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890HEMONCDOCs - The lessons (1-5)

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  • Janice and Ben Haines
    Sep 15, 1998
    • 0 Attachment
      I added Oncology Lesson #5 posted last night by the HEMONCDOC. The
      Hemoncdoc is an anonymous, insightful, articulate, and brilliant man with a
      big heart.


      (under ticker ENMD)


      To see all past posts on NHL-low, go to:


      Message 2475 of 3109 Reply

      Oncology Lesson # 1 Why all the excitement ?

      Jun 23 1998 5:51PM EDT

      "Been their, done that!" Are you so sure? Among the 2400+ msgs. no one
      has explained to the adv. invester why the NCI, oncologists, etc. are so
      excited about AS/ES. When a new drug or treatment is first tested in
      animals it is tested in mice inoculated with one of appox. 50+ standard
      tumor cell lines the NCI maintains for drug testing. These cell lines are
      used because they have been shown to be very predictable in regards to
      rate of tumor grow, tine to death of animal from inoculation etc. If a
      mouse is
      injected with a fixed tumor load you can usually predict to the day when
      the mouse will die. Inoculated mice are then treated with the test drug
      looking for any prolongation of life, shrinkage of tumor, and if applicable
      whether any animals are 'cured'. This method of testing is used to identify
      any drugs that can be given in physiologic doses and show a response
      without killing or severely injuring the animal. Very few drugs pass this
      test. Many compounds show activity in cell cultures [ cyanide would be a
      good example] but are too toxic in test animals. Some drugs, in some tumor
      types, if given early, [ say within 5 days of inoculation ] may actually
      cure the animal. Our most active chemotherapy drugs, radation therapy,
      monoclonal antibodies ect. tend to perform poorly if the tumor has grown to
      any significiant size. No known drug or treatment is effective in all tumor
      types, at any size or stage. AS/ES has shown 100% effectiveness in all of
      the 50+ NCI tumor types tested to date! THIS HAS NEVER BEEN SEEN
      BEFORE !!! No other known drug or treatment has ever shown this degree of
      activity. This 100% activity has been seen in large bulky tumors well
      beyond the point of 'cure' with any other known agent or treatment. THIS
      HAS NEVER BEEN SEEN BEFORE !!! These results have been obtained without any
      appricable toxicity. No myelosupression, weight loss, nephrotoxicity,
      neurotoxicity, hair loss, ect. ect. THIS HAS NEVER BEEN SEEN BEFORE !!!
      There are many new and inovative approaches to the treatment of cancer
      in pre-clinical and clinical trials. No treatment or apporach has yeilded
      these results. NONE !!! These results are unprecendeted. Repeated
      treatment cycles has resulted in no resistance developing to AS/ES. THIS


      Message 2532 of 3109

      Oncology Lesson # 2 ......AS/ES production.

