Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘nuclear factor kappa-B’

It’s been a bad week for vitamins, especially with the publication of data from the SELECT trial that showed healthy men taking 400 IU/day of Vitamin E had a 17% increased risk of prostate cancer.

However, there is some evidence in support of tocotrienols (unsaturated form of Vitamin E) having a potential role to play in anti-cancer therapy.  One paper that caught my attention was the work by Kazim Husain and colleagues from the Moffitt Cancer Center and Research Institute in Tampa.

Published Online First (October 4, 2011) in the American Association for Cancer Research (AACR) journal, “Molecular Cancer Therapeutics” they showed that δ- tocotrienol may have potential to improve the effectiveness of gemcitabine in pancreatic cancer.

In their laboratory and animal based research, the authors showed that δ-Tocotrienol:

  • “augments inhibition of pancreatic cancer cell proliferation by gemcitabine”
  • “augments gemcitabine-induced apoptosis in pancreatic cancer cells”
  • down-regulates constitutively activated NF-κB in gemcitabine-treated pancreatic cancer cells”
  • “enhances the in vivo therapeutic effects of gemcitabine in a pancreatic tumor model in SCID nude mice”

Pancreatic cancer patients have a poor prognosis with less than <5% of patients surviving 5 years.  Current treatment revolves around the chemotherapy gemcitabine, but as the authors note in their Molecular Cancer Therapeutics paper, “tumor resistance is common.”

Various researchers are working on how to improve treatment options for pancreatic cancer.  One company I’m watching is AB Science and their phase 3 trial for masitinib.  You can read more about this on Pharma Strategy Blog and Sally Church’s excellent interview with CEO, Alain Moussy.

The work on the δ-tocotrienol form of Vitamin E shows that it may have a role to play in cancer treatment, notwithstanding the negative data that was published earlier this week in prostate cancer.

Husain and colleagues from Moffitt showed for the first time that δ-tocotrienol inhibited NF-κB activity and the expression of NF-κB regulated gene products. They note that inflammatory transcription factor NF-κB is involved in tumorigenesis, so inhibition of NF-κB may be how tocotrienols exert their anti-cancer effects.

These preclinical results are promising and show that:

“δ-tocotrienol is the most bioactive tocotrienol against human pancreatic cancer cells and provide the rationale for selecting δ-tocotrienol as the lead tocotrienol compound for further studies of the use of tocotrienols for pancreatic cancer prevention and treatment.”

A phase I clinical trial is ongoing (NCT00985777) evaluating the use of δ-tocotrienol in patients with pancreatic tumors.

While Vitamin E supplementation may yet be of benefit to healthy individuals, it could have benefit in patients with pancreatic cancer, so it will be interesting to see how this develops.

ResearchBlogging.orgHusain, K., Francois, R., Yamauchi, T., Perez, M., Sebti, S., & Malafa, M. (2011). Vitamin E  -Tocotrienol Augments the Anti-tumor Activity of Gemcitabine and Suppresses Constitutive NF- B Activation in Pancreatic Cancer Molecular Cancer Therapeutics DOI: 10.1158/1535-7163.MCT-11-0424

I have a long-standing interest in hypoxia (lack of oxygen). Many years ago while completing my Masters degree in human physiology, I undertook research at the RAF Institute of Aviation Medicine at Farnborough on the effects of mild hypoxia on pilot performance.

So I was interested to read an article in the February 17, 2011 issue of the New England Journal of Medicine (NEJM) on hypoxia and inflammation, and how this influences disease.  Inflammation is one of my blog themes for 2011, and in a previous post, I wrote about how its ubiquitous role has been characterized as one of the “Insights of the Decade”.

In the NEJM article on mechanisms of disease, the authors Holger Eltzschig and Peter Carmeliet discuss the cross-talk between hypoxia and inflammation, and how this is implicated in cancer, infections and inflammatory bowel disease.

A lack of oxygen (hypoxia) is something that humans are acutely aware of.  We are all familiar with the flight/fight response that is designed to increase oxygen delivery to the brain and muscles.  Hypoxia can also lead to an inflammatory response.  The flip side is also true, where there is inflammation there is often local tissue hypoxia. An example of this is in solid tumors where the level of oxygen is considerably lower than in normal tissue.

The link between hypoxia and inflammation is regulated by the hypoxia-inducible transcription factor (HIF) that is activated by hypoxia. HIF has two subunits HIF-α (consisting of HIF-1α and HIF-2α) and HIF-β. The article goes into detail (beyond the scope of this blog post) about the interaction between HIF and the nuclear factor kappa-B (NF-κB ) transcription factor that regulates inflammation.

Elevated levels of HIF-1α and HIF-2α correlate with cancer deaths.  HIF-1 overexpression is associated with tumor growth, vascularization and metastasis. This has led to HIF-1 being evaluated as a target for anti-cancer drugs.

EZN-2968, a novel HIF-1α antagonist is in phase I clinical trials.  It is a joint development of two biopharmaceutical companies, Enzon in New Jersey and Santaris pharma in Denmark.

It will be interesting to see whether targeting hypoxia dependent signaling pathways will enable a clinically significant reduction in the inflammatory response.

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