The Jimmy-NCSU V Cancer Therapeutic Program allows young researchers the opportunity to work on multiple facets of cancer research in a set of diverse labs, each investigating different approaches for developing cancer therapeutics.
Enhancing cancer drugs We have discovered molecules that increase the effects of anticancer drugs by several orders of magnitude. Our goal is to reduce the working concentrations of all anti-cancer drugs in order to mitigate serious side effects. We will develop and screen our new molecules with both novel and existing chemotherapeutics against a variety of cancer cell lines in order to define the optimum combination treatment. Initial screens show effects against breast, renal and colon cancer cell lines.
Cell death and tumor formation The life and death of cells must be balanced. Normal cells accommodate this balance by invoking programmed cell death pathways, referred to as apoptosis. In cancer cells, these pathways are defective and normal cell death does not occur, leading to tumor formation. In addition, faulty apoptosis causes tumor cells to be resistant to chemo/radiation therapies. If we could make apoptosis occur properly, we slow down tumor formation and overcome this resistance.
The protein caspase-3 controls apoptosis. If caspase-3 fails to function, cell death does not happen correctly. We also know that the protein calbindin-D28K binds to caspase-3 and stops it functioning. If we can stop calbindin-D28K from interfering with caspase-3, apoptosis would occur normally and the risk of cancer developing would be reduced. Consequently calbindin-D28K is a powerful target for anticancer drug development.
Protein kinases are a family of 518 human proteins which receive and transmit information within the cell, often from one kinase to another. The information flow within the network governs all aspects of cell biology, including cell growth, movement and survival. Not surprisingly, cancer very often re-wires kinase activity and connectivity to support its uncontrolled growth and metastasis. Indeed, protein kinases are the most commonly mutated protein family in human cancer. Protein kinases are also exceptionally ‘druggable’ and constitute the most tractable class of new therapeutic targets. Two significant challenges exist. First, we know a great deal about very few protein kinases. There is no doubt that targeting understudied kinases in cancer will benefit patients, but what kinases and for which patients? Second, several kinase inhibitors have proven immensely effective in certain cancers, however not all patients respond and for those that do respond, resistance inevitably emerges. We now know that cancer reprograms the kinase network to bypass chemotherapy. To tackle these challenges, we have developed a new technology that allows us to identify and quantify the activity of nearly all kinases in a single experiment. This allows us to comparatively study kinase activity in normal cells and in cancer cells, in chemotherapy-sensitive and resistant cancers, and in tumors before and after relapse. We hypothesize that the responsiveness of cancer to targeted therapy is determined by the baseline activity of specific kinases and the nature by which these activities adapt to therapeutic challenge. We will test this hypothesis in tumors of the lungs and head and neck. Together, our experiments may lead to the identification of specific kinase activities which: 1) predict cancer disease progression, 2) predict response to therapy, and 3) suggest new and rationally designed therapeutic strategies for patients with naïve and relapsed cancer.
