Thursday, January 8, 2009

Scientists develop drug delivery system for brain cancers, other diseases ... Melanoma Jim Breitfeller

October 22, 2008

"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-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Geneva today (Wednesday 22 October). 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 tumour 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 tumours such as glioblastoma multiforme and progressive anaplastic astrocytoma. These tumours have a poor prognosis and continue to grow, even after treatment with temozolomide. Therefore, new therapies for these hard-to-treat brain tumours 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 utilises 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 tumours and a shrinking of glioblastoma tumours 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-tumour 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 tumour growth in rats when they were treated with ANG1005, whereas tumours 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-tumour activity,” said Dr Bichat.

The success of these pre-clinical studies enabled Angiochem Inc to start two phase I clinical trials at cancer centres 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 tumours (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 tumours 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 multiforme, 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.”

receptors on the surface. I heard that term before HAAAAAAA!!!!

CTLA-4 with IL-2 YES!!!! ,YES!!!!

The Puzzle!!!!, we now have the corner and we have to work to the inside of the puzzle.

2008 was a very good year. I will Toast to That!!!!

Please Pass the Bottle of Wine, Thank You

Jimmy B

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Greetings to One and All

This Blog is dedicated My Brother Kenny B. who passed away in the late 1970's with Cancer before the Internet.

It was he, who showed me How to live and give back. He was wise beyond his years.

Kenny B

Jimmy and Dee

Carepage: Jimmybreitfeller
Jimmy Breitfeller

My Profile as of 2009

My photo
Last July (2005)I was riding my bicycle to work at the Eastman Kodak Research Labs about 3 miles from home. I was wearing a knapsack to carry my things to and from the labs. I started noticing an ache on my back. So I decide to go to the dermatologist. To make the long story short, it was cancer. I knew from my research that I would be needing adjuvant therapy. So I started communicating with Sloan Kettering, University of Pittsburgh Cancer Center, and a couple of others including the Wilmot Cancer Center at Strong. I realized that by telling my story, I might help someone else out there in a similar situation. So to all who are linked by diagnosis or by relation to someone with melanoma, I wish you well. Stay positive, read as much as you can (information helps to eliminate the fear associated with the unknown), and live for today, as no one can predict what tomorrow may bring. Jimmy B. posted 12/15/08


The information contained within this Blog is not meant to replace the examination or advice of your Oncologist or Medical Team. The educational material that is covered here or Linked to, does not cover every detail of each disorder discussed.

Only your physician/Oncologist can make medical decisions and treatment plans that are appropriate for you. But, An Educated Consumer is a Smart consumer.

As Dr. Casey Culberson Said:

"The BEST melanoma patient is an ACTIVE PARTICIPANT in his or her treatment

Melanoma and the “Magic Bullet” (Monoclonal Antibodies)

Just to let you know I posted the first draft of the Melanoma and the “Magic Bullet” (Monoclonal Antibodies). on Melanoma Missionary In the Shared File Section. you can download it for 19.95 (Only kidding) it is Free for the taking.

It is 33 pages long and may help you in your quest for the Yellow Brick Broad. Just to let you know it is only the first draft. Revisions are sure to come. I wanted to get it to the people that need it the most, the Melanoma Patients.


So, where does Interluekin-2 (IL-2) come into play? According to Byung-Scok et al and recent reports, IL-2 is not needed for developmental CD4+ CD25+ Treg cells in the thymus but does play an important role in the maintenance and function in the peripheral.18 Peripheral is defines as secondary system outside the bone marrow and thymus. It entails the site of antigen, immune system interaction. IL-2 is required for the peripheral generation of Tregs based Abbas’s and colleagues research.19

IL-2 prevents the spontaneous apoptosis of the CD4+ CD25+ Treg cells. It has been reported that patients with multiple advance-stage tumors have elevated levels of Tregs within the tumor microenviroment.20 Interluekin-2 is the survival factor for CD4+ CD25+ Treg cells.21 If the addition of IL-2 is on or before the maximum propagation of the CD4+ T cells, the Tregs population can increase 5-fold in a 96 hour period based on certain growth mediums.

By controlling the addition of the endogenous IL-2, one has a knob to turn and can lead to the control of the expansion of the Tregs. When you combined this control with the anti-CTLA-4 blockage, you can shift the balance of the immune response.

Now here is the catch. The maintenance and function of the CD8+ T-cells require CD4+ cells which secrete IL-2. So we don’t want to deplete the CD4+ cells, we want to control the expansion of the Tregs which are a subset of the CD4+ cells. It has been postulated by some researchers that the Anti-CTLA-4 blockage also suppresses the Treg function in a different mechanism. By using IL-2 as the rate limiting factor, we can suppress the CD4+ CD25+ Treg cell expansion by controlling the concentration and timing of the Inerluekin-2 at the tumor microenvironment.

