Despite unprecedented gains in the basic understanding of cancer genes, only a few moleculartherapies have become standard of care in thirty years. This may reflect the extraordinary molecularheterogeneity of human tumors, but also a relatively narrow path to cancer drug discovery, which typicallyfocuses on individual 'drugable' targets in isolation. Conversely, agents capable of disabling multiple essentialnetworks of tumor maintenance, i.e. pathway inhibitors, may offer broader therapeutic opportunities. Oneattractive candidate for this approach is the molecular chaperone Heat Shock Protein-90 (Hsp90), which,together with its related molecules, orchestrates pivotal cancer networks of cell proliferation, survival andadaptation. Recently, we identified Shepherdin, a novel peptidomimetic inhibitor of Hsp90. Compared to otherHsp90 antagonists currently in the clinic, Shepherdin exhibits superior anticancer activity in vitro and in vivo,efficacy against heterogeneous tumor cell types regardless of their genetic makeup, and no toxicity for normaltissues. New experimental evidence has now uncovered a complex Shepherdin pathway, underlying thisunique anticancer activity. We found that Shepherdin acts on mitochondria, inducing sudden organellecollapse and cell death. At a molecular level, this is due to the inhibition of a pool of Hsp90 chaperonespresent in mitochondria of tumor cells, and orchestrating a novel pathway of cell survival. Therefore, thehypothesis that Shepherdin is a novel 'pathway inhibitor' with a unique mechanism of anticanceractivity can be formulated, and will constitute the focus of the present resubmitted application. Experiments inthe first specific aim will characterize the dynamics of Shepherdin trafficking and import to tumor mitochondria,and dissect the molecular requirements for activation of organelle dysfunction. The second specific aim willelucidate the survival functions of a mitochondrial Hsp90 network in tumor cells, and map their interactions withthe molecular machinery of organelle homeostasis. The third specific aim will test the efficacy of Shepherdin inxenograft and transgenic models of drug-resistant tumors, metastasis, angiogenesis, and eradication of'cancer stem cells', in vivo. The approach combines mechanistic and late-preclinical studies designed toelucidate the Shepherdin pathway and its anticancer activity. The results will complement the clinicaldevelopment of Shepherdin now underway at the National Cancer Institute (NCI), Rapid Access to InterventionDevelopment (RAID) program, and will provide a requisite molecular foundation to direct the upcoming testingof this agent in humans.
New anticancer drugs that target fundamental mechanisms of tumor cell maintenance are urgently needed. The present application will characterize the anticancer activity of Shepherdin: a novel and potent inhibitor of the Heat Shock Protein-90 (Hsp90) chaperone network with a unique mechanism of action.
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