Understanding how a normal healthy cell turns into a cancerous one is our best bet yet for beating the disease. It will help better diagnose the cancer type, and enable the development of more effective, and less toxic therapies. But cells have evolved all sorts of sophisticated ways to become cancerous, and identifying the molecules involved and how they function in each type of cancer is a major undertaking. New research published in the Proceedings of the National Academy of Sciences has provided a major boost for the prostate cancer field by uncovering an unprecedented mechanism for developing cancer.
Doctors and scientists at the University of New Mexico Cancer Center are among the authors of the research paper. The multidisciplinary team identified two new key players in the development of prostate cancer, which is the second most common malignancy in men and can become highly aggressive. The two players, PCA3 and PRUNE2, unusually come from the same location in the genome. They also physically interact and regulate each other’s activity. “It’s a completely new regulatory system,” says Renata Pasqualini, PhD, senior co-author of the paper. Pasqualini and her husband, Wadih Arap, MD, PhD, are prostate cancer experts and led the research team. “We have shown in animals that if we lower PCA3 [in the prostate cells] the animals develop smaller tumors,” says Arap. “If we increase PRUNE2, they develop smaller tumors; indeed, it is the first time that a function for the FDA-approved, clinically-used PCA3 biomarker was discovered."
Dr. Webster K. Cavenee, the Director of the Ludwig Institute for Cancer Research and Distinguished Professor of Medicine at the University of California-San Diego, who is also a collaborator and senior co-author of the PNAS manuscript remarked that the work "essentially enables the first understanding of molecular mechanisms related to the PCA3/PRUNE2 axis in the development of human prostate cancer, which may well lead to more accurate diagnoses and more appropriate application of therapy in patients with this malignant tumor.” Emmanuel Dias-Neto, PhD, senior co-author of the paper and genomics expert at A.C. Camargo Cancer Center in São Paulo, Brazil agrees. “The definition of the PCA3 role in prostate cancer adds value to its importance as diagnostic marker but, more importantly, it opens up new therapeutic avenues,” notes Dias-Neto. “Now, not only can PCA3 be a target of an anti-prostate cancer drug, but also PRUNE2, P54 and ADAR1 can be valuable for the design of new therapeutic strategies.”
The work is still in its early stages, cautions Richard Lauer, MD, FACP. Lauer is among the authors and is an expert in cancers of the prostate, bladder and kidney. But the potential to help patients is there. “PRUNE2 may prevent the development of prostate cancer,” Lauer says. “PCA3 down regulates it so if that access can be manipulated, it may be important therapeutically.”
Wadih Arap, MD, PhD, is a Professor in and Chief of the Division of Hematology/Oncology in the University of New Mexico Department of Internal Medicine. He is the Victor and Ruby Hansen Surface Endowed Chair in Cancer Medicine and serves as Deputy Director of the UNM Cancer Center. Trained at the University of Sao Paulo Medical School in Brazil, Stanford University, Sanford-Burnham Institute, and Memorial Sloan-Kettering Cancer Center in New York, Dr. Arap is an international expert in prostate cancer. His research, for which he has received numerous awards, is focused on the development of new targeted cancer drugs, leading to over 100 patents and several “first in human” clinical trials. With his wife, Dr. Renata Pasqualini, he has developed five new biotechnology companies.
Richard Lauer, MD, FACP, is a Professor in the Division of Hematology/Oncology in the UNM Department of Internal Medicine at the UNM School of Medicine. He serves as Chief Medical Officer at the UNM Cancer Center and is the Maralyn S. Budke Endowed Professor in Cancer Care Delivery. Trained at New York Medical College and Indiana University, Dr. Lauer is an international expert in the treatment of genitourinary cancers and the delivery of high quality, integrated cancer care in academic settings, blending comprehensive cancer diagnosis and treatment with clinical research. He has served as principal investigator for several clinical trials, many for treatment of kidney cancers and some that he created and developed. As Chief Medical Officer of the UNM Cancer Center, Dr. Lauer is responsible for all clinical aspects of the UNM Cancer Center’s operations. Dr. Lauer has published several papers on kidney cancer and serves on the National Cancer Institute’s National Clinical Trials Network Renal Task Force.
Renata Pasqualini, PhD, is Professor and Chief of the Division of Molecular Medicine in the Department of Internal Medicine at the University of New Mexico School of Medicine. She is the Maralyn S. Budke Endowed Chair in Cancer Experimental Therapeutics and serves as Associate Director for Translational Research at the UNM Cancer Center. Trained in Biochemistry at the Ludwig Institute for Cancer Research, Harvard Medical School, and the Sanford-Burnham Institute, Dr. Pasqualini is an international expert in vascular biology, and cancer metastasis and angiogenesis. With Dr. Arap, she developed a novel system to identify tissue and organ-specific “molecular signatures” and has shown that these zip codes can be used to selectively deliver cancer drugs to specific organs and tumors. She has led the development of many new first-in-human clinical trials of new treatments and has developed five new biotechnology companies. Receiving many awards, she has been designated a “Top 400 Inventor” in the United States.
“PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3” was published in the June 15, 2015 online early edition of Proceedings of the National Academy of Sciences (www.pnas.org). Authors are: Ahmad Salameh, Alessandro K. Lee, Marina Cardó-Vila, Diana N. Nunes, Eleni Efstathiou, Fernanda I. Staquicini, Andrey S. Dobroff, Serena Marchiò, Nora M. Navone, Hitomi Hosoya, Richard C. Lauer, Sijin Wen, Carolina C. Salmeron, Anh Hoang, Irene Newsham, Leandro A. Lima, Dirce M. Carraro, Salvatore Oliviero, Mikhail G. Kolonin, Richard L. Sidman, Kim-Anh Do, Patricia Troncoso, Christopher J. Logothetis, Ricardo R. Brentani, George A. Calin, Webster K. Cavenee, Emmanuel Dias-Neto, Renata Pasqualini, and Wadih Arap.
This work was supported by National Institutes of Health Grants CA90270 (to R.P. and W.A.) and CA95616 (W.K.C.), Angel-Works, Gilson-Longenbaugh Foundation, Prostate Cancer Foundation (W.A. and R.P.), Fundação de Amparo à Pesquisa do Estado de São Paulo, and Associação Beneficente Alzira Denise Hertzog Da Silva (E.D-N.).
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