UPENN Orphan Disease Program Grants

For the last three years, Penn Medicine Orphan Disease Center (ODC) has hosted the Million Dollar Bike Ride. The Million Dollar Bike Ride brings over 600 cyclists and volunteers to Penn’s campus to ride either 12, 33, or 73 miles starting in the city, and ranging across the Greater Philadelphia region. All funds raised by Disease Teams through pledges are used by the ODC to expand the scope and depth of the pilot grant program. After the event, a Request for Application (RFA) is distributed to the international scientific community requesting pilot grant applications to study diseases for which designated money has been raised.

The also procures philanthropic and corporate donations that are used to match dollar‐for‐dollar money raised by the cycling participants for their particular diseases.

The LAM Foundation Easy Breathers Cycling Team, led by Team Captain Patricia Ortiz, raised over $60,000 in 2015 which was matched by the OCD. This money was distributed in two pilot grants which support LAM research.

2016 Award Winnersplus

LAM Awards for $50,000
Grant Award Winner
Elizabeth Henske, MD
Brigham and Women's Hospital
Boston

The Role of Regulatory T Cells in the Pathogenesis and Therapy of Lymphangioleiomyomatosis

Pulmonary lymphangioleiomyomatosis (LAM) is a rare progressive multisystem disease, in which smooth muscle-like "LAM cells" proliferate in the lungs resulting in cystic destruction of the lung parenchyma, and is also characterized by lymphatic abnormalities and angiomyolipomas (benign kidney tumors). LAM occurs primarily in women and is caused by inactivating mutations in the TSC genes, resulting in hyperactivation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). Currently, LAM is treated with inhibitors of mammalian target of rapamycin (mTOR) or its analogs (Rapalogs). However, Rapalogs only yield partial response in LAM patients and tumors regrow upon treatment cessation.

This project is focused on using the body’s own immune system to assess and treat LAM, building on the dramatic breakthroughs in the past five years during which it has been discovered that modulating the immune system’s recognition of tumor cells can yield dramatic responses of tumors, including melanoma, kidney cancer, and certain types of lung cancer. Our preliminary data support the hypothesis that LAM cells promote the accumulation of a specific type of T cell called a “T regulatory cell.” We further hypothesize that these cells contribute to the progression of LAM. We will use cells, mouse models, and LAM patient specimens to address these hypotheses.

Grant Award Winner
Victoria Stepanova, PhD
University of Pennsylvania School of Medicine
Philadelphia

Urokinase as a potential biomarker and target in LAM

The clinical features of LAM have been well described, but the clinical course of LAM varies considerably. Uncovering biomarkers with prognostic and target value could help to rectify the clinical course of LAM. LAM lesions and angiomyolipomas in the kidney contain increased levels of the enzyme called urokinase plasminogen activator (uPA). uPA is the proteolytic enzyme which initiates activation of the cascade of the multiple tissue-degrading enzymes and therefore mediates metastasis and tumor angiogenesis. High levels of uPA in tumor tissues and plasma are strong indicators of poor prognosis and metastasis in various common cancers. We propose that up-regulation of uPA facilitates destruction of lung tissue by LAM cells and their spread to other organs.

Our pilot data indicate the increase in uPA is a direct consequence of TSC inactivation. We found that Sirolimus, despite its cytostatic effect, further augments expression of uPA in TSC-compromised cells, which might confer higher propensity to metastasize and cause local tissue destruction by LAM cells in some patients. Our data suggest that uPA may emerge as target to delay the growth and dissemination of LAM and other TSC-related tumors. We posit that measurement of uPA levels in LAM lesions, plasma and urine may be of diagnostic and prognostic value. These studies may also suggest that addition of specific inhibitors of uPA (Mesupron, Midamor), now in clinical studies, to Sirolimus might further attenuate lung tissue destruction and dissemination of LAM cells.

