Accelerated Research Discovery Led By Komen Houston Medical Advisory Council Member

Findings take research to patients in four years

Study Highlights
• Discovered a gene mutation driving formation of most aggressive triple negative breast cancer.
• Identified two proteins predicting overall patient survival.
• Validated a therapeutic compound in animal models that slows tumor growth and increases the efficacy of chemotherapy.

Houston Methodist Hospital researchers have advanced a potential treatment for metaplastic breast cancer—the most aggressive subtype of triple negative breast cancer, into patients in just under four years.

In a study published in the Journal of the National Cancer Institute (early online Dec. 31), a multi-institutional team led by Jenny C. Chang, M.D., director of the Houston Methodist Cancer Center, identified a gene driving the formation of metaplastic breast cancer.

[Click here for video with Jenny Chang, M.D.]

“We not only uncovered the biological pathway stimulating cancer growth, but we found a compound that blocked it, increasing the survival of mice carrying human metaplastic breast tumors,” said Chang, the study’s senior author.

Metaplastic breast cancers account for less than 1 percent of all breast cancers, according to the Susan G. Komen Foundation. This subtype is the most aggressive triple negative breast cancer and remains therapeutically challenging to treat. Highly unresponsive to chemotherapy, these aggressive tumors leave patients with a three-year survival rate of 40 percent, worse than the 70 percent given triple negative breast cancer patients. Identifying the genetic mutation gave Chang and her team a jumpstart on targeting this cancer.

The research team found the same gene mutated in 39 of the 40 tumor samples from metaplastic breast patients. The mutation was in the gene RPL39, which like HER2 (a gene overexpressed in 1 out of 5 breast cancers), is considered an oncogene. This means that cells carrying the erroneous form of this gene divide uncontrollably and result in rapid tumor growth. Identifying RPL39 was the first step in determining how to treat this cancer.

RPL39 regulates the expression of an enzyme called inducible nitric oxide synthase (iNOS). The Houston Methodist researchers found that patients with high expression of RPL39 and iNOS had lower overall survival. Intuitively, the team investigated effects of an iNOS inhibitor on the treatment of metaplastic breast cancer and found the L-NMMA compound shrunk tumors in mice bearing human metaplastic breast tumors.

“The results showed elimination of the cancer in nearly all of the mice when combined with standard chemotherapy,” said Chang, also professor of medicine at Weill Cornell Medicine. “Our goal is to turn metaplastic breast cancer from a debilitating disease into a chronic illness.”

Houston Methodist Hospital is currently enrolling patients diagnosed with metaplastic breast cancer in a phase I clinical trial for L-NMMA.
Co-authors of the study included Bhuvanesh Dave, Ph.D., Daniel D. Gonzalez, Zhi-Bin Liu, M.D., Helen Wong, Sergio Granados, Ph.D., Joe E. Ensor, Ph.D., and Douglas H. Sieglaff, Ph.D. (Houston Methodist); Xianxian Li, M.D. (Shanghai Cancer Center and Cancer Institute of Fudan); Nadeer E. Ezzedine, Ph.D., Agda Karina Etrovic, Ph.D., Gordon B. Mills, M.D., and Michael Z. Gilcrease, M.D. (University of Texas M.D. Anderson Cancer Center); Kathy D. Miller, M.D. and Milan Radovic, Ph.D. (Indiana University Medical School); Steven S. Gross, Ph.D. (Weill Cornell Medical College); and Oliver Elemento, Ph.D. (Institute for Computational Biomedicine).

The research was supported in part by Chan Soon Shiong Institute of Advanced Health (AUP-1010-0025), BCRF, and Houston Methodist Foundation Grants.
To speak with Jenny Chang, M.D., contact Patricia Akinfenwa, Houston Methodist, at 281.740.1402 or pakinfenwa@houstonmethodist.org. For more information about Houston Methodist, visit houstonmethodist.org. Follow us on Twitter and Facebook.

For more information: RPL39 modulates NOS signaling and RNA editing to drive metaplastic breast cancer. Journal of the National Cancer Institute DOI: 10.1093/jnci/djw292 (Online December 31, 2016). B. Dave, D. Gonzalez, Z. Liu, X. Li, H. Wang, S. Granados, N. Ezzedine, D. Sieglaff, J. E. Ensor, K. D. Miller, M. Radovic, A. K. Etrovic, S. S. Gross, O. Elemnto, G. B. Mills, M. Gilcrease, and J. Chang.