Jan. A. Burger, M.D., Ph.D. University of Texas MD Anderson Cancer Center

CLL-STROMA INTERACTION

Understanding and targeting the social network of CLL cells with their neighbors

Update:

The funding through the CLL Global Research Foundation has allowed us to establish several very productive national and international collaborations. These research collaborations are leading to discoveries that were published in 4 articles in Blood over the last year. Moreover, these findings have identified several new therapeutic targets that now will be pursued in pre-clinical development and then in clinical trials.

Our research is based upon the concept that current therapies for CLL patients are not curative because CLL cells survive in the tissues where they are protected from "conventional" drugs by neighbor cells called "stromal" or "nurselike"cells. When CLL cells are placed in cultures with these stromal cells, CLL cells become attracted to the stromal cells, and attach to them. This "fatal attraction" protects CLL cells from drugs, leading to minimal residual disease, and paving the way to relapses. Therefore, the aim of our research is to find out which signals between the stroma and the CLL cells are important, and which of these signals could be targeted therapeutically.

In our first study, we screened over 20,000 genes for their regulation by stromal cells. We found that several genes become activated by the stromal cells. Then, we focused on 2 genes that are called CCL3 and CCL4. These genes are activated by stromal cells, and make CLL cells produce and release high amounts of CCL3 and CCL4 protein. These proteins function as attraction factors for normal immune cells called T cells that help CLL cells survive and proliferate in lymph tissues. This study was done in collaboration with Dr. Rosenwald's group in Wuerzburg,Germany, and was published in Blood. These findings now are further pursued by studying the blood levels of CCL3 and CCL4 in collaboration with Dr. Wierda's group, and by testing a compound from Pfizer that targets this pathway. This may lead to a clinical trial of this Pfizer drug in CLL patients.

In our second study, we tested different stromal cells for their capacity to protect CLL cells from drugs that we commonly use for treatment of CLL patients, such as fludarabine, cyclophosphamide, or steroids. We found that all stromal cells tested were highly effective in protecting CLL cells from fludarabine-, dexamethasone-, and cyclophosphamide-induced cell death, and we established standardized conditions for drug testing with stromal cells in collaboration with our colleagues from the Mayo clinic (Dr. Kay's group), MD Anderson's Department of Experimental Therapeutics (Dr. Plunkett's and Gandhi's groups), and Vienna University, Austria (Dr. Jaeger's group). These findings were presented at the 2008 ASH meeting and are currently in preparation for publication. These findings allow us to standardize in vitro testing of novel and established drugs, and determine the effects of MSC on drug resistance. Collectively, in this project we have developed a novel tool for drug testing that takes into account the effect of the microenvironment. This will have an impact on drug development, and hopefully lead to development of novel therapy strategies that target the CLL stroma.

In our third study in collaboration with Dr. Gandhi's group, we have explored the activity of AT-101, a novel drug that targets the Bcl-2 family of survival proteins in CLL. This work was recently published in Blood.

In our fourth study, in collaboration with Dr. Shokat's group (Pharmacology, UCSF), we have explored the activity of a novel class of drugs called phosphoinoside 3'-kinase inhibitors (PI3K inhibitors) to overcome stromal cell-mediated drug resistance in CLL. These drugs block a signaling pathway within the CLL cells. This pathway becomes activated in CLL cells by stromal cells. These findings will lead to clinical trials in CLL patients with these promising agents. The study has recently been published in Blood.

Collectively, our research on the microenvironment in CLL has produced several discoveries of new pathways that promote CLL cell survival. These can be targeted by new drugs, such as CCL3/4 antagonists, PI3K inhibitors, AT-101, and others. The first microenvironment targeting treatment program, based upon our research, and funded through the CLL Global, opened in May, 2009. In this study, we will co-administer Rituximab with a drug called Plerixafor (Mozobil) that mobilizes CLL cells from the tissues to the blood and thereby makes CLL cells better accessible to Rituximab. Given the rapid progress and the variety of new drugs that can target the microenvironment in CLL, we expect to have several new, targeted treatments available in the near future.