In his keynote speech last week at "Genomics and Cancer," the 2006 General Motors Cancer Research Foundation's Annual Scientific Conference on the NIH campus, Dr. Eric Lander, director of the Broad Institute, noted some of the significant advances that have resulted from the mapping of the human genome, referring to it as "biology's first great community-building infrastructure."
The conference featured some of the world's leading scientists in the field of genomics and cancer research, including Dr. Napoleone Ferrara of Genentech, Inc., who was the Research Award winner for his discovery and cloning of VEGF and his role in developing bevacizumab, and Dr. Victor Velculescu of Johns Hopkins University, who described the genetic alterations in PIK3CA, one of the most highly mutated oncogenes in human cancer.
The completed genome sequence, Dr. Lander stressed, has "lit the fires of imagination" among many researchers, resulting in tools that have fundamentally altered the way in which they work.
He outlined six major goals that must be reached to fulfill the promise of genomics. Among these, he argued, is the need to fully describe, at the molecular and cellular level, all functional elements encoded in the genome and all human genetic variation. By mapping the cancer genome, through projects such as The Cancer Genome Atlas, he added, researchers will continue to break cancer down into distinct diseases and subtypes, and map out that part of the human genome relevant to each.
He also highlighted the need to develop genetic signatures of cellular response, singling out the "connectivity map" being proposed and developed by Dr. Todd Golub and colleagues that "allows researchers to essentially 'Google'" a cell signature they are working on, and get possible matches for drugs and pathway mechanisms they might never have considered. Video of the conference is available at http://videocast.nih.gov/PastEvents.asp?c=1.
Two experimental drugs are expanding treatment options for patients with chronic myeloid leukemia (CML) who cannot tolerate imatinib (Gleevec), the primary treatment. The drugs, dasatinib (Sprycel) and nilotinib, were designed to overcome imatinib resistance, and results from clinical trials suggest that the medicines can be used to treat cases of CML when imatinib fails or is not tolerated.
Dasatinib is expected to be approved in the coming weeks by the FDA based on the recent recommendation of an advisory panel, which reviewed results from early-stage clinical trials. The complete results from a phase I dasatinib trial, led by Dr. Charles Sawyers of UCLA's Jonsson Comprehensive Cancer Center, appear in the June 15 New England Journal of Medicine along with results from a phase I trial involving nilotinib.
The two trials provide "immediate hope for patients" whose CML cells no longer respond to imatinib, says Dr. Brian Druker of Oregon Health & Science University Cancer Institute, who led the development of imatinib, in an accompanying editorial. The results, he says, demonstrate the clinical value of understanding the molecular changes that result in imatinib resistance because this knowledge led to the development of the new drugs at an "impressively rapid" pace.
Dasatinib, manufactured by Bristol-Meyers Squibb, targets nearly all the genetic mutations that cause resistance to imatinib. To create nilotinib, chemists at Novartis modified imatinib so that the drug binds more tightly to its target, the ABL protein. Both drugs, which are pills, are more potent inhibitors of the ABL protein than is imatinib; the drugs inhibited all tested imatinib-resistant mutations except one, called T315I.
Dr. Hagop Kantarjian of the University of Texas M. D. Anderson Cancer Center, who led the nilotinib trial, says that imatinib should remain the standard of care for now because most CML patients respond to imatinib and 93 percent of them are doing well after 5 years of treatment. Phase II studies of the drug are ongoing. Like dasatinib, nilotinib has side effects, and patients should have their heart function monitored, the researchers said.
The editorial suggests that the drugs might be useful at earlier stages of CML, and clinical trials are being planned. "The good news for patients with CML is that the long-term prospects for control of the disease are excellent," writes Dr. Druker.
Melanoma, the most deadly of skin cancers, is resistant to radiation therapy and to many chemotherapeutic drugs, making adjuvant treatment difficult. Currently, the cellular mechanisms behind the multidrug resistance of melanoma are not well understood. A new study from researchers in NCI's CCR, published online June 15 in the Proceedings of the National Academy of Sciences, has identified an important role in resistance to chemotherapy for melanosomes - the organelles within pigment-producing skin cells that protect them from the toxic byproducts of pigment synthesis.
The investigators, led by Dr. Michael Gottesman, administered fluorescently labeled cisplatin to both melanoma cells and control cells from a non-melanoma skin cancer line. The labeled drug was found in the cytoplasm of melanoma cells but not in the nuclei, where it would exert its cytotoxic effect. In contrast, the drug was found in both the cytoplasm and nuclei of control cells. In melanoma cells, cisplatin found near the plasma membrane colocalized with a melanosome marker, suggesting that it was trapped inside the organelles.
Further in vitro experiments indicated that treating melanoma cells with cisplatin caused an increased production of the pigment melanin and a corresponding increase in the number of melanosomes. The melanoma cells then exported the melanosomes containing the cytotoxic drug out of the nucleus through a mechanism called melanosome transfer.
"The components that regulate the dynamics of melanosomes (i.e., melanosome numbers, melanosomal trapping, and export) are likely involved in drug resistance," wrote the authors. "In principle, the components of the entire melanogenic pathway could be molecular targets for the therapy of melanomas."
A study released in May by the Agency for Healthcare Research and Quality (AHRQ) finds there is no clinically significant difference in the medical effectiveness of epoetin and darbepoetin, the two drugs commonly used for managing anemia in cancer patients who are undergoing chemotherapy or radiation treatment. The drugs showed no clinically significant difference in improving hemoglobin concentration and reducing the need for transfusion, according to AHRQ's latest comparative effectiveness review.
The review found that both drugs reduce the need for transfusion. But, it did not find evidence that they improved survival when added to cancer treatment. The report also found that many other significant questions remain unanswered about the safety and best use of both drugs.
The report, Comparative Effectiveness of Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment, was produced by AHRQ's Effective Health Care Program, the first federal program designed to compare alternative treatments for significant health conditions and make the findings public.
Anemia occurs in 13 to 78 percent of patients with solid tumors and 30 to 40 percent of lymphoma patients. Blood transfusion can restore a low hemoglobin concentration, and adverse transfusion-related events are uncommon.
Drugs that mimic the actions of erythropoietin can be used to correct anemia and reduce the need for transfusions. Two drugs are commercially available in the United States - epoetin alfa (Epogen and Procrit) and darbepoetin alfa (Aranesp), a newer, longer acting drug that requires fewer injections.
The review compared the drugs' effectiveness and safety. In particular, it sought to determine whether darbepoetin differed from epoetin in its ability to achieve key treatment goals. The evidence showed that the drugs did not differ significantly in reducing transfusion need; it was uncertain whether either drug had a meaningful effect in improving quality of life.