Report from ASCO: The Year of the Molecule

The American Society of Clinical Oncology, the professional society of Medical Oncologists, just ended its annual meeting in Chicago.  Heavily covered by the media, the meeting was full of blockbuster announcements – seemingly more than usual.

When President Nixon declared war on cancer in 1972, he didn’t think it would take forty years to get a handle on how cancer works and what we could really do about it.  We are finally getting there.

The big news is the explosion of new treatments based on the subtle molecular differences between cancer and normal surrounding tissue.  Small changes in the base sequences in DNA, the building blocks of genes, result in genetic mutations which allow the cancer to grow unchecked by normal growth feedback mechanisms.  That much has been known for a long time.  What is new is the ability of scientists to take advantage of those mutations to create new drugs which attack only the abnormal cells – so-called targeted therapy.

The biggest news from the meeting was T-DM1, code name for a drug which has no brand name yet.  This drug takes Trastuzumab (Herceptin) and hooks a toxin on to it.  Trastuzumab has been around for over ten years; it was one of the first antibodies to exploit the difference between cancer and normal, the overexpression of the Her-2 gene on the surface of the breast cancer cell.  T-DM1 has a toxin on bonded to the Tras molecule, so when Tras binds preferentially to the Her-2 positive cell (about 20% of breast cancers are Her-2 positive and this concept only applies to them) the toxin is ingested by the cell and it dies.  This smart bomb approach has been out there for years as a concept but this is the first case in which such a combination drug has been brought into a big clinical trial and shown to be highly effective.

The BRAF gene seen in half of all malignant melanomas remains a highly specific and vulnerable target.  Last year brought us Vemurafenib which gave BRAF positive melanoma patients very good but short-lived remissions.  At the meeting two newer BRAF related inhibitors were unveiled, Trametinib and Dabrafenib.  All three drugs exploit the tiny molecular differences between melanomas and normal tissues.  Trametinib actually targets MEK a gene downstream from BRAF so that in theory it could be combined with a pure BRAF inhibitor to create a potent drug combination.

Newer drugs for prostate cancer continue to be developed.  They take advantage of the genetic rarity of prostate cancer cells: their ability to make their own male sex hormones (androgens) which stimulate their growth.  Interrupting the intra-prostatic synthesis of androgens has a profound effect on the progression of this disease once cure with surgery or radiation has not succeeded.

Nowhere on this list is the mention of new pure chemotherapy agents.  The era of non-selective chemo drugs (drugs that attack normal cells equally with cancer cells) is over.  There will be no more Cytoxans or Adriamycins.  We have moved beyond.  Thank goodness.

For years the National Cancer Institute owned the engine that drove new drug development.  That role has been ceded to the pharmaceutical industry.  How their profit-driven approach intersects with health-care reform (or what’s left of it shortly) in setting the price of these new drugs will determine whether big pharma stays in or gets out of the cancer treatment business.  Let’s hope that for better or worse drug development remains sufficiently profitable so that the drug companies continue to work on the thorny biologic problem of cancer – one that we are just beginning to understand after a long period of trying.

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James Stark, MD, of Stark Oncology

James Stark, MD, of Stark Oncology Consulting

Dr. James Stark is the founder of StarkOncology, where he practiced Oncology in Hampton Roads for thirty-four years.  He is now a health-care consultant specializing in topics such as breast cancer, colon cancer, lung cancer, chemotherapy complications, and failure to screen. In addition to this new venture he continues to serve as Professor of Medicine at Eastern Virginia Medical School.

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