Updated february 05, 2008

Lyuba Varticovski, M.D.
Associate Scientist
Lung Cancer Stem Cell Core

Biography: Dr. Varticovski was born in Siberia, Russia, where she completed undergraduate and first year medical school. She received her MD degree from the U. of Valle, Cali, Colombia. After two-year research fellowship with Max Wintrobe and James Kushner at the U. of Utah and training in Internal Medicine at Albany Medical College, NY, she completed fellowship in Hematology and Oncology at the New England Medical Center in Boston, MA. She joined the laboratory of Lewis C. Cantley in 1985 where she shared in discovery and biochemistry of phosphatidylinositol 3-kinase (PI 3-Kinase). She subsequently studied the role of PI 3-kinase in protein-tyrosine kinase-mediated signal transduction in cell growth and vesicular trafficking while participating in Clinical Oncology at St. ElizabethÕs Medical Center, Boston, MA and Tufts Medical School where she rose to the rank of Associate Professor. Dr. Varticovski is Board-certified in Internal Medicine and Hematology and Board-eligible in Oncology. She is a member of the American Society for Hematology and American Association for Cancer Research. In 2003, she joined NCI as Staff Clinician and has an Adjunct appointment in the Laboratory of Human Carcinogenesis. Dr. Varticovski directs the Preclinical Models Strategy Team at the Center for Cancer Research and Molecular Targeting Unit in LHC, and participates in clinical trials at the Clinical Center for patients with drug-resistant tumors.

Research Program and Goals:

Molecular Targeting Unit
P53 activation in response to DNA damage is associated with an increase in its protein level and activation as a transcription factor. Downstream targets of p53 include a plethora of genes whose products trigger cell-cycle arrest, apoptosis and DNA repair. P53 mutations and deletions are common features of human cancer, and lead to inability to enter cell cycle arrest and to resistance to some chemotherapeutic agents. We are generating cell lines that are isogenic for p53, and other proteins which are central for cell cycle control to address systematically the role of p53 in inducing apoptosis in response to DNA damaging agents, such as gamma-irradiation or Doxorubicin. These cell lines will be labeled with Luciferase and Red Fluorescent Protein for monitoring tumor progression and response to therapies in vivo. We also use lymphoblastoid cell lines isogenic for p53 and bear wt (TK6), null (NH32) or mutant p53 (WTK1), to investigate the role of molecular targeted drugs in cell cycle arrest and apoptosis.

Lung Cancer
Pulmonary neuroendocrine tumors are a heterogeneous group of tumors which include Small Cell Lung Cancer (SCLC), Large Cell Neutoendocrine Lung Cancer (LCNEC), as well as Typical and Atypical Carcinoid tumors (TC and AC). These tumors vary dramatically in their malignant behavior. Their classification, based on histologic examination, is often difficult. Using cDNA microarray analysis, we identified two novel biomarkers, one indicative of good prognosis and the other correlates with poor survival. These markers are secreted proteins which can be detectable in the serum. We are developing a screening assay for these biomarkers. Use of specific biomarkers should facilitate diagnosis and further understanding of the biology of pulmonary neuroendocrine tumors. In collaboration with Cynthia Dunbar, NHLBI, and Ron McKay, NINDS, we are developing a strategy for isolation and characterization of cancer stem cells from patients with SCLC.

Preclinical Models Strategy Team at the Center for Cancer research, NCI
We developed a strategy of using transgenic mouse models for testing novel molecular targeted drugs. Orthotopically implanted tumors obtained from tumor-bearing transgenic mice are tested for response to conventional and molecular targeted therapies. This strategy provides systematic approach to test tumor progression, prevention and metastasis in response to therapy as well as validation of molecular pathways. We compare tumors transplanted into syngeneic mice with those transplanted into NOD/SCID mice to determine the contribution of immune responses to therapy.

1. Nunez N, Rosenberg J, Oh WJ, Perella C, Anver M, Pekins SN, Varticovski L, Hursting SD, and Vinson C. Accelerated Tumor Formation in a Fatless Mouse with Type 2 Diabetes and Inflammation. Cancer Res. 2006, 66: 5469-5476. .

2. Antony S, Agama KK, Miao Z-H, Hollingshead MG, Holbek SL, Wright MH, Varticovski L, Nagarayan M, Morell A, Cushman M, and Pommier Y. Bisindenoisoquinoline NSC 727357, a DNA intercalator and topoisomerase inhibitor with antitumor activity. Mol Pharm, 2006, 10:1124-1129. .

3. Robles AI, Wright MH, Gandhi B, Feis S, Hanigan CL, and Varticovski L. Schedule-dependent Synergy between the HSP90 inhibitor 17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG) and Doxorubicin restores apoptosis to p53-mutant lymphoma cells. Clin Cancer Res. 2006, 12; 6547-56. .

4. Varticovski L, Hollingshead MG, Robles AI, Carter JP, Borgel SP, Stotler H, Bonomi CA, Anver MR, Nunez N, Hursting S, Qiao W, Deng CX, Green JE, Hunter KW, Merlino G, Steeg PS, Wakefield L, and Barrett JC. Accelerated Preclinical Testing Using Transplanted Tumors from Genetically Engineered Mouse Breast Cancer Models. Clin Cancer Res. 2007, 13: 2168-77

5. Varticovski L, and Robles AI. Harnesing genetically engineered mouse models for drug development. Frontiers in Toxicology, Chemico-Biological Interactions. 2007, 171:159-164

6. Nunez N, Perkins S, Smith N, Berrigan D, Varticovski L, and Hursting SD. Obesity accelerates mouse mammary tumor growth in the absence of ovarian hormones. Nutr Cancer, 2007 (in press).

7. Pine S, Marshall B, and Varticovski L. Lung Cancer Stem Cells. Special Edition of Cancer Biomarkers. Stem Cells and Cancer. 2007, in press

8. Hursting SD., Nunez NP, Varticovski L, and Vinson C. The obesity-cancer link: lessons learned from a fatless mouse. Cancer Res. 2007, 67: 2391-3.

9. Antony S, Agama KK, Miao ZE-H, Hollingshead MG, Holbek SL, Wright MH, Varticovski L, Nagarajan M, Morell A, Cushman M, and Pommier, Y. Novel indenoisoquinolines NSC 725776 and NSC 724998 produce persistent topoisomerase I cleavage complexes and overcome multidrug resistance. Cancer Res. 2007, 67:10397-411

10. Wright MH, Robles AI, Herschkowitz JI, Hollingshead MG, Anver MR, Perou CM, and Varticovski L. Molecular analysis reveals heterogeneity of mouse mammary tumors conditionally mutant for Brca1. Mol Cancer, 2008, in press.