Navigation Links
Hit multiple targets for maximum benefit in HER2-positive breast cancer, studies suggest
Date:3/8/2011

Combining targeted therapies might be required for maximum anti-tumor activity when treating HER2-positive breast cancers, according to two new studies by Vanderbilt-Ingram Cancer Center (VICC) investigators.

The findings, reported in two papers in the Proceedings of the National Academy of Sciences (PNAS), suggest that upregulation of the HER3 receptor limits the effectiveness of two classes of targeted therapies (HER2- and PI3 kinase-targeted therapies). Therefore targeting HER3 together with these agents should improve their clinical utility.

Around 25 percent of breast cancers have increased expression of the HER2 receptor, which is associated with more aggressive tumors and a poorer prognosis. HER2-targeted therapies like trastuzumab (Herceptin) and lapatinib (Tykerb) are effective in many women with HER2-positive breast tumors.

"But even in patients who respond to HER2-targeted therapies, the clinical response tends to be short-lived and tumors become resistant," said Carlos Arteaga, M.D., professor of Medicine and Cancer Biology, and director of the VICC Breast Cancer Research Program.

HER2 is a member of the EGF receptor family involved in signaling pathways that promote cell growth. HER2 must interact and form complexes with other members of the EGF receptor family, and its main partner in activating pathways that promote tumor growth is HER3. This complex of HER2/HER3 is a potent activator of the PI3K/Akt pathway, the key survival pathway in HER2-positive cancers.

"Based on this evidence, we hypothesized that, for these therapies to have maximum effect, HER3 and its output to the PI3K/Akt pathway must be completely shut down," Arteaga said.

A postdoctoral fellow in Arteaga's laboratory, Joan Garrett, Ph.D., led experiments to examine the effect of the HER2 tyrosine kinase inhibitor, lapatinib, on HER3 expression and activity.

She found that inhibiting HER2 with lapatinib led to an increase in HER3 expression and activation in both HER2-positive human breast tumors and cell lines. Inhibiting HER3 in HER2-positive breast cancers growing in mice made tumor cells markedly more sensitive to lapatinib. Additionally, blocking both HER2 and HER3 was more effective at inhibiting the activity of PI3K/Akt pathway than either inhibitor alone.

Those results, published March 7 in PNAS, show that upregulation of HER3 limits the effectiveness of HER2-targeted therapies and that a combination of drugs that target both HER2 and HER3 should be considered for optimal clinical benefit.

Since PI3K/Akt is the key pro-survival signaling pathway downstream of HER2, the investigators also examined the utility of inhibitors of PI3K in HER2-positive breast cancer cells.

Those experiments, led by postdoctoral fellow Anindita Chakrabarty, Ph.D., and published Feb. 28 also in PNAS, showed a similar upregulation of HER3 in response to treatment with a PI3K inhibitor currently in clinical development. In turn, this compensatory upregulation of HER3 partially reactivated the PI3K/Akt pathway and limited the action of the PI3K inhibitor.

"This shows that therapeutic use of PI3K inhibitors would be limited if used as single agents in HER2-positive cancers. These results have implications for other cancers treated with this class of drugs," Arteaga said. However, he notes PI3K inhibitors might have clinical merit when used in combination with HER2-HER3 antagonists.

Since both HER3 inhibitors and PI3K inhibitors are now in clinical development, "these studies provide a scientific rationale for how a combination of the new drugs with HER2-targeted therapies might be used to provide better results for many patients with breast cancer," Arteaga said.


'/>"/>

Contact: Melissa Marino
melissa.marino@vanderbilt.edu
615-322-4747
Vanderbilt University Medical Center
Source:Eurekalert

Related medicine news :

1. Multiple sclerosis blocked in mouse model
2. Psoriasis medication rises hope in the fight against multiple sclerosis
3. How sunlight may reduce the severity of multiple sclerosis
4. Multiple childbirth linked to increased risk of rare, aggressive triple-negative breast cancer
5. Wayne State University researchers publish results settling multiple sclerosis debate
6. VCU Massey first to combine targeted agents to kill multiple myeloma cells
7. Most ADHD Kids Have Multiple Conditions, Study Says
8. More than allergies: Histamine may be a possible drug target for multiple sclerosis
9. Tiny RNA shown to cause multiple types of leukemia
10. Laboratory studies show promise for new multiple sclerosis treatment
11. Common for patients to undergo multiple cardiac imaging tests, with high cumulative radiation dose
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/12/2016)... ... ... The law firm of Morrow, Morrow, Ryan & Bassett is offering scholarships to ... to encourage applicants to pursue a degree in their field of study and upon ... “We have available jobs in St. Landry and Evangeline Parishes that can be filled ...
(Date:2/12/2016)... Falls Church, VA (PRWEB) , ... February 12, ... ... in Store?, Feb. 29, 2016 — 1:30 p.m. – 3:00 p.m. EST, ... burner issue in the life cycle of pharmaceutical products, garnering increased attention from ...
(Date:2/12/2016)... ... February 12, 2016 , ... T.E.N., a ... closed for the ISE Southeast Awards 2016. Finalists and winners of the ISE® ... Southeast Executive Forum and Awards Gala on March 15, 2016 at the Westin ...
(Date:2/12/2016)... , ... February 12, 2016 , ... Fisher House Foundation ... Mayor John J. Lee, Nevada Military Support Alliance president Scott Bensing, and Peggy Kearns ... the VA Southern Nevada Healthcare System. This will be the first Fisher House ...
(Date:2/12/2016)... (PRWEB) , ... February 12, 2016 , ... Erlanger Agency ... the greater Columbus, OH area. The latest campaign focuses on the fight against breast ... Donations are now being accepted here . , Carmen is a loving single ...
Breaking Medicine News(10 mins):
(Date:2/12/2016)...  Memorial Hermann Health System has teamed up with ... bring a one-of-a-kind experience to pediatric patients at ... as 360-degree video and Google Cardboard, Howard was able ... giving the patients and their families an unexpected, and ... on video . Memorial Hermann IRONMAN ...
(Date:2/12/2016)... Feb. 12, 2016  Aralez Pharmaceuticals Inc. (Nasdaq: ... the Company will ring the Nasdaq Closing Bell at ... York at 4:00 p.m. ET on Tuesday, ... Adrian Adams , will perform the ... to 4:00 p.m. ET.  A live webcast will be ...
(Date:2/12/2016)... 2016 --> ... Inflammation Global Clinical Trials Review, H2, 2015 provides ... clinical trials landscape along with top level data ... (G7 & E7), Trial Status, Trial Phase, Sponsor ... companies involved and enlists all trials (Trial title, ...
Breaking Medicine Technology: