- Lauren E. Ball, Ph.D.
- Joe B. Blumer, Ph.D.
- Warren Davis Jr., Ph.D.
- Scott Eblen, Ph.D.
- Perry V. Halushka, M.D., Ph.D.
- John D. Hildebrandt, Ph.D.
- Jennifer S. Isaacs, Ph.D.
- Daniel R. Knapp, Ph.D.
- David T. Kurtz, Ph.D.
- Stephen M. Lanier, Ph.D.
- Carola A. Neumann, M.D.
- John E. Oatis, Ph.D.
- Steven A. Rosenzweig, Ph.D.
- Kevin L. Schey, Ph.D.
- Kenneth D. Tew, Ph.D., D.Sc.
- Thomas Walle, Ph.D.
- Michael J. Wargovich, Ph.D.
- Jerry G. Webb, Ph.D.
Jennifer Isaacs, Ph.D.Assistant Professor
Cell and Molecular Pharmacology
Hollings Cancer CenterPh.D., University of North Carolina Chapel Hill, 1997
isaacsj@musc.edu
Tel: 843-792-8393
Fax: 843-792-3200Link to Isaacs Lab Page
Targeting the Hsp90 chaperone as a potent anticancer strategy
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.
Selected Peer-Reviewed Publications
Annamalai B., Liu X., and Isaacs J.S. Hsp90 inhibitors destabilize EphA2 and impair receptor signaling: Implications for Hsp90 in supporting cell motility. Cancer Research, submitted.
Isaacs J.S., Jung Y-.J., Mole D.R., Lee S., Torres-Cabala C., Merino M., Trepel J., Zbar B., Toro J., Ratcliffe P.J., Linehan M., and Neckers L.M. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability. Cancer Cell 8:143-153, 2005.
Isaacs J.S., Jung Y.-J., and Neckers L.M. ARNT promotes oxygen-independent stabilization of hypoxia inducible factor-1 alpha by modulating an Hsp90-dependent regulatory pathway. J. Biol. Chem. 279:16128-16135, 2004.
Mimnaugh E. G., Xu W., Vos M., Yuan X., Isaacs J.S., Bisht K.S., Gius D., and Neckers L.M. Simultaneous inhibition of Hsp90 and the proteasome promotes ubiquitination, causes endoplasmic reticulum-derived cytosolic vacuolization, and enhances antitumor activity. Mol. Cancer Therapeutics 3:551-566, 2004.
Bisht K.S., Bradbury C.M., Mattson D., Kaushal A., Sowers A., Markovina S., Markovina S., Ortiz K.L., Siek L.K., Isaacs J.S., Brechbiel M.W., Mitchell J.B., Neckers L.M., and Gius D. Geldanamycin and 17-AAG potentiate the in vitro and in vivo radiation response of cervical tumor cells via heat shock protein 90-mediated intracellular signaling and cytotoxicity. Cancer Res. 63:8984-8995, 2003.
Isaacs J.S., Jung Y.-J., Minmaugh E.G., Martinez A., Cuttitta F., and Neckers L.M. (2002) Hsp90 regulates a VHL-independent HIF-1 alpha degradative pathway. J. Biol. Chem. 277:29936-29944, 2002.
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