At the Forefront <strong>of</strong> Discovery TMResearcher Discovers New Method to Kill Cancer CellsTargeted cancer therapies are designed to attack thefeatures <strong>of</strong> tumor cells that are distinct from featuresfound in normal cells. <strong>The</strong>se therapies generally targetsignaling pathways that are deregulated and causeuncontrolled cell growth. Wei Du, PhD, associatepr<strong>of</strong>essor in the Ben May Department for CancerResearch, is an expert in mechanisms that controlcell proliferation. “Single-target drugs are <strong>of</strong>ten notsuccessful in treating cancers because cancer cellscan adapt over time and become resistant to therapy,”explained Dr. Du. “We need to develop more effectivetherapies by targetingmultiple properties that areunique to cancer cells.”In addition to deregulatedsignaling pathways,cancer cells <strong>of</strong>tenacquire inactivation <strong>of</strong>tumor suppressors, such as the retinoblastomaprotein (Rb). Investigators, however, have hadlittle success in developing cancer therapies thattarget cells with inactivated tumor suppressors.“Researchers have not found an approach to restorethe function <strong>of</strong> tumor suppressors in cancer cells,”according to Dr. Du. “We also don’t know howto kill just tumors with loss <strong>of</strong> tumor suppressorfunction because we don’t know what to target.”This study is unique because weare targeting the loss <strong>of</strong> tumorsuppressor function in cancer cells.–Wei Du, PhDTo tackle this problem, Dr. Du conducted a geneticscreen in fruit flies to search for genes that can be usedto target cancers showing loss <strong>of</strong> Rb function. <strong>The</strong>Rb pathway is highly conserved between the fruit flyand mammalian systems. He searched for mutationsthat caused death in cells with loss <strong>of</strong> Rb function butnot normal cells. His screen led to TSC2, a gene thatregulates cell growth. “This study is unique becausewe are targeting the loss <strong>of</strong> tumor suppressor functionin cancer cells,” said Dr. Du. “Our study suggests thatTSC2, which can be used to specifically kill cancerswith inactive Rb, is potentiallya new therapeutic target.”<strong>The</strong>se research findings werepublished in the May 18,<strong>2010</strong>, issue <strong>of</strong> Cancer Cell.Dr. Du is now conductingstudies to understandhow TSC2 inactivation leads to cell death. One <strong>of</strong>his main goals is to develop inhibitors that disruptTSC2 function. “<strong>The</strong>se inhibitors can potentiallybe complemented with inhibitors that targetderegulated signaling pathways. By combining thesetwo types <strong>of</strong> inhibitors, we are more likely to preventdrug resistance in cancer cells,” explained Dr. Du.“This research will open new avenues for findingtherapeutic targets for the treatment <strong>of</strong> cancer.”Wei Du, PhDThree Important Protein Modifications IdentifiedAs researchers worked to complete the HumanGenome Project, it was widely thought that havinga map <strong>of</strong> the human genome sequence woulddramatically accelerate the process <strong>of</strong> identifyingdrug targets and developing diagnostic tools. Thathasn’t happened—largely because <strong>of</strong> the fact that eventhough a person’s genes are almost identical throughouttheir body, the genes that code protein sequencesare interpreted differently in different parts <strong>of</strong> thebody and under diverse physiological conditions.If we want to understand disease,then it is important for us to havea complete understanding <strong>of</strong> acell’s regulatory mechanisms.–Yingming Zhao, PhDOne newer area <strong>of</strong> research is proteomics or the study<strong>of</strong> the proteins—particularly protein structures andfunctions—in an organism, tissue, or cell. YingmingZhao, PhD, an associate pr<strong>of</strong>essor in the Ben MayDepartment for Cancer Research, and his teamfocus their work on the chemical modifications <strong>of</strong>proteins, known as post-translation modifications(PTMs), which are associated with a majority <strong>of</strong>diseases and almost all cellular pathways.Dr. Zhao said that about 300 types <strong>of</strong> PTMs are knownto exist opening the possibility for more than a millionprotein structures—all with potentially differentfunctions. <strong>The</strong> PTM pr<strong>of</strong>iles can be dynamicallychanged in response to environmental, genetic, andpsychological factors. “To date, a huge knowledge gapstill exists about the role <strong>of</strong> PTMs in cellular pathways,and how they regulate physiological conditionsand diseases, including cancer. And this is part <strong>of</strong> amajor knowledge gap in biomedicine,” he explained.Some extensively studied PTMs, such as proteinphosphorylation and lysine acetylation, are dysregulatedin diseases and are popular targets for drug design.For example, Janet Rowley, MD, pioneered studies inthe 1970s that led to the foundation for Gleevec®, ablockbuster leukemia drug that targets a protein kinasemodulating a protein phosphorylation pathway.Dr. Zhao and his team have recently discovered threenovel PTMs—lysine propionylation, lysine butyrylation,and lysine succinylation. Details about the first twoPTMs have already been published, while informationabout lysine succinylation will soon be published.<strong>The</strong> significance <strong>of</strong> these discoveries is that the enzymesthat regulate PTMs can become targets <strong>of</strong> new drugtherapies, and proteins bearing these PTMs could bebiomarkers. “If we want to understand disease, then itis important for us to have a complete understanding <strong>of</strong>a cell’s regulatory mechanisms,” said Dr. Zhao. “<strong>The</strong>senew cellular pathways will provide an additional level<strong>of</strong> understanding about a cell’s regulatory network.”Although it may take years to have a goodunderstanding <strong>of</strong> these PTM pathways and their roles indiseases, Dr. Zhao said he believes his discoveries are animportant first step. “<strong>The</strong> history <strong>of</strong> biomedicine showsbasic research is intimately connected to translationalresearch—it is the foundation for the cures we haveYingming Zhao, PhDtoday, as demonstrated in the case <strong>of</strong> the drugsAvastin® and Herceptin®,” he said. “Many diseasesare caused by dysregulation <strong>of</strong> PTM pathways.That’s why it is essential to characterize the changesassociated with pathogenic processes for disease.”Dr. Zhao and colleagues in the Laboratory <strong>of</strong>Proteomics and Protein Modifications are alsoapplying new bioinformatics tools that they havedeveloped to gain a better understanding <strong>of</strong> PTMsand how they work alone, as well as in combinationwith other PTMs. One such tool is called PTMap, asequence alignment s<strong>of</strong>tware enabling identification<strong>of</strong> all the known PTMs and novel PTMs, aresearch area that has been largely overlooked.cancer.uchicago.edu 3