Biology 446 Unsolved Problems Fall 2007 Albert HarrisHic labor, hic opus est. Fancy Latin quote
1 key fact: Almost all differentiated cell types in humans, and all cell types that can become cancerous, already contain a (hair-trigger!) self-destruct system of caspase enzymes in their cytoplasm, which can either activate each other, or be activated by special trans-membrane proteins. Second key fact: T lymphocytes fight virus diseases by inducing apoptosis in virus-infected cells, which they detect by virus-coded peptides (short amino acid sequences) that are held outside the cell by type I histocompatibility antigens. If you could cause just cancer cells to produce such peptides!! Third key fact. Part of apoptosis is the release of contents of mitochondria, including reactive chemicals and enzymes, such as cytochrome C and super-oxides. THEREFORE, an anti-cancer drug does not need to kill cancer cells directly; it would be enough either to set off apoptosis (in cancer cells), or to cause over-active oncogenes to cause release of peptides with enough similarity to a virus protein, against which the patient has been immunized, or to puncture mitochondria. The problem is specificity! Doing these things only in the cancer cells. These three approaches are pretty obvious, once you think of them, but have not yet been tried.
Newspapers write about "anti-cancer vaccines", but what they mean is vaccines against papilloma viruses. These viruses cause about 5% of human cancers; but the vaccine is against the virus. * Imagine an oncogene that codes for an enzyme. Next imagine a drug that consists of a peptide (with a sequence found in some virus) covalently bound to something that permits the peptide to penetrate into cells, and prevents it from binding to histocompatibility antigens, but which gets separated by the oncogene enzyme. Such a drugs would cause T-cell-induced apoptosis just in those cells with an enzyme that cleaves off the antigenic peptide. You get the idea! Unfortunately, enzymes coded for by oncogenes are ATPases and GTPases rather than proteases; but you get the idea. Design a drug that oncogenic proteins convert into something that either activates kinases or that T-cells will react to as they react to viral peptides.
The proteins encoded by oncogenes include: .
B) Receptors for growth factors C) Underactive GTPases D) Overactive ATP Kinases, especially tyrosine kinases E) Proteins that control checkpoints, either for the start of DNA synthesis or for continuation of mitosis (for example by detecting damage to DNA, or detecting whether forces are balanced on kinetochores) F) The Transcription factor myc G) bcl-2, a protein which inhibits to onset of apoptosis.
It can't be any harder than Russian verbs of motion, Latin "sequence of tenses", or organic chemistry.
Remission is neither understood nor the subject of much (if any?) research. Please invent three kinds of hypothesis. Then figure out what each hypothesis predicts, or what would disprove it. What new treatments might be able to "hold" cancers in their state of remission?
Arthur Pardee invented an ingenious theory , that the specificity of DNA-damaging and microtubule damaging chemotherapy may result from the greater ability of non-cancerous cells to protect themselves from these drugs by halting or slowing down the cell cycle while the drug is around.
There also might be an opposite way of improving chemotherapy, based on Pardee's idea. The famous targeted drug "Gleevec" was found using an odd bioassay. Instead of testing whether different chemicals would inhibit the enzymatic action of an abnormal tyrosine kinase, they found a monoclonal antibody whose binding site exactly fit the active site of this enzyme, and then tested the relative ability of different synthetic chemicals to inhibit the binding of this antibody to the enzyme.
Nobody was surprised (but they ought to have been!) that Gleevec killed the cancer cells, rather than just slowing down their growth. Remember, it's blocking an abnormal enzyme that they are not supposed to have anyway. This drug caused remissions of a certain kind of leukemia in a very high percentage pf patients for two or three years, after which the leukemia returned and killed the patients. In some cases, further remissions were caused by synthetic chemicals with shapes similar to Gleevec, but slightly different. Abnormally anaerobic metabolism is such a common property of many cancers that some of the best researchers once believed that some defect in mitochondria might be the actual cause of cancer. That idea is surely wrong, and the mitochondrial abnormalities must be some kind of secondary or tertiary side effect of over-active oncogenes. Nevertheless, new kinds of chemotherapy might be invented to take advantage of anaerobic metabolism to induce apoptosis, especially because of the normal occurrence of broken-open mitochondria in apoptosis. A major part of the function of the bcl-2 protein is to inhibit release of mitochondrial contents, and there are a family of closely similar proteins that have the opposite effect. You might invent some new kind of drug that selectively damages mitochondria when they or the cytoplasm become abnormally acidic, or that prevents bcl-2 from protecting them, or that magnifies the effect of bax in promoting apoptosis. Enzyme catalysis is often very sensitive to pH, and you might figure out some way to take advantage of that, with some activator of caspases that acts only below some threshold pH. You can probably think of some better ideas. In my opinion, all these suggestions are more likely to work than the popular idea of inhibiting blood vessel formation. At best, that could only kill the interior or tumors, would require permanent treatment, would inhibit wound healing, and has zero chance of helping leukemia or lymphomas (or chondromas, since cartilage isn't vascularized) But enormous amounts of money have been invested in that idea. You can do better. For some reason, most people have been assuming that when the oncogenes are well enough understood, then that knowledge will make it obvious how to design better chemotherapy drugs. Furthermore, drugs like Gleevec that have been designed in this way were meant to block the abnormally active enzyme, instead of being designed to kill any cell in which an oncogene is over-active. This paradox is further increased by the fact that Gleevec (somehow!) does cause the death of the cells that had the over-active kinase. When I have read papers and letters by scientists living just before major breakthroughs were made, they often seem as if they were sleepwalking, and just couldn't see what should have been obvious.
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