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"New Drugs New Hope" Boston Globe - Part 2

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  • Janice and Ben Haines
    Greetings, Here is part two of five, of tremendous research from the Boston Globe: For Graphics, go to:
    Message 1 of 1 , Aug 3, 1998
      Here is part two of five, of tremendous research from the Boston Globe:

      For Graphics, go to:



      CANCER: TURNING THE CORNER New drugs, new hope

      By Richard Saltus, Globe Staff, 08/03/98

      Second of five parts

      HOUSTON - INSIDE JIM Hassmann's bones, out-of-control white blood cells had
      taken over. Dividing unchecked, they were squeezing out the marrow that
      produces life-sustaining red blood cells.

      Conventional drugs failed to slow his rampaging chronic lymphocytic
      leukemia, or CLL. ''The hematologist said there was nothing else to help
      me, that I was at end-stage,'' recalls Hassmann, 54, who was breathless,
      tired, and sick. ''And I was making end-stage plans.''

      As a last resort, the Houston man was referred earlier this year to the
      vast M.D. Anderson Cancer Center here, where besides standard treatment,
      patients can volunteer for a wide range of experimental therapies, from
      cancer vaccines to gene therapy.

      The first two drugs he tried failed. But in April, Hassmann was switched to
      a drug called Campath-1H, made by a Cambridge, Mass., biotech company,
      LeukoSite. The drug worked like a ''smart bomb'' to knock out the cancer
      cells while sparing the marrow that makes new normal white cells. And
      unlike most standard chemotherapies, it didn't cause dangerous, toxic side

      ''I was feeling better within a week,'' says Hassmann, astonished and
      grateful after a course of 12 weekly treatments. ''I came there with no
      hope. Now this could be good for many years.''

      How long Hassman's new lease on life will continue is unknown. Like dozens
      of other novel anticancer agents that have prompted a surge of optimism in
      the field, Campath-1H is still in early testing.

      What is clear, however, is that in 1998, there is marked optimism about
      this new generation of ''targeted'' therapies aimed at controlling cancer
      with vastly more precise and less toxic drugs than those now available.

      ''We've pushed [conventional] chemotherapy about as far as it can go,''
      says Dr. John Mendelsohn, a molecular biologist and president of M.D.
      Anderson. ''It's possible we'll be able to discover new chemotherapy
      agents, but we think the targeting of oncogenes or tumor suppressor genes''
      that malfunction in cancer cells ''is another major attack we can make'' on
      the disease.

      The cancer center, one of the nation's two largest (the other is Memorial
      Sloan-Kettering in New York), houses 800 faculty scientists and treats
      65,000 patients a year. There are 494 clinical trials in progress here,
      including a broad sampling of the novel cancer therapies that have moved
      into the spotlight in the last year.

      Patients come to Houston from all over, many of them staying in high-rise
      hotels that loom over the enormous Texas Medical Center in which M.D.
      Anderson is located. In various clinics, they sit waiting for treatments,
      undergoing infusions of drugs through intravenous lines, or nervously
      anticipating lab results.

      Some, like Hassmann, are receiving drugs based on monoclonal antibodies -
      engineered proteins that recognize and latch onto specific cancer cells.
      Other drugs are designed to block cancerous growth signals from reaching
      the receivers on the surface of cells or inside them - like filling a
      keyhole with gum so the key won't fit, as one researcher put it.

      Others have volunteered for tests of angiogenesis inhibitors. These drugs
      disrupt the network of tiny blood vessels a tumor needs to grow, thus
      halting or shrinking the tumor. In early human testing these inhibitors
      have produced mixed results, but the most powerful ones are not yet ready
      for patient trials.

      Still other patients, including some with lung, head, and neck cancers, are
      undergoing gene therapy. Dr. Jack Roth, chairman of thoracic surgery at
      M.D. Anderson, is leading trials in which a gene that is often defective in
      cancer cells, called P53, is being ferried into tumor cells by means of a
      virus, in hopes of halting malignant growth.

      It is P53's job to detect cells with damaged DNA, and either keep them from
      dividing until they are repaired, or nudge them along a path to programmed
      self-destruction before they can do harm. Mutant P53 genes, by contrast,
      allow damaged cells to keep on reproducing, which can lead to cancer as the
      cells accumulate genetic damage.

