|Department Affiliations||Oncology, Pathology|
|Rank||Professor, Co-Director of Cancer Biology|
|SOM Address||Room 144 Cancer Research Building II|
Alessandro Leal 2015
It is now widely accepted that cancer is a disease mediated by alterations in specific genes. The last decade has witnessed a dramatic increase in our understanding of the genomic characteristics of human cancer. In my laboratory we began these studies through a systematic analysis of gene families in human cancer, identifying PIK3CA as one of the most commonly mutated cancer genes. We extended these approaches with colleagues at JHU and other institutions to perform the first analyses of cancer genomes in breast, colorectal, pancreas, brain and other cancers. These efforts revealed the genomic landscape of human cancers, identifying new therapeutic targets such as mutant IDH genes in brain cancers and dysregulation of chromatin remodeling as a major mechanism of tumorigenesis. These analyses were spurred through novel genomic approaches we developed, including SAGE, Digital Karyotyping, and high throughput sequencing methods.
Despite the progress that has been made, much remains to be discovered in understanding the dynamic changes that occur in cancer genomes during therapy, resistance and progression, and using this information for early detection and intervention. My group currently focuses on identifying genetic alterations in cancer affecting sensitivity and resistance to targeted therapies, and connecting such changes to key clinical characteristics and novel therapeutic approaches. We have recently developed methods that allow non-invasive characterization of cancer, including the PARE method that provided the first whole genome analysis of tumor DNA in the circulation of cancer patients. These analyses provide a window into real-time genomic analyses of cancer patients and provide new avenues for personalized diagnostic and therapeutic intervention.
- Wang TL, Maierhofer C, Speicher MR, Lengauer C, Vogelstein B, Kinzler KW, Velculescu VE. Digital karyotyping. PNAS 99:16156-16161, 2002
- Bardelli A, Parsons DW, Silliman N, Ptak J, Szabo S, Saha S, Markowitz S, Willson JK, Parmigiani G, Kinzler KW, Vogelstein B, Velculescu VE. Mutational analysis of the tyrosine kinome. Science 300:949, 2003
- Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE. High Frequency of Mutations of the PIK3CA Gene in Human Cancers. Science, 304(5670): 554, 2004.
- Samuels Y, Diaz LA Jr, Schmidt-Kittler O, Cummins JM, Delong L, Cheong I, Rago C, Huso DL, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 2005;7:561-73.
- Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber T, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The Consensus Coding Sequences of Human Breast and Colorectal Cancers. Science. 314(5797):268-74, 2006.
- Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. An integrated genomic analysis of human glioblastoma multiforme. Science. 321(5897):1807-12, 2008.
- Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B,Velculescu VE, Kinzler KW. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 321(5897):1801-6, 2008.
- Leary RJ, Kinde I, Diehl F, Schmidt K, Clouser C, Duncan C, Antipova A, Lee C, McKernan K, de la Vega, F, Kinzler KW, Vogelstein B, Diaz LA Jr, Velculescu VE. Development of Personalized Tumor Biomarkers Using Massively Parallel Sequencing. Science TM, 2: 20ra14, 2010.
- Parsons DW, Li M, Zhang X, Jones S, Leary RJ, Lin JC, Boca SM, Carter H, Samayoa J, Bettegowda C, Gallia GL, Jallo GI, Binder ZA, Nikolsky Y, Hartigan J, Smith DR, Gerhard DS, Fults DW, VandenBerg S, Berger MS, Marie SK, Shinjo SM, Clara C, Phillips PC, Minturn JE, Biegel JA, Judkins AR, Resnick AC, Storm PB, Curran T, He Y, Rasheed BA, Friedman HS, Keir ST, McLendon R, Northcott PA, Taylor MD, Burger PC, Riggins GJ, Karchin R, Parmigiani G, Bigner DD, Yan H, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The genetic landscape of the childhood cancer medulloblastoma. Science 331: 435-439, 2010.
- Sausen M, Leary RJ, Jones S, Wu J, Reynolds CP, Liu X, Blackford A, Parmigiani G, Diaz LA Jr, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE, Hogarty MD. Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma. Nature Genetics. 45: 12-17, 2012.
- Leary RJ, Sausen M, Kinde I, Papadopoulos N, Carpten JD, Craig D, O’Shaughnessy J, Kinzler KW, Parmigiani G, Vogelstein B, Diaz LA Jr, Velculescu VE. Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. Science TM. 4:162ra154, 2012.
- Haber DA, Velculescu VE. Blood-Based Analyses of Cancer: Circulating Tumor Cells and Circulating Tumor DNA. Cancer Discovery. 2014 Jun;4(6):650-61.