Experimental Therapeutics of Cancer
To identify and validate novel targets, pathways, and therapies for selective tumor targeting; to establish biomarkers that can predict tumor response; and to test the efficacy of resulting potential medicines in clinical trials.
Program leaders and members interact extensively with the Cancer Center’s disease-oriented teams to focus specific therapeutics on select cancers, based on laboratory research indicating optimal targets and relevant biomarkers.
The program's members represent key oncology disciplines and comprise basic science investigators and clinical investigators from 15 departments or centers. It is also home to the Cancer Center’s Specialized Program of Research Excellence (SPORE) in lung cancer.
- Molecular therapeutic sensitizers
- Tumor microenvironment and protein therapy
- Imaging and drug delivery
- Cancer vulnerabilities
First awarded in 1996, the University of Texas SPORE in Lung Cancer — a collaborative effort with UT M.D. Anderson Cancer Center — leverages the talents and research of some of the world’s top lung cancer scientists, along with progress in genomics, to advance the dream of personalized medicine by moving research findings into the clinic and conveying clinical information back to the laboratory.
The UT SPORE, the largest thoracic oncology effort in the U.S., has discovered alterations between the normal-to-malignant tissue DNA of lung cancer patients that may yield new therapeutic avenues; elucidated differences between individuals that make some more susceptible to lung cancer or more likely to survive, or indicate greater risk of toxicities during treatment; described the role of cancer “stem cells” in lung cancer recurrence; and shed light on potential ways to block cancer growth, invasion, and metastasis in patients.
Selected citation: Augustyn, A. et al. ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers. Proc Natl Acad Sci USA 111, 14788-14793 (2014).
Foundational research by the laboratory of Dr. David A. Boothman on the anti-cancer effects of the natural substance beta-lapachone has led to two major, multidisciplinary projects testing the substance against pancreatic ductal adenocarcinoma (PDA) and non-small cell lung cancer (NSCLC). The first project is pursuing laboratory studies and a phase IB clinical trial involving standard-of-care chemotherapy plus a formulation of beta-lapachone known as ARQ761 (from the biotechnology companies NQ Oncology and ArQule). The project’s lab studies include noninvasive, real-time metabolic imaging of pancreatic cancer in animals using hyperpolarized glucose or pyruvate to better understand ARQ761’s impact on tumor metabolism. The effort also includes examination of biomarkers associated with pancreatic tumors that might predict response to ARQ761 or reflect the treatment’s impact. The other project is exploring the efficacy of combining ARQ761 with PARP (poly[ADP-ribose] polymerase) inhibitors to treat PDA and NSCLC, as well as all other NQO1 over-expressed malignancies. The combination has previously proved effective against pancreatic, breast, and non-small cell lung cancer cells in vitro (see figure), as well as non-small cell lung cancer in mouse xenografts.
Selected citation: Chakrabarti, G. et al. Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by beta-lapachone. Cancer Metabolism 3, 12 (2015).
Groundbreaking work by Dr. Robert Timmerman and colleagues, spanning two decades, has demonstrated the benefits of SABR (also known as stereotactic body radiotherapy, or SBRT) in treating a number of tumor types. In SABR, highly focused beams of radiation are fired from numerous angles, converging to deliver a high therapeutic dose to a tumor target. Among the team’s noteworthy successes are using SABR to treat early-stage lung tumors in frail patients, and in limited metastatic lung cancer. The therapy is also proving promising in treating “radioresistant” tumors such as renal cancer and melanoma, and for inferior vena cava tumor thrombus, an often deadly complication of kidney cancer.
- Physicians pioneer the use of stereotactic body radiation for deadly kidney cancer complication (2015)
- Stereotactic body radiation therapy plus chemotherapy improves survival among stage 4 lung cancer patients (2014)
- Precision radiation therapy may improve survival rates of patients with inoperable early-stage lung cancer (2010)
To Get Involved
ET Program meetings are held quarterly, with Laboratory Correlate meetings for biomarker development every second Thursday of each month. The program seeks additional physicians and scientists with broad understanding of molecular events leading to human cancers for further collaborative research projects.
Contact Dr. Boothman for more details about the program, meetings, and more. firstname.lastname@example.org
- Bey, E.A. et al. Catalase abrogates beta-lapachone-induced PARP1 hyperactivation-directed programmed necrosis in NQO1-positive breast cancers. Mol Cancer Ther 12, 2110-2120 (2013).
- Chang, K.H. et al. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell 154, 1074-1084 (2013).
- Chang, K.H. et al. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. Proc Natl Acad Sci USA 108, 13728-13733 (2011).
- Chung, J.S. et al. The DC-HIL/syndecan-4 pathway regulates autoimmune responses through myeloid-derived suppressor cells. J Immunol 192, 2576-2584 (2014).
- Frankel, A.E. et al. Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients. Blood 124, 385-92 (2014).
- Gerber, D.E. et al. Phase I safety and pharmacokinetic study of bavituximab, a chimeric phosphatidylserine-targeting monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res 17, 6888-6896 (2011).
- Gil del Alcazar, C.R. et al. Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma. Clin Cancer Res 20, 1235-1248 (2014).
- Huang, X. et al. An NQO1 substrate with potent antitumor activity that selectively kills by PARP1-induced programmed necrosis. Cancer Res 72, 3038-3047 (2012).
- Iyengar, P. et al. Phase II trial of stereotactic body radiation therapy combined with erlotinib for patients with limited but progressive metastatic non-small-cell lung cancer. J Clin Oncol 32, 3824-3830 (2014).
- Jeong, Y. et al. Nuclear receptor expression defines a set of prognostic biomarkers for lung cancer. PLoS Med 7, e1000378 (2010).
- Li, L.S. et al. Modulating endogenous NQO1 levels identifies key regulatory mechanisms of action of beta-lapachone for pancreatic cancer therapy. Clin Cancer Res 17, 275-285 (2011).
- Li, X. et al. Aiolos promotes anchorage independence by silencing p66Shc transcription in cancer cells. Cancer Cell 25, 575-589 (2014).
- Ma, X. et al. Ultra-pH-sensitive nanoprobe library with broad pH tunability and fluorescence emissions. J Am Chem Soc 136, 11085-11092 (2014).
- Shao, C. et al. Essential role of aldehyde dehydrogenase 1A3 for the maintenance of non-small cell lung cancer stem cells is associated with the STAT3 pathway. Clin Cancer Res 20, 4154-4166 (2014).
- Singel, S.M. et al. A targeted RNAi screen of the breast cancer genome identifies KIF14 and TLN1 as genes that modulate docetaxel chemosensitivity in triple-negative breast cancer. Clin Cancer Res 19, 2061-2070 (2013).
- Tang, H. et al. A 12-gene set predicts survival benefits from adjuvant chemotherapy in non-small cell lung cancer patients. Clin Cancer Res 19, 1577-1586 (2013).
- Tomimatsu, N. et al. Phosphorylation of EXO1 by CDKs 1 and 2 regulates DNA end resection and repair pathway choice. Nat Commun 5, 3561 (2014).
- Wang, L. et al. A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth. Nat Commun 4, 2035 (2013).
- Wang, Y. et al. A nanoparticle-based strategy for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals. Nat Mater 13, 204-212 (2014).
- Yun, E.J. et al. DAB2IP regulates cancer stem cell phenotypes through modulating stem cell factor receptor and ZEB1. Oncogene 34, 2741-2752 (2015).