The Lucy Engles TSC/LAM Medical Research Program


Pre-Clinical Research

Through this basic science work, the team is creating new cellular and animal models of disease to gain insight into TSC and LAM disease processes and test potential new therapies.

Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation. The Journal of Clinical Investigation, January 2017
Individuals with TSC develop white spots (hypomelanotic macules) on their skin. The reason for this has never been understood. In this important study, it was discovered that TS proteins regulate skin pigmentation—also called melanogenesis—revealing for the first time why white spots occur in TSC. This work, from David Kwiatkowski, MD, PhD, also has implications for a better understanding of how a key protein, MiTF, is dysregulated in TSC2-deficient cells, including LAM and angiomyolipoma cells. Read the abstract here.

Analysis of a Mouse Skin Model of Tuberous Sclerosis Complex. PLOS ONE, December 2016
Previously, there has been no mouse model to study the skin manifestations of TSC. This paper from David Kwiatkowski, MD, PhD, and colleagues describes a new genetic mouse model which shows a prominent skin phenotype. Although the phenotype does not exactly resemble the skin in human TSC, this new model will be useful in furthering our understanding of skin disease in TSC. Read the abstract here.

Inactivation of TSC2 in Mesoderm-Derived Cells Causes Polycystic Kidney Lesions and Impairs Lung Alveolarization. The American Journal of Pathology, September 2016
Many research teams have sought better mouse models of pulmonary LAM, including our own. In this case, Dr. Henske and her team deleted the TSC2 protein in mice in key disease-related cell groups throughout the body. Dr. Henske and her collaborator, Wei Shi, MD, PhD (Children’s Hospital Los Angeles), are excited to observe evidence of cystic lung disease that may resemble LAM. The mice also developed significant kidney disease, which limited their lifespan. Drs. Henske and Shi are continuing this work using a more specific model in which only the lungs will be affected, as part of ongoing efforts to develop a genetically engineered mouse model of LAM. Read the abstract here.

Evidence Supporting a Lymphatic Endothelium Origin for Angiomyolipoma, a TSC2- Tumor Related to Lymphangioleiomyomatosis. The American Journal of Pathology, July 2016
The cellular origin of LAM and angiomyolipomas is an area of uncertainty in the field, and several different theories have been proposed. This paper, from Dr. Henske in collaboration with Lucia Schuger, MD (University of Chicago), lays out evidence that LAM and angiomyolipoma cells may derive from the delicate cells that line the lymphatic channels, known as lymphatic endothelial cells. If proven to be correct, this novel pathway would help to develop critical new models of LAM in mice. Dr. Henske and David Kwiatkowski, MD, PhD, are currently working on a mouse model with inactivation of TSC2 in lymphatic endothelial cells to determine whether LAM-like lesions develop. Read the abstract here.

Clinical Research and Biomarker Development

This area of the program is focused on identifying and validating new disease markers, which are urgently needed to improve diagnosis, monitor disease progression, and identify better treatment options for patients with TSC and LAM.

Aberrant SYK Kinase Signaling Is Essential for Tumorigenesis Induced by TSC2 Inactivation. Cancer Research, March 2017
This study from Souheil El-Chemaly, MD, MPH, in collaboration with Dr. Henske and Carmen Priolo, MD, PhD, identified a previously unknown mechanism that promotes the growth of TSC2 deficient cells in both mouse and cellular models. This pathway, called the SYK pathway, may participate in the production of VEGF-D—an important disease marker—in women with LAM. Importantly, drugs that inhibit the SYK pathway are already in advanced clinical trials, suggesting that this may provide an avenue for future clinical progress. Read the abstract here.

New developments in the genetics and pathogenesis of tumours in tuberous sclerosis complex. Journal of Pathology, November 2016
In this article, Dr. Henske reviewed changes in our understanding of the genetic causes of tumors in TSC, including important new studies on angiofibromas and renal cell carcinoma. We focused on the role of sun-induced mutations in the pathogenesis of angiofibromas and the continued advances in understanding the genetics and pathology of malignant renal tumors that occur in some individuals with TSC. Read the abstract here.

Proapoptotic protein Bim attenuates estrogen-enhanced survival in lymphangioleiomyomatosis. JCI Insight, November 2016
This paper from Dr. Henske, in collaboration with Jane Yu, PhD (University of Cincinnati), identified a new mechanism through which estrogen may promote the survival and metastasis of TSC2-deficient cells, thereby promoting the progression of LAM. A well-known molecule called Bim that regulates cell death was found to enhance the survival of LAM-like cells and promote their growth in the lungs of mice, particularly in the setting of estrogen. Read the abstract here.

Targeting Lipid Metabolism in Cancer, November 2016
Dr. Henske’s group and others have shown that lipid metabolism is fundamentally altered in tumor cells in TSC. This book chapter, written by Carmen Priolo, MD, PhD, in collaboration with Technical Research Assistant Taylor Kavanagh, focuses on how lipid metabolism can be used to therapeutically target tumor cells, including tumor cells in TSC.

Pancreatic PEComa is a novel member of the family of tuberous sclerosis complex-associated tumors: case report and review of the literature. Virchow’s Archiv: European Journal of Pathology, October 2016
The family of Perivascular epithelioid cell tumors (PEComas) includes tumors that develop in TSC, including LAM and angiomyolipomas. Led by David Kwiatkowski, MD, PhD, and collaborators, this case report of PEComas in the pancreas of a woman with TSC extends our knowledge of where PEComas can be found. It is an example of how our knowledge of the clinical manifestations of TSC continues to evolve. Read the abstract here.