      ''If you restore P53 function'' with gene therapy, ''it could trigger this
      cell death'' and turn off cancerous growth, Roth says. The therapy appears
      safe and has shown some activity against tumors in early tests, he adds.

      Strategy takes aim at broken cells

      Another strategy aims not to repair cells with broken P53s, but to wipe
      them out. A bioengineered virus called ONYX-015 specifically attacks and
      kills cells with mutant P53 genes. Scientists reported this spring that in
      combination with two standard chemotherapy drugs, the virus has shrunk
      tumors of the head and neck in 9 out of 10 patients in early trials.

      Cancer vaccines - the name for a strategy of revving up the immune system
      to attack cancer cells - are also being tested here and at a number of
      academic centers and biotech companies. Efforts to harness the immune
      system to fight cancer has had a long history and few real triumphs, but
      scientists now know more about how the complex immune defenses work and are
      more optimistic that selective and powerful vaccines can be made.

      One vaccine that mobilizes the immune system against deadly melanoma is
      heading toward possible approval in Europe and Canada by the end of the
      year and perhaps next year in the United States. Called Melacine, it has
      been tested in patients with advanced melanoma who have dismal prognoses.
      It has proven to be as effective in extending survival by a few months as
      is the standard four-drug chemotherapy treatment. But Melacine is much less
      punishing in its side effects, say officials of RIBI ImmunoChem Research,
      Inc., the vaccine's makers.

      In contrast to the broadly toxic chemotherapies in use today, the new
      agents have been precisely designed to attack, or in some cases, correct,
      specific genetic changes that turn normal cells into malignant ones.

      ''Up to now, we have cured a series of cancers that affect young people,''
      says Dr. Donald Coffey, of the Johns Hopkins Cancer Center, referring to
      diseases like leukemia and Hodgkin's disease in which the war on cancer has
      had its greatest triumphs to date. ''We did this with drugs that blocked
      DNA synthesis'' - meaning they killed tumor cells, but often hammered
      normal cells as well, causing terrible side effects.

      But now, scientists are developing drugs aimed at blocking the effects of
      mutant, cancer-causing oncogenes, restoring broken tumor-suppressor genes,
      and overcoming malfunctioning DNA-repair genes. They hope these therapies
      will bring outlaw cancer cells back into good behavior or prod irrevocably
      damaged cells into apoptosis, or cell suicide.

      If conventional chemo is like bombing an entire city to kill off a
      guerrilla force, the newer drugs aim to pick off the enemy and spare the

      ''I've never seen so many ways to attack cancer,'' says Coffey. Indeed, a
      survey this year by an industry group showed that of 350 biotech drugs
      under development, 151 - more than one-third - target cancer. There were 30
      for melanoma alone, 20 for colo-rectal cancer, and 13 each for prostate and
      breast cancers.

      And, as reports at this spring's meeting of the American Society of
      Clinical Oncology reflected, the early tests of many of these agents are

      ''I've never seen so many positive results in my life,'' says Dr. Dan Von
      Hoff, founder of ILEX Pharmaceuticals and an oncologist at the San Antonio
      Cancer Institute. ''The biology is beginning to pay off. Now you can sit
      down and look a patient in the eye and say there's a good chance of this
      doing you good.''

      Despite a flurry of media reports this spring proclaiming that a cancer
      ''cure'' might be at hand, few scientists will touch that word. Sobered by
      decades of experience with cancer's Houdini-like ability to escape and
      survive, researchers say the new agents may realistically prove more
      successful at taming cancer than destroying it.

      ''We may have cures someday,'' says Samuel Waksal, president of ImClone
      Systems Inc. in New York, which is developing targeted cancer therapies,
      ''but the types of approaches we're developing now may make cancer a
      chronic disease. We would like to kill every cancer cell, but we're
      recognizing that if you can keep people alive for 30 more years, using
      drugs with few side effects - that's pretty dramatic.

      ''And,'' he adds, ''that's a goal that is achievable in the near term.''
      Even in the next two or three years, ''the world [of cancer treatment] is
      going to change.''

