Blood Brain Barrier Program - Anyone have info?

[jones7676]

I am also following this very closely for personal reasons - 2 mets growing in my brain and 2 new mets/one in each lung and trying to make the right decisions. Thanks for all the info that is getting provided by you - all of you. I do not have to post but I am following up on the info provided.

[Joe]

Scientists Develop a New Drug Delivery System for Brain Cancers

EORTC-NCI-AACR Press Release. 2008 Oct 22


GENEVA, SWITZERLAND - Scientists have developed a new drug delivery system that is capable of crossing the blood-brain barrier to reach and kill cancer cells in the brain, according to research presented at the 20th EORTC-NCIAACR Symposium on Molecular Targets and Cancer Therapeutics in Geneva October 22. Following successful preclinical studies, the technology is being evaluated in two phase I clinical trials in patients with malignant glioma and brain metastases.
The blood-brain barrier is formed by a network of closely sealed endothelial cells in the brain’s capillaries, and it expresses a high level of proteins that pump foreign molecules away from the brain, while allowing others (such as glucose and insulin) that are necessary to the functioning of the brain cells to cross the barrier. This makes it very difficult for molecules, including anti-cancer drugs, to cross the blood-brain barrier and reach tumor cells in the brain. Currently, less than five per cent of drugs (made up of very small molecules) are able to cross the barrier; one example is temozolomide, which is the only chemotherapy available for treating brain tumors such as glioblastoma multiform and progressive anaplastic astrocytoma. These tumors have a poor prognosis and continue to grow, even after treatment with temozolomide. Therefore, new therapies for these hard-to-treat brain tumors are needed urgently.
In four related presentations to the symposium, scientists from Canada, the USA and France described how they are investigating a new drug delivery technology that provides a non-invasive and flexible way of transporting different drugs (for example, antibodies, proteins, peptides, siRNA, small molecules, etc.) across the blood-brain barrier and into the central nervous system.
The drug being evaluated in the four abstracts is called ANG1005. It is made up of one molecule of a peptide called Angiopep-2 joined together with three molecules of paclitaxel, a taxane chemotherapy drug.
Dr Reinhard Gabathuler, author of one of the abstracts and chief scientific officer at Angiochem Inc (Montreal, Canada) – the company that is developing the Angiopep technology and ANG1005 – explained: “Unlike invasive or pharmacological approaches to deliver drugs to the brain, the Angiopep technology utilizes the physiological approach by making use of the receptors on the surface of the blood-brain barrier that are responsible for actively transporting necessary molecules across the barrier to the brain. The family of Angiopeps (including Angiopep-2) has been designed to interact with a specific receptor, Low Density Lipoprotein Receptor Related Protein-1 (LRP- 1). This receptor has many functions, binds over 30 ligands [molecules] of various sizes, and is highly expressed at the blood-brain barrier.”
In laboratory-based tests of ANG1005 on mice and rats, Dr Gabathuler, other scientists in the company and collaborators in the US and Canada found that the drug was transported rapidly across the blood-brain barrier and into the functional part of the brain, the parenchyma.
“In contrast to free paclitaxel, which is normally prevented from reaching the brain by the P-glycoprotein efflux pump, ANG1005 is efficiently transported across the blood-brain barrier, with approximately 100-fold higher transport rate compared to free paclitaxel and 10-fold higher transport rate than temozolomide,” he said.
In addition, the drug resulted in a significant, 27% increase of survival of mice with glioblastoma tumors and a shrinking of glioblastoma tumors in rats.
A second study, led by Dr Francis Bichat, head of the scientific platform at Oncodesign (Dijon, France), evaluated the anti-cancer properties of the drug in cancer cell lines and mice, as well as investigating its toxicity and what happened to the drug in mice.
He found that ANG1005 had the same anti-cancer properties as did free paclitaxel (paclitaxel on its own) in cancer cell lines. Speaking before the conference, he said: “The anti-tumor activity of paclitaxel was maintained with ANG1005 compared with free paclitaxel. There was no loss of activity.” He also found a significant inhibition of brain tumor growth in rats when they were treated with ANG1005, whereas tumors in rats that were treated with paclitaxel did not have their growth inhibited. “This is probably because free paclitaxel is not able to enter the brain,” he said.
“The most interesting finding from this study is the potency of ANG1005 to bypass the blood-brain barrier and to allow paclitaxel into the brain where it shows anti-tumor activity,” said Dr Bichat.
The success of these pre-clinical studies enabled Angiochem Inc to start two phase I clinical trials at cancer centers in the US: one in patients with advanced cancer and brain metastases, and the second in patients with recurrent malignant glioma.
These trials are still being conducted, but, as of 23 September 2008, 22 patients with advanced solid tumors (including breast cancer, melanoma, liver cancer and 15 patients with brain metastases) have been treated with ANG1005 in the first trial. The drug is given by intravenous infusion for one hour, every 21 days. At doses up to 500 mg/m2 the drug appears to be safe and well tolerated and no patient has discontinued due to adverse side effects. The researchers are continuing to increase the dose.
Dr Jean-Paul Castaigne, president and chief executive officer of Angiochem Inc, who presented the clinical trials results, said: “To date, the safety and tolerability of ANG1005 has been excellent in patients with advanced solid tumors and brain metastases.”
In the second trial in patients with recurrent malignant glioma, 12 patients had been treated by 23 September 2008 – eight with glioblastoma multiform, one with anaplastic astrocytoma and three with anaplastic oligondendrocytoma.
Dr Castaigne said: “We have demonstrated that the drug is safe and tolerable up to and including doses of 75 mg/m2 and we are currently evaluating doses of 105 mg/m2. No patient has discontinued due to drug-related adverse side-effects. So far, all patients (with the exception of one) dosed up to 50 mg/m2 have had their disease progress following two cycles of treatment at six weeks. However, it should be noted that 50 mg/m2 of ANG1005 has an equivalent paclitaxel dose of only about 25 mg/m2, which is still quite low for appreciable cytotoxic effects.”
He continued: “To date, treatment options for patients with recurrent malignant glioma are limited and prognosis is bleak because of the brain’s highly evolved physiological structure. Results from both these trials show that Angiopep conjugates may provide a potentially safe and effective way to treat gliomas and other currently unmanageable diseases of the central nervous system. The Angiopep technology is well tolerated, since most of the side-effects observed to date with ANG1005 are caused by paclitaxel, the active drug component.”
Both trials will be reporting their most important results by the end of 2008, and researchers are planning a continuation of the trial in patients with brain cancer in 2009.
Dr Castaigne said: “Angiochem's intention is to continue the early development of ANG1005 until proof-of efficacy is obtained in either progressive malignant gliomas or brain metastases. We will seek to find a partner with significant oncology experience to carry forward the later development stages and marketing of ANG1005.
“Although other technologies have demonstrated abilities to cross the blood-brain barrier, we believe that the Angiopep technology is the furthest developed of the physiological approach and has significant advantages. ANG1005 is the company’s first compound in clinical development using the Angiopep technology. We have been successful in conjugating other chemotherapeutics (e.g. doxorubicin and etoposide) to our technology; preclinical data have demonstrated success in delivering these compounds into the brain and retaining cytotoxic activities. Angiochem is also focusing considerable effort on the conjugation and delivery of other drug classes (including monoclonal antibodies, proteins, peptides, siRNA, etc.) to treat other CNS disorders.”




