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Old 03-13-2013, 03:07 PM   #1
gdpawel
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Why Her-2 has not been a magic bullet in Breast Cancer

Nature Reviews Drug Discovery 6, 111 (February 2007) | doi:10.1038/nrd2253

Anticancer drugs: Escaping inhibition

Peter Kirkpatrick

The success of the ABL-kinase inhibitor imatinib in the treatment of BCR–ABL-driven leukaemia raised hopes that drugs that target key kinases underlying other cancers, such as members of the human epidermal growth factor receptor (HER) family, might be similarly efficacious. However, several small-molecule inhibitors of HER family kinases have shown limited efficacy in HER2-driven breast cancers, despite effective inhibition of kinase activity. Writing in Nature, Sergina and colleagues now provide an explanation for this phenomenon: failure to completely inhibit the kinase activity of HER2 allows oncogenic signalling through the kinase-inactive family member HER3 to continue.

Signalling in the HER family, which consists of epidermal growth factor receptor (EGFR), HER2, HER3 and HER4, involves receptor dimerization and transphosphorylation, which leads to the activation of various pathways, including the potentially oncogenic phosphatidyl-inositol 3-kinase (PI3K)/Akt pathway. Given the abundance of preclinical and clinical data indicating the importance of EGFR- and HER2-driven signalling in various cancers, drug discovery programmes have focused on developing tyrosine kinase inhibitors (TKIs) that target one or both of these kinases. However, although these agents are effective at inhibiting EGFR and HER2 phosphorylation in patients' tissues and tumours, Akt activity is not inhibited as might be anticipated in many patients, which could explain the limited clinical activity of the drugs.

To investigate this puzzle, Sergina et al. studied Akt inhibition by various HER TKIs in HER2-driven breast cancer cells in vitro and in tumour xenografts. Surprisingly, although Akt signalling was initially inhibited by the TKIs, this inhibition was not sustained. Assessment of signalling activity by HER family members revealed that although EGFR and HER2 phosphorylation and associated downstream pathways are durably inhibited by TKIs, dephosphorylation of HER3 is transient. This explains why Akt signalling is reactivated, because signalling in the PI3K/Akt pathway is driven primarily by transphosphorylation of HER3.

Further studies showed that inhibition of EGFR and/or HER2 by TKIs leads to compensatory changes in the HER3 phosphorylation– dephosphorylation equilibrium, which seems to be driven by Akt-mediated negative-feedback signalling. The TKI-refractory HER3 phosphorylation is due to HER2 because it can be suppressed by anti-HER2 siRNA transfection. In addition, complete inactivation of HER2 with high doses of TKIs prevents Akt activity being restored by HER3 signalling.

So, it seems that in order to treat HER2-driven breast cancers more effectively, drugs that are able to fully inactivate HER2 kinases are needed to prevent oncogenic Akt signalling being reactivated by HER3. As the authors note, until compounds with the necessary potency and specificity can be found, combinations of agents designed to undermine the resiliency of HER-family signalling might represent the most promising therapeutic approach. Furthermore, whichever strategy is tested, HER3 transphosphorylation should be used as a biomarker to monitor treatment efficacy rather than inhibition of autophosphorylation, which is used at present.

Sergina, N. V. et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 7 Jan 2007 (doi: 10.1038/nature05474)

http://www.nature.com/nrd/journal/v6...l/nrd2253.html
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Old 03-13-2013, 03:08 PM   #2
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A Multitude of Pathways/Mechanisms

Targeted therapy is designed to block a specific gene or protein that has a critical role in the survival, growth, invasion, or metatasis of a specific cancer cell. It takes advantage of the biologic differences between cancer cells and healthy cells by 'targeting' faulty genes or proteins that contribute to the growth and development of cancer.

