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Several years ago, Dr. Chiosis partnered with Dr. Melnick toexamine the effectiveness of PU-H71 in treating breast cancer and lymphomas , and they have previously reported that the drug has dramaticantitumor effects without being toxic to animals. As a result ofthe drug's success in fighting these two aggressive types ofcancer, the research team received approval from the NationalCancer Institute to carry out clinical trials. Patients arecurrently being recruited for the first trial, which will test thedrug's safety in treating a variety of tumor types, and subsequentclinical trials are being planned for patients with lymphomas,breast cancer, chemotherapy-resistant leukemia and other specific types of cancer. In their new study Dr. Chiosis, Dr. Melnick, and collaboratorsdemonstrated that because PU-H71 binds to tumor-Hsp90, andtumor-Hsp90 binds to proteins that are required for tumor survival,it is possible to use PU-H71 as a method to "fish out" entirenetworks of abnormal proteins in tumor cells in an unbiasedfashion, which has not been possible up until now. Importantly,many or even most of the genes encoding proteins that maintaintumor cell survival are not mutated in tumors. Hence geneticscreening would not be able to detect these networks, Dr. Melnicksays. "The value of this method is that it's the first time you cango and probe the functional proteome, or the whole set of proteinsthat are important to maintaining the tumor." This strategy opensup new avenues for understanding in greater detail the molecularbasis of cancer and identifying novel drug targets. For example, in chronic myeloid leukemia cells, the PU-H71 drugpreferentially binds to the Hsp90 complex containing Bcr-Abl, anabnormal protein that is overactive in these cells, rather than toHsp90 associated with the normal protein Abl. Similar findings wereobserved in other tumor types, with PU-H71-Hsp90 complexesprotecting only the tumor-associated proteins. The researchers then used PU-H71 and proteomic analyses to identifyall of the abnormal proteins bound to Hsp90 in chronic myeloidleukemia cells and built networks of these proteins usingbioinformatics analyses. They found that these proteins are part ofsignaling pathways involved in cell death, growth and division.Bcr-Abl is known to use many of these pathways to propagateabnormal signaling in this type of cancer cell. The researchersexperimentally confirmed that proteins from these pathways arecrucial for cancer cell growth, division and survival, suggestingthat their approach can be used to accurately identifyBcr-Abl-related protein networks. Moreover, the same experimentsidentified many proteins not previously known to drive chronicmyeloid leukemia cells. One example of such a protein was CARM1, aregulator of gene expression, which the investigators showedmaintains survival of these tumor cells. Importantly, this PU-H71 cancer proteome method can also be used toidentify networks of abnormal proteins in the cells from individualpatients, paving the way to personalized therapies that targetmultiple pathways. "No two tumors are exactly alike, and we don'treally know what is driving cancer in one patient versus theother," the researchers say. "If you can use this method toidentify in a given individual the factors that are maintainingthat patient's particular cancer, then you could develop targeteddrugs that hit these specific factors -- in effect, designingpersonalized therapy for individual patients." Based on these findings, Dr. Melnick and Dr. Chiosis recentlyreceived a multi-investigator collaborative grant from the NationalCancer Institute to use this new PU-H71 proteome method to identifythe proteins that maintain the survival of lymphoma cells. Thisfunding is an example of how collaboration between investigatorsand institutions can synergistically accelerate the pace ofbiomedical research. Study collaborators include Kamalika Moulick, James Ahn, AnnaRodina, Erica Gomes DaGama, Eloisi Caldas-Lopes, Fabiana Perna, LyVu, Xinyang Zhao, Danuta Zatorska, Tony Taldone, Mary Alpaugh,Stephen Nimer, Peter Smith-Jones, Nagavarakishore Pillarsetty,Thomas Ku, Jason Lewis, Steven Larson, Ross Levine and HediyeErdjument-Bromage of Memorial Sloan-Kettering Cancer Center in NewYork City; Hongliang Zong, Leandro Cerchietti, Katerina Hatzi,Steven Gross and Monica Guzman of Weill Cornell Medical College;and Kristin Beebe and Len Neckers of the National Cancer Institutein Bethesda, Md. This work was supported in part by the National Cancer Institute,Leukemia and Lymphoma Society, the Breast Cancer Research Fund, theSPORE Pilot Award and Research and Therapeutics Program in ProstateCancer, the Hirshberg Foundation for Pancreatic Cancer Research,the Byrne Fund and the V Foundation for Cancer Research. Additional References Citations. 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