      Jun 25 1998 1:05AM EDT

      Or ....You didn't really think the elves cooked all those cookies did you?
      Don't let that hollow tree fool you. Four stories down is a state of the
      art, vertically integreated, computer controlled cookie factory run by
      M.I.T. and Cal. Tect. bioengineers. If AS/ES had been discovered 15 years
      ago there would have been little chance of their production in less than 5
      yrs. Fortunately great strides in recombinate DNA technology have taken
      place in those 15 yrs. We now routinely use Re/DNA products such
      as...TPA, Epogen, Neupogen, Neumega, Factor 8, Pulmozyme, etc. The history
      of the discovery and development of each of these products mirrors the
      AS/ES story and holds many lessons for us; lessons in the production of the
      compounds, their impact on the treatment of their respective diseases and
      the impact on the companies developing and producing the compounds. I will
      not try to retrace the initial laborious task of collecting liters of mouse
      urine to isolate the first mg. of AS/ES or try to explain all the steps in
      purifying, sequencing, and reproducing the first small 'batches' of AS/ES.
      For those not intimately familiar with the technique lets just say its like
      trying to string a necklace with 150 to 175 beads, 20+ colors [Amino Acids]
      all of with have to be in the exact secquence. Now do it in the dark and
      make me one million to one billion copies. All of the 'reports' of
      difficulty with different 'batches' or difficulty duplicating specific
      steps and experiments is typical of all recombinate DNA products as they
      are brought out of the lab through progressively larger production
      facilities. Initial batch is like the recipe that wins the Betty Crocker
      blue ribbon. Its the job of the biotechnology engineers to show you how to
      go from two dozen cookies to two billion without losing that blue ribbon
      winning taste! The reason I'd like ENMD to 'partner' with someone like
      Genetech/Roche, Amgen/J&J, or Genetics Institue/Am. Home etc. is simply
      that they have the 'in house' experince, expertice, personnel, and
      production facility to expidite the development of AS/ES. There is however
      a 'catch 22' problem. No one will build a 100 -500 million $ production
      facility until they know the product will work! We won't know it will work
      {though odd's based on one million yrs of evolution suggest it will, see
      Oncology Lesson #3 } until we go through human testing. We can't do
      human testing without product, so where does this leave us? Fortunately in
      better position than you might think! Researchers at NCI recongize potential
      magnitude of advance of AS/ES and are producing sufficent material to
      begin phase one testing in 3 to six months. In the interim industry will be
      preparing continguency plans to ramp up sufficent material to proceed with
      phase two and three testing.[one point that seems to be frequently
      misunderstood...primate testing this summer will be primarily for
      pharmacologic dosing and toxcity studies not to test activity against
      tumors. Other than to announce that studies are complete there will likely
      be little info. from these studies.] If human phase 1-3 testing shows
      significant activity [read response or stable disease, not "cure"] than
      drugs will be released by FDA for general use. The speed all this will
      happen will to some extent depend on sucess of drugs in clinical trials. If
      we see arrest or regression of tumors that have rarely or poorly
      responded in past with other therapys such as glioblastomas, sarcomas,
      melanomas,etc or if we see heavily pretreated tumors such as breast cancer
      responding without unmanageable toxcity than every thing will be fast
      tracked, faster than we have ever seen before. Watch your grocery sheleves
      ! Those elves are working overtime!


      Message 2637 of 3109

      Oncology Lesson # 3 .From mouse to man....

      Jun 28 1998 11:38PM EDT

      Or why that evolutionary latter has fewer rungs than you might think! There
      seems to be a great deal of spectulation whether AS/ES will 'work' in
      humans. Many of us believe it already does. In contrast with almost all
      other forms of Rx, AS/ES may have a unique advantage of having already
      been tested for ~ a million years in that great lab called Life. These
      molecules[MCS] are not derived from some exotic fungus or plant. They are
      naturally occuring MCS likely to be present in most mammals where they
      play a key role in regulation of angiogenisis [AG]. Evolution doesn't produce
      large complex MCS with no purpose.These MCS seem to be to act as
      regulators or OFF switches for AG. All CA share this charcteristic need,
      and potential weakness for AG. The fact that AS/ES are naturally occuring
      MCS gives them tremendous advantages as theatment options. There should be
      no difficulity with immune rejection or antibody production as we will
      recognize these MCS as 'self'. Biologically their activity should be
      limited to inhibition of AG markedly reducing toxcity to other organ
      systems. This seems to be the finding from mouse and preliminary canine
      studies. A second characteristic of these regulatory MCS is that they are
      usually in most mammals playing essentially the same biologic function.
      There are frequently minor AA changes in the MCS but their function is the
      same! Remember we used pork insulin for fifty years before recombinate
      became available. Some of us won't be susprised if AS/ES 'work' but we will
      be shocked if human recombinate AS/ES doesn't 'work'. { 'work' is defined
      as showing some inhibitory effect on AG }. The ? will likely not be 'does
      it work' but how well, what dose, and what frequency of dosing. Two final
      concerning natural biologic regulators. First as a group they tend to have
      wide therapeutic indexes. A major problem with all forms of chemoRx and
      most other Rxs is that the dose of Rx that shows activity vs.the dose that
      causes toxcity is often dangerously close, most biologic regulators seem to
      have a much wider therapeutic index allowing greater dosing flexability.[
      i.e. g-csf, erythropoeitin etc..] This dosing flexability will be useful as
      we will likely find some human tumors more angiogenic than others. No
      toxcity was seen in mice at dose escalations described in orginal AS/ES
      papers. The main purpose of up coming primate trials is not to look for
      effect on tumor growth but rather to better define limits of dosing and
      toxicity, to try and approximate the therapeutic index for humans. I would
      suggest anyone interested in this aspect of recombinate DNA products just
      pick any recombinate product and read about animal testing in appropriate
      section in PDR. The final point and potientially the most important is lack
      of resistance. theseregulators are directed toward normal tissue not
      against the tumor itself . This is critical because a basic axion of
      oncology is that normal tissue dosn't mutate so even with repeated Rx
      cycles no resistance develops. This observation of a Cancer Rx free from
      resistance was what got the Nov. 97 Nature paper published not the tumor
      dormancy! This freedom from resistance is part of what sets this avenue of
      Rx apart from all others and it is this development of resistance thru
      mutation of the targeted tumor cells that is the achille's heal of
      conventional chemoRx, monoclonal antibodies, vaccines, radiation Rx etc.
      As you stand on that final rung of the latter of evolution remember that
      tickling of your feet are all the little mice on the same rung running by!