In other words, 'targeted' treatments fight cancer by correcting or modifying defective 'pathways' in a cancer cell. In healthy cells, each 'pathway' is tightly controlled. For instance, healthy cells are allowed to divide into new cells, and damaged cells are destroyed. However, in cancerous cells, certain points in the 'pathway' become disrupted, usually through a genetic mutation (change in form).

Designing "targeted" anticancer drugs begins with identifying the genes or proteins that are specific to the development of cancer and testing whether blocking those genes or proteins gets rid of the cancer. Genetic (molecular) tests are instrumental in accomplishing this task.

However, understanding 'targeted' treatments begins with understanding the cancer cell. Every tissue and organ in the body is made of cells. In order for cells to grow, divide, or die, they send and receive chemical messages. These messages are transmitted along specific 'pathways' that involve various genes and proteins in a cell.

Genetic-based testing examines a single process within the cell or a relatively small number of process. The aim is to tell if there is a theoretical predispostion to drug response. Cell-based testing not only examines for the presence of genes and proteins but also for their 'functionality' (their interaction with other genes, proteins, and processes occurring within the cell, and for their response to 'targeted' drugs).

Genetic-based testing involves the use of dead, formaldehyde preserved cells that are never exposed to 'targeted' drugs. Genetic-based tests cannot tells us anything about uptake of a certain drug into the cell or if the drug will be excluded before it can act or what changes will take place within the cell if the drug successfully enters the cell.

Genetic-based tests cannot discriminate among the activities of different drugs within the same class. Instead, it assumes that all drugs within a class will produce precisely the same effect, even though from clinical experience, this is not the case. Nor can Genetic-based tests tell us anything about drug combinations.

Cell-based testing looks at 'fresh' living cancer cells. It assesses the net result of all cellular processes, including interactions, occurring in real time when cancer cells actually are exposed to specific anti-cancer drugs. It can discriminate differing anti-tumor effects of different drugs within the same class. It can also identify synergies in drug combinations.

When considering a 'targeted' cancer drug which is believed to act only upon cancer cells that have a specific genetic defect, it is useful to know if a patient's cancer cells do or do not have precisely that defect. Although presence of a 'targeted' defect does not necessarily mean that a drug will be effective, absence of the targeted defect may rule out use of the drug.

As you can see, just selecting the right test to perform in the right situation is a very important step on the road to personalizing cancer therapy. Sometimes a drug will inhibit the 'target' but not stop the growth of cancer. Not all genes and proteins have a critical role in the survival and growth of cancer cells.

The are many pathways to altered cellular (forest) function, hence all the different 'trees' which correlate in different situations. Improvement can be made by measuring what happens at the end of all processes (the effects on the forest), rather than the status of the individual trees (pathways/mechanisms). You still need to measure the net effect of all processes, not just the individual molecular (gene/protein) targets.
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Old 03-13-2013, 03:09 PM   #3
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Resistance To Anti-HER2 Therapy May Be Delayed By Treatment Targeting PI3K

Patients with HER2-positive breast cancer being treated with anti-HER2 therapy may be able to prevent or delay resistance to the therapy with the addition of a phosphatidylinositol-3 (PI3K) kinase inhibitor to their treatment regimens.

The data, published in Cancer Research, a journal of the American Association for Cancer Research, indicated that failure of the anti-HER2 antibody trastuzumab to block HER2 from activating the PI3K signaling pathway can lead to resistance to treatment. Therefore, dual simultaneous inhibition of both HER2 and PI3K may prolong the use of anti-HER2 therapies in women with breast cancer.

"HER2 breast cancer is a subtype of breast cancer for which we have an increasing number of effective treatments, including trastuzumab, an antibody that targets HER2," said Carlos L. Arteaga, M.D., director of the Breast Cancer Program at Vanderbilt-Ingram Cancer Center in Nashville, Tenn. "Unfortunately, many breast cancer tumors learn how to resist this therapy."

