Newfound effect of cancer drug may expand its use

February 10, 2017

A drug first designed to prevent cancer cells from multiplying has a second effect: it switches immune cells that turn down the body's attack on tumors back into the kind that amplify it. This is the finding of a study led by researchers from NYU Langone Medical Center and published recently in Cancer Immunology Research.

According to experiments in mice, macrophages - immune cells that home in on tumors - take in the drug nab-paclitaxel (brand name Abraxane). Once inside these cells, say the study authors, the drug changes them so that they signal for an aggressive anti-tumor immune response.

"Our study reveals a previously unappreciated role for Abraxane in tumor immunology," says corresponding author Dafna Bar-Sagi, PhD, Vice Dean for Science and Chief Scientific Officer at NYU Langone.

"In doing so, it suggests ways to improve the drug and argues for its inclusion in new kinds of combination treatments," says Bar-Sagi, also a professor in the Department of Biochemistry and Molecular Pharmacology at NYU Langone, and associated with its Perlmutter Cancer Center.

Abraxane over Paclitaxel

Abraxane is comprised of the decades-old cancer drug, paclitaxel, combined with nanoparticles of the protein albumin (nab). Paclitaxel alone is not effective against pancreatic cancer, but Abraxane (nab-paclitaxel) is part of a leading treatment for the disease. Why the albumin-bound form works better has been a major question in the field.

Paclitaxel prevents structures called microtubules inside cancer cells from breaking up, a required step if they are to multiply as part of abnormal growth. Many in the field assume that nab-paclitaxel too primarily targets microtubules in cancer cells, with albumin perhaps helping the drug to get inside cells, and with fewer toxic side-effects.

The new findings suggest that, on top of any effect on cancer cells, Abraxane's effectiveness may proceed from its impact on macrophages, which roam the bloodstream and build up in many tumors.

The study results revolve around the immune system, in which cells like macrophages trigger a massive attack on bacteria or other invading microbes. This system can also recognize and attack cancer cells. Factors secreted by tumor cells, however, dampen the immune response in part by switching macrophages from their immune-stimulating stance, termed M1, into an M2 mode that suppresses their immune function.

In experiments in macrophage cell lines, the study authors found that nab-paclitaxel is more effective than paclitaxel partly because albumin enables macrophages to take up the drug through a natural process called macropinocytosis.

Once inside macrophages, according to experiments in mice with pancreatic tumors, nab-paclitaxel causes the macrophages to switch from immune-suppressing M2 cells back into M1 cells that amplify the body's effort to kill cancer cells. Past studies had found that paclitaxel has a similar structure to substances given off by bacteria that trigger macrophage activation. The study authors show that the same pathway is evoked by nab-paclitaxel in pancreatic tumor-associated macrophages.

"Our findings argue that it may be possible to develop more treatments that selectively target macrophages by coupling albumin to immune-activating agents," said lead study author Jane Cullis, PhD, a postdoctoral fellow in Bar-Sagi's lab. "We may also be able to adjust albumin's structure such that drugs attached to it stay in macrophages longer, or combine Abraxane with T-cell treatments for greater therapeutic effect. In principle, such treatments should be useful against the many tumor types infiltrated by macrophages."
Along with Cullis and Bar-Sagi, authors of the study were Despina Siolas and Antonina Avanzi in the Department of Biochemistry and Molecular Pharmacology at NYU Langone; and Sugata Barui, Anirban Maitra in the departments of Pathology and Translational Molecular Pathology at University of Texas MD Anderson Cancer Center. The work was supported by a grants from the American Association for Cancer Research (AACR PanCAN 13-90-25-VOND), the National Institutes of Health (5-T32 CA 009161-39, 5-T32AI100853-04, and HL007151-36), and a Schwartz Fellowship.

NYU Langone Medical Center / New York University School of Medicine

Related Cancer Cells Articles from Brightsurf:

Cancer researchers train white blood cells to attacks tumor cells
Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program -- be utilized for the treatment of tumors.

New way to target some rapidly dividing cancer cells, leaving healthy cells unharmed
Scientists at Johns Hopkins Medicine and the University of Oxford say they have found a new way to kill some multiplying human breast cancer cells by selectively attacking the core of their cell division machinery.

Breast cancer cells use message-carrying vesicles to send oncogenic stimuli to normal cells
According to a Wistar study, breast cancer cells starved for oxygen send out messages that induce oncogenic changes in surrounding normal epithelial cells.

Breast cancer cells turn killer immune cells into allies
Researchers at Johns Hopkins University School of Medicine have discovered that breast cancer cells can alter the function of immune cells known as Natural killer (NK) cells so that instead of killing the cancer cells, they facilitate their spread to other parts of the body.

Breast cancer cells can reprogram immune cells to assist in metastasis
Johns Hopkins Kimmel Cancer Center investigators report they have uncovered a new mechanism by which invasive breast cancer cells evade the immune system to metastasize, or spread, to other areas of the body.

Engineered immune cells recognize, attack human and mouse solid-tumor cancer cells
CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

Drug that keeps surface receptors on cancer cells makes them more visible to immune cells
A drug that is already clinically available for the treatment of nausea and psychosis, called prochlorperazine (PCZ), inhibits the internalization of receptors on the surface of tumor cells, thereby increasing the ability of anticancer antibodies to bind to the receptors and mount more effective immune responses.

Engineered bone marrow cells slow growth of prostate and pancreatic cancer cells
In experiments with mice, researchers at the Johns Hopkins Kimmel Cancer Center say they have slowed the growth of transplanted human prostate and pancreatic cancer cells by introducing bone marrow cells with a specific gene deletion to induce a novel immune response.

First phase i clinical trial of CRISPR-edited cells for cancer shows cells safe and durable
Following the first US test of CRISPR gene editing in patients with advanced cancer, researchers report these patients experienced no negative side effects and that the engineered T cells persisted in their bodies -- for months.

Zika virus' key into brain cells ID'd, leveraged to block infection and kill cancer cells
Two different UC San Diego research teams identified the same molecule -- αvβ5 integrin -- as Zika virus' key to brain cell entry.

Read More: Cancer Cells News and Cancer Cells Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to