Haploinsufficiency in tumor predisposition syndromes: altered genomic transcription in morphologically normal cells heterozygous for VHL or TSC mutation. Oncotarget, September 2016
This paper focused on TSC and von Hippel-Lindau disease (VHL). These diseases are an interesting comparison since TSC causes primarily benign renal tumors while VHLS causes primarily malignant renal tumors. This study from Dr. Henske and collaborators in Philadelphia found that there were distinctive alterations in the cells that do not have mutations in both copies of TSC or VHL gene (haploinsufficient cells). In individuals with TSC, these haploinsufficient changes may impact the growth and behavior of angiofibromas, angiomyolipomas and LAM. Read the abstract here.

Whole Exome Sequencing Identifies TSC1/TSC2 Biallelic Loss as the Primary and Sufficient Driver Event for Renal Angiomyolipoma Development. PLOS GENETICS, August 2016
It has never been shown whether angiomyolipomas contain genetic mutations other than those in the TSC genes. This is critical to understand because if additional mutations are present, therapies may need to be tailored to those mutations in addition to the TSC gene mutations. In this study, the entire genome of 32 angiomyolipomas were analyzed. As expected, nearly all the angiomyolipomas had loss of both copies of either TSC1 or TSC2. Importantly, sequencing of all other genes revealed very few mutations, even in large angiomyolipomas. These data findings from Dr. Henske and David Kwiatkowski, MD, PhD, suggest that loss of TSC1 or TSC2 is sufficient to develop an angiomyolipoma and to promote the growth of angiomyolipomas and that additional gene mutations are uncommon. Read the abstract here.

Advances and Future Directions for Tuberous Sclerosis Complex Research: Recommendations From the 2015 Strategic Planning Conference, Pediatric Neurology, July 2016
This paper reviewed the recommendations from a recent strategy plan workshop sponsored by the National Institutes of Health (NIH), Department of Defense TSC Medical Research Program, and the TS Alliance. Dr. Henske was a lead organizer of this conference, which was held in March of 2015 and included 82 participants (including David Kwiatkowski, MD, PhD). The comprehensive plan developed at the conference and published in this paper will set the stage for TSC research priorities for at least the next 5 years. Read the abstract here.

Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management, ATS/JRS Committee on Lymphangioleiomyomatosis, May 2016
This collaborative effort provided consensus recommendations for the treatment of LAM. Dr. Henske participated in the development of these guidelines along with 31 other physician authors from the United States and Japan. Read the abstract here.

Nipple Angiofibromas with Loss of TSC2 Are Associated with Tuberous Sclerosis Complex. Journal of Investigative Dermatology, December 2015
Angiofibromas occur primarily on the skin of the face but can also occur in other areas including the nipple. This study from David Kwiatkowski, MD, PhD, shows that TSC gene mutations occur in nipple angiofibromas, similarly to the mutations that occur in facial angiofibromas. Read the abstract here.

Exosomes mediate the acquisition of the disease phenotypes by cells with normal genome in tuberous sclerosis complex. Oncogene, October 2015
This paper, from Dr. Henske in collaboration with Magdalena Karbowniczek, MD, PhD (Texas Tech University), reports on an important discovery that cells with a mutation in the TSC genes can influence the behavior of neighboring cells, even those that do not have TSC mutations. This occurs through the secretion of specialized particles called exosomes, which can travel from one cell to other nearby cells. This discovery may help us understand the mixture of cells with and without TSC gene mutations that are commonly found in both LAM, angiomyolipomas, and angiofibromas. Read the abstract here.

Clinical Trials

Through the development and assessment of potential new therapies, the team is working deliver improved treatment options to patients, including their ultimate goal: a cure.

Sirolimus and Autophagy Inhibition in LAM: Results of a Phase I Clinical Trial. Chest, February 2017
This study from Souheil El-Chemaly, MD, MPH, and Dr. Henske, in collaboration with Joel Moss, MD, PhD (National Heart Lung and Blood Institute), was the first clinical trial of combination therapy in TSC and LAM. Thirteen (13) women were treated with the combination of Sirolimus (brand name Rapamycin) and hydroxychloroquine and followed for 48 weeks. Results demonstrated that the combination of these drugs is well tolerated and sets the stage for future trials involving a larger number of patients. Read the abstract here.

The effect of mTOR inhibitors on respiratory infections in lymphangioleiomyomatosis, European Respiratory Review, January 17, 2017
Sirolimus, which is a type of mTOR inhibitor, is known to suppress the immune system. It has not been previously understood if women with LAM are at higher risk for respiratory infection when receiving treatment with sirolimus. Souheil El-Chemaly, MD, MPH, in collaboration with Dr. Henske, reviewed all published studies on women receiving mTOR inhibitors and compared the rate of respiratory infection for women receiving treatment vs. a placebo. No increased risk for respiratory infection among women receiving mTOR inhibitory therapy was found. This is important information for women with LAM who are considering treatment with sirolimus. Read the abstract here.

Seizures in tuberous sclerosis complex: hitting the target, The Lancet, September 6, 2016
This editorial accompanied a very important new paper demonstrating, in some cases, seizures in TSC can be partially controlled with mTOR inhibitory therapy. Read the abstract here.