lack herceptin response lowered with PI3K inhibitor...

[RobinP]

From Artemis's May 2006 online subscription by Johns Hopkins Hospital

http://www.hopkinsbreastcenter.org/a.../200605/6.html

Lack of Response to Herceptin May Be Reversed with Addition of a PI3K Inhibitor
Breast cancer patients with HER2-positive tumors who don't respond to Herceptin (trastuzumab) may benefit from cocktail therapy that includes Herceptin along with one or more PI3K inhibiting agents, say researchers at TheUniversity of Texas M. D. Anderson Cancer Center.

Their findings, reported at the annual meeting of the American Association for Cancer Research (AACR), were made in cell culture and mice studies, but are so promising that a Phase I/II clinical trial will start at M. D. Anderson in HER2-positive breast cancer patients whose disease has progressed despite Herceptin treatment.

"More than half of patients with HER2-positive tumors don't respond to Herceptin as a single agent, and our research has shown us why that is and what might be done to help these patients," says the study's lead author, Dihua Yu, M.D., Ph.D., professor in the Department of Surgical Oncology.

"If this drug cocktail shows benefit, we hope to be able to identify those patients who won't respond to Herceptin before they start the treatment, and offer them a new and beneficial drug combination," Yu says. "Patients who don't respond to Herceptin have worrisome outcomes, so we hope this strategy will help them."

Combining PI3K inhibitors with existing therapies also might provide additional benefit in treating other breast tumor types.

In 2004, Yu and her research team reported that patients who don't respond to Herceptin have very low levels of PTEN in their breast tumors, whereas women who respond have higher levels of this protein. In normal cells, PTEN is a powerful tumor suppressor gene that helps control cell division. In about half of all of breast tumors (HER2-positive or not), however, PTEN levels are very low or the protein is completely missing.

It was known that when Herceptin, a monoclonal antibody, binds to the HER-2 protein on the outside of tumor cells it takes days for the protein to degrade. But Yu found that within 10 minutes of administration, Herceptin activated PTEN. This suggested that Herceptin works by rapidly mobilizing PTEN in addition to inhibiting HER-2 growth signals, she says.

Further research in Yu's lab demonstrated a correlation between Herceptin response and high levels of PTEN, and a link between lack of response and low or missing PTEN activation. Therefore, the presence of PTEN in a HER2-positive tumor is a powerful predictor of who will respond to Herceptin, Yu says.

The research group then dug a little deeper into the question of how Herceptin might function despite a lack of PTEN in a breast tumor.

PTEN is known to block the effect of a growth-promoting protein known as PI3K, which itself controls an oncogenic pathway that includes the cell proliferation kinases Akt and mTOR. Yu decided to test what would happen if she administered an experimental drug that blocks PI3K, and thus mimics PTEN's tumor suppressor activity.

In this study, the research group tested seven different PI3K inhibitors that are either used or under development for clinical trials. They found that one, RAD001 (everolimus), had better antitumor activity when combined with Herceptin than did Herceptin or RAD001 alone.

Another PI3K inhibitor, TCN-P (triciribine), showed significant benefit when used in combination with Herceptin, Yu says. Even with a low dose of TCN-P, the combination therapy halted growth of PTEN-deficient HER2-positive breast tumors implanted in mice.

We think the combination of Herceptin and a PI3K inhibitor is affecting multiple cancer pathways," she says. "It will be interesting to see if other PI3K inhibiting agents now being developed also will work in HER2-positive, PTEN-negative tumors, as well as in other breast tumors that lack PTEN."

SOURCES:
University of Texas, M.D. Anderson Cancer Center (http://www.mdanderson.org)
Annual Meeting of the American Association for Cancer Research, April 5, 2006, Washington, DC

[Marily]

Robin thank you for the information. I am passing this on to my physician. There are many out there who seem to have this problem, one was a very good friend of mine who we lost this past year. It seems as if I am always saying .."if they only could have hung on"... hugs, Marily

[Tom]

Thanks Robin. I have been giving Mom inositol hexaphosphate each day, which has been shown to be a PI3K inhibitor. This makes me feel better that they are working on more powerful PI3K inhibitors. If you search for PI3K+IP-6, you will find information on it. It has also been shown to stimulate Natural Killer cell activity, which boosts the immune system.

Tom

[fcrcm]

Thanks for this info Robin. I have been on Herceptin (bone & liver mets) since Nov '05, and my June PET scan showed a new bone mets at the hip, From my point of view, this means that Herceptin isn't doing much for me, so I posted a question re P13K inhibitors.

Does anyone out there know if a "break through" bone met after only 8 months of Herceptin is unusually soon?

So glad I found this link!

[RobinP]

I'm glad the information has helped you. Sorry to hear that you have bone mets, others have stayed on Herceptin in such a situation, assuming that Herceptin still is helping. Of course, you don't know for sure you don't have pTEN and that you need a PI3K inhibitor unless you did have pTEN tested like some rare others here on this board. I think there may be other things that causes progression while on Herceptin too like high levels of her1,3 and posssibly IGFR. There is just so much that is unknown yet as to all the specific causes of progression while on Hercpetin and medication remedies for it. I do think at MD Anderson, Dr. Esteva and at Dana Farber's Cancer Center- Dr. Winer are studying progression while on Herceptin and may have more information.Good luck to you, you're in my prayers.

Becky mentioned a natural PI3K inhibitor months ago, I think it was Selenium and Maitake Mushrooms activate pTEN and turn it on. See that posting link...
http://her2support.org/vbulletin/sho...referrerid=454

[R.B.]

Please see references to PI3k in Greek Diet post.

Re stimulating immune system. I am just begining to try and get a minimal grasp on the subject of oxidation as part of the bodies defesive mechanisms.

On very limited knowledge and not much than straws in the wind I think it is important to understand the immune system is a potential double edge system.

When it is already overstimulated as might happen with permenant excess omega six there may be oxidative stress. Stimulation of the immune system in these circumstances may be bad news.

The ideal is that the immune system works when it is meant to and powers down to low level when it is not.

Part of the immune system is the production of super peroxides aldehydes etc.

My guess is these systems if they start over acting and are permenantly "on" in the absence of threat they are the start of oxidative stress, which can lad to telemore degredation and genetic compromise. See Greek Diet post.


RB