污污草莓视频

Researchers identify path to improve HER2+ breast cancer susceptibility to approved therapies

Approximately 15 to 20% of breast cancers are caused by changes in a gene known as HER2, which cause the protein produced by the gene to become constantly active, leading to uncontrolled cell growth. Cancers with these genetic changes are called 鈥淗ER2-positive鈥� or 鈥淗ER2+鈥� breast cancers. While therapies that interfere with the HER2 protein can be very effective in many of these cases they don鈥檛 work for everyone. When they fail, the prognosis for those with the disease is extremely poor. For these people, there is a dire need to understand why they are resistant to the treatment and to develop new strategies to attack the cancer cells. Now, researchers at 污污草莓视频 University鈥檚 Goodman Cancer Research Centre (GCRC) believe they have identified a way to do this, increasing the vulnerability of cancer cells to an approved therapy. Their results were recently published in听Cell Reports.

The major class of therapies for HER2+ breast cancers is known as HER2-targeted monoclonal antibodies. The first such therapy, which remains the go-to drug for these patients, is called Herceptin. Recent data suggest that Herceptin works mainly by flagging the tumour cells for attack and destruction by the patient鈥檚 own immune system.

鈥淥ur study showed that HER2+ breast cancer cells can learn to use epigenetics to make themselves less visible to the immune system, which makes Herceptin therapy much less effective,鈥� explains Dr. Alison Hirukawa, the paper鈥檚 lead author who undertook the research while completing her PhD in the lab of Dr. William Muller at the GCRC. 鈥淲e found that patients who don鈥檛 respond to Herceptin have higher activity of an enzyme that switches off gene activity. When we used drugs or genetic methods to inhibit this enzyme in models of HER2+ breast cancer, it triggered the activation of genes that stimulate the immune system to attack tumour cells in the presence of the HER2-targeted antibody.鈥�

Using mouse models to test a hypothesis

The researchers had a notion from studying cancer cells in the lab that this particular gene-silencing enzyme was involved in resistance to therapies targeting HER2. Dr. Hirukawa decided to test this idea in mouse models of breast cancer, 鈥渋n vivo鈥�, using a HER2-targeted antibody very similar to Herceptin and a drug that blocks the enzyme the researchers were interested in.

鈥淚 noticed that this combination worked well in mice with a normal immune system, but was ineffective when I used mice with an impaired immune system,鈥� notes Dr. Hirukawa. 鈥淭his led us to work backwards to figure out why targeting this epigenetic regulator interacted with the immune system.鈥�

At the same time, the researchers wanted to see if there was any evidence that gene silencing caused by the enzyme they were working on was involved in responses to Herceptin in human cancer patients. 鈥淥ur collaborators at Case Western Reserve University in Cleveland, Ohio had access to a unique collection of patient samples that allowed us to answer this question,鈥� says Dr. Hirukawa. 鈥淲e were struck by how well the models we used in the lab agreed with the data from cancer patients that came from our collaborators. The agreement between data from laboratory model systems and data from patients are never perfect, but in this case our results from the models were supported by observations from patient samples. This makes the results much more compelling.鈥�

鈥淭he gene-silencing enzyme that we found to be involved in Herceptin resistance is itself a drug target,鈥� adds Dr. Muller, who is also a Professor at 污污草莓视频鈥檚 Department of Biochemistry and a senior author on the paper. 鈥淚n fact, drugs that block this enzyme are currently in clinical trials for other cancer types. This means that our work indicates a strategy for reversing Herceptin resistance in HER2+ breast cancers that use the epigenetic mechanism of resistance that we discovered. This strategy could be readily tested in the clinic.鈥�

The way forward

Studies in patients are needed to determine whether the increased activity of the epigenetic pathway found in Herceptin-resistant breast cancers actually causes the resistance, and if so whether the researchers鈥� explanation of how this works is valid in patients.

鈥淲e are currently planning to pursue clinical trials of drug combinations involving HER2-targeted antibodies and drugs that block the activity of the gene-silencing enzyme we found to mediate resistance,鈥� shares Dr. Harvey Smith, a Research Associate at the GCRC and also a senior author on the study. 鈥淲e鈥檙e hoping that we can test patient tumour samples to determine the level of activity of the enzyme in question and use this information to identify patients at high risk of drug resistance. These would probably be the patients who would benefit most from our new strategy.鈥�
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鈥淩eduction of Global H3K27me3 Enhances HER2/ ErbB2 Targeted Therapy,鈥� By A. Hirukawa, H. Smith, W. Muller, et al. was published in the journal听Cell Reports听on October 8, 2019. Doi:听

Funding sources for this research included:听听The Terry Fox Research Institute Program Project Grant #1048, the Canadian Institutes of Health Research Foundation award FDN-148373, Canadian Epigenetics, Environment and Health Research Consortium Team Grant TEC-128089 and a Canada Research Chair in Molecular Oncology 950-231033 to Dr. Muller and the US Department of Defense Congressionally Directed Medical Research Programs, Breast Cancer Research Program W81XWH-11-1-0046 (to Dr. Smith)

Other key collaborators were Dr. Trey Westbrook and his student Jarey Wang, at Baylor College of Medicine in Houston, TX and Dr. Eran Andrechek at Michigan State University, with his group members Dr. Jonathan Rennhack and Matthew Swiatnicki.