Our overall goal is to understand the mechanisms by which dividing cancer and normal cells are killed, or escape death, when treated with diverse anti-mitotic drugs. We seek understanding both at the level of cell population behaviors, and the molecular mechanisms that give rise to those behaviors. We are especially interested in understanding how different classes of anti-mitotic drug differ in their ability to kill cancer cells, and using that information to design better future drugs. We will address these goals in 4 specific aims:
Aim 1. How do drugs with different anti-mitotic mechanisms differ in their ability to kill cancer cells at the level of cell population behavior? We will use microscopy with fluorescent reporters for key molecular events to measure single-cell responses to four anti-mitotic drugs across a panel of cell lines chosen to vary in apoptosis sensitivity. We will also test the effects of blocking different aspects ofthe drug response.
Aim 2. Elucidate the molecular mechanism of cell death during mitotic arrest. To determine how the intrinsic apoptosis pathway is activated by prolonged mitotic arrest we will test candidate regulators of apoptosis, and pursue an unbiased biochemical approach. We will also Identify an alternative cell death pathway cells use when they cannot escape mitotic arrest, and apoptosis is blocked.
Aim 3. Develop small molecule inhibitors of mitotic exit that work independent of the SAC. Our preliminary data suggest that novel anti-mitotic drugs with this mechanism would kill cancer cells more effectively than current drugs. We will test this concept, and identify druggable targets in the mitotic exit pathway, by small molecule screening in Core B using a cell-based assay, followed by identification of protein targets of hits.
Aim 4. Compare drug responses in mouse tumors to those seen in cell culture. Drug response mechanisms elucidated in cell culture in aims 1-3 may not translate to real tumors. We will test whether cells that die during mitotic arrest in mouse tumors cause bystander killing of non-dividing tumor cells, which could explain why some tumors with low mitotic index can be treated with anti-mitotic drugs. Working with Core C we will probe responses to anti-mitotic drugs in mouse tumors at the single-cell level by intravital imaging.

Public Health Relevance

Chemotherapy drugs that block division of cancer cells are important in cancer treatment, but we need better methods for predicting which patients will respond well. We also need new drugs that are more effective at killing dividing cancer cells. We will address these challenges by discovering how cancer cells are killed by current drugs, why some cancer cells escape killing, and by testing a concept for a better future drug.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA139980-05
Application #
8677757
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Shi, Jue; Mitchison, Timothy J (2017) Cell death response to anti-mitotic drug treatment in cell culture, mouse tumor model and the clinic. Endocr Relat Cancer 24:T83-T96
Miller, Miles A; Askevold, Bjorn; Mikula, Hannes et al. (2017) Nano-palladium is a cellular catalyst for in vivo chemistry. Nat Commun 8:15906
Foijer, Floris; Albacker, Lee A; Bakker, Bjorn et al. (2017) Deletion of the MAD2L1 spindle assembly checkpoint gene is tolerated in mouse models of acute T-cell lymphoma and hepatocellular carcinoma. Elife 6:
Fallahi-Sichani, Mohammad; Becker, Verena; Izar, Benjamin et al. (2017) Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de-differentiated state. Mol Syst Biol 13:905
Giedt, Randy J; Fumene Feruglio, Paolo; Pathania, Divya et al. (2016) Computational imaging reveals mitochondrial morphology as a biomarker of cancer phenotype and drug response. Sci Rep 6:32985
Lee, Robin E C; Qasaimeh, Mohammad A; Xia, Xianfang et al. (2016) NF-?B signalling and cell fate decisions in response to a short pulse of tumour necrosis factor. Sci Rep 6:39519
Sarosiek, Kristopher A; Letai, Anthony (2016) Directly targeting the mitochondrial pathway of apoptosis for cancer therapy using BH3 mimetics - recent successes, current challenges and future promise. FEBS J 283:3523-3533
Bhola, Patrick D; Mar, Brenton G; Lindsley, R Coleman et al. (2016) Functionally identifiable apoptosis-insensitive subpopulations determine chemoresistance in acute myeloid leukemia. J Clin Invest 126:3827-3836
Chittajallu, Deepak R; Florian, Stefan; Kohler, Rainer H et al. (2015) In vivo cell-cycle profiling in xenograft tumors by quantitative intravital microscopy. Nat Methods 12:577-85
Krukenberg, Kristin A; Kim, Sujeong; Tan, Edwin S et al. (2015) Extracellular poly(ADP-ribose) is a pro-inflammatory signal for macrophages. Chem Biol 22:446-452

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