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Compositions and methods for the diagnosis and treatment of ovarian cancers that are associated with reduced smarca4 gene expression or protein function

a technology of smarca4 and protein function, applied in the field of diagnosis and treatment of ovarian cancer, can solve the problems of reducing affecting the survival rate of ovarian cancer patients, and generally fatal sccoht, and achieves the effects of reducing or undetectable smarca4 gene expression, reducing or undetectable smarca4 protein levels and/or protein function, and inhibiting growth dysregulation and survival promotion consequences

Inactive Publication Date: 2016-11-10
MEMORIAL SLOAN KETTERING CANCER CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes the discovery that restoring the expression of a gene called SMARCA4 in cancer cells can slow down or stop their growth. Conversely, reducing SMARCA4 expression in cancer cells that do not have the gene can promote cell growth. The text also suggests that targeting specific proteins involved in DNA repair pathways can lead to the development of drugs that can treat cancer cells with reduced SMARCA4 expression. Overall, the patent provides new ways to develop new therapies for cancer patients with reduced SMARCA4 expression.

Problems solved by technology

SCCOHT is generally fatal when spread beyond the ovary.
Nonetheless, most patients relapse and die within 2 years of diagnosis, regardless of stage, with a long-term survival rate of only 33%, even when disease is confined to the ovary at diagnosis.

Method used

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  • Compositions and methods for the diagnosis and treatment of ovarian cancers that are associated with reduced smarca4 gene expression or protein function
  • Compositions and methods for the diagnosis and treatment of ovarian cancers that are associated with reduced smarca4 gene expression or protein function
  • Compositions and methods for the diagnosis and treatment of ovarian cancers that are associated with reduced smarca4 gene expression or protein function

Examples

Experimental program
Comparison scheme
Effect test

example 1

Unbiased Screening of 279 Cancer Genes Identities SMARCA4 as a Novel Gene Underlying Small Cell Ovarian Cancer

[0215]This Example demonstrates that an unbiased screening of 279 cancer genes in 12 ovarian cancer patients identifies the gene coding SMARCA4 protein, a member of several key tumor suppressor complexes, as a novel marker for a variant of ovarian cancer, namely small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Mutations of SMARCA4 were detected in 100% of patients examined, making SMARCA4 an excellent diagnostic marker for this type of rare and aggressive ovarian cancer affecting young women.

[0216]SCCOHT is a rare, aggressive form of ovarian cancer diagnosed in young women that is generally fatal when spread beyond the ovary. Most patients relapse and die within 2 years of diagnosis, regardless of stage, with a long-term survival rate of only 33%, even when disease is confined to the ovary at diagnosis. Seidman et al., Gynecol Oncol 59: 283-7 (1995). Thus, a g...

example 2

Mutations that Reduce SMARCA4 Gene Expression and / or SMARCA4 Protein Expression are Associated with SCCOHT

[0226]This Example demonstrates that the SMARCA4 mutations identified among 12 SCCOHT patients in Example 1 are all loss-of-function mutations, thus suggesting SMARCA4 may be causatively linked to ovarian cancer, especially SCCOHT.

[0227]Examination of the SMARCA4 mutations demonstrated that they occurred throughout various exons and included nonsense, frameshift, and splice site mutations as well as a homozygous intragenic deletion of two exons. FIG. 1A summarizes the mutations among all 12 SCCOHT patients. Interestingly, no SMARCA4 missense mutations were identified in these 12 patients.

[0228]To confirm the results obtained from IMPACT, sequence variants from all 12 cases were validated using Sanger sequencing. cDNA was sequenced in 7 samples, and all were found to have mutations expressed within RNA transcripts. Next-generation sequencing data and sequence-specific Sanger elec...

example 3

SCCOHT Patients Exhibit Dysfunctional or Deficient SMARCA4 Protein

[0233]This Example demonstrates that the inactivating mutations of SMARCA4 identified among 12 SCCOHT patients in Example 2 also result in the loss of protein expression and function. This observation strongly suggests SMARCA4 is not merely a marker of the disease, but it may be causatively linked to SCCOHT.

[0234]SMARCA4 (BRG1) immunohistochemistry (IHC) was performed in the nine cases with available tissue samples. The IHC staining method for SMARCA4 was optimized using several antibodies in a variety of different conditions until one was chosen on the basis of its ability to demonstrate consistent nuclear staining patterns in a small group of high-grade serous ovarian cancers serving as positive controls. One whole FFPE section from each of the available SCCOHT cases was evaluated with a commercially available polyclonal antibody against SMARCA4 (Upstate cell signaling solutions, Cat #07-478). Whole sections underwe...

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Abstract

Provided are compositions and methods for the identification and treatment of ovarian cancers, such as small cell ovarian cancers, in particular small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), which ovarian cancers are characterized by reduced SMARCA4 gene expression and / or protein function and, as a consequence, are sensitive to growth and / or survival inhibition by one or more compounds that restore SMARCA4 gene expression and / or protein function.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Patent Applications No. 61 / 922,710 filed Dec. 31, 2013 and No. 61 / 973,759 filed Apr. 1, 2014 the contents of each of which are incorporated by reference herein.GOVERNMENT SPONSORED RESEARCH OR DEVELOPMENT[0002]The work described in this disclosure may have been funded in part by grants from the National Institutes of Health (National Cancer Institute) to the Core facility of the assignee institution: Cancer Center Support Grant P30 CA008748. The U.S. government may have certain rights in this disclosure.SEQUENCE LISTING[0003]The present application includes a Sequence Listing in electronic form as a txt file in ASCII format titled “Sequence_Listing_60009_0004WPU1” also bearing the designation 8988979_1.txt and having a size of 83.139 kb. The contents of this txt file are incorporated by reference herein.BACKGROUND OF THE DISCLOSURE[0004]1. Technical Field[0005]The present disclosure rel...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12Q1/68
CPCC12Q1/6886C12Q2600/118C12Q2600/156A61K31/7088C12Q2600/106C12Q2600/136C12Q2600/158C12Q2600/112
Inventor LEVINE, DOUGLAS A.BERGER, MICHAEL F.SOSLOW, ROBERT A.JELINIC, PETAR
Owner MEMORIAL SLOAN KETTERING CANCER CENT
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