Signal Transduction Inhibitor Therapy for Lymphoma

Principal Investigator: Thomas Witzig, M.D., Mayo Clinic
Co-Principal Investigator: Scott Kaufmann, M.D., Ph.D., Mayo Clinic

Lymphomas are the fifth most common neoplasms in the United States, with nearly 80,000 new cases of non-Hodgkin lymphoma (NHL) and Hodgkin disease (HD) each year. Treatment advances over the last 35 years include the development of combination chemotherapies CHOP and ABVD, and stem cell transplantation. The only significant new agents to be developed recently have been rituximab and the anti-CD20 radioimmunoconjugates. Researchers have found that the addition of rituximab to CHOP adds about 15 percent to the overall survival for large cell NHL; however, nearly 40 percent of patients still die of disease. Other studies showed that in indolent NHL, addition of rituximab to another combination chemotherapy, CVP, has improved the overall response rate, time to progression, and possibly overall survival. However, 80 percent are still not cured and die of their disease. It is clear that new agents with unique mechanisms of action based on knowledge of signal transduction pathways in lymphoma cells are needed to improve lymphoma therapy.

The overall hypothesis of Project 2 of the University of Iowa/Mayo Clinic (UI/MC) Lymphoma SPORE is that a combination of chemotherapy agents with one or more of the signal transduction inhibitors will improve the response rate and survival of patients with NHL/HD. To test this hypothesis, this project includes clinical trials that assess rational combinations of signal transduction inhibitors with each other and with conventional chemotherapy agents, investigational biomarkers in lymphoma cells from patients participating in these trials, and in vitro studies of new agents and combinations in primary tumor cells that will lead to the next generation of clinical trials.

The collaborating investigators in this research proposal bring complementary expertise to provide a synergistic, multidisciplinary approach to the study of new agents for lymphoma. Dr. Witzig has been involved in clinical and laboratory research on the biology and treatment of lymphoma and myeloma for over 20 years. His knowledge of the disease and the important current clinical issues provide a perspective that will serve to direct and guide the basic laboratory research and clinical trials outlined in this proposal.

Dr. Kaufmann is a basic scientist with expertise in the preclinical evaluation of new drugs and their mechanism of action. Shaji Kumar, M.D., has expertise in the study of antiangiogenic drugs for B-cell malignancies. Raymond Hohl, M.D., Ph.D., is an expert in ras farnesylation, an area pertinent to the clinical trial of the farnesyltransferase inhibitor to be tested in Aim 1. This team, in association with the SPORE Cores, clearly has the experience needed to conduct all aspects of the clinical trial and translational research associated with it.

Stimulation of the phosphatidylinositol-3 kinase (PI3K) pathway via activated ras and receptor tyrosine kinases results in the sequential activation of Akt/protein kinase B and mammalian target of rapamycin (mTOR) kinases, leading to altered regulation of key cellular processes such as cell proliferation and apoptosis. Research has proven that farnesylated proteins are important in multiple cell signaling pathways, including the PI3K pathway. In the past funding period, UI/MC investigators began a Phase II SPORE trial of the oral farnesyltransferase inhibitor tipifarnib. This ongoing trial is the first to demonstrate single-agent activity of tipifarnib in NHL and HD.

In separate studies, UI/MC investigators also demonstrated single-agent activity of mTOR inhibitors in mantle cell lymphoma (temsirolimus) and in large cell NHL and HD (everolimus). Additional preliminary studies demonstrate activity of the Raf kinase and VEGFR inhibitor sorafenib against lymphoma cells in vitro that is synergistic with mTOR inhibitors. Just as combinations of chemotherapy agents were necessary to demonstrate the curability of lymphoma in the 1970's, the central hypothesis of this proposal is that signal transduction inhibitors (STIs) will need to be combined with each other or with known effective chemotherapy agents in order to improve the curability of NHL and HD. To test this hypothesis, Project 2 of the Lymphoma SPORE includes clinical trials that assess rational combinations of STIs with each other and with conventional chemotherapy agents, investigation of biomarkers in lymphoma cells from patients participating in these trials, and in vitro studies of new agents and combinations in primary tumor cells that will lead to the next generation of clinical trials.

This work is organized into three specific aims to:

1. Investigate the safety and efficacy of PI3K/Akt/mTOR pathway inhibitors in combination with Raf-kinase inhibitors and conventional chemotherapy agents

   To evaluate this aim, the SPORE is conducting two separate trials:

   • Phase II trial of tipifarnib plus etoposide for relapsed aggressive NHL at the University of Iowa and Mayo Clinic
   • Phase I/II trial of sorafenib plus everolimus for B-cell malignancies that will be performed as an Inter-SPORE trial between this Lymphoma SPORE and the Myeloma SPORE.

2. Assess the action of combinations of STIs on the targeted pathways and identify potential markers of anti-tumor efficacy using malignant B-cells from patients entered on the trials in Aim 1

   Because tumor response will be heterogeneous, the researchers will utilize tissue samples from patients entering the SPORE trials to assess the impact of treatment on levels of expression of key members of the PI3K and Raf kinase pathways, tumor cell proliferation/apoptosis, and levels of tumor angiogenesis.

3. Investigate novel combinations containing agents targeting the PI3K/Akt/mTOR pathway and other STIs or conventional agents in malignant B-cells in vitro to provide the rationale for the next generation of clinical trials

   Malignant B-cell lines will be used to test combinations of STIs with each other and with conventional chemotherapy agents known to have activity in the B-cell malignancies. Promising combinations will be tested on fresh primary malignant B-cells from patients accrued to the Biospecimens Core.

Project 2's initial studies will focus on drugs that target PI3K/Akt/mTOR pathway components or those of pathways known to connect with the PI3K/Akt/mTOR pathway. Other research will also include compounds being studied through the current Lymphoma SPORE Developmental and Career Development Research programs.

This Project provides a platform that maximizes the SPORE resources by testing new agents in the lab on samples accrued through the Biospecimens Core, conducting clinical trials with the Clinical Research Core and the Biostatistics and Bioinformatic Core, and partnering with basic scientists to test and discover new combinations of treatments that can be moved to future clinical trials. Combinations with substantial clinical activity will then move to large-scale testing in the cooperative groups such as the North Central Cancer Treatment Group or the Eastern Cooperative Oncology Group.