A Conversation With
A Conversation with Dr. Louis Staudt about Targeting New Treatments for Burkitt Lymphoma
Dr. Louis Staudt of NCI’s Center for Cancer Research and his international colleagues used RNA sequencing technology to confirm that Burkitt lymphoma is molecularly distinct from other types of non-Hodgkin lymphoma and to identify promising new targets for treatment. These new targets may be particularly important for lymphoma treatment in the developing world. Dr. Staudt described the findings, published August 12 in Nature, in a conversation with the NCI Cancer Bulletin.
What recent developments in technology allowed you to do this study?
The main development was next-generation sequencing, which gave us a very high-throughput way of determining the sequence of RNA. So, in a very rapid way, in a large number of lymphomas, we could identify likely mutations that could cause the cancer. Sequencing has become more affordable, and, at the same time, it’s become even more high-throughput, so we get more information. For a modest investment, we can survey a large number of tumors.
Did you identify any mutated genes in Burkitt lymphoma that may be targets for new treatments?
We found frequent mutations affecting a transcription factor, TCF3, which might not be a therapeutic target itself. But then we determined what [cellular] pathways were activated or reinforced by these mutations, and that led us to therapeutic targets with available drugs that are being tested in the clinic for other cancer types.
So, our focus turned to a pathway leading from the B-cell receptor to the PI(3) kinase pathway, which is arguably the most commonly mutated and activated signaling pathway in human cancer. In our lymphoma cases, this pathway was activated indirectly, but the end result is that, if you throw drugs at the tumor cells that inhibit the PI(3) kinase pathway, the cells die a swift and horrible death.
We also found a relationship between the transcription factor TCF3 and one of the many genes that it activates, called CCND3, which encodes the protein cyclin D3, an important regulator of the cell cycle. We found that not only does TCF3 activate CCND3 but that CCND3 was itself mutated frequently, and those mutations turn it into an oncogene, a cancer-causing gene.
So, this was another high-frequency mutation that led us to try a drug that inhibits its signaling pathway, and what we observed initially was exactly what we’d expected: the cells stopped dividing at a precise point in the cell cycle. However, the big surprise was that after the cells stopped proliferating, in a matter of days they all started dying, meaning that we will have another potential way of not just stopping the tumor cells from growing but eliminating them.
How will this study affect patients?
With the high-dose chemotherapy regimens that we can use here in the United States and in developed countries in general, we can already cure a high percentage of people with Burkitt lymphoma, maybe 85 percent of patients.
—Dr. Louis Staudt
The situation is quite different in developing countries. In Africa, there’s a high incidence of Burkitt lymphoma, and the high-dose therapies that we use in the developed world cannot be safely delivered in Africa, in those less-developed settings, because they suppress the immune system. That leaves patients highly susceptible to infections, and because of the lack of supportive care in Africa, those infections will end up killing people.
What’s being used to treat Burkitt lymphoma in Africa is a minimal chemotherapy regimen, which thankfully cures about 30 to 50 percent of patients, but that’s way too low a rate. So, we hope that we might be able to supplement that minimal chemotherapy with some of these new targeted agents and improve the outcomes for patients there.
But there’s also still a role for new therapies in the developed world for the 15 percent of Burkitt lymphoma patients who are not treated adequately with current therapies. There’s also a potential role for these new therapies in elderly patients, because high-dose chemotherapy can cause overwhelming infections in older individuals, even with great supportive care.
What does this study add to the overall field of cancer genomics?
I think one of the most remarkable findings is that the frequencies of the mutations we found in this type of lymphoma were extraordinarily high compared to other forms of cancer. For example, [one] transcription factor…was activated by mutations in 70 percent of cases. If you look in many of the other cancer genome projects, you find a much lower frequency of recurrent mutations.
If we can divide cancer into narrowly defined subtypes, we’ll find that within those subtypes there is a very clear, common way for cells to become malignant. That mechanism, that pathway will be used in a high percentage of those cases.
If you were to take all breast cancers, you would not find any mutations that occur at anywhere near the frequency that we found in Burkitt lymphoma. That is simply because breast cancer is not one disease; it’s many diseases rolled into one diagnosis. So, our job in cancer genomics is to divide cancer into precisely defined molecular categories. That will enable a much more rapid understanding of essential pathways that could be responsive to drugs.
—Interviewed by Sharon Reynolds