      Message 3051 of 3108

      Oncology Lesson #4. The Art of War -1998

      Jul 17 1998 11:03AM EDT

      Return with me to the 1920's and watch while an impertinent General Billy
      Mitchell sends the admiral's dreadnaughts to the bottom, and learn how it
      applies to the Cancer Wars in 1998! Required reading..msgs#2475,2532,
      and 2637. Oncology Lessons #'s1,2,+3. Sunday night, Yahoo! channel.

      Oncology Lesson #4....The Art of War
      Aug 23 1998
      9:41PM EDT

      In 1914 war was a two dimensional event with armies and
      navies fighting for superiority on the surface of the land and
      oceans. With the introduction of the airplane a third dimension
      was added.However its importance as a strategic weapon in
      war wasn't recognized for a number of years after its
      introduction in part due to the limited capability of early
      aircraft. It wasn't until the early 1920s that a impertinent Billy
      Mitchell showed that lumbering biplanes with iron bombs
      could easily sink the great dreadnaughts. In less than 20 years
      great naval battles were being fought without the opposing
      forces ever coming within sight of each other, while 1000
      bomber raids laid waste to the German heartland.Early on
      how many people recognized the development of the airplane
      as changing the strategic balance of war? By adding a third
      dimension the great strategic thinkers could no longer simply
      plan on moving armies or navies but now had to plan for a
      three dimensional war.So it is in the War Against Cancer. In
      the War Against Cancer we have traditionally considered our
      weapons to be the surgeons knife, radiation Rx,
      chemotherapy, and to a lesser degree biologic response
      modifiers and monoclonalABs. The pioneering work of Dr.
      Folkman and others in the field of antiangiogenisis have given
      us a new dimension to exploit in the fight against cancer. He
      more than anyone else is our Billy Mitchell. The evolution of
      antiangiogenisis compounds and their use is similar to the
      evolution of the airplane where the first generation compounds
      represent the early biplanes with great promise but limited
      strategic value. As we move into the second and third
      generation inhibitors we are begining to see their strategic
      value and place in our 'war' plans. Some had thought that we
      could win a war with airpower alone but it was shown that
      victory reguired the integration of land, sea and airforces in a
      coordinated fashion to exploit the relative strengths of each.
      Whether we will win the War Against Cancer with any single
      antiangiogenisis compound or combination of compounds
      remains unproven in humans. AS/ES may prove to be our
      'Atom Bomb' but their greatest value will likely not rest in their
      use alone. By exploiting their strengths [ nonmyleosuspressive,
      no induced resistence, and globial application] with the
      strengths of traditional Rxs we will be more likely to expand
      on our meager victories to date. The recent Nature paper
      showing that the combination of AS and RT resulted in tumor
      regression at subtheraputic doses of RT without any increase
      in toxcity is a case in point. Imagine being able to treat
      successfully a cancer of the prostate with 1/2 the dose of RT!
      No radiation proctitis or cystitis, no incontinence or
      impotence. This example alone would change the world of
      radiation Rx. It is possible based on preclinical studies that the
      same effect may be seen with the combination of
      chemotherapy and antiangiogenisis compounds where lower
      doses of chemotherapy can be given with equal effecacy and
      less toxcity. Many on this board have spoke as if for AS/ES
      to succeed they must do so alone. Others have implied it is
      not enough for them to succeed, all other Rxs must fail. I
      would remind everyone that in the Art of War the enemy of
      my enemy is my ally. Our common enemy is cancer. Our goal
      is total victory with a minimum of casualities. We will exploit
      this new dimension and use all the weapons at our disposal to
      reach that goal!

