Enhance anti-tumor therapy efficiency by sequential checkpoint-specific treatment

Project: Monitored by Research Administration

Project Details

Grant Program

Faculty Development Competitive Research Grants 2020-2022

Project Description

Our previous studies reveal that cancer cells treated by microtubule inhibitors undergo mitotic slippage after mitotic arrest even when high concentrations of drugs are used. Mitotic slippage results in either cell death or formation of multinucleated cells. Some of multinucleated cells die, while others survive for a long time and might be able to proliferate. Cells surviving after mitotic slippage undergo transformation and give the aneuploid progeny resistant to anti-microtubule drugs, however direct evidence is lacking.
Multinucleated cells after mitotic slippage enter G1 stage of the cell cycle. These cells upon formation have lower viability and suffer from incomplete DNA damage response. Thus our central hypothesis is that immediate treatment of multinucleated cells by another drug targeting the interphase cells will selectively eliminate residual cancer cells surviving after the first treatment.
In the current project we plan (i) to direct all cells entering mitosis into multinucleated form by mitotic arrest using taxol treatment; (ii) to investigate specific features and behavior of multinucleated cells including clonogenic capacity and evolution of their transcriptome. Study will be performed on the whole population and after FACS isolation of multinucleated cells. (iii) We will further induce DNA damage response stress to trigger apoptosis in multinucleated cells by inhibiting PARP. (iv) After double-hit treatment proliferation and clonogenic potential of surviving cells will be examined. We expect that this double-hit strategy will significantly enhance our ability to selectively eliminate proliferating cancer cells.
In sum, our proposed research has the potential to enhance therapy with anti-mitotic drugs and will broadly impact the cancer therapy field. These findings may be extrapolated to other drugs used in the chemotherapy and to our understanding of cancer development and treatment.
Short titlecheck-point specific cancer treatment
AcronymEATTST
StatusActive
Effective start/end date1/1/2012/31/22

Keywords

  • cell cycle
  • cell division
  • chemotherapy
  • taxol
  • DNA damage response

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