important-- turning her2+ Stage IV into chronic treatable disease

Lani · 04-20-2015, 08:57 PM

or even "curing it" Lock all the doors, bolt all the windows, move all the dressers away from the windows...let's keep this puppy from getting out to the yard to chase the squirrels!!

New signaling pathway discovered in HER2-positive breast cancer, and two potentially powerful drug targets
[Cold Spring Harbor Laboratory]
Cold Spring Harbor, NY -- One of the most promising ideas in cancer treatment is to apply a lesson learned in the fight against AIDS (Acquired Immune Deficiency Syndrome): simultaneously attacking a pathological process at different points of weakness can, in some cases, deal a knock-out blow. Just as the so-called AIDS “cocktail” directs multiple agents against multiple targets, so too might future anti-cancer cocktails be directed at multiple, highly specific targets in known cancer pathways. One key in cancer is knowing precisely which targets to hit, in which combinations, for the illness takes many different forms and works through a stunning variety of biological mechanisms.

A team at Cold Spring Harbor Laboratory (CSHL) has published in the Journal of Biological Chemistry results of experiments that lay bare a previously unknown pathway activated in a highly lethal form of breast cancer. The pathway, they discovered, contains at least two potentially powerful drug targets, according to the team leader, CSHL Professor Nicholas K. Tonks.

The breast cancer type is called HER2-positive. Affecting about one breast cancer patient in four, it is characterized by tumor cells overexpressing a signaling protein called HER2. The drug Herceptin, which targets HER2, is an effective first-line treatment for about one-third of women with HER2-positive breast cancer, but in most cases, resistance to the treatment develops within a year.

HER2-positive breast cancer, which is associated with poor prognosis, has been traced to an excess of signaling through receptors, or docking ports, called HER2 found on the surface of certain mammary epithelial cells. (Scientists also use the name ERBB2 to describe this surface receptor). When an activating protein docks at the receptor, a cascade of signals is sent inside breast cells. Ultimately, these signals change the expression of genes in the cell nucleus, causing the cell to grow abnormally. Herceptin, when it works, blocks the ability of HER2 receptors to send these aberrant, growth-inducing signals inside the cell.

But often Herceptin does not work at all, and even when effective, it stops working after a while. With this in mind, Tonks and a team that included Mathangi Ramesh, a Ph.D. student in his lab and first author of the new paper, set out to find weaknesses “downstream” of the HER2 receptor, inside breast cancer cells. In particular, they looked at the possible involvement in the HER2 pathway of a class of enzymes called protein tyrosine phosphatases, or PTPs. Transmission of signals in a cell is controlled by the coordinated activity of two families of enzymes: protein tyrosine kinases, which add phosphate groups to proteins, and protein tyrosine phosphatases, which remove them. Dr. Tonks purified the first-discovered member of the PTP family of enzymes, called PTP1B, in1988. It has been shown that PTP1B has a role in regulating proliferation in HER2-positive breast cancer cells.

In the new work, the team looked at 37 members of the PTP family to see if any of them also helped to regulate some part of the HER2 pathway. Using a three-dimensional model of mammary cell development created by Dr. Senthil Muthuswamy, formerly of CSHL and now at the University of Toronto, the team tested to see if abnormal growth initiated by HER2 signaling would be either enhanced or reduced if any of the 37 PTPs was experimentally “knocked down.” They went through the list methodically, one at a time. This led them to focus on one in particular, called PTPD2.

In this screen, Mathangi Ramesh found that when PTPD2 was absent in mammary cells grown in 3-D culture, the cells failed to grow abnormally, even when the HER2 signaling pathway was activated. PTPD2, therefore, is what scientists call a “positive regulator” of the pathway. Without it, abnormal growth of the type seen in HER2-positive cancers does not occur. Conversely, a future drug that prevents PTPD2 from acting in cancer cells could generate therapeutic results – by preventing or reducing HER2 signaling.

In other experiments designed to determine how PTPD2 operates in HER2-activated breast cancer cells, the team found an “interaction partner,” a lipid called phosphatidic acid, or PA. PTPD2 binds to PA, the team discovered, and becomes more active as a consequence. Another series of experiments demonstrated that when the enzyme that generates PA in the cell, called PLD2, is targeted with an existing small-molecule drug, abnormal growth does not occur in mammary cells in which the HER2 pathway is activated. Thus PLD2 is also a potential drug target.