      For ethical reasons, the newest drugs are tried first in patients with
      hopelessly advanced cancer. Despite the grim odds, one such drug is already
      sparking a glimmer of hope for patients with aggressive, incurable brain
      tumors called glioblastomas. The drug, called SU101, blocks an overactive
      cell growth-signaling pathway in brain cells and has kept a few patients
      alive for one or two years. Under normal circumstances, they would have
      died within three months, says Dr. Eric Wong, a neuro-oncologist at
      Boston's Beth Israel Deaconess Medical Center, where the drug is about to
      begin testing.

      Last month, Nelba MacMurdo, 66, of Canton, finished her first seven-week
      course of SU101: Her children had read about the experimental drug in a
      newsmagazine and sought out Wong. Whether it has affected the brain tumor
      whose tentacles couldn't be surgically removed wasn't immediately clear.
      But her daughter, Leslie, says she has experienced few side effects and has
      felt ''renewed zest just knowing there's something that could potentially
      help her.''

      No one expects any of the new biological therapies, as effective as they
      may prove, to do the job alone. Most researchers believe they will work
      best when combined with other therapies and with standard chemotherapy
      drugs to attack the elusive cancer cell on many fronts.

      ''We don't have to hit a home run to cure people'' with newer agents, says
      Dr. Christopher Logothetis at M.D. Anderson. ''We just have to get a base
      hit, because we already have one with chemotherapy - this could give us a
      run batted in. That's why many of us are really optimistic that we're going
      to be able to change the course of this illness.''

      For example, ImClone's cancer drug C225, based on an antibody discovery by
      Mendelsohn, is being tested in combination with radiation for head and neck
      cancers. The radiation damages the cell while the C225 antibody blocks a
      chemical growth factor, the EGF receptor, that the cell needs in order to
      divide. The one-two attack has proven successful in halting tumors in the
      early tests, says Mendelsohn.

      If they are cautiously optimistic that the new era of rationally designed
      drugs and targeted therapies may yield major inroads into the disease, the
      researchers are also mindful of the potential pitfalls.

      Normal cells in body tissues are of one kind, but cancer cells - even in
      the same tumor - are genetically diverse, points out Coffey at Johns
      Hopkins. ''Diversity allows cancer to survive'' by becoming resistant to
      drugs that attack just one type of cell, he says. ''Cancer is an
      evolutionary process that spins off variants you can't control.''

      Angiogenesis inhibitors may get around this obstacle because they don't
      attack the cancer cell itself, only its blood supply, and the blood vessel
      cells that are the target don't develop resistance. In animal experiments,
      resistance to the angiogenesis agents has been remarkably absent.

      Hurdles remain before

      drugs reach market

      But there are other hurdles. Turning experimental proteins from the
      laboratory into commercial-scale drugs is difficult. Many of the proteins
      are large, complex, and difficult to make. Genentech is building a new
      manufacturing plant to churn out a drug called Herceptin for what is
      expected to be a large market, once it gains FDA approval. But these
      scale-ups take time and effort. Moreover, large proteins need to be taken
      intravenously; the hope is to produce small molecules that patients can
      take orally.

      Other researchers still labor to find better ways to test promising drugs
      in animals. Though scientists have worked for years to create mice that
      mimic human cancer, mice experiments still often don't predict what a drug
      will do in humans, and the search for still better animal models continues.

      Says Dr. Martin Abeloff, director of the Johns Hopkins Cancer Center:
      ''We're all excited about the potential of really being able to attack this
      disease in a more scientifically-based approach. But we also have to be
      cautious, because we're learning about the complexity of these processes.''

      And, he says, it's not as if cancer treatment is moving into a ''different

      ''I don't feel like what we've done in the past'' with conventional
      treatments will be rendered obsolete, he says. ''We'll never abandon them,
      even when we have the new biologically-based approaches... we'll use them

      Globe Online

      This series is available

      on the Globe Online at

      http://www.boston.com Use the

      keyword: Cancer.

      This story ran on page A01 of the Boston Globe on 08/03/98. Copyright 1998
      Globe Newspaper Company.
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