Deborah A. Lannigan, Ph.D.

Associate Professor

deborah.lannigan@vanderbilt.edu
Faculty Appointments
Associate Professor of Pathology, Microbiology and Immunology Associate Professor of Biomedical EngineeringAssociate Professor of Cell & Developmental Biology
Education
Ph.D., Biophysics, University of Rochester, Rochester, New YorkM.Sc., University of Toronto, Toronto, CanadaB.Sc., University of Guelph, Ontario, Canada
Research Description
Estrogen Homeostasis

Estrogen receptor a (ERa) is essential for reproduction and lactation but it is now appreciated that estrogen signaling via ERa is associated with cancers of the breast, reproductive organs, colon and liver as well as with metabolic syndrome and type 2 diabetes. In fact, ERa has been proposed to be a candidate gene for obesity. All ER+ tissues respond to estrogen signaling and therefore, are subject to the normal fluctuations in the levels of estrogen that occur throughout the estrous cycle. Support for this statement is provided by the observations that substantial changes in metabolic function occur during menopause, ovariectomy or anti-estrogen therapy. Therefore, ERa has key functions in normal energy homeostasis. In vitro or in vivo acute exposure to estrogens results in rapid degradation of ERa by the 26S proteasome pathway. These results would suggest that due to the constant exposure to estrogens prior to menopause that ERa degradation would be ongoing and result in very low levels of ERa. However, ERa protein levels are maintained during chronic exposure to estrogens. The mechanism that is responsible for maintaining ERa levels in the normal adult female is not known. This mechanism is crucial to maintaining estrogen-responsiveness in all tissues that contain ERa and therefore is a critical gap in our knowledge.

We are interested in identifying the mechanism by which the protein levels of ERa are regulated and how this regulation maintains metabolism in the adult. To study estrogen biology we use the mammary gland as a model system because it is possible to regenerate the entire mammary gland in twelve weeks with isolated mammary epithelial cells in which gene expression has been altered. The mammary gland is a relevant organ for investigating metabolism and its dysfunction, as it responds to fluctuating estrogen levels, which impact energy homeostasis. Interestingly, the mammary gland preferentially utilizes glucose as an energy source and unlike muscle does not appear to become insulin resistant. The mechanism that accounts for this maintenance of insulin sensitivity in insulin resistant animals is not fully understood but could provide important insights into restoring insulin function in other tissues.

Breast Cancer and Drug Development

ER+ breast cancer accounts for over 70% of breast cancers and over 80% of invasive breast cancers. Approximately 25% of women with early stage breast cancer go on to develop metastasis and only 30% of women with metastatic disease respond to endocrine-based therapies. Metastatic breast cancer is incurable. Clearly there is a need to understand the causes of ER+ breast cancer and to use this knowledge to develop therapies that target metastatic breast cancer. In several studies the activity of the Ser/Thr protein kinase, RSK, positively correlates with patient responses to anti-estrogen hormonal therapies. However, the mechanistic basis for these observations is unknown. Using multiple in vitro and in vivo models of ER+ breast cancer we found that RSK2 physically interacts with ER¿¿to drive an ER¿¿mediated transcriptional program, ductal epithelial growth, tumorigenesis, and divergent patient responses to anti-estrogen therapies. We hypothesize that a RSK inhibitor will provide new therapeutic options for ER+ metastatic breast cancer. We discovered the first RSK-specific inhibitor, SL0101, which is the only allosteric inhibitor of RSK. Subsequent structure-activity-relationship, crystallography, biochemical and cell-based studies have led to the identification of a second generation analogue, C6”-n-propyl-cyclitol SL0101 (U.S. Patent No. 13/390,389). In preliminary experiments, this analogue inhibited metastasis in vivo. SL0101 and its analogues demonstrate unique biological properties, which we hypothesize support their continued development toward clinical translation.

We are interested in investigating the mechanism by which the interaction of RSK2 with ER¿¿leads to ER+ breast cancer and drives the metastatic phenotype. To study ER+ breast cancer we use engineered cell lines and mouse models. Additionally, we have successfully developed 3D ex vivo organoid cultures using primary human normal or breast cancer tissue that recapitulate the gland in situ and provide a physiologically relevant in vitro system. We are collaborating with Drs. Sulikowski and Waterson and the Vanderbilt Chemical Synthesis Core to generate a new series of RSK inhibitor analogues, which we will evaluate in vitro and in vivo to identify an analogue that can progress to clinical trials.

Ameliorating Chemotherapy-induced Cardiotoxicity

Treatment options for breast cancer patients vary depending on the subtype of breast cancer but disconcertingly many of these treatments result in cardiac damage. Approximately 50% of deaths in breast cancer survivors > 55 years old is due to heart disease with a peak mortality at ~ 5 years after treatment. Adverse cardiovascular effects have been observed with numerous chemotherapies including targeted therapies. We focus on the mechanism and prevention of cardiovascular toxicity due to the chemotherapeutic agent, doxorubicin, because of its frequency of use and associated morbidity. There is a substantial unmet need for the development of cardioprotective agents to be used in conjunction with chemotherapies. We have observed that doxorubicin leads to activation of RSK and it has been reported that in failing human hearts RSK is activated. RSK is also activated in response to ischemia/reperfusion injury. These data suggest that RSK may be involved in mechanisms that result in cardiac damage.

We are interested in identifying the mechanisms by which RSK contributes to doxorubicin-induced toxicity in the heart and in evaluating whether RSK inhibition could provide protection against cardiac damage. We use primary mouse cardiomyocytes, mouse models and will be using human induced pluripotent stem cells to address our hypothesis. Additionally, we will be evaluating our new RSK inhibitor analogues for their ability to inhibit doxorubicin-induced toxicity in vivo.

Development of a Novel Antibiotic Approach

Antibiotic resistance is a major global health problem. Antibiotic development has traditionally focused on drugs that target the pathogen but resistance inevitably develops. An attractive alternative is to develop drugs that target the host response, which enables disease progression. The MEK-ERK-RSK cascade is activated differentially during the infection cycle by various mechanisms in response to a wide variety of medically important pathogens. However, treating patients with drugs that inhibit “global regulators” such as MEK results in a number of side effects and their ability to induce an effective clinical response appears to be limited by their toxicity. We propose that targeting RSK represents an untapped strategy that will generate fewer side effects than a MEK inhibitor because it regulates fewer targets.

The importance of RSK in intracellular bacterial infection has not been thoroughly investigated, although RSK activation has been demonstrated in Yersinia pseudotuberculosis and Klebsiella pneumoniae. In in vitro studies we have found that RSK inhibition within the host reduced viability of Y. pseudotuberculosis and Francisella tularensis. We are currently focusing on understanding the importance of RSK activation in F. tularenis because of its medical importance and the lack of effective vaccines. F. tularensis tularensis is listed as a category A biothreat agent by the Center for Disease Control and Prevention. There are reports of an increase in human cases of tularemia, the disease caused by F. tularensis, in some parts of the United States. Additionally, outbreaks of tularemia continue to occur worldwide. We will also be evaluating our new RSK inhibitor analogues for the ability to inhibit infection in vivo.