Perhaps most exciting, the CSHL team was able to show a specific series of relationships with direct implications for possible future combination drug development. “In this work, Mathangi Ramesh has found a new pathway – a signaling pathway downstream of HER2 that we didn’t know about before,” Tonks says. “Two components of the pathway, the phosphatase PTPD2 and the lipid PA, are together required for HER2 signaling to function in mammary epithelial cells.” Specifically, they are required in processes in which mammary cells lose their normal polarity, or spatial orientation; and in which the cells lose the ability to commit preprogrammed suicide, or apoptosis, upon detection of gross abnormalities. Both of these flaws occur in HER2-positive breast cancer cells.

Both PTPD2 and PLD2 might therefore be the targets of future drugs. So too might the phosphatase PTP1B, which in prior work was shown to be required for a third aspect of HER2-related carcinogenesis – proliferation – that neither PTPD2 or PLD2 specifically affects, as shown in the current phase of the research.

“If you can use combination approaches, hitting multiple targets within the cell to reduce the activity of each, and you see a synergistic effect between them, you may be able to overcome some of their harmful effects in HER2-positive cancer, and perhaps also resistance,” says Tonks. “That is our goal.”

The research described here was supported by the National Institutes of Health; The Gladowksy Breast Cancer Foundation; The Don Monti Memorial Research Foundation; Hansen Memorial Foundation; West Islip Breast Cancer Coalition for Long Island; Glen Cove CARES; Find a Cure today (FACT); Constance Silveri; Robertson Research Fund; Masthead Cover Yacht Club Carol Marcincuk Fund.

ABSTRACT: A Novel Phosphatidic Acid-Protein-tyrosine Phosphatase D2 Axis Is Essential for ERBB2 Signaling in Mammary Epithelial Cells
[Journal of Biological Chemistry] We used a loss-of-function screen to investigate the role of classical protein-tyrosine phosphatases (PTPs) in three-dimensional mammary epithelial cell morphogenesis and ERBB2 signaling. The study revealed a novel role for PTPD2 as a positive regulator of ERBB2 signaling. Suppression of PTPD2 attenuated the ERBB2-induced multiacinar phenotype in three-dimensional cultures specifically by inhibiting ERBB2-mediated loss of polarity and lumen filling. In contrast, overexpression of PTPD2 enhanced the ERBB2 phenotype. We also found that a lipid second messenger, phosphatidic acid, bound PTPD2 in vitro and enhanced its catalytic activity. Small molecule inhibitors of phospholipase D (PLD), an enzyme that produces phosphatidic acid in cells, also attenuated the ERBB2 phenotype. Exogenously added phosphatidic acid rescued the PLD-inhibition phenotype, but only when PTPD2 was present. These findings illustrate a novel pathway involving PTPD2 and the lipid second messenger phosphatidic acid that promotes ERBB2 function.

Rolepaul · 04-20-2015, 10:12 PM

That is very exciting. I would also like to hear if PDL1 or similar type of drugs are being paired with Herceptin to get better activity. Right now, Perjeta plus TDM-1 is over US$23,000 per treatment. I hope that insurance companies do not decide it is better to have treatment declined and pay a fine versus getting good treatments in place. And I hope we in the pharma/Biotech manufacturing community can get people in place to cut the cost of these drugs.

KDR · 04-21-2015, 01:51 PM

Paul,
How fully on board do you think pharma is with immunotherapy?
Karen

Rolepaul · 04-21-2015, 02:39 PM

Immunotherapy is pretty expensive. It is very individualized in many cases. Treatments on the order of $100,000 for cell derived therapies using the patient's cells are common place. I asked for the ability to reduce the cost by 75%, ie get it to $25,000 per patient dose. The client company said they did not think that was possible. Still not sure it is. TDM-1 is $23,000 per dose list price at the hospital. That is a lot for insurance companies to handle. I do not want to go back to the 1950s when cutting was the only option and death was going to occur to disfigured people. I think we need to educate people to think and get meds to be like the computer industry. Get costs down and make healthcare better.

KDR · 04-21-2015, 04:52 PM

I see a huge disparity between immunotherapy costs and long-term treatments costs, much to the dismay of Big Pharma.

Karen

forher · 04-21-2015, 09:31 PM

Two things from this article stuck out to me:
1. "Highly lethal form of breast cancer"
2. "Resistance to treatment (herceptin) within a year" - do any of you find this to be true? I asked my oncologist to put me on perjeta along herceptin, but she won't add perjeta because she said something about resistance. I don't have systemic disease(per scans) but do have shrinking brain mets. I asked to get herceptin to help keep my body clear. Should I even do this? Should I be concerned about herceptin resistance?

Mtngrl · 05-23-2015, 08:57 AM

Lani--

Thank you so much for keeping up on the new developments and posting on this site. I am so grateful for you and your diligence and wisdom.

