Prostate Cancer Research
Young Investigator Award Recipients 2012 - Matthew Galsky, MD
The 2012 Mortimer Sackler – PCF Young Investigator Award
Novel small molecule modulators of FOXO1 localization in prostate cancer: antitumor activity, preclinical pharmacology, and pharmacodynamic marker development
The FOXO (Forkhead transcription factors, Class O) proteins belong to a family of proteins called transcription factors that regulate a variety of critical cellular functions. Dysregulation of transcription factors, in particular the FOXO proteins, has been associated with several different types of cancers.
The protein FOXO1 regulates cellular growth and survival pathways in normal cells. To effect its function, FOXO1 has to move from its location outside the nucleus (the cellular compartment that harbors the genome (DNA)) to inside the nucleus. Prostate cancer (PCa) cells, however, redirect the cellular localization of FOXO1 and sequester it outside of the nucleus, in its inactive form. Scientific approaches to relocalize FOXO1 to the nucleus represent a novel strategy for the treatment of prostate cancer, especially treatment resistant PCa.
A group of chemical compounds called the tricyclic neuroleptics have previously been shown to inhibit the transport of FOXO1 proteins from the nucleus. Tricyclic neuroleptics have been FDA approved to treat psychiatric conditions. Certain properties of this class of compounds make their use in the oncology setting very difficult. However, Dr. Matthew Galsky and his team have ‘reverse engineered’ these parent drugs, generating a novel set of compounds that decouple the potent neurological side effects from the anticancer (FOXO1 relocalizing) property.
Under this PCF-funded study, Dr. Galsky will explore the anticancer effects and mechanism of action of these novel compounds in preclinical prostate cancer models. He will also study circulating tumor cells from castration-resistant prostate cancer (CRPC) patients to identify suitable pharmacodynamic markers that can efficiently report the localization of FOXO1 in patient tumors. Dr. Galsky’s research will set the stage for early phase clinical trials of these experimental medications for the treatment of advanced prostate cancer.
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