In the previously review period we completed a Phase I and II clinical trial targeting telomerase in non-small cell lung cancer (NSCLC). The results of these trials validated modulating telomere biology as an important target in lung cancer. NSCLC patients with short telomeres have poorer progression free and overall survival compared to patients with longer telomeres. In our completed Phase II trial we determined that the patients with the shortest telomeres trended to having better overall responses to our telomerase inhibitor. These results have encouraged us to pursue other novel mechanisms to modulate telomere biology and this is the focus of this renewal project. We also have been conducting preclinical studies on cancer stem cell biomarkers in NSCLC. We have identified ALDH1A1 and ALDH1A3 as candidate lung cancer stem cell biomarkers whose expression correlates with a poor prognosis in lung cancer patients with resected Stage I disease. These putative cancer stem cell populations are telomerase positive with activated Wnt and Hh activated pathways and we have experimental support for the hypothesize that our telomerase inhibitors not only target the bulk of the lung cancer cells but also the stem cell pool. We also have specific inhibitors against ALDH and will test these for reducing clonogenicity and tumorigenicity in direct (never in cell culture) xenografts and in ROCK inhibitor established primary lung cancers. We have a strong commitment and proven track record of being able to advance telomerase inhibitors to clinical trials. We will now progress our patented telomerase inhibitors (telomere modulators) and stem cell candidate therapies. This will include a WNT inhibitor, IWR-1 that targets tankyrase (PARP5A), a telomere associated protein. We will also advance 6-thio-2'deoxyguanosine (6-thio-dG) that is a nucleoside-based telomerase substrate. Both 6-thio-dG and IWR-1 treatments show increased specificity to telomerase expressing cancer cells over normal telomerase silent cells. Both lead to telomere shortening and reduced in vitro and in vivo cell growth. Our long-term goal is to maximize telomere shortening or uncapping and to determine the most effective way to use these SPORE developed inhibitors clinically in patients with NSCLC.
The ability of cancer cells to divide indefinitely is one of the key hallmarks of cancer. Telomerase is the enzyme that permits indefinite divisions in all stages of lung adenocarcinoma. We propose to advance our preclinical studies with two patented home institution developed novel inhibitors as well as cancer stem cell inhibitors and to advance these to clinical trials in lung cancer patients during the next review period.
|Goodwin, Justin; Neugent, Michael L; Lee, Shin Yup et al. (2017) The distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition. Nat Commun 8:15503|
|Cao, Xiaobo; Zhao, Yang; Wang, Jing et al. (2017) TUSC2 downregulates PD-L1 expression in non-small cell lung cancer (NSCLC). Oncotarget 8:107621-107629|
|Zhou, Fei; Wang, Yanru; Liu, Hongliang et al. (2017) Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk-A re-analysis of eight GWASs. Mol Carcinog 56:1227-1238|
|Tagal, Vural; Wei, Shuguang; Zhang, Wei et al. (2017) SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers. Nat Commun 8:14098|
|Jafri, Mohammad Alam; Al-Qahtani, Mohammed Hussein; Shay, Jerry William (2017) Role of miRNAs in human cancer metastasis: Implications for therapeutic intervention. Semin Cancer Biol 44:117-131|
|Cardnell, Robert J; Li, Lerong; Sen, Triparna et al. (2017) Protein expression of TTF1 and cMYC define distinct molecular subgroups of small cell lung cancer with unique vulnerabilities to aurora kinase inhibition, DLL3 targeting, and other targeted therapies. Oncotarget 8:73419-73432|
|Faubert, Brandon; Li, Kevin Y; Cai, Ling et al. (2017) Lactate Metabolism in Human Lung Tumors. Cell 171:358-371.e9|
|Rabellino, Andrea; Andreani, Cristina; Scaglioni, Pier Paolo (2017) The Role of PIAS SUMO E3-Ligases in Cancer. Cancer Res 77:1542-1547|
|Fu, Rong; Wang, Pei; Ma, Weiping et al. (2017) A statistical method for detecting differentially expressed SNVs based on next-generation RNA-seq data. Biometrics 73:42-51|
|Quek, Kelly; Li, Jun; Estecio, Marcos et al. (2017) DNA methylation intratumor heterogeneity in localized lung adenocarcinomas. Oncotarget 8:21994-22002|
Showing the most recent 10 out of 1004 publications