If you are a frequent reader, you probably know that I view the quest for a cure for CLL like the task of completing a jigsaw puzzle. If a researcher only focuses on his or her section of the puzzle, pieces will be absent or unnecessarily duplicated. Ideas, clues and discoveries from researchers at other institutions and countries will be missing. CLL Global encourages the interaction of investigators to develop new pieces. One way we have promoted collaboration is by developing research groups in Australia and Israel. These two groups truly enhance our global reach. Over the last two months, I have had the opportunity to meet with our investigators in both countries. I am truly impressed by the progress being made.
In March, I traveled to Australia and listened to presentations from many of the individuals who have received funding from the CLL Australian Research Consortium (CLLARC). CLL Global provided the seed funding to establish CLLARC. It was refreshing to listen to the energy that these investigators are putting into their research.
Dr. Giles Best (University of Sydney) and colleagues are working with an inhibitor called SNX7081. The compound blocks a protein called heatshock protein 90 (hsp 90). This protein is thought to be significant because of its relationship with ZAP70, an important prognostic factor in CLL. In previous clinical trials, other early-generation inhibitors of this protein were studied. However, the results indicated minimal activity with some toxicity. The initial findings with SNX7081indicate that this drug is effective against CLL cells. There appears to be a strong synergism between SNX7081 and fludarabine, particularly in patients with the most challenging abnormalities. With additional research, clinicians will be able to determine whether SNX7081, alone or in combination, will represent a new treatment strategy.
Dr. David Gottlieb (Westmead Millennium Institute) has been working in the transplant area and is convinced that the development of chimeric antigen receptors (CARs) against CLL is going to be important. CARs force immune cells to recognize and destroy CLL cells. His work to develop methods of reconstituting the immune system is in-line with the members of the US/European Alliance. Gottlieb’s work suggests that the CARs will be active against not only the CLL cells but also a number of viruses such as Cytomegalovirus and Herpes Zoster which causes shingles. These viruses are a frustrating complication of CLL treatment; clinicians and patients would welcome a reprieve of this side effect.
Long term collaborators Dr. Stephen Mulligan and Dr. Richard Christopherson (University of Sydney) have been looking at surface markers on CLL cells to triage patients with aggressive disease. They have also developed a concept of demibodies which only kill cells that express a particular pair of surface molecules (or antigens). Current therapeutic antibodies target a single antigen. With demibodies, it may be possible to selectively target cells co-expressing the molecules CD5 and CD20, the hallmark of CLL cells. While still in pre-clinical development, this technology represents a promising opportunity.
Dr. Stephen Fuller (University of Sydney) and colleagues continue to investigate the genetics of families with CLL in multiple generations. After investigating millions of sequences from these families, the researchers have identified at least two potential genetic areas that might increase the risk of developing CLL. The most promising is an area on chromosome 14q which is highly active in the development of the lymphoid system. Within this region, a gene currently referred to as mutant gene X appears to be strongly associated with familial CLL. One of the next steps will be for collaborators in the global community to provide Dr. Fuller and his group with additional data and samples to evaluate.
Hopefully knowledge gained from studying mutant gene X will help us find answers to questions regarding familial CLL. Of interest, Ashkenazi Jews tend to have a higher incidence of familial CLL compared to the Sephardic Jews. Understanding the incidence in these groups is a top research priority for the Israeli group, the CLL Israel Research Consortium (CLLIRC). CLL Global provided start-up funds for this research group.
In April, I visited the investigators of the CLLIRC. Due to the Israeli populations’ unique structure, it is ideal for studying the effect of ancestry on the clinical, biological and genetic characteristics of CLL. A comparative study of CLL by ethnic groups with different incidences of CLL in Israel is underway. This study could potentially lead to a better understanding of the etiology/biology of CLL which would help current and future generations of CLL patients.
CLL Global continues to search the globe for the necessary pieces to cure CLL. I look forward to providing additional updates on our progress toward this global quest.
