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Posts from the ‘Nanotechnology’ category

nab-Paclitaxel and its potential role in pancreatic cancer

By on March 5, 2012

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.

References:

ResearchBlogging.orgFrese, 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

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Nanotechnology and cancer research: can it improve therapy for cancer?

By on March 31, 2011

Way back in November 2009 at the American Association of Cancer Research (AACR) Molecular Targets meeting in Boston, there was a fascinating poster on the early promise for nanotechnology as a new form of efficient drug delivery for cancer therapeutics (see the blog post here).

Fast forward 18 months and my attention was drawn to a new article published in Cancer Research about how nanotechnology has been used preclinically to deliver therapy for breast cancer into the cancer cells rather than to the cells.  This is a subtle, but important, difference.

For those of your wondering what nanotechnology is, my colleague Pieter Droppert reviewed some basics earlier this month in a blog post:

“Nanotechnology is the application of science and engineering to materials that are between 1 and 100 nanometers (nm) in size.”

He went on to put this in layman terms:

“1nm is one-billionth of a meter.   To put this in context, 1nm is one seven-thousandth of the width of a red blood cell or one eighty-thousandth of the width of a human hair.  These are unimaginably small materials that are engineered to operate at the molecular and atomic level.”

The approach in the latest preclinical research (see references below) is to take trastuzumab (Herceptin) and combine it with biodegradable polymers to form nanoconjugates that are small enough to enter cancer cells because they are more water soluble rather than attack the outside of the cells, thereby potentially reducing toxicities associated with the therapy.

The same group also tried this technique with brain cancer (see references below), allowing the nanocells to cross the usually impenetratable blood-brain barrier, which:

“resulted in a marked inhibition of tumor angiogenesis and growth.”

In the breast cancer research, the group compared the results of their polymer-trastuzumab conjugate with trastuzumab alone in mice:

“Our experiments confirmed that a proper design of the lead nanobiopolymer was possible for efficient blocking of HER2/neu-positive breast tumor growth through dual inhibition of HER2/neu and Akt phosphorylation, and as a result, promoting enhanced tumor cell apoptosis.

The nanobiopolymer’s unique combination of features resulted in highly specific drug accumulation in the tumor tissue and inside tumor cells.”

It will be most interesting to see if this idea is developed clinically in human trials and whether the results will be reproducible or not.

Significance of the findings:

The nanoconjugate concept has promise, not just in allowing a novel drug delivery system to cross impenetrable barriers, but also in reducing the toxicities associated with systemic targeted therapy.  Randomised clinical trials in patients with cancer are required to determine if there is viability in humans.

References:

ResearchBlogging.orgInoue, S., Ding, H., Portilla-Arias, J., Hu, J., Konda, B., Fujita, M., Espinoza, A., Suhane, S., Riley, M., Gates, M., Patil, R., Penichet, M., Ljubimov, A., Black, K., Holler, E., & Ljubimova, J. (2011). Polymalic Acid-Based Nanobiopolymer Provides Efficient Systemic Breast Cancer Treatment by Inhibiting both HER2/neu Receptor Synthesis and Activity Cancer Research, 71 (4), 1454-1464 DOI: 10.1158/0008-5472.CAN-10-3093

Ljubimova, J., Fujita, M., Ljubimov, A., Torchilin, V., Black, K., & Holler, E. (2008). Poly(malic acid) nanoconjugates containing various antibodies and oligonucleotides for multitargeting drug delivery Nanomedicine, 3 (2), 247-265 DOI: 10.2217/17435889.3.2.247

Ding, H., Inoue, S., Ljubimov, A., Patil, R., Portilla-Arias, J., Hu, J., Konda, B., Wawrowsky, K., Fujita, M., Karabalin, N., Sasaki, T., Black, K., Holler, E., & Ljubimova, J. (2010). Inhibition of brain tumor growth by intravenous poly( -L-malic acid) nanobioconjugate with pH-dependent drug release Proceedings of the National Academy of Sciences, 107 (42), 18143-18148 DOI: 10.1073/pnas.1003919107

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