2015 Award Winnersplus

LAM Awards - $50,500
Grant Award Winners
David Kwiatkowski, MD, PhD
Brigham and Women's Hospital
Boston

MITF as a Driver Oncogene and Therapeutic Target in Angiomyolipoma/LAM

Microphthalmia-associated transcription factor (MITF) is the founding member of the MiT family including TFEB, TFE3, and TFEC. MITF and its downstream target genes (PMEL, MLANA, CSTK) are known to be consistently expressed in angiomyolipomas, LAM, and related tumors. MITF and other MiT family members are also known to be oncogenic drivers in melanoma and some types of kidney cancer, respectively. We hypothesize that MITF is an oncogenic driver event that contributes to the development of angiomyolipoma and LAM. To test this hypothesis, we will 1) examine MITF and downstream gene expression in angiomyolipoma/LAM samples; 2) test the effect of MITF on cell growth and tumor formation in LAM cell lines; and 3) Identify the genes and signaling pathways regulated by MITF, and their effects on cell growth and tumor formation. Understanding the effects of MITF expression on angiomyolipoma/LAM development and the underlying mechanism has great potential for the development of novel therapeutic strategies for control of both angiomyolipomas and LAM.

Grant Award Winners
Norbert Perrimon, PhD
Harvard Medical School
Boston

An shRNA based screening method for TSC synthetic lethal screens

We aim to develop a new method to identify candidate drug targets to treat TSC-related diseases such as LAM. We will do this by measuring the effects of partially inhibiting genes to find those that cause selective cell death of TSC deficient tumor cells. Previous methods have focused on strong inhibition of target genes, which is harder to achieve clinically using drugs. In addition, we are focusing on genes that can already be targeted with FDA approved drugs. We therefore hope to identify new drug targets that will be quickly transferrable to clinical use.

2014 Award Winnersplus

LAM Awards - $50,000 each
Grant Award Winners
Vera Krymskaya, PhD, MBA
University of Pennsylvania
Philadelphia

STAT3 in Pulmonary Lymphangieoleiomyomatosis (LAM)

The goal of the study is to determine a molecular and cellular mechanisms of STAT3-dependent LAM cell survival and to perform pilot preclinical study to demonstrate that pharmacological targeting of STAT3 might be a novel therapeutic approach for LAM. The pilot funding from MDBR is critical for advancing our knowledge about the cause of abnormal persistent STAT3 upregulation in LAM and for generating pilot preclinical data targeting STAT3 to eradicate LAM cell survival that will generate preliminary data for federal grant application to the NIH/NHLBI.

Grant Award Winners
Aristotelis Astreinidis, PhD
Texas Tech University Health Sciences Center
Lubbock

Evaluation of PLK1 Inhibitors in a Pre-Clinical LAM Animal Model

The mechanistic target of rapamycin complex 1 (mTORC1) increases translation, cell size and agniogensis and inhibits autophagy. mTORC1 is negatively regulated by hamartin and tuberin, the protein products of the tumor suppresors TSC1 and TSC2 that are mutated in Tuberous Sclerosis Complex (TSC) and sporadic Lymphangioleiomyomatosis (LAM). Hamartin interacts with the centrosomal and mitotic kinase polo-like kinase 1 mitotic progression, and cytokinesis, suggesting that the hamartin/tuberin heterodimer and mTORC1 signaling are involved in centrosome biology and mitosis. Here we report that PLK1 protein levels are increased in hamartin and tuberin deficient cells and LAM patient-derived specimens, and that this increase is rapamycin-sensitive. Pharmacological inhibition of PLK1 by the small-molecule inhibitor BI-2536 significantly decreased the viability and clonogenic survival of hamartin and tuberin deficient cells, which was associated with increased apoptosis. BI-2536 increased p62, LC3B-I and GFP-LC3 punctae and inhibited HBSS-induced degradation of p62, suggesting that PLK1 inhibition attenuates autophagy. Finally, PLK-1 inhibition repressed the expression and protein levels of key autophagy genes and proteins and the protein levels of Bcl(-)2 family members, suggesting that PLK1 regulates both autophagic and apoptotic responses. Taken together, our data point toward a previously unrecognized role of PLK1 inhibitors as novel therapeutics for tumors with dysregulated mTORC1 signaling, including TSC and LAM.