Importance of Animal Studies

In my continuing quest to highlight hot-off-the-press findings from Society researchers that address important themes in blood cancer research, this month I'll discuss mouse models of human cancer. Animal studies are critical to research advances because cancer is a complex, three-dimensional disease that changes as it grows, interacting with normal cells and processes within a patient's body. Cells in laboratory dishes cannot adequately model this complexity and computer models, although more and more promising, are still a long way from teaching us what we need to know. Cancer patients need answers now.

Much of what we know about cancer comes from mouse studies, in particular, and developing therapies are usually first tested in mice. Mice are easy and fast to breed and share enough biology with us to make useful studies possible. But mice are not men (or women). Differences exist in cancer formation and particular genetic alterations can produce different tumor types in human and mouse. Early mouse models were frequently disappointing.

In recent years, the mouse genome has been completely sequenced and researchers have developed tricks to genetically engineer mice so that mouse cancers can accurately represent human cancers. More than ever, mice help us understand the molecular mechanisms of tumor formation because researchers can now control when and where cancer-causing changes occur. In "transgenic" mice, cancer-causing genes are abnormally turned on; in "knock-out" mice, tumor-suppressing genes are abnormally turned off.

Other genetically-modified mice have been developed to allow the growth of human tumors that are rejected by normal, healthy mice.  "Xenografts" of injected human cancer cells can be ready within weeks, whereas transgenic and knock-out mouse models can take months to develop tumors.  Xenograft models are frequently used to evaluate cancer responses to new, experimental therapies.

I have mentioned Society researchers using mouse models in previous commentaries, including Antonio Bedalov, M.D., using xenografts to study an epigenetics-targeting drug in lymphoma, and  Scott Armstrong M.D., Ph.D., who is developing therapies to selectively kill leukemia stem cells. But let me share other recently published findings of Society researchers.

Using cancer cell samples from lymphoma patients and transgenic mice, Michael Teitell, M.D., Ph.D, and his multi-center team found that defects in one gene (TCL1) can cause a particular type of non-Hodgkin lymphoma that involves malignant B-cells (B-NHL). Their findings are now available online in the journal Blood.

Dr. Teitell and his colleagues found that transgenic mice that abnormally express high levels of TCL1 in particular types of B-cells develop B-NHLs at a very high rate, but only when other genetic defects accumulate. This finding is consistent with the widely-accepted idea that cancer usually involves defects in more than one critical gene, and highlights the validity of this lymphoma model. The researchers will next determine which molecular defects that occur in mouse lymphomas also occur in human lymphomas. This information will be used to design improved tests for the diagnosis and classification of NHLs and will provide targets for new, effective therapies.

Another Society-funded researcher, John Byrd, M.D., and his colleagues published results of another TCL1 study in the August issue of Blood. They created a transgenic mouse model that highly expresses TCL1 in another type of B cells and instead produces tumors that closely resemble chronic lymphocytic leukemia (CLL), a distinct B-cell malignancy. This represents the first accurate animal model of CLL and should greatly facilitate the development of new drugs for this largely incurable disease.

Michelle Kelliher, Ph.D., used transgenic mice engineered by her colleague, Anthony Capobianco, Ph.D., in which the Notch1 gene can be abnormally turned on and off at will. Their study has just been posted online by the journal Molecular and Cellular Biology. They found that when Notch1 is hyperactive, mice develop aggressive T-cell cancers that regress when Notch1 is turned off, showing that Notch1 not only can cause these cancers but is needed for their continued growth. These data suggest that new drugs that inactivate Notch1 will halt T-cell cancer growth.

Selina Chen-Kiang, Ph.D, and her team know just how useful mouse models can be in testing new treatments for blood cancers. They are focused on proteins called Cdk4 and Cdk6 that normally control cell proliferation but are abnormally expressed at high levels in myeloma tumors in which plasma cells proliferate unchecked. To study the role these proteins play, they created a mouse xenograft model that replicates many aspects of human myeloma, including rapid spread and bone disease.

Dr. Chen-Kiang and her colleagues found that a drug called PD 0332991 (from Pfizer) potently and rapidly inhibits myeloma tumor growth in tumor-bearing mice in which conventional anti-myeloma drugs are ineffective. These findings were reported in the Aug. 1 issue of the journal Cancer Research. Initial clinical trials are now planned. And, guess what? Preliminary laboratory findings suggest that this drug may help other cancer patients too!

Xenograft models are not always predictive of drug activity, but researchers continue working to improve them. Manipulating the cellular environment into which cancer cells are injected may help, including adding human cells into the mix. Another way to make mice respond to drugs in a more human-like fashion is to give the mice human drug-processing genes, and these humanized mice may be an even more powerful way to test drug candidates that could soon be saving human lives. You know what I say, "stay tuned"!