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Tumor heterogeneity: The fly in the ointment of cancer genomics-driven therapy?

9 January 2012

As I mentioned in my last post, I’m maybe just a little bit excited about the UCSD Moores Cancer Center’s shift in focus toward genomics based cancer therapy: My Answer to Cancer.

Dr. Scott Lippman is the new director of the Moores Cancer Center, and summarized the project:

Until now, cancer treatment has been a one-size-fits-all approach. Recent technological advances have made it possible to generate a profile of all the abnormalities in the genetic code of a tumor. By gathering enough data, we can identify profiles that will allow us to tailor cancer treatments to individual patients. In other words, we will open up a whole new world of cancer treatment that could lead to saving many patients who never had a chance before.

Dr. Lippman continues:

We will implement genomic sequencing and personalized care for all of our patients. To fund this bold new approach to cancer treatment, we are looking to all of you, our donors, to help us raise an initial $5 million to provide personalized cancer treatment for the first 1,000 patients.

New targeted cancer therapies coming into the clinic have a lot of promise, so long as they are given to the correct patients; most will work extremely well with minimal side effects… for a small fraction of cancers. For instance, maybe 10% of patients’ breast cancer will have the correct genetic profile to respond to a new monoclonal antibody or enzyme inhibitor. Cancer genomics promises to make these profiles much clearer, and to much more quickly refine use of new therapeutic tools in the clinic.

In my last post I portrayed fighting cancer as analogous to a medieval siege of a fortified city. The potential of personalized cancer treatment through cancer genomics would be like knowing in advance where the weaknesses are in the walls of the fortified city. Sort of.

Cancer is not a fortified city; it’s hundreds of millions of them. To add to this, they’re not all the same, and do not have the same weak points, even within an individual patient. The Emperor of All Maladies earns this distinction not only from the horrible complications of advanced disease, but the uncanny ability to grow resistant to therapy and come back stronger and more deadly than before.

Cancer is evolution on steroids. Most cancers are genetically unstable to begin with, and as a tumor grows (and begins to spread) it becomes more and more heterogeneous; the same weakness will not work for every fortification. Or worse, using the same strategy against all fortified cancer cells will leave only the resistant cells remaining, which then re-populate the patient (not good!). There is also the conundrum of current therapeutic side effects weakening the patient, making treatment of a second or third wave of cancer resistance even more difficult to treat.

Could cancer genomics be that expert battlefield intelligence to bring down the fortresses? I’ve previous written about another complication with this approach: intratumor heterogeneity and the need to sequence multiple regions of an individual tumor. Simply put, unless multiple regions of an individual tumor are sequenced to give a good idea of the essential and non-essential (“driver” vs. “non-driver”) mutations, there’s a good possibility that even the most directed therapies will no match (after the first or second round) for the Emperor of all Maladies.

According to a genomics expert at the UCSD School of Medicine, with the current technology the costs of genomic sequencing is between $2000 to $4000 per genome. Dr. Lippman’s proposed fundraising would theoretically cover the cost of one or two sequences per patient among the 1000 patients, but that assumption is void of administrative costs, or other sources of funding (grants, etc).

Will that be enough sampling to overcome hurdles of tumor heterogeneity? How many sequences from how many tumor biopsies per patient are needed to breach the fortresses? Do we have he tools to exploit the weaknesses we identify? Do we know enough about cancer biology to recognize a weakness when we see it? These are open-ended questions that I (and quite possibly no one else) have the answers to… yet. It is my hope that this new initiative will successfully answer some of these questions.


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