Systemic Lupus Erythematosus or SLE is considered distinct from other autoimmune diseases because its is association with circulating autoantibodies reactive against host DNA. Now, for the first time, researchers at Yale Cancer Center may have discovered a new way of harnessing lupus antibodies to sabotage cancer cells made vulnerable by deficient DNA repair.[1][2]

The study, supported by an American Cancer Society Institutional Research Grant and led by James E. Hansen, MD, assistant professor of therapeutic radiology at Yale School of Medicine, found that cancer cells with deficient DNA repair mechanisms or the inability to repair their own genetic damage, were significantly more vulnerable to attack by lupus antibodies. The results of the study were published recently in Nature’s journal Scientific Reports.[2]

“Patients with lupus make a wide range of autoantibodies that attack their own cells and contribute to the signs and symptoms associated with lupus. Some of these antibodies actually penetrate into cell nuclei and damage DNA, and we suspected that we may be able to harness the power of these antibodies for use in targeted cancer therapy,” Hansen explained.

… Lupus antibody-based cancer therapy is an emerging new concept, and I believe we are just seeing the tip of the iceberg in terms of the potential of this approach…

Genetic mutations
The genetic code that determines how a cell develops is written in DNA. Damage to this code can cause a cell to malfunction, die, or transform into a cancer cell. Normal cells are equipped to repair damaged DNA and preserve the genetic code, but many cancer cells have defective DNA repair machinery and accumulate genetic mutations.

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This difference between normal cells and certain cancer cells creates an opportunity to develop therapies that damage DNA and only kill cancer cells that cannot repair the damage. However, DNA is sequestered inside cell nuclei, where delivery of therapies can be challenging. Yale Cancer Center researchers are finding that naturally occurring lupus antibodies just may be a solution to this problem.

An emerging concept
“Lupus antibody-based cancer therapy is an emerging new concept, and I believe we are just seeing the tip of the iceberg in terms of the potential of this approach,” Hansen said.

The researchers previously found that a lupus antibody called 3E10 inhibits DNA repair and sensitizes cancer cells to DNA damage, and they have now found that the DNA-damaging lupus antibody 5C6 is toxic to DNA repair-deficient cancer cells. Their researchs showed that the lupus autoantibody 5C6 is a cell-penetrating nucleolytic antibody and confirmed that 5C6 has a differential effect on a matched pair of BRCA2-proficient and deficient DLD1 colon cancer cells. As a result, the researchers noted that 5C6 selectively induced ?H2AX in, and suppressed the growth of, the BRCA2-deficient cells.

DNA repair-deficient malignancies
The findings from this study demonstrate a potential use of 5C6 in targeted therapy for DNA repair-deficient malignancies. In addition, the toxic effect of 5C6 on BRCA2-deficient cells provides further support for the hypothesis that some lupus autoantibodies contribute to the lower risk of specific cancers associated with systemic lupus erythematosus.

“Now that we know that more than one lupus antibody has a selective effect on cancer cells, I am confident that additional lupus autoantibodies with even greater therapeutic potential await discovery,” Hansen concluded.

For more information:
[1] Noble PW, Young MR, Bernatsky S, Weisbart RH, Hansen JE. A nucleolytic lupus autoantibody is toxic to BRCA2-deficient cancer cells. Sci Rep. 2014 Aug 5;4:5958. doi: 10.1038/srep05958.[Article][PubMed]
[2] Hansen JE, Chan G, Liu Y, Hegan DC, Dalal S, Dray E, Kwon Y, et al. Targeting cancer with a lupus autoantibody. Sci Transl Med. 2012 Oct 24;4(157):157ra142. doi: 10.1126/scitranslmed.3004385.[Article][PubMed]

Illustration: Lupus antibodies penetrate a nucleus. Illustration Courtesy: Christian Chang.

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