Siah1/2 Ubiquitin Ligases in ER Stress Signaling in Melanoma

Project Details

Description

Sun exposure is a key driver of skin cancer, including the most devastating form of the disease, melanoma. Young adults (16-25 years) are particularly susceptible to the harmful effects of the sun, highlighting the potential risks for our troops serving in Iraq, Afghanistan, and neighboring countries. As such, our proposal will be addressing one of the Peer Reviewed Cancer Research Program (PRCRP) Congressionally Directed Topic Areas -- melanoma and other skin cancers. Furthermore, we will seek to determine molecular mechanisms by which environmental influences associated with military exposures alter gene structure, stability, and express -- a PRCRP Military Relevance Focus Area.

My laboratory has worked for more than two decades to decipher the pathways underlying melanoma development and to identify how common gene mutations rewire regulatory pathways and promote tumor development. We have also identified new players in disease development and have discovered inhibitors that have potential as new therapeutic modalities. We propose here to focus our efforts on two pathways that we believe are most important for melanoma development and have not yet been studied in depth as possible therapeutic targets. These are termed the ER stress and hypoxia pathways. ER stress refers to the built-in mechanism by which the cell senses malfunction in protein production and folding, thereby assuring proper cellular homeostasis. Hypoxia refers to the cellular state in the presence of low oxygen levels (~1%-5%). The cellular responses to ER stress and hypoxia are particularly relevant for solid tumors that have reduced blood supply and thus grow under harsh conditions. Increasing evidence points to the importance of these two processes not only in melanoma development and metastasis, but also in their response to current therapies. We identified a molecule named Siah1/2 that regulates the cell response to both ER stress and hypoxia and showed that 25% of melanomas exhibit a unique gene expression signature regulated by Siah1/2, known as the Siah1/2-hypoxia-ER stress signature. We propose to determine the importance of the pathways for this select subset of melanomas using genetic and pharmacological approaches. One approach will be to test the effects on melanoma of an ER stress inhibitor and a naturally occurring molecule that inhibits Siah1/2 and reduces the hypoxia response. These inhibitors will be tested in cell culture and animal models to determine their potential as novel therapies to reduce and possibly prevent melanoma development and metastasis. Successful completion of the proposed studies is expected to provide the foundation for novel therapeutic modalities that could augment current treatments for a significant fraction of melanomas.

StatusActive
Effective start/end date1/01/13 → …

Funding

  • Congressionally Directed Medical Research Programs: $585,000.00

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