Four new approaches to treating lymphoma and chronic lymphocytic leukemia (CLL) will move from the lab to early clinical trials under a federal grant to M. D. Anderson. The grant brings together basic and translational scientists, clinical
investigators, hematopathologists and biostatisticians on four projects.
Project director and principal investigator Anas Younes, M.D., says "translating these promising targeted therapies into the clinic extends our progress toward developing drugs that are more effective and gentler on our patients.
What is a SPORE?
Specialized Programs of Research Excellence (SPORE) grants from the National Cancer Institute are designed to advance basic and preclinical discoveries into early stage clinical trials, a difficult step in drug development. Translational research is a strength at M. D. Anderson, which now has 12 SPOREs, the most of any institution.
Epigenetic therapy for Hodgkin lymphoma
Epigenetic factors regulate gene behavior without altering or damaging the gene's DNA by adding or removing chemical groups that attach to genes like bookmarks. Younes and co-principal investigator Yong-Jun Liu, M.D., Ph.D., chair of the Department of Immunology, hypothesize that epigenetic therapy could affect Hodgkin lymphoma two ways: directly by inhibiting growth of malignant cells and indirectly by triggering an anti-tumor immune response.
They will test several new drugs that regulate gene expression by targeting enzymes that chemically alter histone and non-histone proteins for safety and efficacy in relapsed and resistant Hodgkin lymphoma. The same drugs also will be tried in combination with another epigenetic drug that turns on genes by stripping methyl groups from them. The team will conduct lab experiments to design second-generation combination clinical trials.
Testing a novel agent for CLL and lymphoma
Scientists at M. D. Anderson and Northwestern University have developed a unique drug that will be the first of its type to be tested in the clinic. Varsha Gandhi, Ph.D., professor in M. D. Anderson's Department of Experimental Therapeutics, has developed an RNA nucleoside analogue, an artificial version of one of the building blocks of RNA. The drug inhibits synthesis of messenger RNA, which is produced by genes to tell a cell's protein-making machinery which protein to make.
Clinicians on the project, led by co-principal investigator Peter McLaughlin, M.D., professor in the Department of Lymphoma and Myeloma, will conduct a Phase I clinical trial for patients with chronic lymphocytic leukemia. The team will use biomarkers to evaluate the drug's activity and staying power, develop rationales for clinical trials combining the drug with other agents and test it in lymphoma cell lines for translation into a lymphoma clinical trial.
Activating an important tumor suppressor
The protein p53 stifles cancer development by ordering abnormal cells to kill themselves. It is silenced in more than half of blood cancers by overexpression of the HDM2 gene. The research team has shown that inhibiting HDM2/p53 interaction causes programmed cell death in Hodgkin and non-Hodgkin lymphomas, and in acute myeloid and chronic lymphocytic leukemias when the p53 gene is not mutated.
A team led by principal investigator Michael Andreeff, M.D., Ph.D., professor in the Department of Stem Cell Transplantation, and co-principal investigator Susan O'Brien, M.D., professor in the Department of Leukemia, will test the effects of Nutlin 3a, a small-molecule inhibitor of HDM2, in a Phase I clinical trial for CLL. They also will identify the mechanisms of programmed cell death induced by the drug in lymphoma and CLL.
Targeted therapy in peripheral T-cell lymphoma
T-cell and natural killer cell lymphomas have poor clinical outcomes with current treatment but are so rare that only small studies have been performed to understand the disease. In this project, researchers at the University of Nebraska Medical Center will conduct gene expression profiling on samples from 1,320 cases contributed by an international consortium they have assembled.
Genome expression profiling will be used to define the molecular characteristics of both types of lymphoma, identify pathways that may contribute to lymphoma development and evaluate novel treatments based on their findings. The project, led by principal investigator John Chan, M.D., professor of microbiology and pathology, and co-principal investigator Julie Vose, M.D., professor of internal medicine, will then perform clinical trials in patients with relapsed T-cell and NK-cell lymphomas using agents that hit the cancer-causing pathways.