Back in 2009 at the American Association for Cancer Research (AACR) Molecular Targets meeting, a researcher (Anirban Maitra) from Boston had a most interesting poster about the use of nanotechnology to deliver nab-paclitaxel (Abraxane) to pancreatic adenocarcinomas in a more targeted fashion. You can read about it in more detail from the meeting coverage at that time.
Essentially, one of the things that stops chemotherapy being more effective in advanced pancreatic cancer is that the stromal layer forms a physical, almost impenetrable layer, that slows drugs from getting through to the tumour.
Using nanotechnology, the MIT researchers were able to direct nab-paclitaxel to the stromal layer more effectively, wiping it out and allowing subsequent gemcitabine to be more effective in their animal models.
Fast forward two years and there has been a new paper in Cancer Discovery by a different group (see Frese et al., (2012) from the University of Cambridge in the references) looking at the mechanistic role of nab-paclitaxel in pancreatic adenocarcinomas.
Their findings were as follows:
- Combination of nab-Paclitaxel and gemcitabine causes tumour regression and reduces metastasis
- Treatment with nab-Paclitaxel targets tumour epithelial cells
- nab-Paclitaxel promotes elevated intratumoural gemcitabine levels
- nab-Paclitaxel decreases cytidine deaminase protein levels
Taken together, the authors concluded that, mechanistically:
“Paclitaxel reduced the levels of cytidine deaminase protein in cultured cells through reactive oxygen species–mediated degradation, resulting in the increased stabilization of gemcitabine.
Our findings support the concept that suboptimal intratumoral concentrations of gemcitabine represent a crucial mechanism of therapeutic resistance in PDA (pancreatic ductal adenocarcinoma) and highlight the advantages of genetically engineered mouse models in preclinical therapeutic trials.”
In an AACR press release, the leader author, David Tuveson, was quoted as saying:
“We predict from this mechanistic study that nab-paclitaxel may be most effective if we administer it first, and delay administration of the gemcitabine. The next step is to test this prediction, since it could help a great deal with patient treatment.”
Based on the earlier Boston research in 2009, I think that this sequencing approach makes logical sense, because the nab-paclitaxel will wipe out the stromal layer and create an opportunity for the subsequent gemcitabine infusion (or other therapy) to be more effective.
What are significance of these findings?
Firstly, there are a number of trials ongoing in pancreatic cancer, including a phase III trial of gemcitabine plus nab-paclitaxel, which is expected to mature next year. Based on the promising interim data, I’m hopeful that this combination may move the needle in terms of improved survival (as measured by OS) for patients with this devastating cancer.
More recently, Infinity reported that their phase II trial with their Hedgehog inhibitor (saridegib) plus gemcitabine was stopped for futlity. I wasn’t surprised to hear this based on the 2009 data mentioned above, because without blasting out the stromal layer, neither the TKI nor gemcitabine can impact the tumour cells effectively. Another Hedgehog inhibitor, vismodegib (Genentech/Roche) is being evaluated in a triple combination trial with gemcitabine and nab-paclitaxel. I like this trial design a lot better, but we will have to see whether sequencing is also important, as shown in this latest research, ie nab-paclitaxel first, followed by gemcitabine (plus the Hedgehog inhibitor).
All in all, Frese et al., (2012) provide novel insights into the antitumour activity of nab-paclitaxel. They also offer a potential mechanism for improving gemcitabine delivery to pancreatic tumours that deserves research in the clinical setting. This more targeted smart approach to trial design may well yield improved results in the clinic, rather than the old method of throwing random doublets and triplets at the (tumour) wall hoping something will stick.
Frese, K., Neesse, A., Cook, N., Bapiro, T., Lolkema, M., Jodrell, D., & Tuveson, D. (2012). nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer Cancer Discovery DOI: 10.1158/2159-8290.CD-11-0242