Arteaga and colleagues explored the possibility that aberrant signaling through the PI3K pathway was a mechanism of resistance to trastuzumab. They used breast cancer models of trastuzumab resistance with different modes of aberrant PI3K pathway activation, and treated the cells with a PI3K inhibitor with or without trastuzumab.

Inhibiting PI3K reduced cancer cells' ability to proliferate and induced the death of trastuzumab-resistant cells. In addition, combining PI3K inhibitors with trastuzumab resulted in superior anti-tumor effects against trastuzumab-resistant, HER2-positive cells in xenografts compared with the PI3K inhibitor alone.

The investigators also conducted analyses to determine how the drug combination decreased resistance to trastuzumab.

"We found that the trastuzumab-resistant cells in which the PI3K pathway was activated had high levels of an anti-death protein called survivin," Arteaga said. "This implied that if we could get levels of survivin to decrease, these cells would become sensitive to treatment."

They also measured pretreatment levels of survivin in HER2-positive breast cancer tumors and found that higher pretreatment levels of the protein correlated with a poor response to therapy.

"This suggests that we could measure levels of survivin in tumors, and if they are high or do not decrease with treatment, we could predict that the tumor is resistant to anti-HER2 therapy and try to find alternative treatments," Arteaga said.

Arteaga and colleagues plan to continue testing PI3K inhibitors, which are already in early clinical development, in combination with other HER2 drugs in breast cancer. They also plan to measure survivin levels in HER2-overexpressing breast cancer tumors to determine if levels can predict tumors that will benefit from combination treatment.

Citation: American Association for Cancer Research. "Resistance To Anti-HER2 Therapy In Breast Cancer Patients May Be Delayed By Treatment Targeting PI3K." Medical News Today. MediLexicon, Intl., 26 Jan. 2013
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Old 03-13-2013, 03:10 PM   #4
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Use Functionality to Inform Genomics

The PI3K pathway is an area of rapidly growing interest as new compounds target this key regulatory protein complex. Both selective and non-selective (pan PI3K) inhibitors are in clinical testing. Laboratory oncologists have reported their findings on the dual PI3K/mTOR PARP inhibitor BEZ235 (Nagourney, RA et al, Proc AACR, 2586, 2012). Using PI3K/mTOR inhibitors, they explored the activities, synergies and possible clinical utilities of these novel compounds.

Perjeta (pertuzumab) inhibits signaling at the PI3K pathway, upstream from mTOR. Afinitor (everolimus) blocks mTOR itself, thus both drugs are influencing cell signaling that channel through metabolic pathways PI3K is the membrane signal from insulin, while mTOR is an intermediate in the same pathway. Thus, these are in the truest sense of the word, breakthroughs in metabolomics.

New classes of compounds are being developed that inhibit both TORC1 and TORC2. More interesting are the compounds that influence upstream signaling, including phosphoinositol kinase (PI3K) and AKT. What we are coming to learn, however, is that these are not targets but collections of targets. Indeed, the PI3K inhibitors themselves have influence on one, two or all of the distinct classes of phosphoinositol kinases.

Most of the studies to date have used compounds that affect all the classes equally (pan-inhibitors). Pharmaceutical companies are now developing highly selective inhibitors of this fundamental pathway. In addition, duel inhibitors that target both PI3K and mTOR are in clinical trials. What we are coming to realize is the complexity of these pathways. What may prove more vexing still is their redundancy.

One well-established by-product of successful inhibition of mTOR (principally TORC1) is the upstream activity of AKT via a feedback loop. This has the undesirable affect of redoubling mTOR stimulation through the very pharmacological manipulation that was designed to inhibit it. Again, an unintended consequence of a well laid plan.

To unravel the complexities and redundancies of these processes, laboratory oncologists have utilized the primary culture platform. It enables them to examine the end result of signal inhibition and dissect disease specific profiles. Using this approach they can partner with collaborators to define the specific operative pathways in each disease entity. Biological complexity is the hallmark of life.
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