The incredible shrinking tumor
These CT scan images--showing the cross section of the patient’s abdomen--depict how her ovarian tumor (denoted by the red circle) shrunk in response to a new anticancer drug called olaparib. The patient carries a mutation in the BRCA1 gene, impairing her tumor cells' ability to repair DNA damage. Olaparib delivers another blow to the cancer cells' DNA repair machinery, killing them outright.
The New England Journal of Medicine
A personalized therapy targets the molecular mechanism behind a specific kind of tumor.
A drug tailor-made to strike at a tumor cell's Achilles heel shrinks or stabilizes tumors in patients with certain treatment-resistant hereditary cancers while causing few side effects. The results of the early-stage trial were published online today in the New England Journal of Medicine.
The drug, called olaparib, is the first success story from a new and highly personalized approach to anticancer drug development. This strategy harnesses a concept known as synthetic lethality, in which a drug is designed to work in tandem with the molecular glitch underlying a specific kind of cancer.
"It's a whole new way to develop drugs," says J. Dirk Iglehart, a professor of women's cancers and surgery at Brigham and Women's Hospital, in Boston, and coauthor of an editorial accompanying the paper. Iglehart was not involved in the study.
While existing chemotherapeutic agents may take advantage of synthetic lethality to some degree, they do so by accident rather than by design, says Daniel P. Silver, an assistant professor of cancer biology at the Dana-Farber Cancer Institute and coauthor of the editorial. "It's a particularly elegant idea," says Silver. "I do think that this will become an important methodology among many for developing cancer drugs."
A small percentage of breast, ovarian, and prostate cancers are associated with defects in one copy of the BRCA1 or BRCA2 gene, which encode proteins that help proofread the genome during replication. If a BRCA-mutated cell happens to lose its one functional copy of the gene, proofreading is impaired, and mutations begin to accumulate as the cell divides. These mutations can cause a multitude of other cell processes to go awry, opening the door to tumor development.
Because there are several mechanisms for DNA repair, the loss of BRCA function doesn't completely incapacitate a cell. But it does create a weakness not present in normal cells, which still carry a working copy of the BRCA gene. Olaparib targets that weakness by inhibiting an enzyme involved in another DNA proofreading pathway, generating a lethal double whammy to the cancer cell's DNA while sparing healthy cells.
Of 19 patients with BRCA-associated cancer treated by olaparib in the trial, 12 experienced substantial and lasting stabilization or shrinkage of their tumors. "[The drug] was given as a single agent to treatment-resistant advanced cancers--these cancers shouldn't respond to a piddly little enzyme inhibitor," says Iglehart. "So the fact that it was so effective was very exciting to people."
The drug's specificity means that unlike conventional chemotherapy drugs, which are toxic to normal cells and cancer cells alike, olaparib causes remarkably few side effects. "Compared to chemotherapy, this drug's a breeze," says Johann de Bono, a medical oncologist at the Institute of Cancer Research, in Sutton, England, who is co-leading the trial. "It's like taking Tylenol twice a day."
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This work looks promising. However, I believe antineoplaston work, such as that done by Burzynski and others, may be more personalized and more adaptable to all the various forms of cancer.
I cried as I read about this new medication. I was diagnosed in dec. 2004 of OVCA stage 3. Which spread to my liver in 2005. I started chemo again but had an anaphylactic reaction. A year later I had Ablation which worked. Then it spread again this time to a Lymphnode. I had cyberknife threatments I went into remission after only 3 months. Oh, I'm also BRCA 1 pos. as well as 7 other female family members (Mom,Sister, Aunts, Cousins) All Breast or Ovarian or both. Right now I've been in remssion for 6 months. So as a 4 1/2 year survivor of Ovarian Cancer stage 4 I'm praying that I can remain in remission until this medication is available.
Is there a way to get this drug now. Get in any clinical trials?
There are many sites online to help you find clinical trials. You should visit the National Cancer Institute (NCI) website, or something like searchclinicaltrials.org. I know it can be overwhelming, but these websites typically have 800 numbers so you can find a person to help out.
God bless you and your family.
Targeted therapy is not new and has not proven particularly effective. It has worked in CML, that is until the cancer develops resistance which is almost inevitable. It would have been more informative to be given survival benefit results which is the gold standard for cancer trials. There are plenty of very pricey treatments that extend survival by only a few months. If this type of cancer is so crippled for DNA repair then it would seem to be more logical to couple anti-PARP therapy with a DNA damaging agent such a cisplatin. Cancer is not going to be defeated with single agent therapy any more than HIV is going to be held off with a single antiviral drug.
Disease-free survival would certainly be helpful to know, but with such a new drug that will unfortunately just take time. And there are studies underway that look at treating the tumor with a DNA-damaging drug in combination(i.e. cisplatin). However, it's equally important to understand how the drug works alone first. I think the point is that even by itself, this non-toxic drug had significant measurable benefits. Definitely reason for excitement and optimism!!! It would be interesting to follow up with that handful of non-responders and investigate the DNA repair pathways that are still functional while they were on Olaparib.
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67 Comments
Personalized?
The article terms this drug 'personalized' and even 'highly personalized.' This ought to denote that it is specific to each individual person. But there is nothing in the description that shows that this is the case. It seems to be a highly specific drug targeted to a subset of a type of cancer. That is 'specific' - not 'personalized' - unless cancers can be called a person.
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