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Principal Investigator: ANTHONY G LETAI
Organization: DANA-FARBER CANCER INST
Fiscal Year: 2024
Award: $1,007,191
Funding agency: National Cancer Institute
Summary
I am an oncologist and cancer biologist supervising a laboratory focused on identifying therapies that
selectively induce apoptosis in cancer cells. My initial contributions to the apoptosis field came with separating
certain pro-death BCL-2 family BH3-only proteins into “sensitizers” and “activators” based on pro-apoptotic
function. This finding drove my interest in the possibilities of inhibiting BCL-2 function with drugs that mimicked
the BH3 domain of pro-apoptotic proteins. I designed the first mouse model that demonstrated that loss of
BCL-2 function by itself could be sufficient to drive a cancer into remission. Following this, I designed a tool
called BH3 profiling – exposing mitochondria to synthetic oligo-peptides based on the amphipathic alpha-
helical BH3 domains of proapoptotic proteins and measuring mitochondrial outer membrane permeabilization
(MOMP). By using certain selectively-interacting BH3 peptides, I could use BH3 profiling to identify cells that
were especially sensitive to BH3 inhibition. I used BH3 profiling to help launch clinical trial programs of the
BCL-2 inhibitor venetoclax in several diseases. Most successful among these so far have been programs in
chronic lymphocytic leukemia and acute myelogenous leukemia, the former of which has already yielded FDA
approvals.
Using different BH3 peptides, BH3 profiling can measure overall apoptotic priming, or proximity to the threshold
of apoptosis. We used this aspect to demonstrate that differential apoptotic priming is perhaps the most
significant determinant of successful chemotherapy treatment. Moreover, differential apoptotic priming is the
main reason that there is a therapeutic index for conventional chemotherapy – most non-malignant somatic
cells are far less primed for apoptosis than chemosensitive cancer cells. Building on this finding, we asked
whether we could identify drugs that could enhance apoptotic priming selectively in cancer cells. We found
that we could measure increased apoptotic priming within hours of exposing cancer cells to effective drugs
using dynamic BH3 profiling (DBP). Increased priming is measured as increased sensitivity of mitochondria in
treated cells to BH3 peptides compared to untreated controls. Over the past few years, we have found that an
increased priming by a drug in DBP is an excellent predictor of in vivo activity in human and mouse models, in
solid and liquid tumors. An important advantage of DBP over most other ex vivo drug sensitivity strategies is
that DBP requires no more than 24 hours of ex vivo culture. This overcomes the major obstacle to the general
application of such strategies, since many cancers cannot adapt to long-term ex vivo culture, and if they do,
they are phenotypically altered so as to degrade the information they can provide. We are exploring DBP as a
discovery tool and predictive biomarker in many liquid and solid tumors. Moreover, we are using it as a tool to
identify drugs that can make target tumor cells more sensitive to immuno-oncology therapies.
Terms: <AML - Acute Myeloid Leukemia><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Amphipathic Alpha Helix><Amphipathic α-Helix><Apoptosis><Apoptosis Pathway><Apoptotic><B-Cell CLL><B-Cell Chronic Lymphocytic Leukemia><B-Cell Chronic Lymphocytic Leukemia Associated Oncogene><B-Cell Chronic Lymphogenous Leukemia><B-Cell Chronic Lymphoid Leukemia><B-Cell Lymphocytic Leukemia><B-Lymphocytic Leukemia><B-cell Leukemia 1><BCL><BCL1 Oncogene><BH3 Domain><BH3 peptide><Cancers><Cell Body><Cell Communication and Signaling><Cell Membrane Permeability><Cell Signaling><Cells><Cessation of life><Chronic B-Lymphocytic Leukemia><Chronic Lymphatic Leukemia><Chronic Lymphoblastic Leukemia><Chronic Lymphocytic Leukemia><Chronic Lymphogenous Leukemia><Clinic><Clinical Trials><Death><Disease><Disease remission><Disorder><Drug usage><Drugs><Family><Hour><Immunooncology><Induction of Apoptosis><Intracellular Communication and Signaling><Laboratories><Liquid substance><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Measures><Medication><Mitochondria><Non-Malignant><Oligopeptides><Oncologist><Outer Mitochondrial Membrane><Pharmaceutical Preparations><Phenotype><Programmed Cell Death><Protein Family><Proteins><Reading><Remission><Signal Transduction><Signal Transduction Systems><Signaling><Solid><Solid Neoplasm><Solid Tumor><Somatic Cell><Therapeutic><Therapeutic Index><Tumor Cell><acute granulocytic leukemia><acute myeloid leukemia><biological signal transduction><cancer cell><cancer type><cell suicide><cellular suicide><chemotherapy><chronic lymphoid leukemia><design><designing><drug sensitivity><drug use><drug/agent><fluid><human model><immune-oncology><immuno oncology><immunology oncology><in vivo><inhibitor><interest><liquid><malignancy><membrane permeability><mitochondrial><model of human><mouse model><murine model><neoplasm/cancer><neoplastic cell><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><nonmalignant><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><oncoimmunology><predictive biomarkers><predictive marker><predictive molecular biomarker><pro-apoptotic protein><programs><small molecular inhibitor><small molecule inhibitor><success><tool><tumor>