Targeting Heat Shock Factor 1 (HSF1) in NF1-Associated Neoplasms
Abstract
Neurofibromatosis 1 (NF1) is a disorder that causes tumors to grow in the nervous system and usually appears in childhood. It is one of the most common human cancer-disposition syndromes, afflicting approximately 1 in 3,500 births worldwide. The most common tumors in NF1 are neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). While neurofibromas are benign, they can undergo malignant progression to become MPNSTs. Despite the seriousness of NF1 and remarkable progress in our understanding of the disease, no effective chemotherapies are currently available for NF1-associated malignancies. Thus, there is a great need to identify novel therapeutic targets and to then test potential effective therapies against those targets in preclinical animal models. We and others have recently shown that heat shock factor 1 (HSF1), a protein widely known the "master regulator" of a ubiquitous stress response that protects cellular proteins from stress-induced damage, surprisingly also promotes tumor initiation and growth, by maintaining protein stability in cells under the stressful conditions of malignancy. More recently, we showed that HSF1 supports malignant growth of NF1-associated cancer cells, as loss of the Hsf1 gene in mice significantly suppressed MPNST development and promoted animal survival. In other recent studies, we showed that in addition to ensuring the quality of proteins, HSF1 sustains production of cellular proteins and lipids, two substances essential for fueling malignant growth. Based on our results above, we hypothesize that HSF1 potently promotes NF1-associated malignancy and, therefore, represents a particularly promising therapeutic target for NF1 disease. Importantly, in another recent study we showed that, in melanoma cells, HSF1 can be silenced and the ensuing protein damage augmented through combined inhibition of MEK and proteasomes. MEK is key molecule in a biological pathway that plays a pivotal role in NF1-associated tumor initiation, and proteasomes are molecules that play an important role in maintaining cellular health by helping to degrade proteins that are damaged and no longer needed. Excitingly, we showed that this new strategy provokes emergence of amyloids, a toxic form of protein aggregates, thereby potently impeding melanoma growth and metastasis in mice transplanted with human melanoma cells. Importantly, we showed that tumor cells are particularly susceptible to this strategy compared with their normal counterparts. In the proposed project, we will first validate whether HSF1 plays essential roles in suppressing amyloid formation and enhancing protein and lipid synthesis in human MPNST cells (Aim 1). We will then determine whether combined MEK and proteasome inhibition is effective in inhibiting growth of neurofibroma and MPNST tumors in well-established mouse models of NF1 (Aim 2). Our proposed research will directly help NF1 patients inflicted with neurofibromas and MPNSTs by providing them with a potentially effective chemotherapy. The critical preclinical evidence provided by our research will lay the foundation for initiating clinical trials on NF1 patients using the very same therapeutic strategy. Given that the Food and Drug Administration has approved the MEK and proteasome inhibitors proposed in our study for malignancies not associated with NF1, translation of our findings into clinical trials to benefit NF1 patients can be rapidly achieved in months compared to other new or experimental therapeutic agents. The success of our proposed research will not only open a new area for NF1 research, by highlighting a previously unrecognized role of NF1 in regulating cellular protein quality and amyloid production, but also stimulate discovery of new means to treat NF1 patients and broadly impact the health of military beneficiaries, by demonstrating the feasibility of provoking profound cancer proteomic instability.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610487
Entities
People
- Chengkai Dai
Organizations
- National Cancer Institute
- United States Army