Despite unprecedented gains in the basic understanding of cancer genes, only a few molecular therapies have become standard of care in thirty years. This may reflect the extraordinary molecular heterogeneity of human tumors, but also a relatively narrow path to cancer drug discovery, which typically focuses on individual """"""""drugable"""""""" targets in isolation. Conversely, agents capable of disabling multiple essential networks of tumor maintenance, i.e. pathway inhibitors, may offer broader therapeutic opportunities. One attractive 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 and adaptation. Recently, we identified Shepherdin, a novel peptidomimetic inhibitor of Hsp90. Compared to other Hsp90 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 normal tissues. New experimental evidence has now uncovered a complex Shepherdin pathway, underlying this unique anticancer activity. We found that Shepherdin acts on mitochondria, inducing sudden organelle collapse and cell death. At a molecular level, this is due to the inhibition of a pool of Hsp90 chaperones present in mitochondria of tumor cells, and orchestrating a novel pathway of cell survival. Therefore, the hypothesis that Shepherdin is a novel """"""""pathway inhibitor"""""""" with a unique mechanism of anticancer activity can be formulated, and will constitute the focus of the present resubmitted application. Experiments in the 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 will elucidate the survival functions of a mitochondrial Hsp90 network in tumor cells, and map their interactions with the molecular machinery of organelle homeostasis. The third specific aim will test the efficacy of Shepherdin in xenograft 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 to elucidate the Shepherdin pathway and its anticancer activity. The results will complement the clinical development of Shepherdin now underway at the National Cancer Institute (NCI), Rapid Access to Intervention Development (RAID) program, and will provide a requisite molecular foundation to direct the upcoming testing of 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.
|Chae, Young Chan; Angelin, Alessia; Lisanti, Sofia et al. (2015) Corrigendum: Landscape of the mitochondrial Hsp90 metabolome in tumours. Nat Commun 6:7605|
|Chae, Young Chan; Angelin, Alessia; Lisanti, Sofia et al. (2013) Landscape of the mitochondrial Hsp90 metabolome in tumours. Nat Commun 4:2139|
|Vaira, Valentina; Faversani, Alice; Martin, Nina M et al. (2013) Regulation of lung cancer metastasis by Klf4-Numb-like signaling. Cancer Res 73:2695-705|
|Altieri, Dario C (2013) Hsp90 regulation of mitochondrial protein folding: from organelle integrity to cellular homeostasis. Cell Mol Life Sci 70:2463-72|
|Altieri, Dario C (2013) Targeting survivin in cancer. Cancer Lett 332:225-8|
|Tavecchio, Michele; Lisanti, Sofia; Lam, Aaron et al. (2013) Cyclophilin D extramitochondrial signaling controls cell cycle progression and chemokine-directed cell motility. J Biol Chem 288:5553-61|
|Caino, M Cecilia; Chae, Young Chan; Vaira, Valentina et al. (2013) Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells. J Clin Invest 123:2907-20|
|Altieri, Dario C; Stein, Gary S; Lian, Jane B et al. (2012) TRAP-1, the mitochondrial Hsp90. Biochim Biophys Acta 1823:767-73|
|Chae, Young Chan; Caino, M Cecilia; Lisanti, Sofia et al. (2012) Control of tumor bioenergetics and survival stress signaling by mitochondrial HSP90s. Cancer Cell 22:331-44|
|Vaira, V; Faversani, A; Dohi, T et al. (2012) miR-296 regulation of a cell polarity-cell plasticity module controls tumor progression. Oncogene 31:27-38|
Showing the most recent 10 out of 29 publications