Exploring and Leveraging Therapeutic Vulnerabilities in Renal Tumors with TSC1/2 Loss
Abstract
Background: The MiT/TFE family of transcription factors includes four proteins, MITF, TFE3, TFEB, and TFEC, all of which control gene transcription. In normal cells, MiT/TFE activity is thought to be generally inhibited by mTORC1 signaling. However, we recently found that continuously active mTORC1 signaling due to TSC1 or TSC2 loss paradoxically results in increased MiT/TFE activity. This is particularly interesting because data from human tumors suggests that MiT/TFE transcription factors are drivers of kidney tumorigenesis. Genomic alterations leading to continuous expression of TFE3, TFEB or MITF, or folliculin (FLCN) loss (which results in MiT/TFE activation) are well-known drivers of non-clear cell kidney cancers and PEComas (the tumor family that includes angiomyolipoma). Intriguingly, these same tumor types may both also be driven by TSC1/2 loss, and MiT/TFE and TSC1/2 alterations do not occur together, suggesting that they have similar effects and the tumors only require one or the other alteration – but not both – to grow. Hypothesis: We hypothesize that increased MiT/TFE activity is a previously undiscovered driver of growth in tumors with TSC1 or TSC2 loss. In addition, increased MiT/TFE activity in kidney tumors with TSC1 or TSC2 loss may create previously undiscovered therapeutic vulnerabilities, allowing us to develop novel treatments for these tumors. In particular, MiT/TFE activity was identified as the key mediator of sensitivity to inhibitors of an enzyme called PIKfyve. Genetic loss or pharmacologic inhibition of PIKfyve disrupts vesicle fusion and trafficking within the cells, leading to cell death that is most prominent in cells with high MiT/TFE activity. Importantly, several structurally overlapping small molecule inhibitors of PIKfyve exist. Among these, Apilimod can be taken orally; it was found to be safe in humans in a clinical trial for B-cell lymphoma (NCT02594384), and it is being tested in phase 2 trials for COVID-19 (NCT04446377). Specific Aims and Study Design: We propose to further dissect the molecular mechanism by which continuous mTORC1 signaling unexpectedly drives MiT/TFE activity and to test whether MiT/TFE activity creates previously unknown therapeutic vulnerabilities to PIKfyve inhibitors in the setting of TSC1 or TSC2 loss. This work will directly address the TSCRP Focus Area of eradicating tumors associated with TSC, including gaining a deeper mechanistic understanding of TSC signaling pathways. In the first aim, we will genetically manipulate cells lines to better understand the mechanism by which MiT/TFE activity is surprisingly high in cells with TSC2 loss. In the second aim, we will test PIKfyve inhibitors in preclinical models where we implant kidney cancer cells with TSC2 loss in mice or in transgenic mouse models of tuberous sclerosis. It is our hope that these studies may form the basis for future clinical trials of PIKfyve inhibitors in tuberous sclerosis. Innovation: We are the first to find that TSC1 or TSC2 loss results in continuous activation of MiT/TFE factors and to propose that these transcription factors may represent key drivers of renal tumorigenesis in tuberous sclerosis. Here, we will rewrite the classic model of MiT/TFE regulation by mTORC1, adding key mechanistic details to elucidate TSC signaling pathways. Impact: Though mTOR inhibitors have been utilized in TSC1- or TSC2-deficient renal tumors, these inhibitors are largely cytostatic and identifying additional therapeutic targets for human tumors with TSC1 or TSC2 loss is an area of unmet clinical need. Here, we have identified MiT/TFE transcription factors as potential drivers of tumorigenesis in TSC, and we will test whether MiT/TFE activation creates a novel therapeutic vulnerability to PIKfyve inhibition in this disease, potentially creating additional therapies for tuberous sclerosis-related renal tumors.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210264
Entities
People
- Tamara L Lotan
Organizations
- Johns Hopkins University
- United States Army