current sept 06 MAMM issue artile on herceptin + PI3K Inhibitor...

[RobinP]

Just thought this might interest some on these boards who have been resistenct to Herceptin. Although Pten is not routinely tested now, I suspect it will be in the future to tailor care.

Getting Herceptin to Work for More Patients Researchers in Texas may have come up with a way to make the powerhouse drug Herceptin work for more breast cancer patients, which could prevent more recurrences and help patients live longer.

Herceptin (trastuzumab) is a biologic therapy that selectively attacks breast cancer cells while leaving healthy cells alone. The drug, which has been used by more than 220,000 patients with breast cancer, targets tumor cells that make too much HER-2, a protein associated with aggressive disease. About 25 percent to 30 percent of breast cancers are characterized as HER-2 positive, and could potentially benefit from Herceptin.

However, an estimated 50 percent of women with HER-2 disease don't respond to Herceptin alone. Their disease is said to be Herceptin resistant.

Reporting at the annual meeting of the American Association for Cancer Research in April, Dihua Yu, M.D., a breast cancer researcher at the University of Texas M.D. Anderson Cancer Center in Houston, announced that she and her colleagues had identified a way to help patients with resistant disease by combining Herceptin with drugs that interfere with the function of a protein identified as PI3 kinase (PI3K) that stimulates the growth of cancer cells.

Although the findings came from test-tube and mouse studies, they were so promising that in May one of Yu's M.D. Anderson colleagues, breast cancer specialist Francisco Esteva, M.D., launched a phase I and II clinical trial for women whose disease hasn't responded to Herceptin.

Yu's findings, which have been submitted for publication, build on previous research in which she found that tumors of Herceptin-resistant patients have low levels of a tumor-suppressing protein called PTEN. Conversely, tumors of patients in whom Herceptin works have higher levels of this protein.

PTEN interferes with the function of the PI3K protein. But because PTEN is a huge protein that is difficult to work with, Yu looked around for smaller molecules that mimic PTEN's activity. She experimented with seven PI3K pathway inhibitors, and got the strongest results when she combined Herceptin with everolimus, also called RAD0001, and when she combined it with triciribine, or TCN-P.

Women in Esteva's trial will get Herceptin and RAD0001.

Yu suspects that other PI3K inhibitors still in development might prove to be even more effective in making Herceptin work for more women. "I'm encouraged," she said. "I want to see an even better effect."

—Jane E. Allen

[heblaj01]

One of the other PI3K inhibitors that Dr Dihua Yu is alluding to may be the experimental drug SF1126 being considered also at MD Anderson for clinical trial:

http://www.semaforepharma.com/pdf/AARC_040406_FINAL.pdf

NEW DATA PRESENTED AT AACR MEETING FURTHER SUPPORT THE ADVANCE OF SEMAFORE’S TARGETED PI3K INHIBITOR INTO PHASE l TRIALS

--Studies at M.D. Anderson Show First In Vivo FDG-PET Imaging of SF1126 and Demonstrate Mutational Activation of PI3K as a Potential Marker for Selection of Patients—


However in a detailed discussion in the following article of the mode of action of some of the PI3K inhibitors some of their potential serious side effects are considered :

http://www.pubmedcentral.gov/articlerender.fcgi?artid=1236693

The survival kinases Akt and Pim as potential pharmacological targets

[Tom]

I wanted to remind you guys that there are natural inhibitors of PI3k, and that IP-6 (inositol hexaphosphate) is one of them. I have been giving Mom IP-6 for some time now. I am still trying to extrapolate appropriate dosing of IP-6 from research abstracts. IP-6 is readily available from The Vitamin Shoppes as well as Life Extension (www.LEF.org). The inhibition of PI3K is critical to slowing/preventing angiogenesis. The following article is very long, and is more than you could learn in a lifetime about angiogenesis. I read a little bit at a sitting, as it gives me a headache, which ususally means it's thorough. I have linked to it below. Enjoy.

Tom

http://pharmrev.aspetjournals.org/cg...2/2/237?ck=nck

[RobinP]

Thanks Tom. I hope Mom is doing well. Take care to both of you.