The Interluekin-2 plays another role in this Melanoma Maze. In a study by Janas et al, Il-2 increases the expressions of the perforin and granzyme A, B and C genes in the CD8+ T-cells. This increase expression causes the CD8+ T-cells to mature into Cytoxic T Lymphocytes (CTLs). The exogenous IL-2 is required for the granzyme proteins. As stated previously, CTLs have cytoplasmic granules that contain the proteins perforin and granzymes. A dozen or more perforin molecules insert themselves into the plasma membrane of target cells forming a pore that enables granzymes to enter the cell. Once in the tumor cell, these enzymes are able to breakup (lyse) the cell and destroy it. This is the beginning of the end for the cancer cells. The tumors begin to shrink and the rest is history,

On the other hand, prolong therapy with Il-2 can result in causing apoptotic death of the tumor- specific CD8+ T-cells.23

Clearly in a clinical setting, timing, dose, and exposure to these drugs play a major roll in the immunotherapy, and can have dramatic effects on the outcome.

All it takes is that one magic bullet to start the immune reaction..

Melanoma And The Magic Bullet (Monoclonal Antibodies)

Public Service Announcement

A call for Melanoma Patients by Dr. Steven A Rosenberg

"We continue to see a high rate of clinical responses in our cell transfer immunotherapy treatments for patients with metastatic melanoma", Dr. Rosenberg said.

"We are actively seeking patients for these trials and any note of that on a patient-directed web site would be appreciated."

If you would like to apply for his trials, here is the website and information.

Dr. Rosenberg's information

Dr. Rosenberg's Clinical Trials

For the Warriors

The Melanoma Research Alliance has partnered with Bruce Springsteen, the E Street Band, and the Federici family to alleviate suffering and death from melanoma. Please view Bruce Springsteen’s public service announcement inspired by Danny Federici. Danny was the E Street Band’s organist and keyboard player. He died on April 17, 2008 at Memorial Sloan-Kettering Cancer Center in New York City after a three year battle with melanoma.

Source Fastcures blog

Join the Relay for Life!!!


Dear Family and Friends,

I’ve decided to take a stand and fight back against cancer by participating in the American Cancer Society Relay For Life® event right here in my community! Please support me in this important cause by making a secure, tax-deductible donation online using the link below.

To donate on line now, click here to visit my personal page.
Jimmy B AKA Melanoma_Missionary

Relay For Life® is a life-changing event that brings together more than 3.5 million people worldwide to:

CELEBRATE the lives of those who have battled cancer. The strength of survivors inspires others to continue to fight.

REMEMBER loved ones lost to the disease. At Relay, people who have walked alongside people battling cancer can grieve and find healing.

FIGHT BACK. We Relay because we have been touched by cancer and desperately want to put an end to the disease.

Whatever you can give will help - it all adds up! I greatly appreciate your support and will keep you posted on my progress.

Keep the Fire Burning!!!



Jimmy Breitfeller
Turn off Music before you "Click to Play"
Signs of Melanoma Carcinoma Skin Cancer

How Skin Cancer Develops by " : Dermatology"

Call for Patients with Unresectable Liver Metastases Due to Melanoma

Delcath Systems Granted Orphan-Drug Designations for Cutaneous and Ocular Melanoma

Delcath is actively enrolling patients in a Phase III clinical trial testing its proprietary drug delivery system, known as Percutaneous Hepatic Perfusion (“PHP”), with melphalan for the treatment of ocular and cutaneous melanoma metastatic to the liver.

This NCI-led trial is enrolling patients at leading cancer centers throughout the United States. Commenting on these orphan-drug designations, Richard L. Taney, President and CEO of Delcath, stated, “These favorable designations are important steps in our efforts to secure Delcath’s commercial position upon conclusion of our pivotal Phase III trial for metastatic melanoma. We remain steadfast in our commitment to become the leader in the regional treatment of liver cancers and we continue to enroll patients in this study, and advance our technology and the promise that it offers to patients with these deadly forms of melanoma and other cancers of the liver, all with limited treatment options.”

Orphan drug designation, when granted by the FDA’s Office of Orphan Products Development, allows for up to seven years of market exclusivity upon FDA approval, as well as clinical study incentives, study design assistance, waivers of certain FDA user fees, and potential tax credits.

Current Trial Centers

Phase I Study of Hepatic Arterial Melphalan Infusion and Hepatic Venous Hemofiltration Using
Percutaneously Placed Catheters in Patients With Unresectable Hepatic Malignancies

James F. Pingpank, Jr., MD, FACS
Associate Professor of Surgery
Division of Surgical Oncology
Suite 406, UPMC Cancer Pavillion
5150 Centre Avenue
Pittsburgh, PA 15232
412-692-2852 (Office)
412-692-2520 (Fax)

Blog Archive

Call For Melanoma Patients!!!!

Call For Melanoma Patients!!!!

Dr. Rosenberg Has a New Clinical Trial.

Our latest treatment has a 72% objective response rate with 36% complete responses.

We are currently recruiting patients for our latest trial.

Is there some way to post this “Call for Patients” on the web site?

Steve Rosenberg

Dr. Rosenberg's Clinical Trials

(For a copy of the research paper.. see My Shared files)

The news headlines shown above for Melanoma / Skin Cancer are provided courtesy of Medical News Today.