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Thread: Cancer, gene therapy and cancer stem cells

  1. #1 Cancer, gene therapy and cancer stem cells 
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    In the past we were successful in combining two or more medications to combat cancer. Now the vast possibilities of attacking cancer with myriad new drugs using multiple methods of action have come to the forefront. Now we know that the similarities between stem and cancer cells are undeniable and that failures in damaged stem cells or their offspring may become malignant cancer stem cells. Unfortunately, this groundbreaking discovery was pioneered abroad. Shinya Yamanaka at Kyoto University was the first to generate induced pluripotent stem cells after identifying genes active in embryonic stem cells (Oct4, Sox2, c-myc, Klf4) and used retroviruses to transfect mouse fibroblasts with a selection of those genes. These genetically engineered cells can quite possibly be used in place of stem cells to fight various diseases. America was once leading the world in technological advancement and scientific research, yet has been slowing losing its foothold. Japan and India are now emerging as powerful foreign competition.
    Drug therapy has been effective in the past in treating specific cancers. Tamoxifen, for example, in the treatment of breast cancer. Combining new drugs, such as Bevacizumab and Soraferib, however, will attack cancer on two fronts and although Bevacizumab is currently only FDA approved for treating colorectal, non-small cell lung cancer and breast cancer and Soraferib is approved for kidney and liver cancers, research has led us to believe that these drugs may treat other cancers as well.
    Bevacizumab’s method of action is attaching itself to a protein released by cancer cells, called VEGF (vascular endothelial growth factor). VEGF activates receptors on the surface of cells lining blood vessels, which triggers angiogenesis (the forming of new blood vessels that feed a tumor compelling it to grow). This drug is, in fact, the first FDA approved angiogenesis inhibitor. It prevents VEGF from reaching its receptor. Sorafenib latches two proteins onto the surface of cells lining blood vessels: VEGFR (vascular endothelial growth factor receptor) and PDGFR (platelet-derived growth factor receptor). It binds to these receptors and turns off signals that cause the aforementioned angiogenesis. Additionally, this drug attaches to c-kit receptors at the surface of cancer cells and enzymes called protein kinases (such as Ras and Raf) which carry signals from the receptors to the nucleus of cells, normally causing the cell to grow and divide.
    Another potentially useful therapy would include combining Bortezomib and Gefitinib, two small molecule type drugs. Bortezomib is currently approved for the treatment of myeloma and leukemia, while Gefitinib is used in non small cell lung cancer. Bortezomib targets proteasome 26s, which all cells use to degrade proteins. Inhibition of this degradation process disables a key signaling pathway that allows cancerous growth and also allows a build-up within the cells of proteins, which triggers cell death. Gefitinib attaches to a protein at the surface of cancer cells called EGFR (epidermal growth factor receptor), a receptor activated by a protein called EGF which sends signals to the cell nucleus to activate cell growth. Gefitinib blocks the part of EGFR just inside the cellular membrane that activates such signals.
    Drugs such as Trastuzumab, Rituximab and Tositumomab are antibody type drugs. Trastuzumab targets the HER2 receptor, a protein on the surface of a cancer cell. It binds to a part of the receptor on the outside of the cell, keeping grow and divide signals dormant. Rituximab and Tositumomab both target the same protein found on the surface of B-cells, called CD20. Attaching to this protein triggers the destruction of B-cells, both healthy and malignant. Bone marrow transplants are used to replace the lost healthy cells.
    All of these methods of treatment are useful and effective but they don’t get to the core of the problem. Patients who are in remission due to drug therapy may relapse due to the activity of a reservoir of malignant cells. Cancer stem cells, as they are called, are seated in the center of a group of surrounding, sometimes attached cells known as a “niche”. The cells of this niche interact with the cancer stem cell, causing it to create progenitor cells, which in turn produce more cells that produce yet more cells. In blood-forming cells, for example, stromal cells in blood marrow create a multipotent progenitor cell which divides into a myeloid progenitor and a lymphoid progenitor. Myeloid progenitor cells divide into two cells which produce macrophages, neutrophils, basophils, eosinophils, and platelets. Lymphoid progenitor cells divide into B and T cell precursor cells which form plasma cells, T cells and natural killer cells. Turning off the cell factory will halt the outpouring of malignant cells.
    Cancer stem cells are relatively few and being able to pinpoint their trademark properties will be paramount in isolating and studying them since appearance alone will not reveal them.


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  3. #2  
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    Yeah well a lot of that has been explored anyway.
    For example about the EGFR pathway there are MAbs against EGFR like cetuximab/panitumumab which can work on certain mutations which would render kinase inhibitors like gefitinib (which by the way is used in many cancers other than NSC lung cancer e.g. colorectal) as you mentioned, useless.
    We have mapped most mutations at this stage. The main problem is down stream mutations e.g. KRAS in the EGFR pathway.

    I think you're wrong about Bevacizumab. It may be the first inhibitor which is a MAb for that mechanism but there are other known angiogenesis inhibitors such as tholidamide.

    Whats the point of this paper anyway? Who are you writing it for?


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    I posted this to share information...that is all
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    Forum Cosmic Wizard paralith's Avatar
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    Quote Originally Posted by gottspieler
    I posted this to share information...that is all
    It is the administration's hope that people post in order to foster discussion, not make lists of facts. Do you have a question to pose to the members here, or a point of debate based off the information you have provided?
    Man can will nothing unless he has first understood that he must count on no one but himself; that he is alone, abandoned on earth in the midst of his infinite responsibilities, without help, with no other aim than the one he sets himself, with no other destiny than the one he forges for himself on this earth.
    ~Jean-Paul Sartre
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  6. #5  
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    Quote Originally Posted by paralith
    Quote Originally Posted by gottspieler
    I posted this to share information...that is all
    It is the administration's hope that people post in order to foster discussion, not make lists of facts. Do you have a question to pose to the members here, or a point of debate based off the information you have provided?
    What are the side effects of taking these drugs? Are there better alternatives, or are they currently our best shot?
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