Therapeutic Targeting of Telomerase in Lung Cancer Stem Cells

在之前的审查期间，我们完成了针对端粒酶治疗非小细胞肺癌（NSCLC）的I期和II期临床试验。这些试验的结果证实了调节端粒生物学是肺癌的一个重要靶点。与端粒较长的患者相比，端粒较短的非小细胞肺癌患者的无进展期和总生存率较差。在我们完成的II期试验中，我们确定端粒最短的患者倾向于对我们的端粒酶抑制剂有更好的总体反应。这些结果鼓励我们追求其他新的机制来调节端粒生物学，这是这个更新项目的重点。我们也一直在进行非小细胞肺癌的癌症干细胞生物标志物的临床前研究。我们已经确定ALDH1A1和ALDH1A3作为候选肺癌干细胞生物标志物，其表达与切除的I期肺癌患者预后不良相关。这些假定的癌症干细胞群是端粒酶阳性的，激活了Wnt和Hh激活的途径，我们有实验支持的假设，我们的端粒酶抑制剂不仅针对大部分肺癌细胞，也针对干细胞池。我们也有针对ALDH的特异性抑制剂，并将在直接（从未在细胞培养中）异种移植和ROCK抑制剂建立的原发性肺癌中测试这些抑制剂是否降低克隆性和致瘤性。

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.