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Old 01-11-2014, 04:29 PM   #1
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Thumbs up promising new trial for inflammatory bc (starting w Stage IVs)

Novel Agent Set For Unique Clinical Test in Inflammatory Breast Cancer

A drug now used to treat a type of lymphoma has shown surprising benefit in preclinical studies of inflammatory breast cancer, according to a researcher at Thomas Jefferson University’s Kimmel Cancer Center.

The finding, published in the Journal of Experimental Therapeutics and Oncology, has led to development of a phase 1/2 clinical trial at Kimmel Cancer Center to test the agent, Romidepsin (Istodax™), in combination with nab-paclitaxel (Abraxane™) chemotherapy for advanced inflammatory breast cancer (IBC).

"Because this kind of breast cancer is very difficult to treat, we hope this new combination of anticancer agents will change the outcome of this aggressive disease," says the study's senior investigator, Massimo Cristofanilli, M.D., F.A.C.P., Professor of Medical Oncology and Director of the Jefferson Breast Care Center.

The study was conducted in collaboration with the lead author, Fredika Robertson, Ph.D., at The University of Texas M. D. Anderson Cancer Center, and was supported by a Promise Grant from the Susan G Komen Foundation awarded to Cristofanilli and colleagues in 2008.

Inflammatory breast cancer (IBC) is the most metastatic variant of locally advanced breast cancer, Cristofanilli says. Although it accounts for between 2-5 percent of all breast cancers in the United States — and 13 percent of breast cancers globally — it is responsible for a disproportionate number of deaths from breast cancer, he says.

One of the reasons for the lethality of inflammatory breast cancer is that early in the disease onset it produces emboli — small balls of cancer cells — which spread through the lymph system causing the typical breast swelling. These aggregates of cancer cells are resistant to chemotherapy, radiation, and are believed to be responsible for rapid metastasis, Dr. Cristofanilli says.

Experiments in laboratory cells and in mice models of inflammatory breast cancer demonstrates that Romidepsin is able to break the bonds that bind the cancer cells together, which then allows chemotherapy to effectively target single cancer cells, he says.

Romidepsin is a histone deacetylase (HDAC) inhibitor, a new class of drugs that regulates gene transcription in a unique way.

This study tested two other HDAC inhibitors, but found Romidepsin offered the best results. The agent was approved for use to treat cutaneous T-cell lymphoma in 2009. It is also undergoing clinical trials for use in other lymphomas.

"This study is a nice example of a transition from the laboratory to the clinic," says Cristofanilli. "Our laboratory work suggested it might be helpful to treat inflammatory breast cancer, and now we are about to open a clinical trial to test that very promising possibility."

Journal of Experimental Therapeutics and Oncology, December 2013
Thomas Jefferson University (http://www.jefferson.edu)
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Old 01-12-2014, 12:20 AM   #2
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Re: promising new trial for inflammatory bc (starting w Stage IVs)

This is interesting news. Histones are proteins used to clog up genes. They have a normal function, of course. Every cell in your body has the same genes. The genes for making Hydrochloric acid are located in the cornea of the eye just as they are in the parietal cells of the stomach. I imagine it wouldnt be pleasant to have the corneal cells start producing Hydrochloric acid but these genes in the cornea are inactive, at least partially due to their binding with Histone Proteins.

There are genes in the cancer cell that act to stop cancer cell growth. The cancer cells stop their action by wrapping histone protein around the genes. The body tries to fight back by putting acetyl groups on the amino acid Lysine of the DNA. This loostens up the grip of the Histone protein. The cancer cells fight back again. It is as if they could think. They use an enzyme, Histone deeacetylase to remove the acetate groups and tighten the binding of the Histone proteins. The Histone Deacetylase Inhibitors like Romidepsin inhibit this acetate removing enzyme. The only approved use for Romidepsin is the treatment of T cell Lymphoma.
It is administered IV on days 1, 8 and 15 of a 28 day cycle in a dosage of 14mg per square meter.

It has quite a few side effects: anemia, thrombocytopenia, lymphopenia, neutropenia, infections,
itching, edema, increased liver enzymes, fatigue headache and many more. Im glad to see they are starting to use these Histone Deaceylase inhibitors for more than T Cell Lymphoma. This enzyme is overactive in many cancers, and at least theoretically drugs like Romidepsin might have value.

The antisiezure drug Depakote has strong Histone Deacetylase inhibiting action and seems to be much safer than Romidepsin. Im curious if any clinicians have tried Depakote (Valproic Acid slow release) to treat various cancers.

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Old 02-26-2014, 05:14 PM   #3
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Navitoclax a BCL-2 inhibitor.

Navitoclax is a drug (experimental) undergoing clinical trials. It inhibits BCL-2 which is a protein that inhibits apoptosis or programmed cell death. Bax protein does the opposite as it facilitates apoptosis. In treating cancer you want to increase apoptosis. If you can inhibit the an ti-apoptotic BCL-2 protein, apoptosis increases.

The dosage of Nevitoclax is given for 14 days of a 21 day cycle. The first seven doses are 150mg each and the subsequent doses are 325mg. The main side effects are diarrhea, fatigue, nausea and throbocytopenia or decreased platelets. This is the most important side effect. Navitoclax has been involved in some stage 2 trials with various lymphomas. It looks promising. If it is approved it will probably be combined with various chemo drugs as chemo initiates apoptosis. If Navitoclax proves valuable it could be of use in many different kinds of cancers.

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