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
Specialized Program of Research Excellence (SPORE) in Lung Cancer. 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).
Beta-lapachone in pancreatic cancer. 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).
Stereotactic ablative radiotherapy (SABR). 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.
- Stereotactic radiation highly effective for kidney cancer (2017)
- 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)
To Get Involved
Experimental Therapeutics 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. Gerber for more details about the program, meetings, and more. email@example.com
Borromeo, M.D. et al. ASCL1 and NEUROD1 reveal heterogeneity in pulmonary neuroendocrine tumors and regulate distinct genetic programs. Cell Rep 16, 1259-72 (2016).
Burgess, S.C. et al. Limitations of detection of anaplerosis and pyruvate cycling from metabolism of [1-13C] acetate. Nat Med 21, 108-109 (2015).
Dalvi, M.P. et al. Taxane-platin-resistant lung cancers co-develop hypersensitivity to JumonjiC demethylase inhibitors. Cell Rep 19, 1669-1684 (2017).
DeNicola, G.M. et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat Genet 47, 1475-81 (2015).
Elkin, S.R. et al. A systematic analysis reveals heterogeneous changes in the endocytic activities of cancer cells. Cancer Res 75, 4640-50 (2015).
Gerber, D.E. et al. Phase 1 study of romidepsin plus erlotinib in advanced non-small cell lung cancer. Lung Cancer 90, 534-41 (2015).
Goodwin, J. et al. The distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition. Nat Commun 8, 15503 (2017).
Huang, X et al. Leveraging an NQO1 bioactivatable drug for tumor-selective use of poly(ADP-ribose) polymerase (PARP) inhibitors. Cancer Cell 30, 940–952 (2016).
Khan, S.A. et al. Prevalence of autoimmune disease among patients with lung cancer: implications for immunotherapy treatment options. JAMA Oncol 2, 1507-8 (2016).
Kim, J. et al. CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. Nature 546, 168-172 (2017).
Kim, J. et al. XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer. Nature 538, 114-117 (2016).
Larsen, J.E. et al. ZEB1 drives epithelial-to-mesenchymal transition in lung cancer. J Clin Inves 126, 3219-35 (2016).
Lea, J. et al. Detection of phosphatidylserine-positive exosomes as a diagnostic marker for ovarian malignancies: a proof of concept study. Oncotarget 8, 14395–14407 (2017).
Mender, I. et al. Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2-deoxyguanosine. Cancer Discov 5, 82-95 (2015).
Miao, L. et al. Disrupting androgen receptor signaling induces Snail-mediated epithelial-mesenchymal plasticity in prostate cancer. Cancer Res 77, 3101-3112 (2017).
Morales, J.C. et al. XRN2 links transcription termination to DNA damage and replication stress. PLoS Genet 12, e1006107 (2016).
Padanad, M.S. et al. Fatty acid oxidation mediated by Acyl-CoA synthetase long chain 3 Is required for mutant KRAS lung tumorigenesis. Cell Rep 16, 1614-28 (2016).
Skoulidis, F. et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov 5, 860-77 (2015).
Suresh, S. et al. SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer. PLoS Genet 13, e1006650 (2017).
Tagal, V. et al. SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers. Nat Commun 8, 14098 (2017).
Tang, K.J. et al. Focal adhesion kinase regulates the DNA damage response and its inhibition radiosensitizes mutant KRAS lung cancer. Clin Cancer Res 22, 5851-5863 (2016).
Yan, Y. et al. Functional polyesters enable selective siRNA delivery to lung cancer over matched normal cells. Proc Natl Acad Sci USA 113, E5702-10 (2016).
Zhou, X. et al. PROTOCADHERIN 7 acts through SET and PP2A to potentiate MAPK signaling by EGFR and KRAS during lung tumorigenesis. Cancer Res 77, 187-197 (2017).