What’s New in Leukemia Research at Siteman
What is “Translational Research?”
Translational research is the novel application of what scientists learn in the laboratory about the biology of a disease to the care of patients with that disease. This type of research tends to be highly innovative and “cutting edge.” Some of the most important advances to cancer treatment have occurred because of translational research.
Translational research is actually a process. Scientists conduct “basic” research (also called “bench” research) in the laboratory to understand the biology of cancer. Their results form the basis for clinical trials designed to improve the treatment of cancer patients (so-called “bench-to-bedside” research). The trials not only indicate whether a treatment is safe and effective, but also whether the laboratory models accurately reflect what happens in the patient. In addition a trial may reveal unforeseen information about how patients’ bodies react to a treatment or new vulnerabilities in the cancer. This feedback sparks more basic research (“bedside-to-bench”). The continual cycling of new information between basic research and clinical studies is known as translational research.
Washington University in St. Louis is one of only 3 sites in the nation selected by the National Cancer Institute (NCI) to receive a $12.2 million Specialized Program of Research Excellence (SPORE) in Leukemia grant to focus on translational research in leukemia and myelodysplastic syndromes (MDS).
The projects supported by this five-year award are described here.
Do genes in cancer cells affect whether a patient’s cancer will be affected by the drug, decitibine?
(SPORE project: Molecular determinates of decitibine responsiveness. Co-leaders: Timothy Ley, MD and John Welch, MD, PhD)
Cancer arises from normal cells whose genes have gone awry. When cells prepare to divide to make new cells, the internal machinery that copies the DNA sometimes makes errors that result in “mutations” or changes in the DNA sequence. Genes encode proteins. Mutations in genes can result in proteins that work poorly, better, in a new way, or not at all. Many mutations have little or no long-term consequences. However some particularly bad mistakes, or an accumulation of many mistakes, can lead to rogue cancer cells that grow and divide faster than normal cells. Cancer cells may also cease to respond to “signals” that would typically tell them how to behave or where to go. Sometimes they change their appearance, and no longer wear the “markers” that identify them to other cells whose job as part of the immune system is to police the area and destroy intruders. Some of the cancer cell offspring acquire their own new mutation(s), and as these cells divide, they unfortunately pass on to their descendants not only the mutations they inherited, but also the new ones. In this way many different related clones can evolve, and tracing their heritage essentially creates a “family tree” of the cancer clones in an individual patient. Scientists at Washington University and the Siteman Cancer Center in St. Louis are recognized nationwide for their expertise in sequencing entire genomes of patients and comparing these to the genes found in cancer cells. By doing so, they can determine not only the number and variety of cancer clones present, but also characteristics of the probable starting cell, and changes in its descendants.
The machinery for cell division can make errors other than those that result in an actual change in DNA sequence. For example, this machinery is also involved in putting tags on DNA or chromatin, such as methyl or acetyl groups, that affect whether that gene gets “expressed,” in other words, whether its protein is made, as well as how much of it is made. Every cell in the body has every gene that is needed to make any organ in the body, but expressing all of the genes would lead to chaos. Instead brain cells only express genes brains need, and blood cells only express genes that they need. Scientists, especially those at Washington University and the Siteman Cancer Center in St. Louis, are adept at following these “gene expression profiles.” Individual cancer cell clones have characteristic expression profiles, and the particular genes expressed may give some clones an advantage over others, thus making them grow faster (more aggressively) and overtake other clones in number.
Decitabine is a drug that has been used safely in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The drug is believed to have two actions. First, it is an “anti-metabolite,” preferentially killing rapidly dividing cancer cells. Second, it is a “hypomethylating agent” that alters the tagging of DNA, and consequently the gene expression profile. Some patients treated with the drug go into complete remission, i.e., no longer have any detectable cancer cells, while other patients do not respond as well.
Drs. Ley and Welch are collaborating on studies both in the lab and in patients to determine whether patients who have a better response to decitibine treatment have cancer cells with distinct mutations or gene expression profiles. If a patient relapses, these investigators will also look to see if particular clones of cancer cells have characteristics that helped them continue to thrive in the presence of decitibine or whether these are new members of the cancer family tree. The scientists hope to use information from their studies to predict which patients will respond well to decitibine treatment and which might do better with another drug.
Can cancer cells be chased out of the bone marrow and into the blood so they can be killed more easily?
(Spore project: Targeting the bone marrow microenvironment in acute lymphocytic leukemia. Co-leaders: Daniel Link, MD and Geoffrey Uy, MD)
Bone marrow, the soft tissue inside bones, is the blood cell manufacturing center. Special cells called “hematopoietic stem cells (HSC)” live in the bone marrow and divide as needed to make all types of white and red blood cells. HSC and their immature offspring stay in the bone marrow, a very nurturing environment, because they are tethered by particular molecules on their surface to other cells in the marrow. More mature blood cells lack the molecules to keep them tethered, so they are free to move into the blood stream and circulate throughout the body.
