Methods and compositions for increasing susceptibility to radiation treatment by inhibiting suppression of numerical chromosomal instability of cancer cells

Inactive Publication Date: 2018-01-11
MEMORIAL SLOAN KETTERING CANCER CENT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

The patent text describes a method for increasing the susceptibility of cancer cells to radiation treatment, by enhancing chromosome missegregation and instability during mitosis. This can be achieved by inhibiting the process of chromosome segregation or by using a radioprotective agent that reduces the damage to non-cancerous cells. The technical effect of this method is to improve the effectiveness of radiation treatment and decrease the likelihood of resistance in cancer cells, while also increasing the safety of radiation therapy by protecting normal organs.

Problems solved by technology

This overwhelming damage generally overcomes the ability of tumor cells to repair DSBs, leading to a reduction in cellular viability and to cell death.
Acentric chromatin fragments exhibit a high likelihood of missegregation during the subsequent mitosis, as they are incapable of establishing canonical attachment to spindle microtubules at the kinetochores.
It is thus clear that DNA breaks generated by IR in dividing cells can directly lead to structural chromosomal instability (s-CIN), whose hallmarks are chromatin bridges and acentric chromatin fragments.
These micronuclei are defective in DNA replication and repair and possess a faulty nuclear envelope leading to the pulverization of their enclosed chromosomes.

Method used

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  • Methods and compositions for increasing susceptibility to radiation treatment by inhibiting suppression of numerical chromosomal instability of cancer cells
  • Methods and compositions for increasing susceptibility to radiation treatment by inhibiting suppression of numerical chromosomal instability of cancer cells
  • Methods and compositions for increasing susceptibility to radiation treatment by inhibiting suppression of numerical chromosomal instability of cancer cells

Examples

Experimental program
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example 1

Ionizing Radiation Leads to Numerical Chromosomal Instability In Vitro

[0118]High-resolution fluorescence microscopy was used to examine various types of errors during anaphase in three human cell lines derived from normal human retinal epithelium (RPE1), colorectal cancer (HCT116) or glioma (U251). These cells were either near-diploid and chromosomally stable (RPE and HCT116) or aneuploid and chromosomally unstable (U251). RPE1 and HCT116 had an intact p53-signalling pathway (Thompson et al. Cell Biol. 2010; 188:369-381, whereas U251 contain defective p53 signalling (Gomez-Godinez et al. Nucleic Acids Res. 38:e202-e202. (2010). Briefly, cells were exposed to various doses of IR and evaluated 25 minutes later for signs of chromosome segregation during anaphase. 25 minutes provided sufficient time for many of the cells that were in mitosis during DNA damage induction to enter anaphase, but not sufficient time for cells that were in G2 to proceed through to anaphase. High-resolution fl...

example 2

Frequency and Type of Chromosome Segregation Error is Dependent on the Time Interval Between Radiation and Chromosome Segregation Analysis

[0120]The inventors sought out to evaluate whether the frequency and types of chromosome segregation errors are dependent on the time interval between IR exposure and the analysis of anaphase chromosome segregation. HCCT116 cells devoid of tumor suppressor, p53, were used in this experiment, to allow for the proliferation of aneuploidy cells should they emerge (Thompson and Compton, J Cell Biol. 188(3):369-81, 2010). HCT116 p53− / − cells were exposed to 0 or 6 Gy of IR and chromosome segregation errors were evaluated at 25 minutes, 12 h, 25 h, and 1 month following the IR exposure. As shown in FIG. 1e, anaphase spindles examined 25 minutes after irradiation exhibited similar chromosome missegregation profiles compared with p53-competent HCT116 cells 25 minutes after IR exposure. However, 12 h after irradiation there was a significant increase in ch...

example 3

IR Induces w-CIN In Vivo

[0121]To determine whether IR can directly perturb the process of chromosome segregation in vivo, the inventors used tumour-forming HCT116 p53− / − cells that normally exhibit low rates of chromosomes missegregation and are thus considered chromosomally stable and near-diploid (Thompson and Compton, J Cell Biol. 188(3):369-81, 2010). HCT116 p53− / − cells were subcutaneously injected into nude mice and after 25 days transplanted tumours were exposed to 0 or 10 Gy of IR. Following formalin-fixation of tumours 25 min later, tumour sections were stained with hematoxylin and eosin and the effects of radiation on mitotic cells were evaluated (FIG. 2a, b). FIG. 2b shows an example of normal anaphase and anaphase cells containing lagging chromosomes in HCT116 p53− / − xenografts after IR exposure. As demonstrated in FIG. 2c, tumours exposed to 10 Gy of IR exhibited significantly higher rates of chromosome segregation errors during anaphase compared with control, non-irrad...

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Abstract

Disclosed is a method for increasing susceptibility of cancer cells to ionizing radiation by delivering to the cells a radiosensitizing agent that has one of the following properties: (a) it perturbs the process of chromosome segregation thereby increasing chromosome missegregation; or (b) it is an inhibitor of an agent that promotes faithful chromosome segregation induces numeric chromosome instability in said cells and this instability is induced substantially simultaneously with or closely prior to or closely after irradiating the cells. Examples of such radiosensitizing agent include inhibitors of one or more of the following: Kif2b, MCAK, MPS1, Eg5 / Kinesin-5 5, Polo-like kinase 4, MCAK, Bub1 and Hec1. Such agents specifically target proteins involved in maintaining or promoting faithful chromosome segregation.

Description

STATEMENT OF RELATED APPLICATIONS[0001]This patent application claims the priority of U.S. Provisional Patent Application 62 / 106,204 filed Jan. 21, 2015; the contents of this provisional application are hereby incorporated by reference in their entirety.GOVERNMENT SUPPORT[0002]Work described in the present disclosure may have been supported by Grant No R37GM051542 from the National Institutes of health. Accordingly, the U.S. government may have rights in this invention.BACKGROUND OF THE DISCLOSURETechnical Field[0003]The present disclosure relates to the field of cancer therapy using agents that promote whole-chromosomal instability, as irradiation sensitization agents, and thus to make patients more sensitive to radiation therapy, thereby increasing the effect of radiation therapy.[0004]Background and Description of Related Art Radiation therapy is an integral modality in cancer treatment. The lethal effect of ionizing radiation (IR) lies in its ability to cause widespread genomic ...

Claims

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Application Information

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IPC IPC(8): A61K41/00A61N5/10
CPCA61K41/0038A61N5/10A61N2005/1098A61P35/00A61K31/5377A61K45/06A61K38/1709A61K38/45
Inventor BAKHOUM, SAMUEL F.BASSEM, ZAKI I.COMPTON, DUANE A.
Owner MEMORIAL SLOAN KETTERING CANCER CENT
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