repeat assay, with DNA from the patients tumor and/or from a blood sample used as a reference. Cell cultures are initiated in "standard" oxygen tension, i.e. room air, but as that is non-physiologic, samples are also initiated in physiological hypoxia (5% O2 = bone marrow level oxygen) and for selected tumors in 2% O2 as well. Cultures are also initiated using serum-free medium that has been reported to enhance the growth of "stem cell" populations from cancers. For all lines established basic characterization to insure the line is from the appropriate cancer, and to rule out EBV lymphoblastoid lines if morphology suggests such), will be undertaken and then model cryopreserved for future more extensive characterization and banking.

The TXCCR anticipates that direct xenografts may prove to be more informative than xenografts established from cell cultures. Thus, direct xenografts are attempted from viable tumor samples for many of the cancers also put into cell culture. As our experience is that lymphoid leukemias grow more often as direct xenografts than they do in vitro, for lymphoid malignancies the priority is direct xenografts and cell cultures are also initiated if sufficient material Similarly, cell lines established in culture in physiological hypoxia may more faithfully maintain the biology of cancer cells in vivo than cell lines grown in atmospheric oxygen, which is ~4-fold higher than bone marrow level oxygen and ~10-fold higher than the usual oxygen levels found in solid tumors.

Another key goal of the new model development is to establish paired cell lines and xenografts from patients at diagnosis (prior to therapy) and at time of progressive disease on or after standard therapy, and also after 2nd and 3rd line therapy. Such cell line and xenograft pairs will be invaluable for drug testing and also for biological studies aimed at understanding mechanisms of drug resistance and identifying molecular targets to overcome such resistance. As drug testing of new agents benefits greatly from being able to test models of cancers which manifest the major forms of drug resistance, establishing additional models from patients after therapy is valuable even if no pre-therapy match is available for that particular patient. Also, as therapeutic options change, novel mechanisms of drug resistance may emerge. Thus, until sufficient models of a particular disease and biological phenotype have been accrued, the TXCCR labs will establish new cell lines and direct xenografts whenever possible.