Cancer

J. Li, C. Yen, D. Liaw, K. Podsypanina, S. Bose, S.I. Wang, J. Puc, C. Miliaresis, L. Rodgers, R. McCombie, S.H. Bigner, B.C. Giovanella, M. Ittman, B. Tycko, H. Hibshoosh, M.W. Wigler, R. Parsons, "PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer," Science, 275:1943-7, 1997. (Cited in more than 270 papers since publication)Comments by Ramon Parsons , professor of pathology and medicine, Columbia University Cancer Center, New YorkP.A. Steck, M.A. Pershouse, S.A. Jasser, W.K.A. Yung, H. Lin, A.H. Ligon, L.A. Langford, M.L. Baumgard, T. Hattier, T. Davis, C. Frye, R. Hu, B. Swedlund, D.H.F. Teng, S.V. Tavtigian, "Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers," Nature Genetics, 15:356-62, 1997. (Cited in more than 235 papers since publication)Comments by Peter A. Steck, department of neuro-oncology, M.D. Anderson Cancer Center at the University of Texas Southwestern in Houston, and Sean V. Tavtigian, Director of Cancer Research, Myriad Genetics Inc., Salt Lake CityPeter A. SteckTwo groups starting at different points reached the same destination: identification of a tumor suppressor gene whose inactivation may signal malignant progression in breast, prostate, and brain cancers. Both groups began their search on chromosome 10, because large allelic losses there had been implicated years before.1,2 But those losses had never been narrowed to a specific region of the chromosome. Peter Steck and colleagues at the M.D. Anderson Cancer Center began by examining cell lines of glioblastoma, a malignant brain cancer. "We started the project by using somatic cell hybrids and reinserting chromosome 10, more or less as proof of principle to show that there was a tumor suppressor gene on chromosome 10." The reintroduced chromosome restored a normal phenotype, confirming chromosome 10's tumor suppressor role. So the team turned to allelic deletions and homozygous deletions to home in on a specific gene. "Our break came from identifying homozygous deletions in four glial cell lines," Steck recalls.Since the M.D. Anderson lab lacked sequencing firepower, the group turned to Myriad Genetics. While the two sides hammered out an intellectual property agreement, a team led by Ramon Parsons had taken the same approach, but in breast cancer cell lines. A paper on Cowden's disease aided their hunt.3 "We said, 'Maybe this is real, because often there is an inherited syndrome associated with a tumor suppressor gene,'" Parsons recalls.Ramon ParsonsUnaware of the other effort, the Columbia group teamed with scientists at Cold Spring Harbor lab, who provided expertise in the genomic technique of representational difference analysis. Meanwhile, M.D. Anderson and Myriad finally inked an intellectual property agreement. Myriad assembled the gene's sequence within a week. Then, in accordance with Securities and Exchange Commission guidelines, the company announced in a press release that it had helped identify a new brain cancer gene. "Oh no, it has to be our gene," Parsons remembers thinking, upon learning of the release. Both groups began to screen other tumor types to see how broadly the gene was mutated or deleted. "Once you know you're in a place that could be fertile, you want to check as many areas as possible," Parsons recalls, adding that seeing the mutation spring up in several cell lines of several tumor types was "stunning." The two groups published virtually identical results--but gave the gene a different name--within a week of each other. Sean V. Tavtigian suspects the two publications gave the findings both credibility and visibility. He also suspects that the frequency of mutation to MMAC1/PTEN in cancers--frequent, but slightly less so than mutations to the p16/Rb pathway or p53 pathway--also created more interest for the findings. Knockout experiments following the gene's discovery have since demonstrated that the gene is developmentally important and confirmed that it affects a variety of cancers.4,5,6 However, its role varies from cancer to cancer. In inherited diseases, such as Cowden's, the mutation tends to be early. In prostate, breast, melanoma, melingioma, bladder, and brain cancers, it occurs later, meaning that other mutations may trigger cancer; but loss of MMAC1/PTEN may help the cancer invade neighboring cells, Tavtigian suspects. In those cancers, the gene's mutation means a poorer prognosis. Endometrial cancer is an exception. A MMAC1/PTEN mutation in that disease occurs earlier and indicates relatively easy treatment.MMAC1/PTEN's prevalence may have caught some attention, but Parsons and Steck suspect that its products' complicated biochemistry may account for some as well. In hindsight, mutations affecting the chromosome 10 gene's phosphatase activity seem an ideal way to drive tumor progression, Parsons reflects. "It's probably the first