TRAIL Ahead in Cancer Treatment

Capitalizing on cellular apoptotic pathways to eradicate cancer cells holds much interest because it harnesses the body’s natural defense systems, and because dysregulation of apoptosis occurs frequently in cancer.

Capitalizing on cellular apoptotic pathways to eradicate cancer cells holds much interest because it harnesses the body’s natural defense systems, and because dysregulation of apoptosis occurs frequently in cancer. One way to engage apoptotic mechanisms is via ligands of the TNF superfamily, such as TNF-related apoptosis-inducing ligand (TRAIL).

Research presented recently describes 2 different approaches to optimize the use of TRAIL as an anticancer therapy. To date, clinical studies using TRAIL and derivatives, including agonistic antibodies that target TRAIL receptors, have been disappointing, likely due to several factors, one of which being resistance to TRAIL in human cancers. However, investigators hope that by gaining a better understanding of the complex TRAIL system they can overcome cancer cell resistance.

TRAIL is known to preferentially induce apoptosis in cancer cells and, importantly, is nontoxic in vivo. Henning Walczak, PhD, professor of cancer biology at University College London, focuses on finding ways around the obstacles in the apoptosis pathway that render cancer cells invulnerable to TRAIL. He envisions future TRAIL-based therapies as using sensitizing agents to remove blocks in the TRAIL apoptosis pathway. “Igniting the fuse that causes lung cancer cells to self-destruct could pave the way to a completely new treatment approach—and leave healthy cells unharmed,” he said.

In order to identify cellular agents that block TRAIL-mediated apoptosis, Walczak and colleagues systematically screened kinases in resistant non-small cell lung cancer (NSCLC) cells and found that cyclin-dependent kinase 9 (CDK9) was responsible for TRAIL resistance. They next paired a clinically used inhibitor of CDK9 with TRAIL to test efficacy in vitro on NSCLC cell lines and in vivo on an orthotopic lung cancer model.¹

The CDK9-inhibitor/TRAIL combination induced apoptosis in highly TRAIL-resistant cell lines, even at low concentrations of TRAIL. As an initial indication of nontoxicity, primary human hepatocytes did not undergo apoptosis at similar concentrations. In vivo, the combination eradicated established orthotopic NSCLC tumors.

“The next step of our work will be to try the approach in other cancer types, and we hope it could ultimately lead to testing this technique in trials to see if it can help patients,” said Walczak.

While the inhibition of intracellular obstacles, such as CDK9, along the apoptosis pathway may be one way to successfully employ TRAIL in cancer therapy, within the highly complex TRAIL-mediated system, other approaches to overcoming resistance show promise as well.

Michael King, PhD, professor of biomedical engineering at Cornell University, recognizes the difficulty in treating metastatic cancer and sees potential for TRAIL to target circulating cancer cells. Inspired by the cytotoxic activity of natural killer cells, which, when induced, express TRAIL on their surface, King and colleagues developed their own version of “unnatural killer cells.” They attached 2 proteins to the surface of nanoscale liposomes: TRAIL and an adhesion protein (E-selectin) that sticks to leukocytes. The leukocytes, functionalized with TRAIL/E-selectin liposomes, provide an extensive surface area to display TRAIL proteins, which then incidentally contact circulating tumor cells in the blood stream.²

“We have found that in liposomal form, attached to the surface of white blood cells, TRAIL is quite effective in killing circulating cancer cells,” said King.

The group found that leukocyte-tethered TRAIL reduced the number of viable cancer cells in mouse circulation and increased apoptosis of cancer cells lodged in mouse lung.

In contrast to the low efficacy seen in clinical trials of soluble TRAIL, the success so far of the liposome approach is probably due to several factors. Soluble TRAIL has a short half-life in circulation of only about 15 minutes, but the protein tethered to leukocytes avoids renal clearance mechanisms. Circulating cancer cells have different cell surface characteristics, and TRAIL may be ideally suited to target cells in the blood stream.³

In the future, the “unnatural killer cell” approach could be combined with targeted therapies and immunotherapies to neutralize metastatic cancer cells. Studies have reported that up to a million cancer cells may detach from a primary tumor (per gram per day), but the circulating cells are difficult to detect and target. This technology may reduce the number of metastatic cells and the formation of new tumors. Clinically, liposomes might one day be used as a preventative measure with highly metastatic hematogenous cancers, such as breast, prostate, and lung cancer.

“As a means of preventing metastasis, targeting cells in the blood stream represents a broad, under explored area of cancer biology. We hope to develop new therapies based on this principle,” adds King.

Through better understanding of the complex molecular mechanisms underlying TRAIL signalling, these different approaches show promise in surmounting the obstacles to the successful use of TRAIL as a nontoxic, targeted therapy that efficiently triggers apoptosis in cancer cells.

References

1. Montinaro A, Lemke J, von Karstedt S, et al. Selective CDK9 inhibition overcomes TRAIL resistance in NSCLC. Poster presented at: NCRI Cancer Conference, 2014 Nov 2-5; Liverpool, UK. http://conference.ncri.org.uk/abstracts/2014/abstracts/LB052.html
2. Mitchell MJ, Wayne E, Rana K, et al. TRAIL-coated leukocytes that kill cancer cells in the circulation.Proc Natl Acad Sci. 2014 Jan 21; 111(3): 930-935.
3. Chandrasekaran S, Marshall JR, Messing JA, et al. TRAIL-Mediated Apoptosis in Breast Cancer Cells Cultured as 3D Spheroids.PLoS One. 2014 Oct 24; 9(10): e111487.