Increased mitochondrial apoptotic priming with targeted therapy predicts clinical response to re-induction
Jacqueline S Garcia1, Shruti Bhatt1, Geoffrey Fell1
1Dana-Farber Cancer Institute, Boston, Massachusetts.
Abstract:
Most patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) do not benefit from current re-induction or approved targeted therapies. In the absence of targetable genetic mutations, there is minimal guidance on optimal treatment selection particularly in the R/R setting highlighting an unmet need for clinically useful functional biomarkers. Blood and bone marrow samples from patients treated on two clinical trials were used to test the combination of lenalidomide (LEN) and MEC (mitoxantrone, etoposide, and cytarabine) chemotherapy in R/R AML patients. The bone marrow samples were available to test the clinical utility of the mitochondrial apoptotic BH3 and dynamic BH3 profiling (DBP) assays in predicting response, as there was no clear genetic biomarker identifying responders. To test whether LEN-induced mitochondrial priming predicted clinical response to LEN-MEC therapy, we performed DBP on patient myeloblasts. We found that short-term ex vivo treatment with lenalidomide discriminated clinical responders from non-responders based on drug-induced change in priming (delta priming). Using paired patient samples collected before and after clinical LEN treatment (prior to MEC dosing), we confirmed LEN-induced increased apoptotic priming in vivo, suggesting LEN enhanced vulnerability of myeloblasts to cytotoxic MEC chemotherapy. This is the first study demonstrating the potential role of DBP in predicting clinical response to a combination regimen. Our findings demonstrate that functional properties of relapsed AML can identify active therapies.
Insights
Dynamic BH3 profiling (DBP) predicts treatment response in relapsed acute myeloid leukemia (AML). Lenalidomide (LEN) ex vivo priming identified patients who responded to LEN-MEC therapy, validating DBP as a functional biomarker.
Area of Science:
- Hematology
- Cancer Biology
- Biomarker Discovery
Background:
- Relapsed or refractory (R/R) acute myeloid leukemia (AML) presents a significant unmet need, lacking effective treatments and predictive biomarkers.
- Current therapies offer limited benefit for R/R AML patients without targetable mutations.
- Functional biomarkers are crucial for guiding treatment selection in R/R AML.
Purpose of the Study:
- To evaluate the clinical utility of mitochondrial apoptotic assays, specifically dynamic BH3 profiling (DBP), in predicting response to lenalidomide (LEN) and MEC chemotherapy in R/R AML.
- To determine if ex vivo LEN-induced mitochondrial priming could identify patients likely to respond to LEN-MEC therapy.
- To confirm LEN-induced changes in apoptotic priming in vivo.
Main Methods:
- Collected blood and bone marrow samples from R/R AML patients treated with LEN-MEC on clinical trials.
- Performed dynamic BH3 profiling (DBP) on patient myeloblasts to assess mitochondrial priming.
- Analyzed ex vivo LEN-induced change in priming (delta priming) to correlate with clinical response.
- Utilized paired patient samples (pre- and post-LEN treatment) to confirm in vivo priming changes.
Main Results:
- Ex vivo DBP successfully discriminated between clinical responders and non-responders to LEN-MEC therapy based on delta priming.
- Lenalidomide treatment in vivo increased the apoptotic priming of myeloblasts prior to MEC chemotherapy.
- These findings suggest LEN enhances AML cell vulnerability to cytotoxic chemotherapy.
Conclusions:
- Dynamic BH3 profiling (DBP) is a promising functional biomarker for predicting clinical response to combination therapy in R/R AML.
- LEN-induced mitochondrial priming is a valid indicator of treatment response.
- Functional assessment of cancer cells offers a viable strategy for identifying effective therapies in AML.
More Related Videos
Related Concept Videos
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...
01:31The Intrinsic Apoptotic Pathway
02:56Treatment Resistant Cancers