Dr. Petra Jans Pederson was first author on the paper “Triple-Negative Breast Cancer Cells Exhibit Differential Sensitivity to Cardenolides from Calotropis gigantea” which was published on July 10 in the Journal of Natural Products.

Dr. Pederson is a recent graduate and received her Ph.D. in Integrated Biomedical Sciences (Pharmacology and Physiology discipline. As a 5th year dual degree student (M.D./Ph.D.) in the South Texas Medical Scientist Training Program, she will be returning to medical school to finish her M.D. training. The Pipette Gazette recently virtually interviewed her about this accomplishment.

1. Tell me about the paper? Can you summarize briefly what it is about?

This paper tells the story of one of the successful “hits” from a high-throughput screening program that is a colaboration between the Mooberry Laboratory at UT Health SA and the Cichewicz Laboratory at the University of Oklahoma. Our goal is to identify new targeted therapies for subtypes of triple-negative breast cancer. Triple-negative breast cancers (TNBC) make up 10-20% of all breast cancers and are defined by a lack of expression of 3 receptors: the estrogen and progesterone receptors, and the human epidermal growth factor receptor 2 (HER2). Because of this, the available therapies that we have targeting these receptors do no benefit patients with TNBC. Furthermore, these cancers are highly heterogeneous, so it is unlikely that a single targeted therapy will be identified for all TNBC. To address this problem, we used a panel of diverse TNBC cell lines to screen for potential drugs that selectively target subgroups of TNBC. What was unique about our approach was that, rather than screening a library of synthetic small molecules, we screened a library of plant extracts from the National Cancer Institute. In this study, we identified an extract from Calotropis gigantea, a species of milkweed, that had selective cytotoxic activity against the BT-549 cell line. With the help of natural products chemists in the Cichewicz laboratory, we identified 9 pure compounds from this plant that were responsible for the selective activity. These compounds are part of a known family of naturally occurring chemicals called cardenolides or cardiac glycosides, which inhibit the sodium/potassium ATPase. One such compound, digoxin, is actually clinically approved for the treatment of heart failure. In our study, we also identified a second TNBC cell line sensitive to cardiac glycosides, and discovered that both of these cell lines expressed higher levels of the sodium/calcium exchanger (NCX1) than resistant TNBC cell lines. We propose that NCX1 could be used as a biomarker to identify TNBC patients that might benefit from the clinical administration of a repurposed cardiac glycoside, like digoxin.

As I said before, drug discovery for TNBC is particularly important because these patients do not benefit from the major targeted therapies for breast cancer that are at our disposal, and unfortunately this disease is more aggressive and associated with a relatively poor prognosis. I think it is also important to note that TNBC disproportionately affects African American and young women.

The other point I want to make is about the role of natural products in drug discovery. Many people might confuse what we are doing with naturopathic medicine or natural remedies, but that could not be further from the truth. Many of the most successful pharmaceutical drugs in history are actually natural products, their derivatives or inspired by a naturally occurring compound. Two classic examples are aspirin, a derivative of a natural product originally isolated from the bark of the willow tree, and penicillin, an antibiotic that is produced by the fungus, Penicillium notatum. If you were to look at all of the small molecule anticancer drugs approved by the FDA over the last 40 years or so, more than 60% were natural products, their derivatives or natural product-inspired. In fact, some of our most powerful (and toxic) chemotherapeutic drugs come from nature, such as doxorubicin (Adriamycin) or paclitaxel (Taxol).

As I am leaving the lab at the end of the summer to return to medical school as part of the M.D./Ph.D. program/MSTP, I will not be taking this specific project any further. However, the Mooberry laboratory is continuing this screening program and is currently following up on other “hits.”  I defended my Ph.D. back in May and this summer I am wrapping up two other projects that were part of my dissertation and also relate to the treatment of triple-negative breast cancer. I hope to submit those manuscripts for publication in the near future.