Signal Transduction Inhibitors in Lymphoproliferative Diseases (LPD).

There are a wide variety of diseases characterized by abnormal proliferation of lymphocytes, with differing clinical manifestations and in a spectrum from benign to malignant. Underlying all of these disorders, however, are subversions of normal lymphocyte signaling pathways that contribute to the pathologic process, can be characterized, and can potentially be targeted. Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood and an example of malignant LPD, while patients with nonmalignant LPD, such as autoimmune lymphoproliferative syndrome (ALPS), can be difficult to diagnose, suffer from chronic infections that can be life-threatening, have a decreased life expectancy, and often require long-term treatment with immunosuppressive agents, including steroids, which can result in long-term debilitating consequences. In order to improve outcome and potentially reduce side effects and long-term sequelae from current cytotoxic therapy, the development of novel, biologically relevant, molecular, and cellular targeted therapies is critical. Potential targeted therapies can be identified and tested using in vitro assays, in vitro bone marrow stromal cell culture systems, murine models of ALL and LPD, and xenografts of primary human ALL. These pre-clinical assays have indentified promising and clinically relevant targets in the mTOR, IL-7, and Notch pathways, some which are now being tested in clinical trials. These include

1. rapamycin, being tested in both ALL and ALPS;

2. temsirolimus, a second generation rapamycin analogue that shows promise in combination with cytotoxic chemotherapy in ALL;

3. inhibitors of IL-7 signaling; and

4. DAPT, a gamma-secretase inhibitor that has shown pre-clinical activity against both lymphoproliferation and autoimmune manifestations including nephritis in ALPS.