Inter- and intra-tumoral mitochondrial heterogeneity in response to chemical perturbation in cancer Response to therapy is heterogeneous between tumors of different histology, between different tumors of the same histology, and even among different tumor cells within the same tumor. Much of the cytotoxic response to therapy in cancer is governed by the mitochondrial pathway of apoptosis. Therefore, we hypothesize that heterogeneity in response at all three of these levels is governed by functional and molecular heterogeneity of mitochondria. BH3 profiling provides a functional measure of how close a cell is to the threshold of apoptosis by measuring mitochondrial sensitivity to BH3 peptides, a property we also refer to as apoptotic priming. We have previously shown, in both hematologic and solid tumors, that pretreatment baseline priming of patient tumors predicts clinical response to conventional chemotherapy. Our approach to understanding response to targeted therapies is distinct. In contrast to the ubiquitous nature of the DNA and microtubules that are the targets of conventional chemotherapy, targeted therapies attack vulnerabilities that are selectively present in certain cancer cells. To identify where these vulnerabilities exist, we briefly (less than 24 hours) expose cancer cells to drugs and measure whether the drugs increase apoptotic priming. We have shown that this approach, which we call dynamic BH3 profiling (DBP), can predict death of tumor cells from targeted agents in vitro and in vivo for both hematologic and solid tumors. There are two important advantages of DBP over conventional measures of cytotoxicity. First, DBP can be applied much more efficiently to primary patient samples. Experiments measuring cytotoxicity in cancer cells often require days of culture. Because the long-term culture of primary patient samples is so unreliable, cytotoxic measurements in primary tumors are unreliable. DBP requires no more than a day of ex vivo culture since we measure well before frank cell death occurs, and we have demonstrated its predictive power in primary liquid and solid tumors. Second, there are many useful anti-cancer agents that do not cause frank cell death, but which nonetheless provoke apoptotic signaling that facilitates killing in combination regimens. Classical cytotoxic measurements do not identify these, but DBP does. We propose to study intra- and inter-tumoral heterogeneity based on differential response to compounds that sensitize mitochondria for apoptosis. We will focus on colon cancer tumors, as we have access to primary and PDX specimens of these tumors. Our main goals are to develop a therapeutic toolbox of potentially useful drugs, determine how best to combine these in a personalized way, and also to understand the molecular basis of the heterogeneity of mitochondrial function that underlies differences in response to these drugs.
One of the main challenges to cancer therapy is understanding and predicting what tumors will respond to individual therapies. Here we present a novel approach to identifying drugs that are selectively toxic to individual tumors based on differences in the function of mitochondria between and within individual tumors. We use this approach to create a precision medicine strategy for rationally assembling individualized drug combinations for cancer patients based on differences in the mitochondria of their tumors.
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| Deng, J; Isik, E; Fernandes, S M et al. (2017) Bruton's tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia 31:2075-2084 |