tumor suppressor gene that has an enzymatic function or activity that would fit into the model system of what we thought a tumor suppressor should do," Steck comments. "Of course, it had to send us a curveball by being a lipid phosphatase." That curveball has made characterizing the pathway more difficult than discovering it, the three scientists agree. "Both groups looked at the gene and said, 'It's either a tyrosine phosphatase or a dual-function phosphatase,'" Tavtigian recalls. "But subsequent experiments have shown that that was too tight of an inference. Not only can it dephosphorylate at tyrosine and a little bit at serine and threonine residues, but it can also dephosphorylate phosphatidylinositol.""Phosphatidylinositol phosphate metabolism plays roles in cell metabolism, growth, survival, and adhesion," Tavtigian notes. However, those downstream events remain complex. One in vitro experiment used Akt/protein kinase B, a gene whose antiapoptotic function is regulated by phosphatidylinositol-3,4,5-triphosphate, to rescue cells from PTEN-dependent death. The study illustrated that PTEN suppresses tumor growth by regulating phosphatidylinositol 3'-kinase signaling.7 "But phosphatidylinositol kinase may not even be the whole story because MMAC1/PTEN probably has bona fide protein substrates as well," Tavtigian comments. "It's a murky business," agrees Parsons. "All these pathways talk with each other. So one has to be very careful to not be sucked into thinking everything talks with everything. There have got to be areas that are more strongly defined than others, pathways that are more strongly regulated by PTEN than others."The tumor suppressor gene's upstream events remain equally elusive, Parsons notes. "What regulates PTEN? This thing is such a potent tumor suppressor--it can't be always on. I just can't imagine that something that regulates so many other things cannot be regulated itself. Is it regulated at the level of localization? Is it regulated at the level of enzymatic activity? Or is it regulated at the level of half-life?"Tavtigian says that tumor suppressor genes themselves do not often provide good small-molecule antitumor targets: "Usually, the goal is to first understand the biochemical pathway in which the tumor suppressor functions and then to identify an oncogene-like protein with an inhibitable function that plays a role within that pathway. While phosphatidylinositol kinase plays such a role, it was already a target for drug development before MMAC1 was found and before it shed more light on that pathway. So if there is an important antitumor drug that is going to come out of efforts to inhibit phosphatidylinositol kinase, that probably will happen independently of the discovery of MMAC1." Instead, Myriad, with Canji Inc. of San Diego and Schering-Plough of Madison, N.J., is attempting to restore the tumor suppressor function through gene therapy. The collaborators have developed an adenoviral construct and have completed as-yet-unpublished preclinical work, Tavtigian reports. They initially focused on glioblastoma but are now expanding their studies to prostate cancer.Gene therapy will likely remain a distant goal, since technical problems still must be resolved,8 Steck predicts. However, he suspects that the gene's identification could have a more immediate clinical impact. Since the gene's mutation indicates that the tumor will likely be more malignant, the mutation's early detection in some cancers could aid in what treatment an oncologist should administer. "If you have a marker that may be related to progression in the primary tumor, then the alteration of this marker would suggest that this tumor needs to be treated very aggressively," Steck remarks. "Alternatively, you don't want to treat someone very aggressively if they don't need it."D. Fults et al., "Allelotype of human malignant astrocytoma," Cancer Research, 50:5784-9, 1990.B.K. Rahseed et al., "Loss of heterozygosity for 10q loci in human gliomas," Genes, Chromosomes and Cancer, 5:75-82, 1992.M.R. Nelen et al., "Localization of the gene for Cowden disease to 10q22-23," Nature Genetics, 13:114-6, 1996.A. Di Cristofano et al., "PTEN is essential for embryonic development and tumour suppression," Nature Genetics, 19:348-55, August 1998.A. Suzuki et al., "High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice," Current Biology, 8:1169-78, October 1998.G.P. Robertson et al., "In vitro loss of heterozygosity targets the PTEN/MMAC 1 gene in melanoma," Proceedings of the National Academy of Sciences, 95:9418-23, Aug. 4, 1998.S. Ramaswamy et al., "Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway," PNAS, 96:2110-15, March 2, 1999.P. Smaglik, "Gene therapy: the next generation," The Scientist, 12[10]:4, May 11, 1998.

Cancer

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