New Effect Against Cancer Identified in Cancer Drug

A research team from NYU Langone Medical Center has found that a drug which was designed to block the multiplication of cancer cells could also switch certain immune cells from lowering the body's attack on tumors into the kind that leads to amplification of immune response. The study was published in the journal Cancer Immunology Research and highlighted aspects of the drug nab-paclitaxel that were so far unknown. The experiments were carried out on mice and the drug nab-paclitaxel, with a brand name Abraxane (protein-bound paclitaxel), entered the macrophages and altered them into mounting an aggressive tumor response. Dr. Dafna Bar-Sagi who is the Vice Dean for Science and Chief Scientific Officer at NYU Langone said that the study unearthed a role of Abraxane that was not associated with it till now. She further stated that these findings could be used to improve the drug and to include the drug in new combinations.

Abraxane above Paclitaxel

Paclitaxel is a drug used for cancer for over many decades and Abraxane is a combination of this cancer drug with nano particles of the protein albumin (nab). Paclitaxel is not found to be effective in the treatment of pancreatic cancer when it is used alone but Abraxane is a leading method of treatment of the disease condition. There have been many questions raised among the scientific community about how the drug that consists of the albumin is more effective in treatment.

Mode of Action of Paclitaxel

Cancer cells break-up microtubules inside the cells that aid in their multiplication. Paclitaxel does not allow these microtubules from breaking up which arrests cancer growth.

Mode of Action of Abraxane (nab-paclitaxel)

The nab-paclitaxel are also believed to primarily target the break-up of microtubules in cancer cells, with albumin aiding the drug in getting into the cells, resulting in lower toxic side-effects.

Apart from its effect on cancer cells, Abraxane also exerts its influence on macrophages that are present in large numbers in the blood stream. Macrophages are known to mount a strong immune reaction against invading bacteria and other microbes. These cells also recognize cancer cells and can mount an immune response. However, certain factors secreted by cancer cells are found to switch off these macrophages, from M1 cells into M2 cells, and prevent them from attacking the cancer cells.

Macrophages in Tumor Cells

Macrophages are referred to as Type I(M1) or Type II(M2) cells based on their activation state. The difference between the two types of macrophages is due to the difference in expression of receptors, production of cytokine and the variation in function between the two cells.

Advertisement

M1 cells: Studies have shown that Type I macrophages (M1) can

• Produce high level of proinflammatory cytokines
• Express large amount of Major Histocompatibility Complex (MHC) molecules
• Associated with the killing of pathogens and of tumor cells.
• The M1 macrophages lead to an antitumor response by secreting the factors TNF-α, IL-12, IFN-γ.

M2 cells: These cells are responsible for moderating the inflammatory response by

• Eliminating cellular wastes
• Promoting angiogenesis and tissue remodeling
• Suppressing immune response
• The M2 cells are associated with an immune response by secreting the factors IL-10 or TGF-β
• Stimulating angiogenesis and tumor growth by secreting IL-23, fibroblast growth factors (FGFs), IL-17, vascular endothelial growth factors (VEGFs).

Study on Cell Lines

In macrophage cell lines it was found that the albumin in nab-paclitaxel allowed the drugs to enter the macrophages through macropinocytosis which made this drug more effective than paclitaxel. Studies conducted on mice with pancreatic cancer showed that once the drug nab-paclitaxel entered macrophages, they changed from suppressing tumor response (M2 cells) into multiplying the immune response against cancer cells (M1 cells).

A postdoctoral fellow in Bar-Sagi's lab, Dr. Jane Cullis who is the lead author of the study said that the findings show that the treatment target macrophages by associating albumin with immune activating agents. This could give rise to drugs that alter the structure of albumin, making it last longer in macrophages. Alternatively, drug therapy for cancer could involve a combination of Abraxane with T cell therapy for better results. Such form of therapy will prove to be effective in treatments against certain tumors that consist of infiltration of a large amount of macrophages.

Advertisement

Macrophages infiltrate a large number of cancer cells in many different types of cancers and a system that aids in switching the type of macrophages into a cancer-fighting response could improve treatment of cancer.

References:

1. Jane Cullis, Despina Siolas, Antonina Avanzi, Sugata Barui, Anirban Maitra, Dafna Bar-Sagi. Macropinocytosis of Nab-paclitaxel Drives Macrophage Activation in Pancreatic Cancer. Cancer Immunology Research, 2017; DOI: 10.1158/2326-6066.CIR-16-0125
2. Role of Macrophages in Malignancy - (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591014/)

Source-Medindia