Experimental Therapeutics

Mission

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.

Overview

Polymeric Micelle
Polymeric micelle nanoparticles (illustrated) home in onto solid tumors for the delivery of therapy (see Ma et al., 2015).

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.

Themes

  • Molecular therapeutic sensitizers
  • Tumor microenvironment and protein therapy
  • Imaging and drug delivery
  • Cancer vulnerabilities

Research Highlights

Stained cells
The UT SPORE in Lung Cancer studies all major forms of the disease, including (clockwise, from top left) small cell carcinoma and squamous cell carcinoma, heavily associated with smoking, and large cell carcinoma and adenocarcinoma, less strongly associated with smoking.

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.

Diagram of B-lap LD-50
In NSCLC cell lines exposed to beta-lapachone (ARQ761), NQO1-positive wild-type (wt) and heterozygous (hets) cells are killed (top) irrespective of mutations (red, blue) in oncogenic drivers or passengers (bottom). In contrast, NQO1-negative cells with polymorphisms (pm) in the gene are resistant (top right) ( Huang et al., 2014).
Click on image to see enlarged version.

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.

CAT scan
SABR plan for treating a lung cancer

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.

News releases:

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. Boothman for more details about the program, meetings, and more. david.boothman@utsouthwestern.edu

Selected Publications

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).

Chang, K.H. et al. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell 154, 1074-1084 (2013).

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).

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).

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 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).

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).

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).

Li, X. et al. Aiolos promotes anchorage independence by silencing p66Shc transcription in cancer cells. Cancer Cell 25, 575-589 (2014).

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).

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).

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).

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).

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).