Treatment advances for non-Hodgkin Lymphoma (NHL) and Hodgkin Disease (HD) over the last severaldecades have improved the survival of patients with these common malignancies. However, nearly 40% ofpatients with large cell NHL, 80% with indolent NHL, and 20% with HD are not cured and die of their disease.It is clear that new agents with unique mechanisms of action based on knowledge of signal transductionpathways in lymphoma cells are needed to advance lymphoma treatment. This proposal focuses on thephosphatidylinositol-3 kinase (PI3K) and Raf kinase pathways in lymphoma cells. We have demonstratedsingle agent activity in patients with NHL/HD using inhibitors of the PI3K pathway (temsirolimus/everolimus)and inhibitors of farnesyl transferase (tipifarnib). Preliminary in vitro studies demonstrate activity of the Rafkinase/VGFR inhibitor sorafenib against lymphoma cells that is synergistic with the PI3K pathway inhibitors.The overall hypothesis of this proposal is that a combination of chemotherapy agents with one or more of thesignal transduction inhibitors (STIs) will improve the response rate and survival of patients with NHL/HD. Totest this hypothesis, this project includes clinical trials that assess rational combinations of STIs with eachother and with conventional chemotherapy agents, investigational biomarkers in lymphoma cells from patientsparticipating in these trials, and in vitro studies of new agents and combinations in primary tumor cells that willlead to the next generation of clinical trials. This work is organized in 3 specific aims.
Aim 1, to investigate the safety and efficacy of PI3K/Akt/mTOR pathway inhibitors in combination with Raf-kinase inhibitors and conventional chemotherapy agentsAim 2, to assess the action of combinations of STIs on the targeted pathways and identify potential markers ofanti-tumor efficacy using malignant B-cells from patients entered on the trials in Aim 1Aim 3, to investigate novel combinations containing agents targeting the PI3K/Akt/mTOR pathway and otherSTIs or conventional agents in malignant B-cells in vitro to provide the rationale for the next generation ofclinical trials. Our initial studies will focus on drugs that target PI3K/Akt/mTOR pathway components or thoseof pathways known to connect with the PI3K/Akt/mTOR pathway. Combinations with substantial clinicalactivity will then move to large-scale testing in the cooperative groups such as NCCTG or ECOG.Lay Language Statement: Lymphoma cells respond to signals that are transmitted from the outside to theinside of the cell resulting in cell growth. This project focuses on new drugs for patients with lymphoma thatinterfere with those signals. Preliminary studies with several of these drugs are promising and the goal of thisproject will be to combine these agents together and with other common chemotherapy agents to advance thetreatment of lymphoma.
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