Awarded Grants

Awarded Grants

MDBR, LAM Million Dollar Bike Ride MDBR, LAM Million Dollar Bike Ride

Targeting immunosuppression in LAM

Yan Tang

Brigham and Women's Hospital, Harvard Medical School

$71,051.00

Awardee: Yan Tang

Institution: Brigham and Women's Hospital, Harvard Medical School

Grant Amount: $71,051.00

Funding Period: February 1, 2024 - January 31, 2025

Summary:

Lymphangioleiomyomatosis (LAM), pulmonary manifestation of TSC, is a destructive and often fatal lung disease of women, which can lead to lung failure and the need for lung transplantation. LAM can occur as an isolated disorder (sporadic LAM) or in association with TSC. TSC-LAM patients often have angiomyolipoma (AML), the kidney manifestation of TSC. About 60% of sporadic LAM patients also have AML. It seems that LAM and AML share same genetic mutations. We performed single cell analysis on five LAM lungs and six AML specimens and found that subsets of candidate TSC-deficient cells exhibit elevated stemness and dormancy transcriptional programs in both LAM and AML. TSC diseases also exhibit an altered immune microenvironment. We have analyzed adjacent normal kidney tissues for four of the six AML specimens and found that AML tumors are enriched with dysfunctional T cells compared to paired normal kidney. In depth analysis further revealed that stemness-dominant samples are deprived of proliferating T cells, key component in immune system to control tumor growth. In this project, we will investigate how the stemness state of TSC-deficient cells affects immune microenvironment in LAM and assess whether targeting tumor stemness can rejuvenate T cells to better control LAM development.

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MDBR, LAM Million Dollar Bike Ride MDBR, LAM Million Dollar Bike Ride

Exploring adjuvant immunotherapy to treat lymphangioleiomyomatosis

Katharina Maisel

University of Maryland, College Park

$75,110.00

Awardee: Katharina Maisel

Institution: University of Maryland, College Park

Grant Amount: $75,110.00

Funding Period: February 1, 2023 - January 31, 2024

Summary:

Lymphangioleiomyomatosis (LAM) is a rare lung diseases that causes cystic destruction of the lungs caused by the abnormal growth of smooth-muscle-like LAM cells that have cancer-like features. To date, rapamycin is the only FDA approved treatment for LAM and this treatment is not a cure. Additionally, about 30% of patients do not respond to the treatment. Therefore, new therapeutic avenues are desperately needed. We and other have recently shown that LAM may cause suppression of the local immune response, similar to cancer, and that re-activating this immune response through checkpoint inhibitor or CAR T cell therapies can enhance survival in a murine model of LAM. Immune adjuvants are another immunotherapy currently under investigation for cancer treatments. We have found that one particular adjuvant, CpG, which activates toll-like receptor 9 (TLR9) on antigen presenting cells can enhance survival in murine LAM. However, this survival is incomplete and thus further investigation is necessary. We have found that repeated dosing of CpG causes an overall reduction of immune cell recruitment to the lungs but does not reduce immunosuppressive regulatory T cells. Repeated TLR stimulation on immune cells can lead to ‘TLR tolerance’, in which the cells become less responsive to the stimulus over time. We hypothesize that TLR tolerance is one of the reasons for incomplete survival after CpG treatment in LAM. Research has also shown that spacing out TLR stimulating treatments or alternating the specific TLR that is stimulated may reduce TLR tolerance. Thus, we will investigate the mechanisms of TLR tolerance in LAM and explore alternative treatments to further increase survival. Overall, this proposal will shed new light onto mechanisms of immunosuppression in LAM and also define new treatment avenues for LAM. Furthermore, this work is the first to use adjuvant immunotherapies as treatments for neoplastic growths with loss of TSC expression and could thus open up the use of these treatments for diseases beyond LAM. Finally, understanding the interplay of immune cells, LAM cells, adjuvant immunotherapies, and loss of TSC expression could lead to new treatment targets/strategies for LAM and other diseases for which adjuvant immunotherapies is used.

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MDBR, LAM Million Dollar Bike Ride MDBR, LAM Million Dollar Bike Ride

Identify genetic regulatory circuitry driving the development of rapamycin tolerance

Yan Tang

Brigham and Women's Hospital

$73,491

Awardee: Yan Tang

Institution: Brigham and Women's Hospital

Grant Amount: $73,491

Funding Period: February 1, 2022 - January 31, 2023

Summary:

Rapamycin (and its analogues, rapalogs) are the only effective treatment for TSC-associated diseases, including lymphangioleiomyomatosis (LAM). However, rapalogs can only stabilize lung function in LAM, but lung function continues to decline upon treatment cessation. It’s of paramount importance to understand the mechanisms of why and how LAM cells can survive rapamycin treatment and regrow after treatment cessation. Our single cell RNA-seq analysis of five LAM and six AML (angiomyolipoma, kidney manifestation of TSC) samples identified a subset population of LAM/AML cells with elevated stemness and dormancy programs, two typical features of drug tolerant/resistant tumor persister cells. These cells exhibited stabilized tumor cell phenotypes upon rapamycin treatment, including maintaining high expression of many TSC marker genes, suggesting a rapamycin tolerance mechanism. To identify drivers of development of rapamycin tolerance in a heterogeneous population, we have adopted a high-complex barcoding lineage tracing system that enables simultaneous assessing of each cell’s origin/lineage and transcriptomic/epigenomic profiles at single cell level. This novel approach will enable us to identify lineage-specific drivers for the development of rapamycin tolerance.

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MDBR, LAM Million Dollar Bike Ride MDBR, LAM Million Dollar Bike Ride

Role of CTHRC1 in the Pathogenesis and Therapy of LAM

Elizabeth Henske

BWH

$70,769

Awardee: Elizabeth Henske

Institution: BWH

Award Amount: $70,769

Funding Period: February 1, 2021 - January 31, 2022

Summary:

This project is focused on a protein, CTHRC1 (collagen triple-helix repeat containing 1), that has never before been studied in LAM.  CTHRC1 is a protein that is usually secreted by cells and can be detected in the blood.  In other diseases, CTHRC1 is linked to the rate of cellular growth, and in several types of cancer, a high level of CTHRC1 in the blood is associated with a poor clinical prognosis.  

 In a new line of investigation in our lab, Dr. Nico Alesi has discovered that levels of CTHRC1 are elevated in cellular models of LAM.  CTHRC1 is also increased in human angiomyolipomas and in LAM cells.   Interestingly, levels of CTHRC1 are not suppressed by Rapamycin.  In TSC2-deficient cells, inhibition of CTHRC1 decreases cell growth. 

 These data suggest that CTHRC1 is a newly recognized driver of LAM cell growth.  Because levels of CTHRC1 are not affected by the mTOR inhibitor Rapamycin, CTHRC1 could help to explain why LAM cells are not eliminated during therapy with mTOR inhibitors.  Identifying therapeutic strategies to eliminate LAM cells is a key goal of this work. 

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2017, LAM Million Dollar Bike Ride 2017, LAM Million Dollar Bike Ride

Targeting transcription in LAM

David Kwiatkowski

Brigham and Women's Hospital/Harvard

$50,060

Awardee: David Kwiatkowski

Institution: Brigham and Women's Hospital/Harvard

Award Amount: $50,060

Funding Period: January 1, 2018 - December 31, 2018

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