A new method for disrupting genes that promote the formation and spread of tumors may promise to treat a type of breast cancer that is aggressive and difficult to treat, according to new study results.
In the study, a drug that blocks the activity of an enzyme called CDK7 stopped the proliferation of tumor cells in triple negative breast cancer cell lines and reduced tumors in murine models of this cancer.
Unlike the so-called targeted therapies, the drug does not work by targeting directly to cells with specific genetic alterations. Instead, the drug acts indirectly through CDK7 to interfere with the expression that the authors, Dr. Jean Zhao, of the Dana-Farber Cancer Institute and his colleagues call the “Achilles cluster” of genes, and Group of genes of which the cancerous cells depend a lot.
The report was published on 24 September at Cell.
The type of drug tested in the study, the authors write, may represent an especially effective option for treating cancers such as triple negative breast cancer that do not appear to have individual “driving” genes.
Triple negative breast cancers, which account for approximately 13% of breast cancer cases, often return after initial treatment and have a high probability of spreading. This type of breast cancer is diagnosed more often in African Americans and in younger women than in other women.
In addition to being more active than other subtypes of breast cancer, triple negative breast cancers are more difficult to treat. Since their growth is not powered by hormones, for example, hormonal therapies like tamoxifen and aromatase inhibitors are not useful for treating them.
And, from the genetic point of view, most triple negative breast cancers have little resemblance to each other. Although they often contain many genetic alterations, few, if any, are shared in all triple negative breast cancers, and none seem to be particularly responsible for their growth and dissemination. Thus, unlike the case of HER-2 breast cancers, the individual genes that drives this type of cancer still need to be identified that could be targeted by specific therapies.
But, according to Dr. Zhao and colleagues, evidence from other studies indicates that many triple negative tumors consistently express a common set of genes that collectively appear to promote the formation and spread of these cancers. The researchers hypothesized that maintaining the expression of this gene pool would require a transcript – a continuous part of the process of decoding instructions into the genes – and that, consequently, triple negative tumors could “be more sensitive to drugs than Focus on transcription.”
Interference with an addiction
The researchers then tested a drug, THZ1, which targets a protein called CDK7, in a series of cell lines and animal models of triple negative breast cancer. CDK7 is a member of a family of enzymes known as cyclin-dependent kinases that help control transcription.
In experiments with cell lines, THZ1 suppressed the proliferation of triple negative breast cancer cells but had no effect on the proliferation of breast cancer cells expressing hormone receptors, even though THZ1 blocked the activity of CDK7 in both cell lines. This finding indicates that triple negative cells “appear to be much more dependent on CDK7 activity” than cells with hormone receptors, the researchers wrote.
The drug also reduced tumors in several murine models of triple negative breast cancer, including tumors derived from tumor fragments from two patients with metastatic disease whose cancers had advanced after multiple lines of treatment.
Further studies in cell lines that used gene-editing technologies to block CDK7 activity, including the CRISPR / Cas-9 system, provided further confirmation that triple negative cancer cells were highly dependent – or “addicted” -to the group of Genes regulated by CDK7. However, triple negative cells were not addicted to genes regulated by other members of the CDK family, reported Dr. Zhao and colleagues.
Previous studies have found that triple negative breast cancer and aggressive forms of some other cancers, including ovarian and lung cancers, have similar expression patterns in this cluster of Achilles. As a result, they wrote, this treatment method “may be applicable to other difficult-to-treat cancers.”
Promise and Warning
In addition to providing a target for treatment, the gene cluster could be a biomarker to identify patients who may be candidates for THZ1 or other drugs targeting CDK7, wrote Dr. Héctor L. Franco and W. Lee Kraus of the University of Texas Southwestern Medical Center, in an accompanying editorial.
“However, because of the universal role and biological importance of transcription in all cells, it may be problematic to apply transcription as a therapeutic strategy because of the possible lack of selectivity of cancer cells over normal cells,” they cautioned. “It is therefore imperative to determine whether the therapeutic window between efficacy and toxicity for malignant and non-malignant cells is large enough to produce a therapeutically effective effect.”
The study revealed no evidence of any of the out-of-place effects, Dr. Daniel Stover, a co-author of the study, said in an e-mail. “However, the effects cannot be completely ruled out of place because this [substance] has not been tested in humans,” he warned. The research team hopes they will be able to test substances that target CDK7 in patients with triple negative breast cancer, he added.
Pharmaceutical company Syros, a company founded by co-authors of the study, Drs. Nathanael Gray and Richard Young, has been licensed by Dana-Farber to formulate targeted therapies for CDK7.
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