Celebrating the 10th Anniversary
A decade of discoveries in Cancer Discovery. For the community. By the Community.
Authors
Their impactful studies. In their words.
Dana-Farber Cancer Institute
AbbVie
MD Anderson Cancer Center
Dana-Farber Cancer Institute
I think any cancer biologist’s dream is to have research on the bench translate into something meaningful in the clinic—so it was incredibly exciting to see venetoclax go into the clinic and show clinical activity relatively quickly after we started the preclinical work.
Selective BCL-2 Inhibition by ABT-199 Causes On-Target Cell Death in Acute Myeloid Leukemia
March 2014
Q: What unanswered questions in the field were these studies addressing?
A: (Rongqing Pan) Before our work, targeting BCL-2 had largely been investigated in lymphoid cancers. We studied whether acute myeloid leukemias (AML) depend on BCL-2 for survival and whether BCL-2 antagonist ABT-199 has single-agent anti-leukemia activity using AML cell lines, patient samples, and PDX models. We also found that BH3 profiling and other assays demonstrate ABT-199 activity at the mitochondrion level that correlated well with its cellular toxicity, supporting an on-target mechanism of ABT-199.
A: (Anthony G. Letai) Before these studies, there was skepticism that AML could be dependent on BCL-2 for survival. It is easy to forget now, but for many, BCL-2 (B cell Leukemia/lymphoma 2) was considered strictly a B-cell malignancy gene. There were not BCL-2 gene abnormalities in AML. How could AML be dependent on it? These studies delinked genetics from dependence on BCL-2.
Q: What surprised or excited you most about the findings?
A: (Rongqing Pan) I was very excited to see how fast and effectively ABT-199 killed primary AML cells. Also, BH3 profiling, a functional assay developed by us to measure cell proximity to apoptosis and cell antiapoptotic dependence, accurately predicted AML response to ABT-199.
A: (Leah J. Hogdal) I think any cancer biologist’s dream is to have research on the bench translate into something meaningful in the clinic—so it was incredibly exciting to see venetoclax go into the clinic and show clinical activity relatively quickly after we started the preclinical work. Finding out that the first patient on M14-212 (monotherapy venetoclax relapsed/refractory AML trial) was dosed with venetoclax was one of the best days of my graduate school career.
A: (Anthony G. Letai) I was surprised simply at how effective venetoclax was in killing AML cells, first in vitro, then in vivo. It was startling that a single oral dose a day could induce complete remissions in some patients with AML (2016 paper). The frequency and depth of these remissions improved a lot in subsequent combination regimens that brought in agents known already to be active in AML.
A: (Marina Konopleva) We anticipated efficacy of targeting BCL-2 in AML based on our prior work. What was most amazing to me is the safety of BCL-2 inhibitors seen in clinical trials, with a large therapeutic window that allowed future combination studies with low-intensity chemotherapies and led to FDA approval in most challenging AML patients, older and unfit for standard chemotherapy. The field has now moved into “triple” combinations with targeted therapies and immune therapies, which would not be possible if BCL-2 inhibitors were more toxic.
Q: What has been the paper’s greatest impact in the years that followed?
A: (Rongqing Pan) The preclinical study (2014) served as the basis for a successful multicenter trial. It also promoted dozens of clinical trials combining ABT-199 with other drugs in AML, leading to numerous publications and eventually FDA approval of ABT-199/venetoclax to treat AML. ABT-199 thus became one of the first targeted therapeutics approved for AML over the past four decades. The success also motivated the development of many other selective BH3 mimetics to target BCL-2, BCL-XL, and MCL-1, which are being intensively studied in laboratories and in the clinic.
A: (Anthony G. Letai) The greatest impact is that now elderly patients with AML have a realistic therapeutic option, approved by the FDA, to undergo a remission that will let them live longer and better. Most patients with AML are elderly, and when I started as an oncologist 20 years ago, we had to tell all too many of them that we had little to offer. Another source of impact is the fantastic spread of these observations. The success of venetoclax in AML (and chronic lymphocytic leukemia) has prompted the development of many related inhibitors of BCL-2, BCL-XL, and MCL-1, which are now in over 100 clinical trials worldwide.
A: (Marina Konopleva) The greatest impact has been the approval in older patients with AML in combination with hypomethylating agents or low-dose cytarabine. Ongoing clinical trials support the notion that adding venetoclax to chemotherapy in younger patients markedly boosts the efficacy and depth of response. Combinations with FLT3 inhibitors also appear highly promising.
