Jennifer Isaacs, Ph.D.
Co-Director, Graduate Program
Member, Developmental Cancer Therapeutics Program
1997 Ph.D., University of North Carolina Chapel Hill
Role of cancer secreted extracellular Hsp90 (eHsp90) in cell migration and metastasis, and in promoting tumor-associated reactive stroma
Key Words: HIF, Hsp90, hypoxia, signal transduction, kinase, angiogenesis, migration, renal cancer, glioblastoma, prostate
How can you predict whether a cancer drug will be effective? In many cases, it is a guessing game. However, the more we learn about how a drug works - what molecular proteins are targeted and which cancers depend on those proteins for survival - the more accurately we can predict drug efficacy in specific cancers. Due to factors such as genetic instability and redundancy in signaling pathways, cancers often develop resistance to drugs that specifically target one protein and one pathway. Our lab studies a class of drugs that target a specific protein, the chaperone Heat Shock Protein 90 (Hsp90). Unlike other many molecular targeting drugs, the inhibition of Hsp90 affects the cellular protein folding machinery and interferes with a multitude of signaling pathways required for cancer survival and progression. Hsp90 inhibitors are already being assessed in a variety of clinical trials and we believe that they will be widely used in cancer therapy in the near future.
What does protein folding have to do with cancer? Cellular proteins must be properly folded prior to becoming active and Hsp90 facilitates many of these folding reactions. Cancer cells are unique in that their transformation and survival are driven by overexpressed or mutated signaling proteins, a majority of which are dependent upon Hsp90 for their activity. This dependence upon Hsp90 is the Achilles' heel of many cancers, thus creating a therapeutic window of opportunity. When Hsp90 function is pharmacologically inhibited, these dependent proteins (known as Hsp90 clients) become misfolded and inactive, and are subsequently degraded via the proteasomal pathway (Fig 1). Cancers are highly susceptible to Hsp90 inhibition because a majority of their signaling pathways are dependent upon Hsp90. Hsp90 inhibitors simultaneously target multiple oncogenic signaling pathways, thus amplifying their anti-cancer effects and minimizing the chances of drug resistance.
Our long-term goal is to better understand Hsp90-dependent tumor progression and to ultimately optimize the use and potency of Hsp90 inhibitors in the clinic (Fig 2). We undertake a multi-faced approach, employing molecular biology, biochemistry, and relevant animal models to analyze whether Hsp90 inhibitors are successfully targeting specific pathways unique to that cancer. We investigate the tumor-promoting roles of Hsp90 in various invasive cancers, such as prostate, renal, and glioblastoma. In particular, we focus on how Hsp90 impacts upon two fundamental aspects of cancer progression: angiogenic processes and cell migration. For survival, almost all cancers activate signaling pathways allowing adaptation to tumor hypoxia (low oxygen), which results in increased angiogenesis. Similarly, almost all cancers are invasive and have higher rates of cell migration. Hsp90 inhibitors are known to negatively impact upon both of these processes, although the molecular events involved are not well-defined. We focus on the interplay between Hsp90 and key molecular targets involved in these fundamental processes. Additionally, we are seeking novel Hsp90 targets to expand the repertoire of cancers likely to be treated by Hsp90 inhibition. The three main projects underway in the lab are described.
1. DeFee MR, Qin Z, Dai L, Isaacs JS, Parsons CH. Role of Hsp90 in viral pathogenesis. American Journal of Cancer Research. 2011. In Press.
2. Gopal U, Bohonowych JE, Lema-Tome C, Liu A., Garrett-Mayer E, Wang B, Isaacs, JS. A novel extracellular Hsp90 mediated co-receptor function for LRP1 regulates EphA2 dependent glioblastoma cell invasion. PLOS One. 2011 6(3):e17649
3. DeFee MR, Qin Z, Dai L, Toole BP, Isaacs JS*, Parsons CH* (*co-corresponding author). Extracellular Hsp90 facilitates KSHV-dependent NF-κB activation during de novo infection. American Journal of Cancer Research. 2011 1(5):687-700.
4. J. E. Bohonowych, U. Gopal, and J. S. Isaacs. Hsp90 as a Gatekeeper of Tumor Angiogenesis: Clinical Promise and Potential Pitfalls. J. Oncology. 2010, Volume 2010, Article ID 412985
5. Qin Z, Defee M, Isaacs JS, Parsons C. Extracellular Hsp90 serves as a co-factor for MAPK activation and latent viral gene expression during de novo infection by KSHV. Virology. 2010 May 5. [Epub ahead of print] PubMed PMID:20451233.
6. Annamalai B, Liu X, Gopal U, Isaacs JS. Hsp90 is an essential regulator of EphA2 receptor stability and signaling: implications for cancer cell migration and metastasis. Mol Cancer Res. 2009 Jul;7(7):1021-32. Epub 2009 Jun 30. PubMed PMID: 19567782.