Targeting chromosomal instability and downstream cytosolic DNA signaling for cancer treatment

A chemotherapeutic agent, cell technology, applied in recombinant DNA technology, DNA/RNA fragments, gene therapy, etc., can solve problems such as limitation and toxicity

Pending Publication Date: 2020-06-16
CORNELL UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Immunotherapy is largely limited by the use of cytokines or therapeutic cancer vaccines
Cytokines can cause severe toxicity and continued use of vaccines can lead to immune tolerance

Method used

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  • Targeting chromosomal instability and downstream cytosolic DNA signaling for cancer treatment
  • Targeting chromosomal instability and downstream cytosolic DNA signaling for cancer treatment
  • Targeting chromosomal instability and downstream cytosolic DNA signaling for cancer treatment

Examples

Experimental program
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example 1

[0264] Example 1: Materials and methods

[0265] This example describes several materials and methods used to develop the invention.

[0266] Genomic Analysis of Primary-Metastatic Pairs

[0267] Complete exome DNA sequence data for 61 brain metastases and normals with matched primary tumors were downloaded from the Genotype and Phenotype (dbGAP) database (Brastianos et al., Cancer Discovery 5 , 1164–1177 (2015)) and processed as described (McGranahan et al., Science 351, 1463–1469 (2016)) to obtain an allele-specific score for each sample. Segment DNA copy number data. The Weighted Genome Instability Index (wGII), which describes the proportion of genomes classified as abnormal relative to tumor ploidy, was determined as described (Burrell et al., Nature 494, 492-496 (2013)).

[0268] Mitelman database analysis

[0269] The Mitelman database was analyzed (Mitelman et al., "Database of Chromosome Aberrations and Gene Fusions in Cancer" cgap.nci.nih.gov Available at: cgap.n...

example 2

[0332] Example 2: Increased Chromosomal Instability in Human Metastases

[0333]This example describes experiments demonstrating that chromosomal instability is associated with human metastases.

[0334] To investigate whether chromosomal instability is associated with human metastases, whole-exome sequence data from 61 primary tumors (comprising 13 tumor types) were compared with data from a recently published group (Brastianos et al., Cancer Discovery 5, 1164–1177 (2015)) were matched with brain metastases. These data were reanalyzed using the Weighted Genome Integrity Index (wGII) as a genomic indicator of chromosomal instability. wGII assesses copy number heterogeneity by measuring the percentage of genomes that deviate from the average tumor ploidy (Burrell et al., Nature 494, 492–496 (2013)). There is a significant bias whereby metastases are more likely to have higher wGII scores than their matched primary tumors ( Figure 1A-1B-1 to 1B-4, 1H).

[0335] Using the se...

example 3

[0337] Example 3: Chromosomal instability drives metastasis

[0338] To determine whether chromosomal instability is associated with metastasis, a genetic approach was devised (Bakhoun et al., Nat. Cell Biol 11, 27–35 (2009); Bakhoun et al., Nature Communications (NatCommun)》6, 5990 (2015)) to alter the rate of chromosomal missegregation in transplantable tumor models of human TNBC (MDA-MB-231) and lung adenocarcinoma (H2030). Cells from these highly metastatic tumor models exhibited elevated basal rates of chromosomal instability, with 47% and 67% of anaphase cells, respectively, showing evidence of chromosome segregation errors during anaphase ( Figure 2A , 2B-1 to 2B-2). These cells with undisturbed chromosomal segregation rates are called CIN-neutral cells. Overexpression of Kif2b or MCAK / Kif2c in these cells resulted in significantly suppressed chromosome segregation errors (termed CIN-low cells). Instead, MCAK 24 (dnMCAK) overexpression of the dominant-negative for...

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Abstract

As described herein, chromosomal missegregations, chromosomal micronuclei, cytosolic DNA, and combinations thereof are indicative of metastatic cancer. Methods and compositions are described herein that are useful for detection and treatment of patients with chromosomal instabilities such as chromosomal missegregations, chromosomal micronuclei, cytosolic DNA, and combinations thereof. For example,some of the methods and compositions include use of kinesin-13 proteins such as Kif2b, MCAK / Kif2c, or KIF13A. The methods and compositions can also include inhibitors of STING, ENPP1, cGAS, NF-kB transcription factor p52, NF-kB transcription factor RelB, or any combination thereof. Methods are also described for identifying compounds that are effective for treatment of cancer, including metastatic cancer.

Description

[0001] This application claims priority to US Provisional Application Serial No. 62 / 530,661, filed July 10, 2017, the contents of which are hereby incorporated by reference in their entirety. [0002] federal funding [0003] This invention was made with Government support under Grant Number CA197588 awarded by the National Institutes of Health and Grant Number W81XWH-16-1-0315 awarded by ARMY / MRMC. The government has certain rights in this invention. Background technique [0004] Cancer is the uncontrolled growth of abnormal cells in various parts of the body. Currently, cancer can be treated with surgery, radiation therapy, chemotherapy, immunotherapy, etc., all with varying degrees of success. However, surgical therapy cannot completely remove widely metastatic tumor cells. Radiation therapy and chemotherapy are not selective enough to kill cancer cells in the presence of rapidly proliferating normal cells. Immunotherapy is largely limited by the use of cytokines or th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/6886A61K31/00
CPCA61K31/00C12Q1/6886C12Q2600/118C12Q2600/136C12Q2600/158A61K45/06A61P35/00A61K31/04C12N15/113G01N33/5011A61K48/0066G01N2400/00G01N33/5005
Inventor L·C·坎特利B·恩格S·F·巴库姆
Owner CORNELL UNIVERSITY
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