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STAT

An MUSC blog
Keyword: oncogene

SUMMARY: A genomics approach at the Medical University of South Carolina (MUSC) has unmasked genetic signatures in breast cancer cells that predict their sensitivity to certain drugs. The findings, published in the May 2, 2016 issue of Oncotarget, provide proof of concept for personalized pharmaceutical therapies that target the genes responsible for driving tumor growth.

Drug treatments for breast cancer patients might soon be designed based on the unique genetic autograph of their tumor.

A genomics approach at the Medical University of South Carolina (MUSC) has unmasked genetic signatures in breast cancer cells that predict their sensitivity to certain drugs. The findings, published in the May 2, 2016 issue of Oncotarget, provide proof of concept for personalized pharmaceutical therapies that target the genes responsible for driving tumor growth.

Dr. Stephen EthierCertain oncogenes drive solid tumor growth in some breast cancer patients but are just passenger genes in others—expressed but not essential for growth. As a result, tumors in different breast cancer patients may respond differently to the same treatment depending on which oncogenes are active and which are just along for the ride. Identifying the panel of active genes in a patient’s tumor—called the functional oncogene signature—could help an oncologist select therapies that target its growth, according to Stephen P. Ethier, Ph.D., Interim Director of the Center for Genomic Medicine at MUSC and senior author on the study.  

“In order to move the field forward, we now need to be able to use oncogene signatures to tailor therapies using combinations of targeted drugs so that multiple driving oncogenes can be targeted at once,” said Ethier.  “Doing this successfully requires the identification of the oncogenes to which the cancer cells are addicted, as this allows the use of targeted drugs at very low doses. Low doses are essential if we are to use combinations of different targeted drugs.”

Ethier’s group identified unique functional oncogene signatures in four different human breast cancer cell types. Using next-generation genome sequencing and genome silencing as each cancer cell type grew and multiplied, they assembled a list of genes for each cell type’s functional oncogene signature—those genes that were copy number amplified or point mutated, and most essential to cancer cell survival. Although thousands of candidate oncogenes were screened during experimentation, only a handful made the list—fewer than 20 for each cell type.

The brevity of each list facilitated selection of the best oncogene for pharmaceutical targeting. Because lower doses of targeted drugs can be highly effective, side effects could be reduced. For example, Ethier’s group found that targeting two or more members of a signature with much lower total drug concentrations in combination still killed cancer cells better than one higher-concentration drug alone.

Remarkably, a BCL2L1-targeted drug  that worked in one cell line also then worked in a fifth breast cancer cell line with a similar oncogene signature containing BCL2L1, an oncogene not normally associated with breast cancer. This work demonstrates that one signature-targeting treatment can be extended to more than one cancer cell type. This means that patients with other types of cancer who have a similar functional oncogene signature might benefit from drugs that target BCL2L1, which are already in development.

Ethier thinks that oncogenes identified in a tumor biopsy might one day soon provide a rational and individualized approach to pharmaceutical treatment with targeted drug combinations. Meanwhile, these findings from his laboratory—showing the importance of considering a patient’s functional oncogene signature before testing a new drug— could provide a rationale for redesigning clinical trials for breast cancer.

Stephen T. Guest, Ph.D., of the MUSC Department of Pathology & Laboratory Medicine, was first author on the study.

Dr. Robert StuartDr. Azizul Haque

The body’s own immune system could be a potent weapon in the war on cancer if the cloaking mechanisms tumor cells use to elude it could be deactivated. In an article published in the February 15 issue of the Journal of Immunology, one of those cloaking mechanisms was identified in B cell tumors by a team of MUSC immunologists led by Azizul Haque, PhD (above right), MUSC Health hematologist/oncologist Robert Stuart, M.D. (above left), and their colleagues at the University of Indiana and German Research Center for Environmental Health. They reported that overexpression of the c-MYC protein, one of the most commonly activated genes in human cancers that is implicated in the cancer-related deaths of about 100,000 people worldwide, is linked to the ability of B cell tumors to “hide” from the immune system.1 Specifically, they showed for the first time that overexpression of the c-MYC protein in Burkitt’s lymphoma interferes with human leucocyte antigen (HLA) class II antigen presentation. T cells can mount an immune response against antigens only if they can “see” them; they “see” them when TCRs (T cell receptors) on their surface recognize antigen fragments bound to HLA class II molecules on the surface of antigen-presenting cells. When tumor antigen is not presented properly due to c-MYC overexpression, it remains invisible to the T cells. The article also provided evidence that treatment of c-MYC-overexpressing cells with a c-MYC inhibitor decreased c-MYC expression and partially restored HLA class II-mediated antigen presentation. These results suggest that c-MYC inhibitors could help “unmask” B cell lymphomas and promote a more robust immune response. According to Haque, “This study uncovers a mechanism by which c-MYC impairs immune detection of malignant tumors, which could be targeted in future treatments for B cell lymphomas and other malignancies.” The article by Haque and colleagues was highlighted in the “In This Issue” section of the Journal of Immunology, reserved for the top 10% of articles published in the journal.

References

1 God JM, Cameron, C, Figueroa J, Amria S, Hossain A, Kempkes B, Bornkamm GW, Stuart RK, Blum JS, Haque A. Elevation of c-MYC Disrupts HLA Class II–Mediated Immune Recognition of Human B Cell Tumors. The Journal of Immunology 2015;194:1434–1445.

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