[Dean's World] Dave Schuler: Drug Resistance: and, the Return of Cancer and New Frontier or Yet Another Unfulfilled Promise?

[notify at powerblogs.com]

Posted by Dave Schuler:
Drug Resistance: and, the Return of Cancer and New Frontier or Yet Another Unfulfilled Promise?
http://www.deanesmay.com/posts/1185982040.shtml


   by George L Gabor Miklos PhD and Phillip John Baird MD PhD

  DRUG RESISTANCE AND THE RETURN OF CANCER

    Normal cells are inflexible in a crisis

   When normal cells are subjected to chemotherapeutic drugs, the cells
   have a limited capacity to either inactivate the drug or to expel it
   using various pumps that are found at the cell surface (42,43). Some
   cells respond better than others, since they have more efficient
   versions of these pumps and/or more efficient drug inactivating
   systems. As the level of the drug increases, however, the inactivation
   and pump systems are overwhelmed and normal cells die from drug
   toxicity. They lack operational flexibility, even in times of crisis,
   because they can only implement the fixed instructions in their
   two-book operating manuals.

    Cancer cells have additional flexibility in a crisis

   By contrast, when cancer cells encounter a chemotherapeutic drug, the
   diversity within the cell population is so great that some cells
   always have a novel combination of instructions courtesy of their
   massively disrupted DNA contents. Some cells survive and grow back
   even in the face of different drug combinations. Thus the return of
   cancer is understandable when viewed from the perspective of cancer
   cell populations, the members of which have diverse and flexible
   operating systems. These attributes have yet to be recognized by most
   cancer researchers who are generally unfamiliar with classical
   manipulations of large chunks of DNA and the consequences of the
   additive effects of genes that are slightly sensitive to abnormal
   dosage (44).

   The flexibility inherent within a massively disrupted DNA cell
   population was clearly demonstrated by the experimental removal of the
   main drug pumps from cells (45-48). With their frontline multidrug
   defences completely missing, such cells were nevertheless rapidly able
   to become drug resistant because of their massively disrupted DNA
   contents.

    How different is drug resistance in each person?

   Every human being (except for identical twins) is unique at the DNA
   level. Hence each cancer cell population follows a unique trajectory
   as the cells leave the primary tumor. Each woman with breast cancer
   will not only differ in terms of drug resistance, but also in her
   intrinsic ability to control the growth of any particular cancer. For
   example, breast cancers in African-American women are more aggressive
   and less responsive to treatment than breast tumors in Caucasian women
   (49). Some women will have cancers that return quickly, others more
   slowly. The majority of women who respond to Herceptin will develop
   drug resistance within a year (50), but others take longer. Some
   cancers will even remain dormant for years.

    Handling the truth

   The earlier statements of Dina Rabinovitch, "My cancer keeps
   recurring. Nobody can tell me why", are now less mysterious when
   viewed in the context of the differences in flexibility between normal
   and cancer cells.

   Most cancers rapidly become drug resistant because each population of
   cancer cells is different in terms of its massively altered DNA
   contents. Each cancer reacts to drugs in its own way leading to the
   selection of those cells with novel genetic operating systems that
   resist drug effects. It is the ability of any cancer population to
   continuously adapt that makes it so dangerous.

  NEW FRONTIER OR YET ANOTHER UNFULFILLED PROMISE?

    Personalized treatment for the individual patient

   Examining a personâs DNA profile has been popularized by forensic
   medicine and is now being applied to cancer patients. Dr Victor
   Velculescu of John Hopkins University explains personalized cancer
   treatment (51).

   A cancer patient comes into a clinic and has her tumor analyzed. Then
   she is treated based on a spectrum of her mutations with a cocktail of
   drugs. It doesnât mean a new drug for each person, just a different
   combination of drugs.

   The above seems like a dream come true and is being heavily promoted
   as the new frontier in cancer, with billions of taxpayers dollars due
   to be spent in this new area (52-55). Pharmaceutical companies have
   recognized the potential of increased sales and are designing new
   drugs to target cancer-based gene products in order to obtain the
   biggest slice of this upcoming $60-$70 billion market.

    DNA profiling

   Current DNA profiling technology of single letter DNA mutations is
   straightforward, but how relevant is a drug combination prescribed on
   the basis of profiling a primary tumor to shutting down metastatic
   growths?

    Single letter mutations

   When fully sampled, a primary breast tumor will harbor millions of
   mutations (6,32,56). In addition, each breast and colorectal patient
   analyzed to date (6) has been found to have a unique combination of
   mutations (15). This huge number of mutations, plus the unique
   combination of them in an individual, poses enormous challenges in
   demonstrating the clinical relevance of mutations. Clinical relevance
   cannot be sufficiently emphasized.

   Since only about 1 in 50,000 of the cells in a primary tumor has the
   potential to become metastatic (34-38), which of the millions of
   mutations are in the dangerous cells that leave? It is not possible to
   determine this without first isolating these maverick cells from the
   bulk of the solid tumor. Since this is not done, DNA profiling
   reflects the sum total of all the mutations in the primary tumor. Any
   clinically relevant mutations remain diluted by millions of clinically
   irrelevant mutations. A DNA profile from a primary tumor consists
   almost entirely of noise.

    Drug combinations

   Future personalized drug combinations will require clinical trials and
   separate FDA approval. There are currently only five FDA-approved
   combination regimens for one of the most intensely trialled major
   cancers, colorectal cancer (57), but the number of possibilities for
   new drug targets generated by the millions of mutations in a primary
   tumor is astronomical. The mere thought of developing new drugs each
   specific to one of the millions of potential new targets, given the
   current ten year time frame for the development and testing of each
   new drug, is delusory.

   Drug combinations can be dangerous. As Dr Steven Hirschfeld of the FDA
   points out; "These are all myths having to do with anticancer
   drugsâ¦that theyâre very targeted, when in fact all these drugs have
   multiple targets. That theyâre nontoxic, when in fact the latest ones
   have their own set of side effects. And that theyâre cures, when they
   are not." (58). There are no anticancer drugs that are specific for a
   single target; all bind to several (59,60).

   The data show that each cancer cell population is unique, each
   anticancer drug is nonspecific and each patient differs with respect
   to drug resistance. Personalized cancer medicine in its currently
   practiced form of determining the extensive DNA profile of a primary
   tumor via single letter changes and then prescribing drug combinations
   is simply another promotional exercise (52,53,61-65). The glib
   statement that, "it doesnât mean a new drug for each person, just a
   different combination of drugs"(51), is completely out of touch with
   the reality of clinical, pharmaceutical and FDA implementations.

    The reality of massively disrupted DNA contents

   Current personalized cancer medicine focuses on single letter
   mutations rather than the massively disrupted DNA component of cancer.
   Half a century of genetics, however, shows that the effects of massive
   changes involving many genes dwarf the effects of single letter
   mutations. Analyses of additions and deletions of DNA in
   experimentally manipulable organisms reveal that varying the dosage of
   large chunks of DNA has far more important biological effects on the
   flexibility of genetic operating systems than the small scale
   mutational changes that can be induced in normal cells (44).

   So how have we reached this preoccupation with personalized DNA
   profiling of mutations when our answer lies not in the bulk of the
   tumor, but in the tiny population of maverick cells with their
   massively disrupted DNA contents? The answers lie in the fashions that
   dictate cancer research.

   (Next up: The Earliest Stages of Cancer, The Mutationists, and Breast
   Cancer.--Dean)