Regards
Joe

[jones7676]

I will be asking my doctor about this tomorrow. Interestingly enough, I can remember about 3 1/2 years ago an acquaintance telling me of women flying in and out for putting the Herceptin treatments where she was. Sometimes it just seems like things move too slow in regards to that.

[hutchibk]

OK, a question for a propellor head... all this talk of Boswellia Serrata is confusing me, but I am interested.

I have had IMRT and my brain mets are gone. I am now on Tykerb with Herceptin to keep me stable in the brain (LOL) and in the torso, and it is working well in all regards.

Am I a candidate for Boswellia Serrata? Would it do me any good?

[CourtneyL]

Hi Brenda - I can't answer your question about whether or not you are a good candidate but I can share my experience with you and tell you what my doctor said. I am NED in body and have 6 small spots on my brain. I added Tykerb in January to see what kind of an effect it would have by itself on the brain mets (before we do Gamma or WBR we wanted to see if Tykerb could do the trick alone). So far Tykerb is stabalizing things and I asked my onc if I could add Boswellia to the mix to see what it can do too. He read the literature and whole heartedly agreed to let me try it. I go for a follow-up scan in 4 weeks to see if the brain mets are gone, shrinking, or the same. Then we'll decide which radiation treatment to proceed with. However, I am totally optomistic that Tykerb and Boswellia will be enough to have gotten rid of the little buggers. I will keep you posted on what kinds of success I have with it. Definitely ask your doctor about supplementing with Boswellia. I am thrilled that you are doing so well!!!

[hutchibk]

That's good news Courtney. I was put on Tykerb with Xeloda for a year and a half when I was dxed with 5 small brain mets (ranging in size from 1mm - 9mm) almost 2 years ago. My spots shrunk within 3 months and went dormant for a year and a half while I remained on T/X. It was heavenly! Then, this past August, they started to shine/wake-up again on my MRI (no new ones, just the old ones), so we quickly scheduled me for IMRT brain radiation to zap them before they had a chance to grow or take hold again. They are now gone, daddy, gone, and we changed my treatment to Tykerb/Herceptin, which is also heavenly as far as treatments go, and now I think I might want to consider Boswellia. Wonder if it comes with a protective action once mets have existed or disappeared, or does it just have a "mets zapping" action?
Will mention to my onc and see what he says. I can probably guess, though...

[CourtneyL]

That is great news, Brenda! I am hoping for a similar outcome. Sounds like we are on similar treatment regimens. I am currently on Tykerb/Herceptin/Zometa too. Good luck to you and keep me posted on your status! You are in my thoughts and prayers!