      #5....Faster than a speeding bullet.
      Sep 14 1998
      11:34PM EDT

      We already know AS/ES are more powerful than a steaming locomotive, but
      to be real 'Super' drugs are they faster than a speeding bullet and can
      they leap tall buildings in a single bound? First things first, lets
      discuss speed. Many of the posters on this site still like to imply that it
      may be as much as 5 years or more until AS/ES are available for general
      use. This assumption is largely based on the average time to development
      for various drugs. There is nothing average about AS/ES including their
      development to date or their projected time to clinic. First keep in mind
      AS was not
      discovered until 1996 and ES one year later in 1997. If phase one trials
      start as predicted in early 1999 this will be in itself a remarkably short
      time from discovery to clinic. However the real speed records should be set
      in time to completion of phase 1 and phase 2 trials. Here are the reasons
      why........When a new drug enters phase 1 or phase 2 testing someone has to
      first write the protocol outlining all the various parameters such as
      dosing guidelines, appropriate patients for study, criteria for response,
      monitoring for toxcity, end points of study, etc., etc. The speed that this
      gets done is to some extent driven by how enthused the protocol people are
      over the study. Obviously the more promising the protocol the more
      enthusiastic the
      protocol people! There is no phase 1 or phase 2 study out there that has
      people more fired up than the pending AS/ES studies. It will be a real
      professional accomplishment to be one of the investigators and to have your
      institution be the lead or a participating organization. The word on the
      street is that the N.C.I. and Dana Farber [Harvard Medical School] will do
      the phase 1 testing then the phase 2 will likely go to the the largest of
      the various comprehensive cancer centers i.e. M.D.Anderson, Sloan
      Kettering, Mayo, U.C.L.A., Duke, etc.,etc. The point of all this is that
      fair or not the most promising drugs get pushed to the front of the line
      and at this time there is nothing more promising than AS/ES. This virtually
      assures early
      and rapid testing for the drugs with completion of the trials in what
      will likely be record time! Keep in mind that the expected relative lack of
      toxcity and broad applicability will mean that virtually all patients will
      be potential candidates for Rx meaning there will be maximum potential
      patient entry into the studies. Also keep in mind there is still a
      tremendous interest among patients in these two drugs. Even now, 4 months
      after the N.Y. Times article I still have, almost every day patients asking
      about the status of their development. For probabily the first time in
      cancer research we will be able to reach projected patient accrual as fast
      as the protocol offices can process the paperwork! So for all the neysayers
      who think it will take 3-5 years to complete the studies I say these
      'Super' drugs will be brought along
      faster than a speeding bullet! So we've previously shown that AS/ES are
      more powerful than a steaming locomotive and now faster than a speeding
      bullet but before we change the 'S' on Supermans chest to
      angioStatin/endoStatin there is one last feat, can they leap a tall
      building [read F.D.A. headquarters] in a single bound? Tune in for
      Oncology Lesson #6 and find out! For those with way too much time on their
      hands refer to prior lessons #1-4, msgs.#2475,2532,2637, and 3490. [This is
      dedicated to my neice Jessa and NHLlowKIA's wife.]