[Rich66]

Semafore's SF1126, a Vascular Targeted Pan-PI3K/mTOR Inhibitor, Is Well Tolerated and Demonstrates Activity in Phase I Solid Tumor Patients

Posted on : 2009-05-30 | Author : Semafore Pharmaceuticals, Inc. News Category : PressRelease

INDIANAPOLIS, May 30 IN-Semafore-at-ASCO Clinical Data Presented at the 2009 ASCO Meeting INDIANAPOLIS, May 30 /PRNewswire/ -- Semafore Pharmaceuticals, Inc., a privately held cancer drug discovery and development company, today presented data from a Phase I clinical trial of its vascular targeted pan-PI3K/mTORC1/2 inhibitor, SF1126, at the 2009 American Society of Clinical Oncology (ASCO) Annual Meeting, being held in Orlando, Florida. Dr. E. Gabriela Chiorean, from the Indiana University Simon Cancer Center in Indianapolis, IN presented the interim Phase I data on SF1126 in 36 advanced solid tumor patients. The majority of patients were heavily pretreated with a median of four prior chemotherapy regimens. Sixteen of 36 (44%) patients achieved disease stabilization with a median duration of 12 weeks. Of note, a GIST, endometrial, and prostate cancer patient each achieved durable stable disease for 20 weeks (5 mos.). These specific tumor types are associated with aberrations of the PI3K pathway that commonly lead to resistance and poor prognostic outcomes. Pharmacodynamic analysis of tumor tissue confirmed inhibition of the PI3K pathway by complete absence of a downstream target (pS6). In contrast, a normal tissue (skin) demonstrated no inhibition providing evidence of tumor selectivity of SF1126. Pharmacokinetics displayed dose proportionality and no accumulation between cycles. SF1126 was well tolerated. The most common side effects were grade 1 or 2 vomiting (42%), nausea (39%), diarrhea (33%), fever (22%), fatigue (19%), chills (14%), and puritis (11%). There were two patients with grade 3 toxicity, one with diarrhea, the other with urticaria and pruritis. Notably, there were no clinically significant changes in glucose or insulin levels reported. "Based on these Phase I results we are encouraged that SF1126 is well tolerated and may hold promise for the treatment of solid tumor malignancies," said Dr. Chiorean. This multi-center Phase I study was conducted at: Indiana University Simon Cancer Center, Indianapolis, IN; Arizona Cancer Center, Tucson, AZ; Winship Cancer Institute, Emory University, Atlanta, GA; Scottsdale Clinical Research Institute, Scottsdale, AZ. About SF1126 SF1126 is the only clinical stage vascular targeted pan-PI3K inhibitor that selectively inhibits all PI3K class I isoforms and other key members of the PI3K superfamily, including mTORC1/2, DNA-PK, PLK-1, CK2, ATM and PIM-1. SF1126 is designed to inhibit both angiogenesis and cell proliferation by targeting and binding to integrins that are expressed on the surface of new tumor vasculature and within the tumor compartment. In preclinical xenograft models SF1126 has demonstrated broad activity as a single agent; synergy with commonly used chemotherapy agents, targeted agents, and radiation; and has been shown to reverse resistance mediated through the PI3K/PTEN pathway. About PI3 Kinase Phosphatidylinositol 3 kinases (PI3K) are involved in one of the major pathways of intracellular signal transduction and are important in controlling cell growth/angiogenesis, differentiation, proliferation and survival/apoptosis. Dysregulation of the PI3 kinase signaling cascades can lead to cancer and aberrant PI3K pathway activity is observed with high frequency in a variety of tumor types. PI3K signaling through its downstream effectors AKT and mTOR is also known to promote tumor cell survival, proliferation, and growth. Dysregulation of PI3K signaling is also thought to contribute resistance to a variety of anticancer therapies. Thus, PI3K is considered a high value target in treating cancer. About Semafore Pharmaceuticals, Inc. Semafore is a clinical stage drug discovery and development company focused on small molecule modulators of the PI3 kinase and PTEN cell signaling pathway, a promising target pathway for multiple disorders, including the company's focus - cancer. Semafore is a leader in the development of PI3K inhibitors and one of the first biopharmaceutical companies to focus on both PI3K and PTEN inhibitors. The Company has successfully discovered and is developing a portfolio of drug candidates addressing these targets. Semafore is also leveraging its experience in the PI3K arena to identify and design inhibitors that block multiple pathways. For more information visit the Company's web site at www.SemaforePharma.com. SOURCE Semafore Pharmaceuticals, Inc.

[Laurel]

Tom,

What dose is your mother taking of IP-6?

[Ellie F]

Tom
Am I right that IP-6 is found in peas, beans, legumes and other high fibre foods?

Did your mum have any side effects taking it?

It seems that the evidence keeps mounting about anti inflammatory foods and their synergy together including the whole debate about omega 3/6 ratio.

Does this inflammation pattern seem to relate to all bc sub-types or does it have a particular relevance to her2?

Wondered if Lani or Rich or RB may have a view.

Ellie