I am pleased to see there's further work being done on my specific kind of cancer, and I'm also excited about the implications for cancer treatment in general. I get the impression that Herceptin ushered in a whole new era in cancer research. Looking for "on" and "off" switches that can be regulated seems like a very promising idea.

Cancer is so complex, and so cunning. I can't say I feel "blessed" to have gotten it, but having a strong incentive to learn more about the history and science of cancer is, for me, sort of a silver lining. Maybe it's more like a rusty tin lining (an expression I stole from someone else, but I love it). Anyway, I'm always interested in learning more.

Amy

laura4252 · 06-03-2015, 07:39 AM

I've been Stage 4 since 2009, with mets to the lungs in 2011. 2014 I noticed heaviness in upper respiratory area, then in April I decided I needed oxygen to deal with shortness of breath. I was on oxygen (I was consistently below 90, in the mid 80's), so I went on oxygen 24/7--Very strange for me since I've always been extremely active. I decided to try Abraxane after years of saying NO to non-targeted chemo. Within three weeks I was completely off oxygen, but the side effects of the chemo are huge, and I'm not inclined to do Cycle 3 and 4......PET/CT on June 12.

suzan w · 06-03-2015, 06:44 PM

Once again, Lani, you have provided valuable info in (sort of !) easy to understand terms. It is one of my greatest life accomplishments to have gotten the upper hand on Her2+ breast cancer.

agness · 07-29-2015, 03:06 PM

It sounds like the connections they are finding are related to liver functionality - for insulin and repair. I wonder if a ketogenic diet might adjust for some of this to add to the mix in the meantime.

http://articles.mercola.com/sites/ar...-benefits.aspx

I feel like my liver and adrenals haven't ever recovered from the stress that caused my initial disease to start.

norkdo · 10-03-2015, 08:49 PM

thank you for this post.
amazing info.
RolePaul:
re: the $23000 cost of one dose of the medicine you discussed.
Rather than us pressuring our govt's (meaning taxpayers) to pay the ransom charges, what would it take for women with HER2 to band together and get other people on board, to form mobs of rocket-launching, hostage taking angry public demonstrations on the streets in front of the pharmaceutical company? Just sayin'. I will settle for a "get arrested in large numbers" peaceful demonstration alternative and drop the violent part of it, even. What say, ladies? Who's with me?

Juls · 10-27-2015, 07:50 AM

I read this post months ago and reread today. I'm with forher. Not to take away from the rest of the article but the "in most cases resistance to the treatment develops within a year" really bothers me.
If true why are some of us on this for years. I have been on H for 2 1/2 years, another lady at my clinic has been on it for 8-9 years & many others just as long. I do realise that Doctors are unsure about when to stop treatment in case it comes back.
In another recent post Dr Slamon suggests if no progression at 3 years , consider stopping herceptin. So who or what do we trust or do?

Nora - In UK at the moment many drugs cancelled here due to cost. TDM-1 is another one at risk. There is a petition here aiming to get 50,000 signatures to send to Roche to bring cost down. Its just under the 50k at the moment. (change.org) The problem is it seems quite low key!

Mtngrl · 10-27-2015, 10:08 AM

Yeah--we're definitely not there yet.

I don't know if I'm "resistant" to Herceptin, but it's pretty clear I need to have something else with it. My most extensive progression was when I was on Herceptin with an aromatase inhibitor (which did no good because I was no longer ER+) for five months.

Amy

laura4252 · 10-27-2015, 11:06 AM

I agree with Amy-- We have similar history and diagnosis, and Herceptin stopped "cutting it" after two years....I tried all kinds of other targeted therapies, Xeloda, Navelbine, Gemzar- none worked. After two years of Stage IV (lungs), I was preparing for mastectomy of the right breast when TDM1 came on the scene. I decided against mastectomy and did TDM1 with Heceptin for 18 months when it stopped working. I tried Doxil October 2014 (found out I'm allergic to that and Taxotere)....Lungs worsened in 2014 into 2015, so we added Perjeta to Herceptin Jan. 2015, lungs worsened to the point that I was on oxygen 24/7 April 2015. I tried Abraxzane--my body agreed to that, and in six weeks there was remarkable improvement (two cyles, two weeks on, one week off). Chemo was horrible, and for the first time since I started Herceptin in 2011 I lost my hair, shaved my head and joined the ranks of bald women ravaged by chemo.....but it worked, kind of.....I'm doing two more cycles at 75% dose (just finished the first) and this whole cancer crap is getting really old.....I'm wary of the alternative therapies, so I just keep going along eating well, taking care of my body and soul, and hoping for a pill so I can get this lousy port out someday soon.....