Paraskevi Giannakakou   Professor of Pharmacology in Medicine

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Dr. Paraskevi Giannakakou’s laboratory focuses on the cellular events that depend on the microtubule cytoskeleton, and on gaining a deeper understanding of the mechanism of action of clinically used microtubule targeting drugs (MTDs) in order to develop more effective and individualized therapies. Dr. Giannakakou’s laboratory uses functional cellular and molecular biology assays coupled with highresolution microscopy and live-cell imaging to gain new information on the spatial and temporal regulation of microtubule-cytoskeleton dynamics and its effects on cancer-cell survival. The clinical success of taxanes, and other microtubule inhibitors, together with their broad spectrum of antitumor activity, argue that tubulin represents the single best target identified in clinical oncology. However, today, 15 years following the FDA approval of Taxol® for clinical oncology, there is still no understanding of the molecular basis of clinical response to Taxol treatment. Dr. Giannakakou believes that important, heretofore unrecognized, determinant underlying taxane sensitivity is the involvement of the microtubule cytoskeleton in intracellular trafficking and signaling. As such, her laboratory has identified new roles for the microtubule cytoskeleton in the transport and activation of important cancer transcription factors such as the tumor suppressor p53, the hypoxia-inducible factor 1α, and most recently the androgen receptor in prostate cancer. Dr. Giannakakou’s laboratory has previously shown that MTDs exert their antiangiogenic effects through significant down-regulation of HIF-1alpha protein levels and transcriptional activity. More recently, her laboratory has demonstrated that the androgen receptor, a major driver of prostate cancer that remains active even after androgen-deprivation therapy, traffics on microtubule tracks for its translocation from the cytoplasm to the nucleus where it activates target genes such as PSA. Her team has also showed that MTDs, by disrupting the microtubule cytoskeleton, sequester the androgen receptor within the cytoplasm, therefore inhibiting its subsequent transcriptional activation. These results provide a rationale for why the taxanes represent the sole class of chemotherapy agents that improves survival of metastatic prostate cancer patients. However, despite their clinical success, not every patient responds to MTD-based chemotherapy and the development of clinical drug resistance makes patients, previously sensitive to chemotherapy, insensitive. Thus, a better understanding of the molecular basis of clinical drug resistance to taxanes and other widely used MTDs is imperative in order to prolong patient survival. One of the major impediments to understanding MTD drug resistance has been the lack of tumor tissue for molecular analyses. To overcome this, new technologies have been developed to capture and analyze circulating tumor cells (CTCs) from the peripheral blood of patients, which provides a readily accessible source of tumor material. Dr. Giannakakou is collaborating with Dr. Brian Kirby from the Department of Engineering at Cornell University and Drs. David Nanus and Linda Vahdat from the Division of Hematology/Oncology at Weill Cornell to develop microfluidic devices that specifically capture CTCs from metastatic prostate or breast cancer patients. The ultimate goal is to utilize these devices to capture and molecularly analyze tumor derived CTCs using a simple, non-invasive blood draw to determine the best treatment for each patient based on the molecular make-up of their tumor cells. Ultimately, Dr. Giannakakou seeks to identify new molecular targets that affect or are affected by microtubule dynamics and can be used to develop better targeted therapies.


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  • Paraskevi Giannakakou

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