Robert C. Bast Jr., M.D.
VP, Translational Research
Translational Research, VP Ofc
University of Texas MD Anderson Cancer Center
1515 Holcombe Blvd, Unit 1439, FCT8.5066
Houston, TX 77030
United States of America
(713) 792-7743 office
(713) 404-2765 pager
Our laboratory is addressing three of the critical problems in the management of ovarian cancer, including late detection, drug resistance and tumor dormancy, while attempting to understand the heterogeneity of ovarian cancers at a cellular and molecular level. Projects in which trainees would be welcome include:
- Function of imprinted tumor suppressor genes that are downregulated in ovarian cancer. Over the last decade, we have identified several imprinted tumor suppressor genes whose expression is decreased or lost in ovarian cancer. Among these, we have best characterized ARHI (DIRAS3) which encodes a 26kD GTPase with 50% homology to Ras, but with an opposite function that can be attributed to a 34 amino acid N terminal extension. ARHI is downregaulated in 60% of ovarian cancers associated with decreased disease free survival. Expression from the single functioning allele can be inhibited by LOH, hypermethylation or transcriptional regulation by E2F1 or E2F4 in different cancers. Re-expression of ARHI inhibits proliferation and motility while inducing autophagy and tumor dormancy. Current studies, funded by an R01, concern mechanisms underlying ARHI-induced autophagy and requirements for survival of dormant ovarian cancer cells. For these studies, we have developed the first inducible model for tumor dormancy in ovarian cancer.
- Individualized enhancement of primary sensitivity to paclitaxel in different ovarian cancers. Through a high throughput kinome siRNA screen, my laboratory has identified more than 30 kinases that regulate paclitaxel sensitivity in ovarian cancer cell lines by modulating centrosome function (SIK2), paclitaxel retention (CDK5) or microtubule stability (ILK, FER). Both fundamental studies of mechanism and translational studies of siRNA therapy in combination with paclitaxel are being pursued.
- Identification of biomarkers and strategies for early detection of ovarian cancer. Having developed the CA125 serum assay for monitoring ovarian cancer, we have tested some 115 potential biomarkers to identify four biomarker panels for early stage disease. Currently, we are testing several such panels for their ability to discriminate women with pre-clinical and early stage disease from healthy women. Supported by an Ovarian SPORE, a multi-year screening trial is being conducted in 3000 apparently healthy postmenopausal women to evaluate the specificity and positive predictive value of ultrasound in a small fraction of women with rising levels of biomarkers from year to year. To date, the trial has prompted 8 operations to discover 5 cases of ovarian cancer, all in early stage, consistent with a positive predictive value of 37%, i.e. only 3 operations per case of ovarian cancer detected. To facilitate these studies, we are collaborating with investigators at Rice to place assays on nanobiochips for testing at point of service. Recent work with protein expression arrays has identified a panel of 115 auto antibodies which promise to detect pre-clinical disease in a larger fraction of women.
- Bast RC Jr, Feeney M, Lazarus H, Nadler LM, Colvin RB, Knapp RC. Reactivity of a monoclonal antibody with human ovarian carcinoma. J Clin Invest 68:1331-1337, 1981. PMID: 7028788.
- Bast RC Jr, Klug TL, St John E, Jenison E, Niloff JM, Lazarus H, Berkowitz RS, Leavitt T, Griffiths CT, Parker L, Zurawski VR Jr, Knapp RC. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med 309:883-887, 1983. PMID: 6310399.
- Feig LA, Bast RC Jr, Knapp RC, Cooper GM. Somatic activation of rasK gene in a human ovarian carcinoma. Science 223:698-701, 1984. PMID: 6695178.
- Jacobs IJ, Kohler MF, Wiseman RW, Marks JR, Whitaker R, Kerns BA, Humphrey P, Berchuck A, Ponder BA, Bast RC Jr. Clonal origin of epithelial ovarian carcinoma: analysis by loss of heterozygosity, p53 mutation, and X-chromosome inactivation. J Natl Cancer Inst 84:1793-1798, 1992. PMID: 1433368.
