James C. Cusack Jr., MD
The Tucker Gosnell Center for Gastrointestinal Cancers, Massachusetts General Hospital Cancer Center
Associate Professor of Surgery
Harvard Medical School
Overcoming Anti-Apoptotic Responses to Chemotherarpy and Irradiation
Our laboratory focuses on understanding the biological response of inducible chemotherapy therapy resistance. The ability to inhibit apoptosis appears to be a principal mechanism by which resistant cancer cells are protected from the DNA damaging effects of chemotherapy and radiation. We found that the inducible activation of the nuclear transcription factor NF-kB inhibits the apoptotic response to chemotherapy and irradiation. NF-kB, a key transcription factor involved in immune and inflammatory responses, and cancer cell growth, is regulated primarily through interactions with an inhibitor protein known as IkB. Stimuli that activate NF-kB typically induce the recently identified IkB kinase (IKK) to phosphorylate IkB on N-terminal serines, leading to ubiquitination and subsequent degradation of the inhibitor protein by the proteasome. Following IkB degradation, NF-kB translocates to the nucleus where it regulates genes involved in a variety of processes, including the suppression of apoptosis.
One effective strategy for the inhibition of NF-kB activation is facilitated by inhibition of proteasome function. Inhibition of the proteasome effectively blocks degradation of cellular proteins that have undergone ubiquitination, such as phosphorylated IkBa. We have shown that small molecule inhibitors of the proteasome such as bortezomib or Salinosporamide A inhibit chemotherapy-induced activation of NF-kB. In preclinical studies, inactivation of proteasome function blocked inducible NF-kB activation, and resulted in increased levels of apoptosis and a significant tumoricidal response to chemotherapy. Phase I clinical trials that explore the ability of this approach to augment chemosensitivity in patients with refractory malignancy have been completed and phase II studies are ongoing. Future studies will explore the role of newly developed small molecular compounds to selectively inhibit the chemotherapy-induced NF-kB activation by targeting the upstream mediators of this response mechanism and the downstream mediators of inducible chemotherapy resistance.
Currently we are evaluating the specific NF-kB dependent mechanisms that are responsible for promoting cancer cell survival and proliferation following the exposure of cancer cells to genotoxic stress that is induced by chemotherapy. One such downstream pathway involves the phosphorylation of heparin-binding EGF-like growth factor (HB-EGF), resulting in increased cellular growth and survival signaling. We have found that the NF-kB dependent anti-apoptotic response to chemotherapy is due in part to the regulatory effect of HB-EGF on E-cadherin expression. Ongoing studies are underway to evaluate small molecule inhibitors of these response mechanisms to determine the potential therapeutic benefit of selective molecular targeting of the HB-EGF pathway.
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