Patients with acute leukocytic leukemia (ALL) have an overgrowth of immature cancerous white blood cells. These cells, called “blasts,” still retain the molecules that tether them to the bone marrow lining. By staying in the nurturing bone marrow they are protected from many anti-cancer drugs.
Drs. Link and Uy want to break or block the tether between the cancerous blasts and the bone marrow using a combination of Neupogen (filgrastrim) and POL6326, a new investigational drug. It is believed that this treatment will “mobilize” leukemic cells out of the protective bone marrow so that they move into the blood, where they will be more sensitive to destruction by chemotherapy. The investigators are developing a clinical trial testing this idea in patients with acute lymphocytic leukemia whose cancer is resistant to therapy or whose cancer comes back or “relapses.” It is hoped that the addition of Neupogen and POL6326 will roust out more cancerous cells so as to improve responses to chemotherapy and reduce the chance that the cancer relapses. This hope stems from the theory that therapy resistance and relapse occur because some immature cancerous blasts hide out in the marrow after chemotherapy. If the blasts are prevented from staying and being nurtured in the marrow in the first place, they shouldn’t be able to take refuge there, and then re-emerge later to cause a relapse of disease.
Will Vidaza (5’-azacytidine) treatment prevent or diminish the severity of graft versus host disease after a bone marrow transplant?
(SPORE project: Epigenetic modulation of graft vs. host disease and graft vs. leukemia Co-leaders: John DiPersio, MD, PhD and Peter Westervelt, MD, PhD)
Patients sometimes need a bone marrow transplant from a donor to treat their leukemia, MDS, or other hematological cancer. An unfortunate side-effect of this treatment is called “graft vs. host disease (GvHD).” It affects ~40 % of transplant patients and results in death in ~25% of these. The disease is a direct effect of one type of cell that gets administered from a donor to patients: a white blood cell called a “T cell.” T cells have a Jekyll and Hyde personality. As part of the immune system they are the primary leukemia-fighting cell. However when they become overzealous, the donated T cells may also attack the patient’s skin, intestines, liver, and mucosa.
As a result of preliminary funding by the Bryan T. Campbell Foundation, the DiPersio lab discovered that after giving T cells to leukemic mice, it is possible to administer the drug azacitidine and thereby increase the number of a particular type of T cell called “T regulatory cells.” These cells patrol the immune system and keep it in check. Administering azacytidine to transplanted mice increases the number of T regulatory cells from less than 1% to up to ~15% of all T cells. Azacytidine treatment minimizes the severity of GvHD, sometimes totally preventing it, while still allowing the T cells to combat the leukemia. As a result all treated mice survive, whereas nearly all untreated mice die.
This observation encouraged Drs. DiPersio and Westfeld to begin a trial in which patients are treated with azacytidine (Vidaza), which has been safely used in patients for other purposes. The scientists hope to reduce GvHD while maintaining the anti-leukemic effect in patients.
Do mutations in RNA splicing genes provide a new target for leukemia therapy?
(Spore project: Development of RNA splicing modulators for myelodysplatic syndromes and AML Co-leaders: Timothy Graubert, MD, and Matthew Walter, MD)
DNA acts as a master blueprint for all the proteins that any cell in the body might need. Various proteins have specific roles in a cell. Some proteins read the DNA and direct the production of a short-lived smaller blueprint called RNA. Ultimately, all proteins are synthesized from these RNA blueprints and different types of proteins, with different functions, can result from the way a cell stiches together these blueprints from the DNA. The process that cells use to stitch pieces of RNA together is called “splicing.”
What happens when one of the proteins involved in RNA splicing is mutated (i.e., changed due to errors in the DNA in cancer cells)? This may result in too much or too little material included in the RNA blueprint. Now a new protein is made that has only some characteristics of the original protein, and possibly some new characteristics. Consequently, as with a genetic mutation in the DNA, the new protein may not work, or it may work better or differently, thus wreaking havoc in the cell.
The Walter and Graubert laboratories recently found that a subset of patients with MDS have a mutation in a gene called U2AF1. The protein encoded by this gene is one of the engineers that create RNA blueprints. As can be imagined, such a mutation could result in the “downstream effect” of repeatedly making many different types of faulty blueprints and ultimately new proteins. The end result can be uncontrolled growth of a cell with unexpected characteristics, i.e., a cancerous cell. These investigators are studying how U2AF1 works in normal cells and how mutations in it lead to the development of leukemic blood cells with the hope that someday drugs may be developed to treat cancers with this mutation.