- Lidor YJ, O'Briant KC, Xu FJ, Hamilton TC, Ozols RF, Bast RC Jr. Alkylating agents and immunotoxins exert synergistic cytotoxic activity against ovarian cancer cells. Mechanism of action. J Clin Invest 92:2440-2447, 1993. PMID: 8227359.
- Yu Y, Xu F, Peng H, Fang X, Zhao S, Li Y, Cuevas B, Kuo WL, Gray JW, Siciliano M, Mills GB, Bast RC Jr. NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas. Proc Natl Acad Sci U S A 96:214-219, 1999. PMID: 9874798.
- Lu KH, Patterson AP, Wang L, Marquez RT, Atkinson EN, Baggerly KA, Ramoth LR, Rosen DG, Liu J, Hellstrom I, Smith D, Hartmann L, Fishman D, Berchuck A, Schmandt R, Whitaker R, Gershenson DM, Mills GB, Bast RC Jr. Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis. Clin Cancer Res 10:3291-3300, 2004. PMID: 15161682.
- Le X-F, Bedrosian I, Maw W, Murray M, Lu Z, Keyomarsi K, Lee M-H, Zhao J, Bast RC Jr. Anti-HER2 antibody trastuzumab inhibits CDK2-mediated NPAT and Histone H4 expression via the PI3K pathway. Cell Cycle 5(15):1654-1661, 2006. PMID: 16861913.
- Wen XF, Yang G, Mao W, Thornton A, Liu J, Bast RC Jr, Le XF. HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy. Oncogene 25:6986-6996, 2006. PMID: 16715132.
- Le XF, Arachchige-Don AS, Mao W, Horne MC, Bast RC. Roles of human epidermal growth factor receptor 2, c-jun NH2-terminal kinase, phosphoinositide 3-kinase, and p70 S6 kinase pathways in regulation of cyclin G2 expression in human breast cancer cells. Mol Cancer Ther 6:2843-57, 11/2007. PMID: 18025271.
- Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast RC, American Society of Clinical Oncology. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25(33):5287-312, 2007. PMID: 17954709.
- Lu Z, Luo RZ, Lu Y, Zhang X, Yu Q, Khare S, Kondo S, Kondo Y, Yu Y, Mills GB, Liao WS, Bast RC. The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. J Clin Invest 118(12):3917-29, 12/2008. e-Pub 11/2008. PMCID: PMC2582930.
- Le XF, Mao W, Lu C, Thornton A, Heymach JV, Sood AK, Bast RC. Specific blockade of VEGF and HER2 pathways results in greater growth inhibition of breast cancer xenografts that overexpress HER2. Cell Cycle 7(23):3747-58, 2008. PMID: 19029832.
- Bast RC Jr, Hennessy B, Mills GB. The Biology of Ovarian Cancer: New Opportunities for Translation. Nat Rev Cancer 9(6):415-28, 6/2009. NIHMSID: NIHMS140471.
- Kurzrock R, Pilat S, Bartolazzi M, Sanders D, Hood J, Tucker S, Webster K, Mallamaci M, Strand S, Babcock E, Bast RC Jr. Project zero delay: A process for accelerating the activation of cancer clinical trials. J Clin Oncol 27(26):4433-40, 9/2009. e-Pub 8/2009. PMID: 19652061.
- Bast RC Jr, Mills GB. Personalizing therapy for ovarian cancer: BRCAness and beyond. J Clin Oncol. 2010 Aug 1;28(22):3545-8. Epub 2010 Jun 14. PMID: 20547987
- Bast RC Jr, Markman M. Chemotherapy: A new standard combination for recurrent ovarian cancer? Nat Rev Clin Oncol. 2010 Oct;7(10):559-60. PMID: 20877420
- Ahmed AA, Lu Z, Jennings NB, Etemadmoghadam D, Capalbo L, Jacamo RO, Barbosa-Morais N, Le XF; Australian Ovarian Cancer Study Group, Vivas-Mejia P, Lopez-Berestein G, Grandjean G, Bartholomeusz G, Liao W, Andreeff M, Bowtell D, Glover DM, Sood AK, Bast RC Jr. SIK2 is a centrosome kinase required for bipolar mitotic spindle formation that provides a potential target for therapy in ovarian cancer. Cancer Cell. 2010 Aug 9;18(2):109-21.PMID: 20708153