Finally, a breakthrough in cancer therapy: a transition of genius!

Posted on June 30th, 2009 in General by Robert Miller

When I entered medical school in the early 1960s, treatment for leukemia was beginning to use drugs that inhibited rapidly dividing cells, with the approach we now refer to as chemotherapy.  In time, physicians learned how to dose those drugs, combine them with radiation and begin to better control all types of cancers with some “cures” established by early diagnosis and sometimes very drastic, potentially life-threatening forms of treatment, such as bone marrow transplant. I have often referred to this era as “better living through chemistry.” Despite the enormous progress we have made in understanding the cellular and molecular mechanisms related to cancer development in cells, the strategy for cancer treatment has often been to go out and look for novel compounds that might have a magic bullet for one type of cancer or another. And, while some very useful agents and treatments have been developed with this strategy, it still relies on the objectives and broad treatments of the “better living through chemistry” era, where you expose virtually every cell in the body to the toxins and often make the patient very sick. You might say that we have been patiently waiting for many years for a breakthrough in cancer therapy based on our new understanding of cellular mechanisms of cancer, which will allow us to get away from the “kill all rapidly dividing cells and then hope that the patient survives strategy.”

Finally things have started to change and I see no reason why we won’t see a great acceleration of these new kinds of strategies in the near future. An element of genius has crept into these new cell and molecular tools for cancer therapy and with them, we can visualize the promise of drastically reducing the toxicity that has long been a hallmark of cancer treatment. We are at the early stage of finally entering the new “molecular era” of cancer therapy and we are beginning to close the door on the “better living through chemistry” era of the last half century. In a very remarkable study reported in Nature Biotechnology, but summarized very nicely in the New York Times, a new ingenious method of killing cancer cells was described that promises to revolutionize all future strategies and thinking.  I’ll try to explain it as simply as I can: first, this was an experimental approach using human cancer cells that had been injected into mice, so it’s not yet a human story, but there’s no reason why this strategy can’t be transferred to human cancers in relatively short order. Second, this therapeutic method targets primarily the cancer cells and leaves unperturbed other non-cancerous, normal cells of the body. Third, the targeting of the cancer cells was done through a two stage strategy, one of which included the injection of an RNA interference set of molecules that turned off a protein that cancer cells commonly have, which functions to transport toxic chemicals out of the cell and makes them invulnerable to chemical treatments that might otherwise do them in–that’s part of the genius of cancer cells. Now the problem with injecting RNA sequences into the cell is that you can’t inject them into the blood stream because they are rapidly degraded by endogenous nucleases or enzymes within the blood. So, the Australian group who authored the report used small derivatives of bacteria called “minicells.” Minicells were coated with an antibody that recognized surface proteins on the cancer cells (abundance of receptors for “Epithelial Growth Factor” or EGF). Once the mincells were injected into the mouse, they attached themselves to the cancer cells; the cancer cells immediately responded by engulfing the minicells, but in doing so, they exposed their interiors to whatever chemicals were in the minicells. In this case, the minicells contained  RNA sequences which entered into the cancer cells and eliminated the expression of the toxin pump proteins that normally served to extrude toxins out of the cell. Once this was accomplished, after a delay, a second group of minicells were prepared that had high levels of the cytotoxic drug, doxorubicin, a chemotherapy agent. This cytotoxic drug was delivered at high concentration into the cancer cells, which could no longer pump the toxin out because the pump protein was disabled. In a very short period of time the cancer cells were eliminated from the mice. The untreated mice which served as the controls died within a month of the tumor injections. The human cancers injected into the mice were highly virulent tumors, one of which was a type of colon cancer and the second was a breast cancer explant. They had not metastasized, so it remains to be seen if metastatic tumors can be treated in this same way.

You cannot read the paper or the NYT article without getting excited when thinking about the future of cancer therapy. We have finally crossed the bridge into the molecular arena where no doubt we will find new formidable challenges, but we can foresee a vast new array of clever strategies available to us as we get more sophisticated in targeting tumor cells with ingenious strategies designed for their destruction. You can also appreciate that our new molecular chemotherapy targeting can be achieved without significant downtime for the patient, as so few normal cells will be done in. I don’t foresee that we will one day go to the drug store and get a pill based on the kind of cancer we have, but we are surely turning an important curve on the way to better, more effective therapies.  This new strategy requires some design skills at the molecular and cellular level, but conceivably we will one day soon have a small group of minicells or something similar, each of which will provide a powerful cure to one or more types of cancer. At long last a breakthrough of an ingenious character has surfaced. While I am not a cancer researcher and others more familiar with the field might offer appropriately tempering notes of caution, this is the most exciting paper I have read in many years on new therapeutic strategies and I can see this breakthrough spreading like wildfire throughout the research and cancer treatment community. This result was no lucky accident–it’s design was made possible by the long, difficult struggle to understand how cells work and how to manipulate them successfully to our advantage. You couldn’t get to where we are today without heavy, prolonged research funding. And just think about the possibility of ingenious cures for cancer which may be arriving just in time to cure us all of our cancers so we can die of some grotesque global climate disease–maybe some type of new flesh-eating fungus! How inglorious to die of jungle rot in Minnesota, coming at a time when we finally will have two senators!

RFM

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